affection and indicate that CC chemokines should be further studied to clarify a
role as biomarkers or novel therapeutic targets in JDM.
ACR/ARHP Poster Session B
Cytokines, Mediators, and Gene Regulation
Monday, November 12, 2012, 9:00 AM–6:00 PM
Disclosure: T. Schwartz, None; I. Sjaastad, None; B. Flatø, None; M. Vistnes, None;
G. Christensen, None; H. Sanner, None.
873
Monocyte Chemoattractant Protein-1 and Eotaxin Are Associated with
Parameters of Cardiac Dysfunction in Juvenile Dermatomyositis.
Thomas Schwartz1, Ivar Sjaastad2, Berit Flatø1, Maria Vistnes1, Geir Christensen1 and Helga Sanner1. 1Institute for Clinical Medicine, University of
Oslo, Oslo, Norway, 2Institute for Experimental Medical Research, Oslo
University Hospital, Oslo, Norway
Imbalance Between Histone Acetyl Transferase and Histone Deacteylase
Activities and Modulation of HDAC Activity and Tnfa Production by
HDAC Inhibitors in Patients with Ankylosing Spondylitis or Rheumatoid Arthritis. Eric Toussirot1, Wasim Abbas2, Kashif Aziz Khan3, Marion
Tissot2, Alicia Jeudy2, Lucile Baud2, Ewa Bertolini4, Daniel Wendling5,
Georges Herbein6 and CIC Biotherapy7. 1CIC Biotherapy 506 and Rheumatology and EA 4266 Pathogens and Inflammation, Besançon, France, 2EA
4266 Pathogens and Inflammation, Besançon, France, 3EA Pathogens and
Inflammation, Besançon, France, 4Rheumatology, Besançon, France, 5Minjoz
University Hospital, Besancon, France, 6Virology and EA 4266 Pathogens
and Inflamamtion, Besançon, France, 7University Hospital, Besançon, France
Background/Purpose: Juvenile dermatomyositis (JDM) is a vasculopathic disease affecting not only skeletal muscle and skin, but other organs as
well. Previously we have shown that JDM patients can have cardiac
dysfunction (measured by E/e’). Considering the systemic nature of the
disease, it is reasonable to believe that inflammation of the myocardium can
occur, similar to what is seen in skeletal muscle. Increased abundance of
pro-inflammatory cytokines has been shown in cardiac and rheumatic
diseases. We examined associations between cytokine levels and cardiac
parameters in patients with JDM and matched controls.
Methods: 54 JDM patients (estimated to represent the vast majority of known
cases in Norway diagnosed from 1970–2006) were clinically examined,
follow-up time median 16.8 years (range 2–38 years) after disease onset, and
compared with 54 age- and sex-matched controls. Disease activity score (DAS)
and myositis damage index (MDI) were assessed at follow-up by clinical
examination and at 1 year post-diagnosis by chart review (DAS and MDI 1 year).
Cytokines were analyzed by Luminex technology. Echocardiography with tissue
Doppler was performed and analyzed blinded to patient information.
Results: Early diastolic tissue velocity (e’) that reflects diastolic cardiac
function, was lower in JDM patients than in controls (11.2 vs.12.6 cm/s,
p⫽0.004), suggesting diastolic dysfunction in JDM. E’ correlated with MDI 1
year, MDI at follow-up and DAS 1 year (rsp⫽0.46, rsp⫽0.59 and rsp⫽0.60, all
p⬍0.001). Also, DAS 1 year predicted a low e’ (diastolic dysfunction), at follow
up after correcting for gender and age in a linear regression model (standardized
␤⫽0.38, p⬍0.001). In patients, the serum level of the two CC chemokines,
monocyte chemoattractant protein-1 (MCP-1) and eotaxin, correlated with e’
(rsp⫽0.65 and rsp⫽0.59, both p⬍0.001) (Figure). For MCP-1, association with
e’ was also present after adjusting for disease duration and gender in a linear
regression model (standardized ␤⫽0.36, p⫽0.001). No correlations were seen
between the two CC chemokines and systolic parameters. MCP-1 and eotaxin
also correlated with diastolic blood pressure (rsp⫽0.46 and rsp⫽0.50 both
p⬍0.001). In controls, the CC chemokines did not correlate with any echocardiographic or clinical parameters.
Background/Purpose: TNFa is a major cytokine involved in conditions
such as ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Epigenetic
regulation corresponds to different processes including modifications in
histone proteins. These mechanisms regulate the transcription of genes coding
for inflammatory cytokines such as TNFa. The acetylation of histone proteins
(dependent on histone acetyl transferase-HAT-) promotes gene transcription
while deacetylation (controlled by histone deacetylase) prevents this reaction.
Limited data are available on HAT and HDAC activities in AS or RA. HDAC
inhibitors (HDACi) are currently in development and may be of interest in
modulating TNFa production in RA or AS.
Objectives: To determine the levels of HAT and HDAC activities in
patients with AS or RA compared to healthy controls (HC) and to evaluate the
ex vivo effects of HDACi (trichostatin A-TSA- and sirtinol -Sirt-) on HAT
and HDAC activities and TNFa production by PBMC.
Methods: 21 patients with AS (New York criteria, 18 M, mean age
⫾SEM 44.3 ⫾ 3.2 years, disease duration 14.1 ⫾ 2.2 years), 52 patients
with RA (ACR 1987 criteria, 16 M, mean age 56.9 ⫾ 1.6, disease duration
11.3 ⫾ 1.2) and 38 healthy controls (HC) (12 M, mean age: 34.6 ⫾ 1.8) were
evaluated.No patient received biologics. HAT and HDAC activities were
assessed on nuclear extracts of PBMC isolated by Ficoll hypaque using a
colorimetric assay (EpiQuick HAT Activity/inhibition Assay kit, and
EpiQuick HDAC Activity/inhibition Assay kit, Epigentek). These activities
were measured prior and after ex vivo treatment of PBMC by HDAC
inhibitors. TNFa was evaluated in PBMC culture supernatants after 1 and 3
days (TNFalpha Quantikine ELISA kit, R&D Systems).
Results: HAT activity was decreased in patients with AS compared to HC
(68.2 ⫾ 8.1 vs 111.3 ⫾ 15.5 ng/h/mg) (p⫽ 0.05) while RA patients had
increased HAT activity (126.8 ⫾ 16.4 vs 111.3 ⫾ 15.5 ng/h/mg; NS).
Compared to HC, HDAC activity was decreased in both AS (p⫽0.01) andRA
(NS) (HC vs AS vs RA: 4778.9 ⫾ 752 vs 1984. 6 ⫾ 249 vs 3915.9 ⫾ 790
pmol/min/mg). No correlation was observed between clinical disease assessment in RA or AS and HAT or HDAC activity. Ex vivo addition of TSA or
Sirt to PBMC reduced HDAC activity by 51.1% in HC and by 37.7% in RA
but had no effect in AS.HAT activity was not modulated by HDACi. TNFa
production by PBMC was down regulated by the addition of TSA or Sirt to
cell culture in HC and RA but this regulation was only obtained with Sirt in
PBMC culture from patients with AS.
Conclusion: HAT and HDAC activities are dysregulated in AS and RA
with a balance between HDAC and HAT favoring HAT activity and
promoting gene transcription. Ex vivo treatment of PBMC by HDAC
inhibitors may regulate HDAC activity and TNFa production especially in
HC and RA but seems less effective in AS.
Disclosure: E. Toussirot, None; W. Abbas, None; K. Aziz Khan, None; M. Tissot,
None; A. Jeudy, None; L. Baud, None; E. Bertolini, None; D. Wendling, None; G.
Herbein, None; C. Biotherapy, None.
874
Figure.
Conclusion: Patients with JDM had subclinical diastolic dysfunction (measured by e’) compared to controls, and those with sustained early disease activity
seemed to be at risk later in life to develop diastolic dysfunction. Considering the
correlation with e’, MCP-1 and eotaxin might be involved in an inflammatory
response in JDM, leading to myocardial fibrosis and subsequently diastolic
dysfunction. The findings give new insight in the mechanism of myocardial
TNF␣ Induces Sustained Signaling and a Prolonged and Unremitting
Inflammatory Response in Synovial Fibroblasts. Angela Lee, Galina
Grigoriev, Janice Chen, Lionel B. Ivashkiv and George D. Kalliolias.
Hospital for Special Surgery, New York, NY
Background/Purpose: The non resolving character of synovial inflammation in rheumatoid arthritis (RA) is a conundrum. To identify the
S381
Monday, November 12
872
Monday, November 12
contribution of fibroblast-like synoviocytes (FLS) to the perpetuation of
synovitis, we investigated the molecular mechanisms that govern the
TNFa-driven inflammatory program in human FLS.
Methods: FLS obtained from synovial tissues of patients with RA or
osteoarthritis were stimulated with TNFa and assayed for gene expression
and cytokine production by qPCR and ELISA. NF-kB signaling and
chromatin accessibility were evaluated using Western blotting and restriction enzyme accessibility (REA) assays.
Results: In FLS, TNFa induced prolonged transcription of IL-6
and progressive accumulation of IL-6 protein over four days (Figure 1A).
Similarly, induction of IL-8, CCL5, MMP1 and MMP3 mRNA, after
TNFa stimulation, was sustained for several days (data not shown).
This contrasted with the macrophage response to TNFa, which characteristically involved a transient increase in the expression of proinflammatory genes (Figure 1B). In FLS, TNFa induced prolonged
activation of NF-kB signaling (Figure 2A) and a sustained increase in
chromatin accessibility at the IL-6 promoter (Figure 2B).Furthermore,
FLS expressed low levels of the feedback inhibitors ABIN3, IRAK-M,
ATF3 and SOCS3 that terminate inflammatory responses in macrophages
(Figure 3).
875
Discovery of Pharmacologic MIF Antagonists by Structure-Based Molecular Design. William L. Jorgensen1, Alissa A. Hare1, Zoe Cournia1,
Sunilkumar Gandavadi1. Xin Du1, Lin Leng1 and Richard J. Bucala2, 1Yale
University, New Haven, CT, 2Yale University School of Med, New Haven,
CT
Background/Purpose: Cytokine inhibition is becoming a mainstay for
the therapy of autoimmunity but current antibody-based approaches remain
limited by high cost, parenteral administration, and anti-idiotype responses.
Orally available, small molecules offer considerable advantages, yet the
discovery of molecules that effectively disrupt the molecular interactions
between cytokines and their receptors remains to be achieved. Macrophage
migration inhibitory factor (MIF) is an attractive drug target because of its
genetic association with autoimmunity and its role in counter-regulating
glucocorticoid immunosuppression. The discovery of the MIF receptor
(CD74) together with X-ray crystallography of MIF has enabled structurebased design using ligand docking, moleculegrowing computational methodologies, and receptor binding assessment. By this approach, we are pursuing
the discovery of potent and selective MIF antagonists with auspicious
pharmacologic properties.
Methods: Utilizing a high resolution MIF crystal structure, virtual
screening was performed by docking 2.1 million compounds into the MIF
tautomerization site, which was judged to interface with the MIF receptor.
Validation by in vitro functional analyses revealed novel compounds with
␮M inhibitory activity in several molecular series. Structure optimization was
pursued by synthesis of substituted benzoxazol-2-ones and MIF receptor
binding, MIF ligand selectivity, and MIF-dependent signal transduction
evaluated in vitro.
Results: Binding analysis of MIF interaction with the MIF receptor
ectodomain revealed 11 novel compounds with IC50s in the ␮M range.
Beginning with a 1 ␮M candidate, substituted benzoxazol-2-ones were
discovered with IC50 values as low as 80 nM for MIF receptor antagonism.
One such molecule: 3-(3-hydroxybenzyl)-5-methylbenzo[d]oxazol-2(3H)one (Debio 1036) was evaluated more closely and functional inhibition
established in synovial fibroblasts for MIF-dependent ERK1/2 phosphorylation (IC50⫽5 nM) and invasive phenotype. Debio 1036 also was 1000-fold
more selective for MIF than for its close structural homolog, DDT (MIF-2).
Conclusion: Several highly potent, small molecule MIF receptor antagonists have been identified by a combination of structure-based molecular
design and functional analysis. Compounds with oral bioavailability and
auspicious pharmacologic properties are anticipated to provide promising
candidates for the treatment of human autoimmunity.
Disclosure: W. L. Jorgensen, None; A. A. Hare, None; Z. Cournia, None; S.
Gandavadi, None; X. Du, None; L. Leng, None; R. J. Bucala, None.
876
Xanthine Oxidase-Derived ROS Direct Context-Dependent Action of
NFAT5 Toward Inflammatory Response in Macrophages. Nam Hoon
Kim. Catholic university of Korea, Seoul of Korea, Seoul, South Korea
Conclusion: TNFa signaling is not effectively terminated in FLS,
leading to an uncontrolled inflammatory response. The results suggest that
prolonged and sustained inflammatory responses by FLS, in response to
synovial TNFa, contribute to the persistence of synovial inflammation in
RA.
Disclosure: A. Lee, None; G. Grigoriev, None; J. Chen, None; L. B. Ivashkiv, None;
G. D. Kalliolias, None.
Background/Purpose: NFAT5, a well known osmo-protective factor,
can be activated by isotonic stimuli, such as Toll-like receptor (TLR)
triggering. Here, we identified a novel signal pathway activated in macrophages upon TLR ligation.
Methods: We demonstrated that high salt and TLR ligation activate
distinct sets of downstream target genes in a NFAT5-dependent manner.
While ROS are essential for this, their source differs depending on the
context; mitochondria for high salt and xanthine oxidase for TLR. The two
pathways are mutually suppressive. Moreover, the xanthine oxidase-NFAT5
pathway is required for TLR-mediated inflammatory arthritis, inducing the
proinflammatory cytokine production.
Results: we identified a novel xanthine oxidase- reactive oxygen species
(ROS)-p38-NFAT5 pathway activated in macrophages upon TLR ligation.
Conclusion: Together, xanthine oxidase-derived ROS function as molecular sensors to discriminate TLR ligation from osmotic stimulus in macrophages, directing NFAT5 action toward innate immunity.
Disclosure: N. H. Kim, None;
S382
877
Aberrant Expression of BAFF Receptor (BR3) in Peripheral Monocytes
of Patients with Primary Sjögren’s Syndrome Impacts Abnormal Activation of BAFF Signaling Through IKK-Alphaand IKK-Beta. Keiko
Yoshimoto1, Maiko Tanaka1, Masako Kojima1, Hideko Ogata1, Hideto
Kameda1, Katsuya Suzuki1, Tohru Abe2 and Tsutomu Takeuchi1. 1Keio
University School of Medicine, Tokyo, Japan, 2Saitama Medical School,
Kawagoe-shi Saitama, Japan
Disclosure: K. Yoshimoto, None; M. Tanaka, None; M. Kojima, None; H. Ogata,
None; H. Kameda, None; K. Suzuki, None; T. Abe, None; T. Takeuchi, None.
878
Differential Regulation of Cytokines by Extracellular-Signal Regulated
Kinase and c-Jun N-Terminal Kinase in Map Kinase Kinase-3 and -6
Deficiency. Deepa Hammaker, Katharyn Topolewski, Monica Guma, David
L. Boyle and Gary S. Firestein. UCSD School of Medicine, La Jolla, CA
Background/Purpose: p38 inhibitors have limited efficacy in rheumatoid
arthritis (RA), possibly because p38 blockade suppresses IL-10 production
and increases JNK and ERK phosphorylation in macrophages. This positive
feedback mechanism elevates IL-6 levels and decreases IL-10 production. In
contrast, bone marrow derived macrophages (BMDM) deficient in upstream
p38 regulators (MKK3 or MKK6) have normal ERK and JNK responses and
near normal IL-10 gene expression. The goals of this study were (1) to
determine if dual ERK and JNK inhibition avoids reflex increases in
pro-inflammatory cytokine expression and (2) to dissect the mechanisms of
IL-10 regulation in MKK-deficient and p38 inhibitor treated BMDM.
Methods: Bone marrow derived macrophages from wild type (WT),
MKK3⫺/⫺ and MKK6⫺/⫺ mice were pre-treated with p38 inhibitor
SB203580 (SB), JNK inhibitor SP600125 (SP) and/or ERK inhibitor
PD98059 (PD) and stimulated with LPS. Supernatant IL-6 and IL-10 levels
were measured by immunoassay. IL-10 mRNA half-life was measured using
LPS-stimulated BMDM treated with actinomycin D and qPCR. IL-10
promoter activity was determined in BMDM transfected with a mouse IL-10
promoter luciferase construct and normalized to a Renilla construct.
Conclusion: Increased JNK and ERK activation, along with suppressed
IL-10 production contribute to the pro-inflammatory effects of p38 inhibition
in BMDM. Combining a p38 inhibitor with a JNK inhibitor might be more
effective than a selective p38 inhibitor by preserving anti-inflammatory
responses and blocking the reflex pro-inflammatory response.
Disclosure: D. Hammaker, None; K. Topolewski, None; M. Guma, None; D. L.
Boyle, None; G. S. Firestein, None.
879
Fucosyltransferase 1 (fut1) Is Overexpressed in Rheumatoid Arthritis
Synovial Tissue and Modifies Cytokine Production. Takeo Isozaki1, Jeffrey H. Ruth1, M. Asif Amin1, Phillip L. Campbell1, Steven E. Domino1, G.
Kenneth Haines III2 and Alisa E. Koch3. 1University of Michigan, Ann
Arbor, MI, 2Yale University, New Haven, CT, 3University of Michigan
Medical School, Ann Arbor, MI
Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. Angiogenesis and cytokine production are involved in the pathogenesis of RA. We
have shown that soluble H and Lewisy antigens are mediators of angiogenesis
and are upregulated in the RA joints compared to normal (NL) or osteoarthritis (OA) joints. Fucosyltranseferase 1 (fut1) is an ␣(1,2)-fucosyltransferase
responsible for synthesis of the H blood group and Lewisy antigens. However,
a direct role for fut1 in RA has not been demonstrated. In this study, we
examined the expression of fut1 in RA synovial tissue (ST) and determinedthe functional consequences of fut1 expression.
Methods: Fut1 expression was determined in RA, OA and NL ST
samples by immunohistological staining. To determine whether fut1 was
expressed by the human microvascular endothelial cell line (HMEC-1) and
human dermal microvascular endothelial cells (HMVECs), real time polymerase chain reaction (RT-PCR) was performed. To block the expression of
fut1, HMEC-1s and HMVECs were transfected with fut1 sense or antisense
oligonucleotides (ODNs). After treatment, cells were stimulated with
interleukin-1␤ (IL-1␤), IL-17 or phorbol 12-myristate 13-acetate (PMA) to
stimulate cytokine expression. We examined monocyte chemotactic protein
(MCP)-1/CCL2 expression as this chemokine has been shown to be decreased
in mouse KRN arthritis induced fut1 knockout joints. We also examined
angiogenic vascular endothelial growth factor (VEGF) and regulated upon
activation and normal T-cell expressed, and secreted (RANTES)/CCL5
expression, as these cytokines have been shown to be important in RA
pathogenesis. In addition, we isolated endothelial cells (ECs) from wild type
(wt) and fut1 knockout mice. To confirm the role of fut1 in angiogenesis, we
S383
Monday, November 12
Background/Purpose: B cell activating factor belonging to the TNF
superfamily (BAFF) regulates proliferation, differentiation and survival of B
cells and plays a pivotal role in the pathogenesis of autoimmune diseases such
as primary Sjögren’s syndrome (pSS). BAFF is a ligand for three TNFreceptor family members; i.e., BAFF receptor (BR3), TACI and BCMA.
Several lines of evidence demonstrate that BR3 is the receptor that mediates
BAFF-dependent B cell biology and that BAFF activates alternative NF-kB
signaling in B cells. However, the regulatory mechanisms of BAFF signaling
in other immune cells, such as monocytes, are not well understood. In our
previous study, we revealed that BAFF induced robust increase in the
production of IL-6 by pSS monocytes. We also found that the expression
levels of BR3 and several transcription factors such as NF-IL-6 and NF-kB2
were enhanced in pSS monocytes compared to normal monocytes. These data
suggest that BAFF signaling is abnormal in pSS monocytes. The purpose of
the present study is to elucidate these possible abnormalities.
Methods: Whole blood was prepared from pSS patients and age-matched
normal individuals, and the expression level of BR3 on monocytes was
analyzed by FACS. Peripheral monocytes were stimulated in vitro with
soluble BAFF (sBAFF), and the production of IL-6 by the cells was measured
by ELISA. The expression levels of IKK-alpha and IKK-beta, which are
involved in NF-kB pathways, were analyzed by western blotting analysis.
Results: In accordance with our previous findings with quantitative PCR,
FACS analysis showed that the expression level of BR3 was significantly
elevated in pSS monocytes compared to normal monocytes.Interestingly, the
expression level of BR3 on monocytes was positively correlated with the
amount of IL-6 produced by pSS monocytes triggered by sBAFF. When the
monocytes were cultured with sBAFF in the presence of NF-kB activation
inhibitor, the production of IL-6 by the cells was strongly suppressed in a
dose-dependent manner. In addition, phosphorylation level of IKK-alpha was
elevated in pSS monocytes compared to normal monocytes without stimulation, whereas that of IKK-beta was not significantly different between pSS
and normal monocytes. Moreover, phosphorylation levels of IKK-alpha and
IKK-beta in the monocytes were enhanced upon stimulation with sBAFF.
Conclusion: BAFF acts through BR3 to activate the expression of the
IL-6, and that IKK-alpha and IKK-beta are involved in the signal transduction
pathway triggered by sBAFF.
Results: We evaluated the role of JNK and ERK in BMDM IL-6 and
IL-10 production. SB increased IL-6 production induced by LPS while SP
and PD significantly reduced IL-6 levels in WT, MKK3⫺/⫺, and
MKK6⫺/⫺ cells (Figure 1, SP % inhibition: WT (91⫾1%), MKK6⫺/⫺
(81⫾8%), and MKK3⫺/⫺ (84⫾4%, n⫽3/group, p⬍0.008) (PD % inhibition: WT (85⫾3%), MKK6⫺/⫺ (65⫾3%), and MKK3⫺/⫺ (65⫾1%, n⫽3,
p⬍0.02). SP or PD alone or in combination with SB reduced IL-6production,
indicating that blocking JNK and/or ERK overcame thepro-inflammatory
effect of p38 inhibition.IL-10 levels were significantly reduced by SB in
WTBMDM (62⫾9%), MKK6⫺/⫺ (62⫾6%), and MKK3⫺/⫺ (57⫾4%)
(n⫽3/group, p⬍0.034). SP also inhibited IL-10 levels while PD had no effect.
Surprisingly, the combination of SB and SP prevented the p38-mediated
reduction in IL-10 production suggesting that JNK and p38 pathways have
opposing effects on this cytokine. We then looked at the effect of SB and
MKK-deficiency on IL-10 promoter activity in BMDM treated with LPS.
IL-10 promoter activity in WT cells was reduced by 43⫾6% by SB
(n⫽3/group, p⫽0.02). However, MKK3- and MKK6-deficient cells had
normal promoter activity, indicating that IL-10 transcription is not impaired in
MKK-deficient cells. IL-10 mRNA half-life was unaffected by MKKdeficiency or SB-treatment in LPS-stimulated BMDM.
Monday, November 12
performed EC chemotaxis using wt and fut1 knockout ECs in modified
Boyden chambers.
Results: RA STs contained a greater percentage of fut1 ECs than did OA
or NL STs [mean ⫾ SEM; RA ST (n⫽18) 34 ⫾ 8%; OA ST (n⫽18) 14 ⫾
6% and NL ST (n⫽18) 11 ⫾ 4%, p⬍0.05 between RA ST and OA ST; RA
ST and NL ST]. To determine if fut1 expression was inducible by inflammatory cytokines, we stimulated ECs with IL-1␤ and found that fut1
messenger RNA (mRNA) was IL-1␤ inducible in HMEC-1s and HMVECs.Fut1 antisense ODN transfected HMEC-1s and HMVECs had significantly decreased expression of MCP-1/CCL2 and RANTES/CCL5 compared to fut1 sense ODN transfected cells stimulated withIL-1␤, IL-17 or
PMA at the mRNA and protein levels (p⬍0.05). Fut1 knockout mouse ECs
stimulated with IL-1␤ expressed less VEGF mRNA than wt ECs (p⬍0.05).
These results indicate that fut1 regulates EC expression of cytokines important in RA pathogenesis. Finally, fut1 knockout mouse ECs had decreased
migration to VEGF compared with wt mouse ECs (10 ⫾ 1 vs. 16 ⫾ 1 cells
migrated, n⫽6 experiments, p⬍0.05).
Conclusion: These data show that fut1 is overexpressed in RA ST, and
that by blocking fut1 expression, we can modify the production of many
proinflammatory cytokines. In addition, we show that fut1 regulates EC
migration, a facet of angiogenesis in response to VEGF. Hence, fut1 may be
an important new target for RA therapy.
Disclosure: T. Isozaki, None; J. H. Ruth, None; M. A. Amin, None; P. L. Campbell,
None; S. E. Domino, None; G. K. Haines III, None; A. E. Koch, None.
880
Interferon Regulatory Factor 8 Regulates BAFF Production in Murine
Macrophages and Is a Nexus for Cross Talk Between IFN-␥ and TGF-␤.
Weijia Yuan, Sanjay Gupta, Jane E. Salmon and Alessandra B. Pernis.
Hospital for Special Surgery, Weill Cornell Medical College, New York, NY
Background/Purpose: Lupus is a systemic autoimmune disease that can
lead to severe end-organ damage characterized by unabated inflammation and
aberrant tissue repair. Macrophage dysregulation plays a key role in mediating this tissue damage. Interferon regulatory factor 8 (IRF8) is a crucial
controller of macrophage function and has been identified as a susceptibility
locus for lupus. The cellular pathways regulated by IRF8 may be important in
tissue damage in lupus. IRF8 is known to mediate macrophage activation in
response to IFN-␥.Infiltrating macrophages stimulated by IFN-␥ produce
B-cell activating factor (BAFF) which may perpetuate local immune responses. TGF-␤, a cytokine linked to tissue repair via Rho-kinase (ROCK),
can augment BAFF production. Here we use the regulation of BAFF as a
model to dissect the cross talk between IFN-␥ and TGF-␤ and identify a novel
and crucial role for IRF8 in this process.
Methods: Bone marrow derived macrophages (BMDM) were stimulated
with IFN-␥ and/or TGF-␤. In selected experiments a ROCK inhibitor,
Y-27632, was added. Cytokine production was evaluated by ELISA and/or by
qPCR. ROCK activity was assessed by in vitro kinase assay. Chromatin
immunoprecipitation (ChIP) assays were performed to determine the binding
of IRF8 to the BAFF promoter.
Results: TGF-␤ augmented IFN-␥-induced BAFF production in BMDM
(untreated: 24 ⫾ 5 pg/ml, IFN-␥: 508 ⫾ 181, TGF-␤: 57 ⫾ 13, IFN-␥ ⫹
TGF-␤: 990 ⫾ 291, n⫽5, p⬍0.01). This amplification was specific for BAFF
and was not seen when TNF-␣ or CTGF was examined. IFN-␥ increased the
expression of IRF8, which was not further increased by the addition of
TGF-␤. In the absence of IRF8, BAFF production by macrophages was
markedly diminished (C57/B6 IFN-␥: 505 ⫾ 207 pg/ml, IRF8 KO IFN-␥:
17 ⫾ 10, n⫽4, p⬍0.02; C57/B6 IFN-␥ ⫹ TGF-␤: 867 ⫾ 336, IRF8 KO
IFN-␥ ⫹ TGF-␤: 14 ⫾ 6, n⫽4, p⬍0.02). IRF8 KO BMDM exhibited normal
differentiation and maintained the capacity to upregulate CTGF in response to
TGF-␤. In line with these results, we found that IRF8 directly binds to the
BAFF promoter upon IFN-␥ stimulation. Interestingly, the binding of IRF8 to
the BAFF promoter was augmented by the concomitant addition of TGF-␤.
Given that TGF-␤ did not change the expression of IRF8, we explored the
possibility that TGF-␤ could modulate IRF8 function by post-translational
mechanisms. TGF-␤, but not IFN-␥, activated the serine-threonine kinases
ROCK1 and ROCK2 in BMDM. ROCK inhibitor Y-27632 decreased BAFF
production by BMDM stimulated with IFN-␥ and TGF-␤ and diminished the
binding of IRF8 to the BAFF promoter.
Conclusion: We have shown that IRF8 is a critical regulator of BAFF
production in BMDM. Our data indicate that while IFN-␥ increases IRF8
expression, TGF-␤ may modulate its function via ROCK activation. We
speculate that activated ROCK phosphorylates IRF8 and that increased
binding of phosphorylated IRF8 to the BAFF promoter leads to the enhanced
BAFF production when macrophages are simultaneously exposed to IFN-␥
and TGF-␤. The pathways that mediate the cross talk between IFN-␥ and
TGF-␤ uncovered by this study identify novel processes that could lead to
aberrant macrophage function in chronic inflammatory state and define new
targets to ameliorate tissue damage in SLE.
Disclosure: W. Yuan, None; S. Gupta, None; J. E. Salmon, None; A. B. Pernis,
None.
881
Microrna-155 Regulates Chemokines and Chemokine Receptors in
Rheumatoid Arthritis Monocyte. Aziza Elmesmari, Derek S. Gilchrist,
Alasdair R. Fraser, Diane Vaughan, Ross McQueenie, Gerard J. Graham,
James Brewer, Iain B. McInnes and Mariola Kurowska-Stolarska. Institute of
Infection,Immunity and Inflammation, College of Medical, Veterinary and
Life Sciences, University of Glasgow, Glasgow, United Kingdom
Background/Purpose: Rheumatoid arthritis (RA) is characterized by
synovial tissue inflammation leading to joint destruction. Monocytes/macrophages are major effector cells in RA synovitis, principally by releasing
TNF-␣, IL-6 and other inflammatory cytokines and chemokines. MicroRNAs
are a recently discovered class of post-transcriptional regulators –in particular
miR-155 is upregulated in RA synovial macrophages where it regulates
cytokine expression. We hypothesized that miR-155 regulates migration of
monocytes by modulating the chemokine and chemokine receptor system.
Methods: Peripheral blood (PB) was obtained from healthy controls and
RA patients who met the 2010 ACR/EULAR diagnostic criteria. Purified
CD14⫹ PB monocytes obtained by magnetic bead isolation were transfected
with miR-155 mimic or scrambled mimic using an N-TER nanoparticle
system. Taqman Low Density Array and Luminex multiplex assay was used
to evaluate chemokine receptor gene expression and chemokine production,
respectively. Absolute copy numbers of miR-155 transcripts in PB and SF
monocytes of RA and healthy controls were assessed by QPCR. The role of
mir155 was investigated further using bone marrow monocytes (BMM) from
miR-155⫺/⫺and WT mice.
Results: RA PB and SF macrophages showed higher copy number of
miR-155 compared with healthy controls. Overexpression of miR-155 induced the production of chemokines CCL4, CCL5, CCL8 and CCL22 in RA
monocytes and CCL3 in both RA and healthy controls. However, overexpression of miR-155 in healthy control and RA monocytes did not affect the
production of CCL2, CCL7, CCL21, CXCL5, CXCL8, CXCL7, CXCL10
and CX3CL1. Analysis of chemokine receptors in BMM of miR-155⫺/⫺ and
WT mice revealed significantly higher levels of CCR1, CCR2, CCR5 and
CXCR4 in miR-155 deficient cells suggesting that miR-155 can act as a
negative regulator of these receptors in homeostatic state. TLR-4 ligand
significantly suppressed expression of these receptors in both WT and
miR-155⫺/⫺cells. Analysis of 3’UTRs of chemokine and chemokine receptor
(TargetScan) suggests that miR-155 likely interferes with signaling pathways
implicated in chemokine and chemokine receptor system expression.
Conclusion: Deregulation of miR-155 in RA monocytes can contribute to
the production of pro-inflammatory chemokines by these cells and to their
accumulation at sites of inflammation.
Disclosure: A. Elmesmari, None; D. S. Gilchrist, None; A. R. Fraser, None; D.
Vaughan, None; R. McQueenie, None; G. J. Graham, None; J. Brewer, None; I. B.
McInnes, None; M. Kurowska-Stolarska, None.
882
Anti-Inflammatory Effects of Phosphodiesterase 4 Inhibition Are Mediated by Mitogen-Activated Protein Kinase Phosphatase-1. Riku
Korhonen, Tuija Hömmö, Mirka Laavola, Tiina Keränen, Mari Hämäläinen
and Eeva Moilanen. University of Tampere School of Medicine and Tampere
University Hospital, Tampere, Finland
Background/Purpose: MAP kinase phosphatase-1 (MKP-1) is a nuclear
tyrosine/threonine phosphatase that limits p38 MAP kinase activity. MKP-1
KO mice display excessive inflammatory response, and exhibit increased
disease severity and more extensive bone destruction in experimental arthritis
models. Anti-inflammatory effects of glucocorticoids are partly mediated by
increased MKP-1 expression. Phosphodiesterase (PDE) 4 is expressed in
several inflammatory and immune cells, and it hydrolyzes cAMP to 5’AMP
down-regulating cAMP signalling in cells. PDE4 inhibitors are under investigation for treatment of arthritis, and they have already entered the clinics in
the treatment of COPD as an anti-inflammatory remedy. In the present study,
S384
Disclosure: R. Korhonen, None; T. Hömmö, None; M. Laavola, None; T. Keränen,
None; M. Hämäläinen, None; E. Moilanen, None.
883
Role of Phospholipase D1 (PLD1) in the Expression of Proinflammatory
Genes in Rheumatoid Arthritis Synovial Fibroblasts (RASF). Sean C.
Friday1 and David A. Fox2. 1The University of Michigan, Ann Arbor, MI,
2
Univ of Michigan Med Ctr, Ann Arbor, MI
Background/Purpose: Interleukin-17 (IL-17) and Tumor Necrosis Factor alpha ((TNFa), when co-applied to RASF, induce synergistic expression
of proinflammatory genes such as IL-6 and IL-8.Work from our laboratory
using co-cultures of cytokine-activated T cells and RASF has demonstrated
that this synergy is largely contact-dependent (Tran et al., 2007).Recently, Hot
et al (2011) showed that PLD1 mRNA was similarly upregulated by IL-17A
and the less potent IL-17F in RASF.Another recent report (Sethu et al., 2010),
used a mouse model of peritonitis to show that blocking PLD1 mitigates
TNFa-driven inflammation in vivo. In light of these observations, we sought
to examine the potential role of PLD1 in pro-inflammatory gene expression
by RASF stimulated with IL-17A and/or TNFa.
Methods: We used quantitative real-time PCR to characterize the
cytokine-mediated effects on mRNA levels for a cluster of genes encoding
cytokines, chemokines, and tissue remodeling enzymes important in the
pathogenesis of RA.Also, secretion of IL-6, IL-8, and CCL20 was measured
by ELISA.To investigate the relevance of PLD1 activity, we added various
concentrations of the PLD1 inhibitor 1-butanol, knocked down PLD1
expression with siRNA, and used the two approaches together.
Results: PLD1 mRNA was weakly induced by IL-17 and/or TNFa
(⬍2-fold increase).1-butanol had complex effects on cytokine-induced target
gene mRNA expression, in a manner that was dose-dependent and biphasic
for all targets except ICAM1, IL-8, and MMP-14.Compared with the 10 other
targets studied, including PLD1 itself, ICAM1 mRNA expression showed the
least sensitivity to treatment with 1-butanol.When RASF were transfected
with PLD1-specific siRNA, there was an effect on induction of mRNA and
secreted protein, particularly for induction of IL-6, IL-8, and CCL20 when
IL-17 was co-applied with TNFa.Effects on mRNA and secreted protein were
not always positively correlated.For example, interference with PLD1 activity
resulted in increased CCL20 mRNA, but inhibited CCL20 secretion. Effects
of PLD1 knockdown were in part distinct from effects of 1-butanol.
Conclusion: PLD1 might be an important modulatory target for reducing
cytokine-evoked expression of proinflammatory genes by RASF, because it
exhibits gene-specific effects on mRNA levels and effects on efficacy of
regulated secretion/exocytosis.Stability of mRNAs and modulation of tran-
scription efficiency are likely mechanisms by which PLD1 affects cytokineinduced expression of proinflammatory genes.The effects of 1-butanol may
reflect inhibition of not only PLD1 but also PLD2 and possibly other
enzymes.
Disclosure: S. C. Friday, Johnson & Johnson, 2; D. A. Fox, None.
884
Receptor Activator of Nuclear Factor ÊB Ligand-Mediated Osteoclastogenesis Is Augmented by Interleukin-1â Via up-Regulation of Endoplasmic Reticulum Stress Signals. Myong-Joo Hong1, Myung-Soon Sung1,
Eun-Gyeong Lee1, Yoon Kyung Hong1, Chang-Hoon Lee2, Myeung Su Lee3
and Wan-Hee Yoo1. 1Department of Internal Medicine, Chonbuk National
University Medical School and Research Institute of Clinical Medicine,
Jeonju, South Korea, 2Department of Internal Medicine, School of medicine,
Wonkwang university, Iksan, Chonbuk, South Korea, 3Reumatology, Iksan,
Chonbuk, South Korea
Background/Purpose: Interleukin-1␤ (IL-1␤) and thapsigargin (TG)augmented endoplasmic reticulum (ER) stress modulate the receptor activator
of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis.
However, the mechanism by which IL-1␤ and TG affect osteoclastogenesis
remains elusive. Thus, we investigated the relationships between RANKLmediated osteoclast specific pathways and ER stress relevant signals in
osteoclast differentiation of bone marrow-derived cells.
Methods: Bone marrow cells (BMCs) were obtained from 5-week-old
male ICR mice. The cells were cultured to be differentiated into osteoclasts
with macrophage-colony stimulating factor (M-CSF) and RANKL in the
presence or absence of IL-1␤, thapsigargin (TG, ER stress inducer), or
4-phenylbutyric acid (PBA, ER stress inhibitor). The formation of osteoclasts
was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and
resorption pit assay with dentine slice. The molecular mechanisms of IL-1␤
and ER stress in osteoclastogenesis of BMCs were investigated using reverse
transcription-polymerase chain reaction (RT-PCR) and immunoblotting. Osteoclast specific and ER stress relevant signaling molecules were analyzed.
Transfections of small interfering RNA (siRNA) for glucose-regulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK) and inositolrequiring enzyme 1 (IRE1) were performed to knockdown ER stress initiating
signals to verify the relationships between osteoclast specific pathways and
ER stress signals.
Results: The formation of osteoclasts was increased by IL-1␤ and TG
augmented ER stress. PBA significantly inhibited IL-1␤ and TG induced
osteoclats formation. The expressions of osteoclast specific pathways such as
c-Fos and NFATc1, and ER stress associated signals such as PERK, IRE1,
GRP78, and eIF2␣ were significantly increased by IL-1␤ and TG which was
inhibited by PBA. Inhibition of ER stress initiating signals by siRNA
inhibited the expression of above mentioned osteoclast specific signals, thus
reduced IL-1␤ and/or TG-induced osteoclastogenesis.
Conclusion: IL-1␤ and/or TG-augmented ER stress significantly increased osteoclast formation which was inhibited by PBA. The mechanisms
were mainly associated with up-regulation of ER stress signals such as
GRP78, PERK, p-eIF2␣ and IRE1. Thus the modulation of ER stress signals
affecting osteoclast formation might be a new therapeutic strategy to prevent
inflammatory and destructive arthritis diseases such as rheumatoid arthritis
(RA) and diverse osteoporotic diseases.
Disclosure: M. J. Hong, None; M. S. Sung, None; E. G. Lee, None; Y. K. Hong,
None; C. H. Lee, None; M. S. Lee, None; W. H. Yoo, None.
885
Interferon ␣ and Self-Organized Criticality Theory. Shunichi Shiozawa1,
Yumi Miyazaki2 and Ken Tsumiyama1. 1Kyushu University Beppu Hospital,
Beppu, Japan, 2Kyushu University Beppu Hospital/ Kobe University Graduate School of Health Sciences, Beppu/ Kobe, Japan
Background/Purpose: One of the biggest obstacle we face in elucidating
the pathogenesis of autoimmunity today is the mechanism how autoreactive
lymphocyte clones could survive or emerge beyond the firewall called
‘forbidden clone’ of Burnet. We have proposed that autoreactive clones
emerge via de novo T cell receptor (TCR) revision from thymus-passed
non-autoreactive clones at periphery, and we named this T cell as
autoantibody-inducing CD4 (aiCD4) T cell (Tsumiyama K et al. PLoS ONE
4(12):e8382, 2009). Our novel ‘self-organized criticality theory’ explains that
systemic autoimmunity or systemic lupus erytematosus (SLE) necessarily
S385
Monday, November 12
we found that a PDE4 inhibitor rolipram enhanced MKP-1 expression which
was involved in the anti-inflammatory effects of rolipram.
Methods: The effect of MKP-1 and a PDE4 inhibitor rolipram on
inflammatory gene expression was investigated in mouse J774 and human
THP-1 macrophage cell lines, and in primary mouse peritoneal macrophages
(PM) from wild-type (WT) and MKP-1(–/–) mice. In cell lines, MKP-1
expression was silenced by siRNA. We also investigated the effect of
rolipram on carrageenan-induced paw inflammation in WT and MKP-1(–/–)
mice.
Results: TNF and IL-6 production was increased in macrophages with
impaired MKP-1 (that is in cells transfected with MKP-1 siRNA or macrophages from MKP-1 KO mice), and it was related to increased p38 MAP
kinase phosphorylation. p38 MAP kinase phosphorylation was inhibited by
rolipram and by a cAMP analog 8-Br-cAMP. LPS-induced MKP-1 expression was enhanced by rolipram, by a non-selective PDE inhibitor IBMX and
by 8-Br-cAMP in J774 and THP-1 cells and in PMs. Rolipram, IBMX and
8-Br-cAMP also inhibited TNF production in J774 and THP-1 cells. p38
MAP kinase inhibitor BIRB 796 inhibited TNF production in macrophages,
as expected. Rolipram inhibited TNF production in PMs from WT mice (63%
inhibition) but, interestingly, the inhibition of TNF production by rolipram
was greatly attenuated (27% inhibition) in PMs from MKP-1(–/–) mice.
Furthermore, rolipram attenuated carrageenan-induced paw inflammation in
WT but not in MKP-1(–/–) mice.
Conclusion: The results showed that a PDE4 inhibitor rolipram suppressed p38 MAP kinase pathway, and inhibited TNF production and
carrageenan-induced inflammation, and these effects were mediated by
MKP-1. The results suggest that the anti-inflammatory effects of PDE4
inhibitors are, at least partly, mediated by MKP-1. The findings emphasize
MKP-1 as a potential mediator of anti-inflammatory drug effects. Compounds
that enhance MKP-1 expression and/or MKP-1 activity hold potential as
novel anti-inflammatory drugs.
Monday, November 12
takes place when host’s immune system is overdriven by repeated exposure to
antigen to levels that surpass the immune system’s stability-limit, i.e., selforganized criticality. This aiCD4 T cells not only induced varieties of autoantibodies but also helped final maturation of CD8 T cell into cytotoxic T lymphocyte
(CTL) via antigen cross-presentation to induce tissue injuries identical to SLE.
We here examine the role of interferon ␣ (IFN␣) in relation to the aiCD4 T cell.
Methods: BALB/c mice were repeatedly immunized with ovalbumin
(OVA), keyhole limpet hemocyanin (KLH) or staphylococcal enterotoxin B
(SEB), and sera and tissues were examined using ELISA, immunohistopathogy, PCR, southern blotting and flow cytometry. Because IFN␣ transgenic
(Tg) mice are basically infertile, we adopted a Tet-off expression system.
Mouse IFNa1 (mIFN␣)cDNA integrated under TetOp promoter (TetOpmIFN␣) was microinjected into fertilized eggs of C57BL/6 to obtain
TetOp-mIFN␣ Tg mice. They were mated with E␮SR-tTA Tg mice under the
control of IgH chain enhancer/SR␣ promoter (E␮SR-tTA) to obtain double
Tg TetOp-mIFN␣/E␮SR-tTA mice. IFN␣ was inducible 12 weeks after
doxycycline cessation.
Results: Repeated immunization with antigen caused lesions identical to
SLE including anti-dsDNA and anti-Sm autoantibodies in the mice otherwise
not prone to spontaneous autoimmune diseases. Overstimulation of CD4 T
cells led to the development of aiCD4 T cell which had undergone TCR
revision and was capable of inducing autoantibodies and overdriving CD8 T
cell to become CTL via antigen cross-presentation leading to tissue injuries
identical to SLE. However, in the IFN␣ Tg mice, the lesions identical to SLE
just except for anti-Sm antibody were induced by solely increasing IFN␣.
Pathological lesions included IC-deposited glomerulonephritis, alopecia, epidermal liquefaction and positive skin lupus-band test and splenic onion-skin
lesion. The IFN␥⫹ activated CD4 and CD8 T cells with effector phenotype
(CTL) and activated CD3⫹CD4⫺CD8⫺ double negative (DN) T cell pathognomonic for SLE were increased. This DN T cell not only infiltrated to
glomeruli, but also induced de novo glomerulonephritis and alopecia upon
transfer to naı̈ve mice.
Conclusion: IFN␣ causes SLE. However, IFN␣ does not represent the
whole picture of SLE and thus, antigen induced mechanism, i.e., ‘selforganized criticality theory’, was discussed in relation to aiCD4 T cell and a
classical DN T cell.
Disclosure: S. Shiozawa, None; Y. Miyazaki, None; K. Tsumiyama, None.
886
Association Between Neutrophil Gene Signature and Disease Characteristics in Systemic Lupus Erythematosus Patients. Michelle Petri1, Hong
Fang1, Jadwiga Bienkowska2, Norm Allaire2, Jeff Browning2 and Susan
Kalled2. 1Johns Hopkins University School of Medicine, Baltimore, MD,
2
Biogen Idec Inc., Cambridge, MA
Background/Purpose: Neutrophils and neutrophil death (“netosis”) are
now understood to play a role in the pathogenesis of SLE. A neutrophil gene
signature exists in SLE, although its association with the clinical phenotype is
unknown.
Methods: A total of 292 SLE patients were included in the analysis.
Among these patients, 91.1% were female; 58.9% were Caucasian, 33.9%
were African-American, and 7.2% were other ethnicities. Mean age (standard
deviation) at baseline was 46.0 (⫾11.9) years. Neutrophil gene expression
was high (⬎6) in 31.9% (N⫽93), medium (5–6) in 31.5% (N⫽92), and low
(⬍5) in 36.6% (N⫽107) of patients.
Results: The neutrophil gene signature was more common in Caucasians
(p⫽0.045). The neutrophil gene signature is strongly associated with same
day disease activity, serologies (anti-dsDNA and low complements), and
need for prednisone. It is also strongly associated with poor outcomes
(myocardial infarction, deep venous thrombosis, diabetes, malignancy).
Table 1. Association between Same-day Visit Disease Activity and Neutrophil
Gene Signature
Variable
Ethnicity African-American
Caucasian
Other
Physician’s global
assessment ⬎1
SELENA SLEDAI ⱖ2
Age at visit (years) ⱕ30
⬎30
Low
Neutrophil
(<5)
(%, Nⴝ107)
Med
Neutrophil
(5–6)
(%, Nⴝ92)
High
Neutrophil
(>6)
(%, Nⴝ93)
36.5
57.9
5.6
11.2
42.4
52.2
5.4
16.3
22.6
66.7
10.8
30.1
47.7
13.1
86.9
60.9
9.8
90.2
65.6
12.9
87.1
Adjusted
P-value for
Ethnicity
0.045*
0.003
0.012
0.75
Use of Prednisone
Use of Plaquenil
Use of Aspirin
Anti-dsDNA ⱖ10
Lupus Anticoagulant
C3 ⬍79 mg/dl
C4 ⬍12 mg/dl
ESR ⬎20
25.2
77.6
30.8
10.3
10.3
8.4
5.6
40.2
32.6
88.0
41.3
26.1
12.0
8.7
9.8
53.4
49.5
71.0
51.6
31.2
23.7
20.4
18.3
61.5
0.0007
0.016
0.011
0.0005
0.023
0.031
0.034
0.0018
* Unadjusted p-value.
Table 2. Association between SLICC/ACR Damage Index and Neutrophil Gene
Expression in SLE
Variable
Low
Neutrophil
(<5)
(%, Nⴝ107)
Med
Neutrophil
(5–6)
(%, Nⴝ92)
High
Neutrophil
(>6)
(%, Nⴝ93)
Adjusted
P-value
for
Ethnicity
Myocardial Infarction
Deep Venous Thrombosis
Diabetes
Malignancy
0.0
1.9
4.7
2.8
6.5
0.0
6.5
12.1
5.4
6.5
14.1
15.2
0.0056
0.016
0.024
0.0043
Conclusion: This is the first gene signature to be associated with
myocardial infarction, deep venous thrombosis and malignancy. Targeting the
neutrophil gene signature appears to be promising for disease activity. Given
that atherosclerosis disease is the major cause of death in late SLE, this gene
signature may be the “missing link” in understanding how SLE accelerates
atherosclerosis. A limitation of the technique is that the neutrophil gene
signature will go up when there is lymphopenia.
Disclosure: M. Petri, HGS, 5, GlaxoSmithKline, 5, Medimmune, 5, UCB, 5, Anthera,
5, Pfizer Inc, 5, TEVA, 5; H. Fang, None; J. Bienkowska, Biogen Idec, 3; N. Allaire,
Biogen Idec, 3; J. Browning, Biogen Idec, 3; S. Kalled, Biogen Idec, 3.
887
Microrna-155 Protects Against Pulmonary Fibrosis by Targeting the
Transcription Regulator LXR Alpha. Mariola Kurowska-Stolarska1,
Manhl Hasoo1, Derek G. Gilchrist2, Eva Ruzicska2, Darren Asquith2, David
Welsh3, Lynn Crawford2, Nik Hirani4, Iain B. McInnes2 and Charles
McSharry2, 1 Institute of Infection,Immunity and Inflammation, College of
Medical, Veterinary and Life Sciences University of Glasgow, Glasgow,
United Kingdom, 2University of Glasgow, Glasgow, United Kingdom,
3
Western Infirmary, Glasgow, United Kingdom, 4University of Edinburgh,
Edinburgh, United Kingdom
Background/Purpose: MicroRNAs (miRs) are a novel class of posttranscriptional regulators. A single miR can have profound effects on cell
activation due to its ability to modulate multiple pathways at once. We have
previously shown that miR-155 is upregulated in rheumatoid arthritis (RA)
synovial macrophages and promotes the development of autoimmunity and
joint inflammation. Pre-clinical arthritis may be associated with lung changes
e.g. bronchial wall thickening, thus the aim of this study was to investigate the
contribution of miR-155 regulated pathways to lung homeostasis.
Methods: Normal human lung tissue was tested by in situ hybridisation
with miR-155 and control probes. To model the fibrotic response, WT and
miR-155⫺/⫺ mice were given bleomycin (0.06 unit/mouse) intranasally.
Intervention included intraperitoneal injections of the Liver X Receptor
(LXR) agonist (GW3965 daily; 40 mg/kg). End-points included bronchial
lavage (BAL) cytology, lung tissue histology, evaluation of the expression of
inflammatory and fibrotic genes by qPCR and concentrations of soluble
mediators in serum and BAL fluid by multiplex assays. The validation of
miR-155 binding to LXR, and the LXR response element in collagen gene
promoters were performed with reporter assays.
Results: In situ hybridisation showed an abundant expression of miR-155
in the normal human lung suggesting that this miR may contribute to normal
lung homeostasis. miR-155⫺/⫺ mice developed more severe bleomycininduced lung fibrosis compared to WT mice, as seen by increased collagen
1a/3a mRNA expression and protein deposition in the lungs, as well as
accumulation of macrophages and lymphocytes in BAL. Gene expression
analysis of lung extracts revealed an increase in the M2 pro-fibrotic macrophage markers Arginase 2, IL-13R and Ym1. In addition, the levels of
pro-fibrotic cytokines such as VEGF and bFGF were significantly higher in
BAL and serum of miR-155⫺/⫺ mice. Primary lung fibroblast lines derived
from miR-155⫺/⫺ mice showed higher proliferation rates and motility
compared to WT cells in wound healing assays. Computational analysis
followed by functional luciferase assays revealed that the transcription
activator LXR alpha is a direct target of miR-155 in the lungs. Expression of
S386
LXR alpha was significantly upregulated in the lungs of naı̈ve miR-155⫺/⫺
mice and was further increased in mice given bleomycin compared to
similarly treated WT controls. Injection of the LXR agonist to WT mice
increased LXR expression and mirrored the same phenotypic response to
bleomycin as the miR-155 deficient mice; shown by increased collagen
deposition and M2 macrophage and fibroblast activation. Promoter analysis
revealed that LXRs could directly induce collagen production by binding to
col1a and col3a promoters.
Conclusion: miR-155 appears important for lung homeostasis, likely by
fine tuning levels of LXR␣ thereby protecting from excessive remodelling.
Given this and the emerging contribution of miR-155 to development of
autoimmunity, this miR may act as a master-switch determining the duration
of inflammation and the initiation of remodelling, as well as the balance
between the immune and auto-immune responses.
888
Plasma Cells Express the Novel Cytokine Interleukin-36␣ in Psoriatic
and Rheumatoid Arthritis Synovium. Anja Derer1, Silke Frey1, MariaElena Messbacher1, Serena Bugatti2, D. Baeten3, Carlomaurizio Montecucco4, Georg A. Schett1 and Axel J. Hueber1. 1University of Erlangen,
Erlangen, Germany, 2Division of Rheumatology, University of Pavia School
of Medicine, IRCCS Policlinico San Matteo Foundation, Pavia, Italy, 3Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands,
4
University of Pavia School of Medicine, IRCCS Policlinico San Matteo
Foundation, Pavia, Italy
Background/Purpose: IL-36␣ is a recent described IL-1 cytokine family
member with proinflammatory and clear pathogenic properties in psoriasis.
Aim of this study was to determine IL-36␣ expression in psoriatic arthritis
(PsA) compared to rheumatoid (RA) and osteoarthritis (OA).
Methods: Synovial tissue gathered from arthritis patients were stained for
IL-36␣, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by
immunohistochemistry and immunofluorescence. Lysates were tested for
IL-36␣ by western blot analysis. Synovial fibroblasts (FLS) stimulated with
IL-36␣ were assessed for cytokine expression.
Results: The IL-36R and its ligands IL-36␣ and IL-36Ra could be
detected in inflammatory arthritis in the synovial lining layer as well as
cellular infiltrates. IL-36␣ was significantly higher expressed in PsA and RA
synovium compared to OA (p⫽0.0011 and p⬍0.0001, respectively). No
differences were seen in IL-36R and IL-36Ra. The expression of IL-36␣ was
confirmed by western blot analysis. IL-36␣ induced expression of IL-6 and
IL-8 in FLS. CD138-positive plasma cells were determined as major cellular
source for IL-36␣.
Conclusion: We described that the novel cytokine IL-36␣ is upregulated
in PsA and RA synovium mainly expressed by plasma cells. This insight
needs further studies to determine if the IL-36 family can function as a
potential target for arthritis therapy.
Disclosure: A. Derer, None; S. Frey, None; M. E. Messbacher, None; S. Bugatti,
None; D. Baeten, None; C. Montecucco, None; G. A. Schett, None; A. J. Hueber,
None.
889
Modeling Environmental and Genetic Determinants to Identify the
Association of Risk Genes in Anti-Ro60-Mediated Injury: Relaxin Receptor I and Tumor Necrosis Factor. Joanne H. Reed1, Paula S. Ramos2,
Jiri Zavadil1, Jill P. Buyon1 and Robert M. Clancy1. 1New York University
School of Medicine, New York, NY, 2Medical University of South Carolina,
Charleston, SC
Background/Purpose: Fetuses exposed to maternal anti-Ro60 antibodies
can develop cardiac conduction abnormalities and life threatening cardiomyopathy; manifestations of neonatal lupus (NL). Recent data support an injury
model in which immune complexes (IC) comprised of Ro60, ssRNA, and
anti-Ro60 engage Toll-like receptors (TLR) and promote secretion of proinflammatory and profibrotic factors.To identify risk genes related to TLRdependent fibrosis, a novel strategy was designed based on: 1) gene expression of macrophages stimulated by Ro60-related hY3 ssRNA as a proxy of
the in utero environmental contribution and 2) the association of genetic
variation with cardiac NL. This is the first approach to employ environmental
Disclosure: J. H. Reed, None; P. S. Ramos, None; J. Zavadil, None; J. P. Buyon,
NIH 5R37AR042455, 2, NIH AR42220, 2; R. M. Clancy, None.
890
The Role of Adipocytokines in Osteophyte Formation in Osteoarthritis.
Susann Junker1, Grit Krumbholz1, Klaus Frommer1, Angela Lehr2, Stefan
Rehart2, Jürgen Steinmeyer3, Markus Rickert4, Georg A. Schett5, Ulf MüllerLadner1 and Elena Neumann6. 1Justus-Liebig-University of Giessen,
Kerckhoff-Klinik, Bad Nauheim, Germany, 2Markus-Hospital, Frankfurt,
Germany, 3University Hospital Gie␤en and Marburg, Gie␤en, Germany,
4
University Hospital Giessen and Marburg, Giessen, Germany, 5Department
of Internal Medicine III and Institute for Clinical Immunology, University of
Erlangen-Nuremberg, Erlangen, Germany, 6Justus-Liebig-University of
Gie␤en, Kerckhoff-Klinik, Bad Nauheim, Germany
Background/Purpose: Obesity is an established risk factor in osteoarthritis (OA), but there is not much known about the interaction between bone
formation and the so-called adipo(cyto)kines. Adipokines, such as adiponectin (Ad), visfatin (Vis) or resistin (Res), are adipose tissue-derived factors,
which are associated with the pathogenesis of rheumatoid arthritis (RA) and
OA. Adipokines can be produced by other cell types, e.g. fibroblasts,
osteoblasts, osteoclasts and chondrocytes. However, in contrast to their
joint-destructive effects in RA, their role in joint remodeling in OA,
specifically in osteophyte formation, is still unclear. Therefore, the expression
of adipokines in osteophyte development and cells of bone formation and
their effect on these cells were analyzed.
Methods: Osteophytes, cartilage and osteoblasts were obtained from OA
patients during joint replacement surgery. Serial sections of bone tissue were
stained (Masson trichrome, TRAP) and scored from grade one (no ossification, mainly connective tissue and cartilage) to five (ossified, mineralized
osteophyte, ⬍10% connective tissue). For analysis of adipokine localization,
immunohistochemistry was performed to detect alkaline phosphatase,
collagen-type II, Ad, Vis, and Res. Immunoassays for Vis were performed on
cartilage and isolated primary chondrocyte lysates. Osteoblast cultures were
stimulated with Ad or Res and measurements of IL-6, IL-8, and MCP-1 were
performed in cell culture supernatants.
S387
Monday, November 12
Disclosure: M. Kurowska-Stolarska, None; M. Hasoo, None; D. G. Gilchrist, None;
E. Ruzicska, None; D. Asquith, None; D. Welsh, None; L. Crawford, None; N.
Hirani, None; I. B. McInnes, None; C. McSharry, None.
and genetic determinants to identify the association of risk genes in antiRo60-mediated injury.
Methods: Human macrophages obtained from PBMCs were transfected
with hY3 or cultured with IC containing Ro60, anti-Ro60,and hY3 to ligate
TLR7 with or without IRS661, a specific TLR7 inhibitor. Affymetrix
HG-U133A 2.0 microarray analysis using RNA isolated from the test
conditions (n⫽6) was employed.Selection was prioritized to expression of
genes common to both hY3 and IC stimulation in which the copy number
increased by 50%. Ingenuity Pathway Analysis was used to generate a list of
genes with fibrotic functions.Variants from our previously published genomewide association study (GWAS) were used to test for an enrichment of
association in these genes. This list was then compared to the overexpressed
transcripts, and shared genes were ranked using a weighted composite score
with a focus on the TLR7 pathway (ratio of transcript copy number for
IC/IC⫹IRS661, high to low, and by the P-value of the variant, most
significant to least).
Results: In hY3 and IC stimulated conditions 1184 shared genes were
upregulated of which 1110 and 891 were reduced by 50% with IRS661
co-treatment, respectively. Among these, there was an enrichment of genes
known to be related to inflammation and fibrosis.Based on our previously
published GWAS, 327 fibrotic genes showed a significant enrichment of
associations with cardiac NL (P⫽2.27 ⫻ 10⫺9).Of these genes, 20 were
overexpressed in the macrophage array in a TLR7-dependent manner.To
select candidates with a potential functional role in mediating cardiac injury,
the candidate list was narrowed to three genes based on a ranking of a
composite score. The risk gene with the highest score was the relaxin receptor
1 (RXFP1) (transcript copy number (IC/(IC⫹IRS661)) ratio⫽21.2 and
rs10517692 P⫽0.035), a G-protein coupled receptor that binds relaxin and
plays a role in collagen and connective tissue remodeling. Key inflammatory
mediators included C5 (ratio⫽6.4, rs2269066 P⫽0.008) and TNF (ratio⫽4.1,
rs2844482 P⫽0.004). The latter was previously reported to have both genetic
variation and biologic relevance associated with cardiac NL.
Conclusion: These data support the applicability of a novel model in
which causal alleles can be identified by combining expression and association datasets to delineate the molecular mechanisms by which anti-Ro60
antibody mediates cardiac injury. The identification of RXFP1 and the further
confirmation of TNF provide important targets for consideration.
Monday, November 12
Results: Ad, Res and Vis were detectable in all osteophyte grades. In
osteophytes without ossification (grade 1), especially Ad and, to a lower extent,
Res and Vis were localized in connective tissue fibroblasts. In ossified osteophytes
(grade 2–5), Res and Vis protein expression was co-localized with osteoclasts and
osteoblasts. Vis was detectable additionally in chondrocytes in osteophytes of all
grades (50 % stained chondrocytes). Vis expression in human cartilage and
cultured chondrocytes was confirmed on protein and mRNA level. Ad was
detectable in co-localization with osteoblasts as well as around blood vessels.
Vis expression in osteoblasts was confirmed on mRNA level. Immunocytochemistry on cultured osteoblasts confirmed the expression of Ad, Res and Vis.
Stimulation of osteoblasts with Ad and Res led to an increased IL-6, IL-8 and
MCP-1 release when compared to unstimulated controls (Ad: 5,7-fold, 9,5-fold,
3,6-fold, respectively/Res: 1,7-fold, 1,6-fold, 1,3-fold, respectively). The immunomodulatory effect of Ad on osteoblasts was stronger than the effect of Res.
Conclusion: The expression of Ad and Vis in osteophyte connective
tissue and cartilage suggests an involvement in early osteophyte formation.
Res and Vis expression by osteoblasts and osteoclasts in ossified osteophytes
suggests a role in bone remodeling of osteophytes at later stages. Osteoblasts
respond to the stimulation with Ad and Res with an increased secretion of
inflammatory mediators. Therefore, adipokines are most likely involved in
osteophyte formation at different stages of OA and affect different cell types
of cartilage and bone formation.
Acknowledgement: Funded by the ANCYLOSS project of the German Ministry of
Research and Education (BMBF).
Disclosure: S. Junker, None; G. Krumbholz, None; K. Frommer, None; A. Lehr,
None; S. Rehart, None; J. Steinmeyer, None; M. Rickert, None; G. A. Schett, None;
U. Müller-Ladner, None; E. Neumann, None.
891
Fatty Acids Promote Secretion of Proinflammatory and Prodestructive
Factors by Synovial Fibroblasts. Klaus W. Frommer1, Andreas Schäffler2.
Stefan Rehart3, Angela Lehr3, Ulf Müller-Ladner1 and Elena Neumann1,
1
Justus-Liebig-University of Gie␤en, Bad Nauheim, Germany, 2University of
Regensburg, Regensburg, Germany, 3Markus-Hospital, Frankfurt, Germany
Background/Purpose: Due to their role in inflammatory metabolic
diseases, we hypothesized that free fatty acids (FFA) are also involved in
primary inflammatory joint diseases including rheumatoid arthritis (RA) and
psoriasis arthritis (PsA) as well as in degenerative joint diseases with
secondary inflammatory properties, specifically osteoarthritis (OA). To test
this hypothesis, we analyzed the effect of FFA on synovial fibroblasts (SF), a
key cell type in the pathophysiology of arthritis. We also investigated whether
FFA need to be internalized to have an effect and if the innate immune system
is involved in the modulation of this effect.
Methods: RASF, OASF and PsASF were stimulated in vitro with
different saturated and unsaturated FFA within their physiological range of
concentrations. Immunoassays were used to quantify FFA-induced protein
secretion. Sulfosuccinimidyl oleate sodium (SSO) was used to inhibit the fatty
acid translocase (FAT), which is responsible for transporting long-chain fatty
acids into the cell. In addition, TLR4 signaling, which can contribute to
driving arthritis, was inhibited intracellularly and extracellularly.
Results: In RASF, FFA dose-dependently enhanced the secretion of the
proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as
the matrix-degrading enzymes MMP-1 and MMP-3. Cell population, cell
source (RA, OA, or PsA) and the respective molecular parameters were
factors that influenced the changes of protein secretion (e.g. for lauric acid
[100 ␮M] with RASF/IL-6: 9.1-fold increase; IL-8: 14.9-fold increase;
MCP-1: 2.4-fold increase; pro-MMP1: 5.1-fold increase; MMP-3: 83.6-fold
increase). At equal concentrations, both saturated and unsaturated fatty acids
showed similar effects, while responses to FFA were generally stronger for
OASF and PsASF than for RASF (e.g. for palmitic acid [10 ␮M] with
RASF/IL-6: 2.8-fold increase; with OASF: 15.2-fold increase; with PsA-SF:
39.3-fold increase). Pre-incubation of RASF with SSO almost completely
abrogated the effect of palmitic acid on IL-8 secretion. However, both
intracellular and extracellular TLR4 signaling inhibition blocked the palmitic
acid-induced IL-6 secretion of RASF.
Conclusion: The data show that FFA are not only metabolic substrates
but also directly contribute to articular inflammation and degradation in
various joint diseases. Moreover, the data support the hypothesis that
FFA-induced joint destruction is mediated through the innate immune system.
Disclosure: K. W. Frommer, None; A. Schäffler, None; S. Rehart, None; A. Lehr,
None; U. Müller-Ladner, None; E. Neumann, None.
892
The Epigenetically Repressed Long Noncoding RNA Hotair Influences
the Expression of Matrix Metalloproteases in Synovial Fibroblasts.
Michelle Trenkmann1, Matthias Brock2, Renate E. Gay1, Beat A. Michel3,
Lars C. Huber2 and Steffen Gay1. 1Center of Experimental Rheumatology,
University Hospital Zurich, Zurich, Switzerland, 2Department of Internal
Medicine, University Hospital Zurich, Zurich, Switzerland, 3Department of
Rheumatology, University Hospital Zurich, Zurich, Switzerland
Background/Purpose: Long noncoding RNAs (lncRNA, ⬎200nt) have
recently emerged as regulators of gene expression functioning as signals,
decoys, guides or scaffolds for transcription factors and/or the epigenetic
machinery of the cell. The repressive epigenetic mark trimethylated histone 3
lysine 27 (H3K27me3) is transferred by the histone methyltransferase EZH2
which is up regulated in rheumatoid arthritis (RA) synovial fibroblasts (SF)
and inducible by tumor necrosis factor (TNF)-␣ (Trenkmann M et al., ARD,
2011). The lncRNA HOX transcript antisense RNA (HOTAIR) has been
associated with cancer and metastasis; it was shown to interact with EZH2
and proposed to guide H3K27 trimethylation of target genes (Wang KC and
Chang HY, Mol Cell, 2011). Here, we studied expression, regulation and
function of HOTAIR in SF.
Methods: Gene expression in SF was measured by SYBR Green or
TaqMan real-time PCR with normalization to GAPDH. SF were stimulated
with TNF␣ (10ng/ml; n⫽11) and interleukin (IL)-1␤ (1ng/ml; n⫽5). Osteoarthritis (OA)SF were transfected with a vector encoding EZH2 (n⫽4) or
siRNA targeting HOTAIR (n⫽11). Chromatin from SF was precipitated with
antibodies for histone 3 (H3), H3 methylation H3K4me3 and H3K27me3,
and H3 acetylation (Ac), and the HOTAIR promoter was analyzed for
epigenetic regulation.
Results: The expression of HOTAIR was strongly decreased (12.7-fold)
in RASF (n⫽9) compared to OASF (n⫽13) (⌬Ct 14.3⫾3.3 vs. 10.6⫾1.7,
p⫽0.005). EZH2 over expression in OASF reduced the expression of
HOTAIR by 30⫾17% (p⬍0.05) suggesting that EZH2-mediated methylation
of H3K27 may regulate HOTAIR expression. Indeed, HOTAIR levels in
RASF and OASF inversely correlated with the repressive H3K27me3
epigenetic mark in the promoter of HOTAIR (Spearman R⫽⫺0.8725,
p⬍0.0001). In detail, the H3K27me3 to H3 ratio in RASF was 0.51⫾0.35
whereas the HOTAIR promoter in OASF showed much less H3K27 trimethylation (ratio to H3 0.25⫾0.23; p⫽0.0309). Interestingly, neither in RASF
nor in OASF H3K4me3 or H3-Ac could be detected at the HOTAIR
promoter. Stimulation of OASF with TNF␣ for 24h and 48h decreased
HOTAIR levels by 63⫾16% and 56⫾26% (p⬍0.0001). IL-1␤-stimulation
reduced HOTAIR expression by 54⫾10% and 63⫾6%, respectively
(p⬍0.0005). To identify a functional role for HOTAIR repression in RASF,
we silenced HOTAIR in OASF using RNA interference. The silencing of
HOTAIR significantly increased mRNA levels of the matrix metalloproteases
(MMP) 3, 13 and 14 (MMP3 by 1.8⫾0.7-fold, MMP13 by 4.3⫾3.1-fold and
MMP14 by 2.1⫾0.7-fold, p⬍0.05); in contrast, results for MMP1 were
inconsistent. The TNF␣-induced expression of MMP3 (51.6⫾21.2-fold) and
MMP13 (6.9⫾2.6-fold) was further increased by silencing of HOTAIR
(71.5⫾28-fold and 18.8⫾8.6-fold, p⬍0.05) whereas the IL-1␤-stimulated
expression was not significantly changed (n⫽5 each).
Conclusion: This is the first report of a differential expression of a
lncRNA in RA. The expression of HOTAIR is strongly reduced in RASF via
the repressive epigenetic mark H3K27me3. We demonstrate that HOTAIR
silencing may account for the up regulation of matrix-degrading enzymes
indicating a potential role for HOTAIR repression in the activated, matrixdestructive phenotype of RASF.
Disclosure: M. Trenkmann, Masterswitch-FP7, IMI-BTCure, IAR, 2; M. Brock,
ZIHP, IAR, 2; R. E. Gay, Masterswitch-FP7, 2; B. A. Michel, None; L. C. Huber,
None; S. Gay, IAR, 2.
893
Nuclear Factor-␬B Activation by Type II Collagen Peptide in Osteoarthritic Chondrocytes: Its Inhibition by Hyaluronan Via CD44. Tadashi
Yasuda. Tenri University, Tenri, Japan
Background/Purpose: Some proteolytic products of cartilage matrix
may contribute to cartilage destruction through their catabolic activities.
Recently, we have found that a 24-mer synthetic peptide of type II collagen
named CB12-II stimulates type II collagen cleavage with induction of matrix
metalloproteinase (MMP)-13 in cartilage explant culture. Although the
intracellular signaling that leads to cartilage destruction is mediated by a
S388
Disclosure: T. Yasuda, None;
894
Genetic Variants in the IL-4 and IL-4 Receptor Genes in Association with
the Severity of Joint Damage in Rheumatoid Arthritis: A Study in Seven
Cohorts. A. Krabben1, A. G. Wilson2, R. Knevel1, A. Zhernakova3, E.
Brouwer3, E. Lindqvist4, T. Saxne4, G. Stoeken-Rijsbergen1, J. A. B. van
Nies1, D. P. C. de Rooy1, T.W.J. Huizinga1, B. P. C. Koeleman5, R. E. M.
Toes1, P. K. Gregersen6 and A. H. M. van der Helm-van Mil1. 1Leiden
University Medical Center, Leiden, Netherlands, 2University of Sheffield,
Sheffield, United Kingdom, 3University of Groningen, University Medical
Center, Groningen, Netherlands, 4Lund University, Lund, Sweden, 5University Medical Center Utrecht, Utrecht, Netherlands, 6Feinstein Institute Medical Research and North Shore-Long Island Jewish Health System, Manhasset, NY
Background/Purpose: The severity of RA is reflected by the severity of
radiological joint destruction. It is highly variable between patients and up to
58% of this variance is explained by genetic factors. In order to increase the
understanding of the processes underlying joint damage progression, it is
relevant to identify individual risk factors. In vitro studies and mice studies
showed that IL-4 has a role in suppressing arthritis severity. The effect of IL-4
is mediated by a heterodimeric receptor composed of the IL-4R alpha chain.
Several genetic variants in IL-4 and IL-4R have been described to associate
with RA severity, though these findings have not been replicated. Together
these data prompted us to investigate the association between IL-4 and IL-4R
tagging SNPs and progression rate of joint damage in a multi-cohort
candidate gene study.
Methods: IL-4 and IL-4R tagging SNPs (8 and 39, respectively) were
genotyped in 600 RA patients of whom 2,846 sets of hands and feet X-rays
were collected during 7 years follow-up. Subsequently, significantly associated SNPs were genotyped and studied in relation to 3,523 X-rays of 2,064
RA patients of several European and North-American cohorts. These concerned data-sets from Lund (Sw) (781 X-rays in 147 patients), Sheffield (UK)
(391 X-rays in 391 patients), Groningen (NL) (872 X-rays in 280 patients),
NARAC (USA) (385 X-rays in 385 patients), Wichita (USA) (337 X-rays in
101 patients) and NDB (USA) (757 X-rays in 757 patients). Three SNPs of
phase-2 were not available for the latter two cohorts. In all cohorts X-rays
were scored with high reproducibility. The relative increase in progression
rate per year in the presence of a genotype was determined, as this outcome
measure is comparable between cohorts. Subsequently, since the individual
replication cohorts had less number of X-rays than the discovery cohort, an
inverse variance weighting meta-analysis was done on the cohorts that
together formed the replication phase.
Results: In the discovery phase none of the IL-4 SNPs and seven of the
IL-4R SNPs were significantly associated with joint damage progression rate.
In the replication phase, two SNPs in IL-4R gene were significantly associated
with joint damage progression rate (rs1805011, p⫽0.017 and rs1119132,
p⫽0.001). After Bonferroni correction for testing seven SNPs in phase-2
rs1119132 remained significantly associated with joint progression rate
(pcorrected⫽0.007). Leiden RA-patients carrying both minor alleles of
rs1119132 had a 1.09 fold rate of joint destruction compared to other patients,
which corresponds to 81% higher rate of joint destruction over a period of 7
years.
Conclusion: rs1119132 in IL-4R was identified as well as independently
replicated to associate with progression rate of joint damage in RA.
Disclosure: A. Krabben, None; A. G. Wilson, None; R. Knevel, None; A. Zhernakova, None; E. Brouwer, None; E. Lindqvist, None; T. Saxne, None; G. StoekenRijsbergen, None; J. A. B. van Nies, None; D. P. C. de Rooy, None; T. W. J.
Huizinga, None; B. P. C. Koeleman, None; R. E. M. Toes, None; P. K. Gregersen,
None; A. H. M. van der Helm-van Mil, None.
895
Transcriptomics of Synovial Tissue of Early Human (CHECK) and
Experimental OA Identify Pathways Associated with Cartilage Damage.
Arjen B. Blom1, Peter L.E.M. van Lent1, Martijn H. van den Bosch1, Hans
Cats2, Peter M. van der Kraan1 and Wim B. van den Berg3. 1Radboud
University Nijmegen Medical Centre, Nijmegen, Netherlands, 2Sint Maartenskliniek, Nijmegen, Netherlands, 3Rheumatology Research and Advanced
Therapeutics, Department of Rheumatology, Radboud University Nijmegen
Medical Centre, Nijmegen, Netherlands
Background/Purpose: Many osteoarthritis (OA) patients show synovial
inflammation, even relatively early during the disease. Mechanisms through
which synovial activation contributes to the joint pathology that characterizes
OA, are not known. The objective of this study is to identify common
pathways in the synovium that determine cartilage damage during OA.
Methods: From patients that entered the CHECK Cohort study (Cohort
Hip and Cohort Knee) and from controls (n⫽7) synovial biopsies were
collected. CHECK is a prospective 10-year follow-up study on participants
with early osteoarthritis-related complaints. Kellgrenn&Lawrence score (KL)
was determined at inclusion (n⫽18). In addition, biopsies of 7 control synovia
were collected. A longitudinal expression analysis was performed on murine
synovial tissue at day 7, 21 and 42 after induction of collagenase induced OA
(CIOA). CIOA was induced by intra-articular injection of collagenase and
contra lateral knee joints served as controls. Microarray experiments were
performed on all synovial tissues. Functional annotation clustering (FAC) and
pathway analysis was done using DAVID.
Results: Gene expression profiles of control synovia were compared to
CHECK synovia. Enrichment analysis revealed several annatations, including
regulation of macrophage differentiation, innate immune responses, cell
migration, TGF␤-, BMP- and wnt-signaling. This signifies clear activation of
the synovium in CHECK patients compared to controls. Next we compared
synovial tissue of patients with radiological damage (KLⱖ1) with patients
without damage (KL⫽0). Genes that showed the strongest association with
cartilage damage were MMP-1, MMP-3, S100A8 and cartilage
glycoprotein-39 (18, 10, 6 and 6-fold), all of which have been associated with
cartilage damage. Response to wounding, chemotaxis, innate immune response and metalloproteases were strongly and significantly enriched and thus
associated with joint damage. Pathway analysis demonstrated that in the
synovium of patients with joint damage the complement-activation pathway,
TGF␤- and BMP-signaling and TLR-activation were significantly upregulated. These results were underlined by analysis of synovium from CIOA.
Among the genes that were strongly upregulated on all time points after
induction were MMP-3, MMP-13, MMP-14 and COMP (6, 16, 6 an 13-fold).
Again, wound healing, innate immune response and metalloproteases were
significantly enriched, as were the complement pathway, the TLR-, TGF␤,
BMP and wnt-signaling pathways. A recent publication demonstrated complement to be essential in experimental OA. We therefore determined
expression of complement binding proteins, and found a strong upregulation
of COMP, lumican, osteomodulin, biglycan, decorin and fibromodulin.
Conclusion: These data suggest an active role for the synovium in OA
pathology, and identify pathways that are likely to be involved. In particular
the association of cartilage damage with the complement pathway was strong.
S389
Monday, November 12
cluster of catabolic pathways including nuclear factor-␬B (NF-␬B), the effect
of CB12-II on NF-␬B remains unclear.
Hyaluronan (HA) of high molecular weight is widely used in the
treatment of osteoarthritis (OA) by intra-articular injection. An increasing
body of evidence indicates that HA suppresses catabolic actions by proinflammatory cytokines like interleukin-1 and matrikines such as fibronectin
fragments. However, little is known of HA effect on actions of CB12-II
through interaction with HA receptor such as CD44.
This study was aimed to examine activation of NF-␬B in association with
MMP-13 production by CB12-II and its inhibition by HA in chondrocytes.
Methods: Cartilage explants harvested from OA knee joints or isolated
chondrocytes in monolayer were incubated with CB12-II or its scramble
peptide with or without pretreatment with 2700 kDa HA. In another set of
experiments, following preincubation with anti-CD44 antibody or nonspecific IgG, cartilage explants were incubated with or without HA, followed
by coincubation with CB12-II or the scramble peptide.
Enzyme-linked immunosorbent assays for phosphorylated p65 NF-␬B
and MMP13 were performed using total cell lysates and culture supernatants,
respectively.
Results: When cartilage explants or chondrocytes in monolayer were
incubated with CB12-II, the type II collagen peptide activated NF-␬B in
association with enhanced MMP-13 production. Inhibition studies with the
specific inhibitor indicated the requirement of NF-␬B for CB12-II-induced
MMP-13 production. Pretreatment with HA resulted in significant suppression of CB12-II-stimulated MMP-13 production in cartilage as well as in
chondrocyte monolayer cultures. HA suppressed NF-␬B activation by CB12II, leading to a decrease in MMP-13 production. Anti-CD44 antibody
reversed HA effect on CB12-II action.
Conclusion: The present study clearly demonstrated that HA suppressed
CB12-II-activated NF-␬B via CD44 in OA articular chondrocytes, leading to
decreased MMP-13 production. HA could down-regulate the catabolic action
of type II collagen fragments in osteoarthritic joints through the mechanism
demonstrated in this study.
In addition, TGF␤-, BMP- and wnt-signaling in the synovium, may contribute
to further joint damage. The enhanced expression of cartilage damaging
MMP-1, MMP-3 and MMP-13 suggests an active role of the synovium in OA
pathology.
Disclosure: A. B. Blom, None; P. L. E. M. van Lent, None; M. H. van den Bosch,
None; H. Cats, None; P. M. van der Kraan, None; W. B. van den Berg, None.
896
Monday, November 12
Tyro3, Axl, MerTK-Receptor Activation by Gas6 or Pros1 Gene Delivery, ameliorates Collagen-induced arthritis. Fons A.J. van de Loo1, Ben T.
van Den Brand1. Shahla Abdollahi-Roodsaz1, Eline A. Vermeij2, Miranda B.
Bennink2, Onno J. Arntz2 and Wim B. van den Berg1, 1Radboud University
Nijmegen Medical Centre, Nijmegen, Netherlands, 2Nijmegen, Netherlands
Background/Purpose: Insufficient controlled activation of innate immunity by cytokines and pattern recognition receptors could develop into
auto-immune diseases. Stimulation ofdendritic cells via the Axl receptor in
conjunction with IFNAR leads to upregulation of suppressor of cytokine
signaling (SOCS) proteins 1 and 3 and broadly inhibit both Toll-like Receptor
(TLR) signaling and TLR-induced cytokine-receptor cascades (Rothlin et al.
Cell 2007). This study evaluated whether Tyro3 Axl MerTK (TAM)- receptor
stimulation by Growth arrest specific 6 (Gas6) and Protein S (Pros1) as
natural negative feedback for Toll-Like Receptor and cytokine signaling can
be used to treat collagen-induced arthritis.
Methods: Adenoviruses (1 ⫻ 10E7 FFU) overexpressing Gas6 and Pros1
were injected intravenously (i.v.) or 3 ⫻ 10E8 FFU intra-articularly (i.a.) into
mice before onset of collagen-induced arthritis. Splenic T-helper subsets of
intravenously injected were studied by flow cytometry and knee joints of
mice injected i.v. and i.a. were assessed histologically. Messenger RNA
expression was analyzed in synovium of i.a. injected mice. Ciruclating
cytokines were measured on a Luminex-100 System (Luminex corp.) using a
magnetic bead-based multiplex immunoassay (Milliplex, Merck Millipore).
Joint inflammation was imaged using the ProSense probe with the IVIS
Lumina (Caliper Life Sciences), using the Cy5.5 filter.
Results: Gas6 or Pros1 did not affect arthritis incidence in either IV or IA
injected animals. However, Pros1 did significantly reduce ankle joint swelling, and circulating levels of KC and IL-6. Histological analysis of knee joints
revealed a moderate reduction of joint pathology and a significant reduction
of splenic T-helper 1 cells when Pros1 was overexpressed systemically. Local
overexpression of Gas6 decreased joint inflammation (as assessd histologically or imaged by ProSense) and joint pathology. Pros1 treatment showed a
similar trend of protection. Consistently, Gas6 and Pros1 markedly reduced
cytokine (IL-1␤, IL-6, and TNF␣) production in synovium. Moreover, IL-12
and IL-23 mRNA levels were reduced by Gas6 and Pros1, corresponding to
a decrease in IFN␥ and IL-17 production in synovium.
Conclusion: We provide the first evidence that TAM receptor stimulation
by Gas6 and Pros1 can be used to ameliorate arthritis when applied
systemically or locally. TAM receptor stimulation limits proinflammatory
signaling and the adaptive immunity. This pathway provides a novel strategy
to combat rheumatoid arthritis.
Disclosure: F. A. J. van de Loo, None; B. T. van Den Brand, None; S. AbdollahiRoodsaz, None; E. A. Vermeij, None; M. B. Bennink, None; O. J. Arntz, None;
W. B. van den Berg, None.
897
IL-33 Promotes Mast Cell Survivial Via Inhibition of Apoptosis Associated with Enhanced Expression of Bcl-XL. Shinjiro Kaieda1, Jun-Xia
Wang1 and Peter A. Nigrovic2. 1Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA, 2Brigham and Women’s Hospital, Boston, MA
Background/Purpose: Mast cells (MCs) are potent innate immune cells
that frequently accumulate in chronically inflamed tissues, including the
arthritic synovium. The factors that regulate MC persistence and survival in
such tissues are unknown. Recent studies have found that the mesenchymalderived cytokine IL-33 exerts potent effects on MC phenotype and function.
Knowing that IL-33 can inhibit apoptosis in cardiac myocytes and hepatocytes, we tested the hypothesis that IL-33 might also regulate MC proliferation and survival, including the development of synovial mastocytosis in the
context of inflammatory arthritis.
Methods: Murine bone marrow derived MCs (mBMMCs) were generated from wild-type (WT) mice and animals lacking the IL-33 receptor
IL1RL1. Cell viability, proliferation and apoptosis were examined after
exposure to IL-33, and compared with exposure to IL-3, a known survival
factor for MCs.Expression of the anti-apoptotic molecules Bcl-2 and Bcl-XL
were determined both as mRNA and as protein. To examine the role of IL-33
in vivo, fluorescently-labeled mixed WT and IL1RL1⫺/⫺ mBMMCs were
transferred into the peritoneum of IL1RL1⫺/⫺ mice. Following 6 days of
treatment with IL-33 (100ng/d/mouse, i.p.), peritoneal MCs were harvested
and analyzed using flow cytometry.WT and IL1RL1⫺/⫺ mBMMCs were
sorted and the levels of Bcl-2 and Bcl-XL mRNA were examined by
qRT-PCR. Synovial tissue MCs were enumerated in WT and IL1RL1⫺/
⫺animals at baseline and after induction of K/BxN serum transfer arthritis.
Results: While the viability of WT and IL1RL1⫺/⫺ mBMMCs was
similar in IL-3-supported culture, exogenous IL-33 was able to support the
survival of WT but not IL1RL1⫺/⫺ mBMMCs after IL-3 withdrawal. CFSE
dilution studies confirmed that this effect did not reflect enhanced proliferation, but rather arose via inhibited apoptosis as evident by a reduction in the
number of Annexin V positive cells. Exploring the mechanism of this effect,
we found that IL-33 increased expression of Bcl-XLbut not Bcl-2, unlike IL-3
which supported mBMMC survival via enhanced Bcl-2 but not Bcl-XL.
Correspondingly, WT mBMMC persisted better than IL1RL1⫺/⫺ BMMC in
IL-33-treated recipients, an effect again mediated not by proliferation but by
impaired apoptosis and Bcl-XL expression. While WT and IL1RL1⫺/⫺
demonstrated no difference in the number of synovial MC at baseline, after
K/BxN serum transfer the number of MC in ankle synovium was significantly
reduced in IL1RL1⫺/⫺ compared with WT mice. However, since IL-1RL1⫺/
⫺mice also exhibited less inflammation, the density of MC was similar in
both strains, suggesting the IL-33 is not uniquely required for maintaining
these cell populations in vivo.
Conclusion: These findings identify a novel role for IL-33 as a promoter
of murine MC viability, an effect likely mediated by enhanced expression of
the anti-apoptotic protein Bcl-XL. This effect could represent a new mechanism by which IL-33-producing cells, such as fibroblasts, support the
maintenance of tissue mastocytosis.However, at least in the short term K/BxN
arthritis model, other pathways appear sufficient to enable and maintain tissue
MCs even when this mechanism is interrupted by genetic deletion of the
IL-33 receptor IL1RL1.
Disclosure: S. Kaieda, None; J. X. Wang, None; P. A. Nigrovic, None.
898
Nuclear Receptor Related 1 Induces Synovial Hyperplasia Via Transcriptional Regulation of Novel Target Genes. Kimberlee S. Mix. Loyola
University New Orleans, New Orleans, LA
Background/Purpose: Nuclear receptor related 1 (NURR1/NR4A2) is
an orphan member of the nuclear receptor super-family that functions as a
constitutively active transcription factor. This receptor has critical functions in
the central nervous system, where it is required for the proper development of
dopaminergic neurons. Furthermore, recent studies suggest that NURR1
promotes inflammatory diseases such as cancer, multiple sclerosis, and
diabetes. We have documented over-expression of NURR1 in inflamed
synovial tissues and cartilage from patients with rheumatoid arthritis and
osteoarthritis. NURR1 is rapidly and potently induced by inflammatory
cytokines, suggesting that this receptor may promote disease progression and
tissue destruction.We have recently demonstrated that NURR1 induces a
hyperplastic phenotype in fibroblast-like synoviocytes by increasing proliferation, anchorage-independent growth, and invasion. In the current study, we
seek to elucidate the molecular mechanisms of NURR1 and identify downstream transcriptional targets of this receptor that may contribute to synovitis
and cartilage degradation.
Methods: To achieve elevated levels of NURR1 similar to those observed
in inflamed synovial tissues, NURR1 cDNA was transduced into normal
human synoviocytes.Transcriptional activity was confirmed by the activation
of a consensus NURR1 reporter construct. Quantitative RT-PCR arrays were
used to identify genes that were differentially regulated by NURR1.
Results: Paralleling the effects of TNF-alpha, NURR1 regulates a subset
of genes involved in angiogenesis, proliferation, and apoptosis. NURR1
potently induces expression of prolactin (300-fold), a peptide hormone that
enhances synoviocyte activation and lymphocyte recruitment.
Angiopoietin-1, a ligand for endothelium-specific tyrosine kinase receptors
involved in synovial angiogenesis was induced by NURR1 (6-fold). Expression of the tyrosine kinase receptor TEK was also induced (30-fold),
suggesting activation of an autocrine signaling pathway in synoviocytes.Raf
kinase and the downstream mitogenic transcription factor c-Myc were both
induced 3-fold by NURR1. Furthermore, the tumor suppressor gene p53 was
S390
synergistically repressed by NURR1 and TNF-alpha, suggesting that NURR1
may block DNA repair mechanisms and prevent apoptosis of synoviocytes.
Conclusion: Taken together, we have identified a novel set of NURR1
target genes that converge on multiple pathways regulating synovial hyperplasia.We hypothesize that antagonizing NURR1 activity with a small
molecule inhibitor may provide an innovative strategy to block pannus
formation and tissue destruction.
Disclosure: K. S. Mix, None;
899
A Role for Soluble Interleukin-6 Receptor As an Antagonist of
Interleukin-27 Signaling. Misato Hashizume, Keiko Esaki and Yoshihiro
Matsumoto. Chugai Pharmaceutical Co., Ltd., Gotemba, Japan
Disclosure: M. Hashizume, None; K. Esaki, None; Y. Matsumoto, None.
900
Deletion of RBP-J in a Murine Model of Inflammatory Arthritis Reveals
Differential Pro-Inflammatory Cytokine and FoxP3 Gene Expression.
Soumya D. Chakravarty, Karmen Au, Xiaoyu Hu and Lionel B. Ivashkiv.
Hospital for Special Surgery, New York, NY
Background/Purpose: The DNA-binding protein RBP-J serves as the
central transcriptional regulator of the Notch signaling pathway. Prior work
done using a knockdown approach of RBP-J in human macrophages and
conditional deletion of RBP-J in mouse macrophages has demonstrated
diminished LPS-induced expression of TNFa, IL-6 and IL-12p40, with IL-1
induction preserved. Elsewhere, it has been observed that host regulatory T
cells in RBP-J deficient mice have an attenuated ability to suppress effector
Disclosure: S. D. Chakravarty, None; K. Au, None; X. Hu, None; L. B. Ivashkiv,
None.
901
Colony-Stimulating Factor (CSF) Receptor 1 Blockade Overcomes
Overlapping Effects of M-CSF and Interleukin-34 On Myeloid Differentiation and Gene Expression to Reduce Inflammation in Human and
Murine Models of Rheumatoid Arthritis. Samuel Garcia1, Linda M.
Hartkamp1, Inge E. van Es1, Haishan Lin2, Li Long2, Emma L. Masteller2,
Brian R. Wong2, Paul P. Tak3 and Kris A. Reedquist1. 1Academic Medical
Center, University of Amsterdam, Amsterdam, Netherlands, 2Five Prime
Therapeutics, Inc., South San Francisco, CA, 3Academic Medical Center,
University of Amsterdam and GlaxoSmithKline, Amsterdam, Netherlands
Background/Purpose: Disease activity and response to therapy in RA
correlates with changes in synovial macrophage numbers and their products.
M-CSF or IL-34 stimulation of their receptor CSFR1 promotes macrophage
differentiation, activation and osteoclastogenesis.Pharmacological inhibition
of CSFR1 is beneficial in animal models of arthritis but the relative
contributions of M-CSF, IL-34 and their receptor to inflammation in RA are
unknown.
Methods: M-CSF, IL-34, and cellular markers were detected by immunohistochemistry and digital image analysis in synovial tissue from 18
biological-naı̈ve RA patients, 14 PsA patients, and 4 controls without
inflammatory disease (2 healthy donors and 2 OA patients). Gene expression
in M-CSF and IL-34 –differentiated human macrophages was assessed by
FACS analysis and q-PCR arrays. RA synovial explants were incubated with
M-CSF, IL-34, control antibody (Ab), or a humanized CSFR1-blocking Ab.
Prophylactic effects of control and CSFR1-blocking Ab were examined in
murine collagen-induced arthritis (CIA).
Results: Expression of M-CSF and IL-34 was similar in RA and PsA
synovial tissue, but lower in controls (p⬍ 0.05). M-CSF expression was
restricted to endothelial cells and IL-34 was observed in sublining mononuclear cells and intimal lining layer cells. CXCL5, CXCL6, FN1, COL1A1,
COL6A1–2, COL14A1, COL15A1, MMP7, MMP8 and MMP9 mRNA
S391
Monday, November 12
Background/Purpose: Recently, it has been reported that interleukin
(IL)-27 treatment reduces inflammation and ameliorates arthritis in collageninduced arthritis mice. IL-27 is a heterodimeric cytokine composed of
IL-27p28, which is similar to IL-6, and EBI3, which is similar to soluble IL-6
receptor (sIL-6R). Notably, each subunit is produced independently, allowing
IL-27 to associate with other proteins. sIL-6R is highly concentrated in serum
from patients with rheumatoid arthritis (RA). We elucidated the role of
sIL-6R in regulating IL-27 signaling.
Methods: Surface Plasmon Resonance analysis was used to examine the
binding of IL-27 to sIL-6R. Competitive ELISA was performed to evaluate
the binding to IL-27p28 and the dissociation of EBI3 from IL-27p28 in the
presence of sIL-6R. CD14⫹ cells were isolated from peripheral blood
mononuclear cells of healthy subjects. CD14⫹ cells were incubated with
IL-27 and sIL-6R for 20 minutes, and phosphorylation of STAT3 was
measured by FACS. CD14⫹ cells were incubated with M-CSF, TNF-␣, IL-27
and sIL-6R for 48 hours, and MCP-1 production from CD14⫹ cells was
measured by ELISA. CD14⫹ cells were cultured with RANKL and M-CSF
in the presence of IL-27 and sIL-6R for 4 days, and the number of osteoclasts
was counted after tartrate-resistant acid phosphatise (TRAP) staining. Concentrations of IL-27p28/sIL-6R complex and IL-27p28/EBI3 complex in
serum from healthy subjects and those with RA were determined by ELISA.
Results: Surface Plasmon Resonance analysis showed that binding curves
were generated from experiments in which IL-27 was exposed to a highdensity of sIL-6R coated on a sensor chip. sIL-6R promoted the dissociation
of EBI3 from IL-27p28 and the formation of IL-27p28/sIL-6R complex in a
dose-dependent manner. Anti-IL-6 receptor antibody (tocilizumab) inhibited
the formation of IL-27p28/sIL-6R complex. To examine the effect of sIL-6R
on IL-27 signaling, we measured phosphorylation of STAT3, which is
increased by IL-27, after stimulating sIL-6R and IL-27, and found that sIL-6R
decreased phosphorylation of STAT3. Next, we examined whether sIL-6R
inhibited the IL-27-mediated anti-arthritic effect. Whereas IL-27 reduced
TNF-␣-induced MCP-1 production from CD14⫹ cells, IL-27 did not decrease
TNF-␣-induced MCP-1 production in the presence of sIL-6R. Similarly,
RANKL-mediated osteoclast formation was inhibited by IL-27 but was not
inhibited by IL-27 in the presence of sIL-6R. Finally, we examined whether
IL-27p28/sIL-6R complex was formed in serum from healthy subjects and
from those with RA. Surprisingly, IL-27p28/sIL-6R complex in RA serum
was significantly higher than that in healthy serum.
Conclusion: We elucidated that sIL-6R binds to IL-27p28, antagonizes
IL-27 signaling, and blocks IL-27-mediated anti-arthritic effect. In addition,
we showed that IL-27p28/sIL-6R complex was more abundant in serum from
RA patients than in that from healthy subjects. These data suggest that sIL-6R
may be involved in regulating the IL-27 function in RA.
T cell responses in vitro, with augmented proliferation and function of
effector T cells noted in vivo, raising the possibility that dysregulation in the
frequency or function of regulatory T cells may contribute to RBP-J’s
selective modulation of pro-inflammatory mediators. Here, we evaluated the
in vivo effects of RBP-J’s conditional deletion in the myeloid cell compartment on pro-inflammatory cytokine expression, as well as lymphoid tissue
immunocyte composition, using a K/BxN serum transfer model of inflammatory arthritis.
Methods: RBP-Jflox/flox LysM-Cre knock-out (KO) mice with littermate
RBP-J⫹/⫹LysM-Cre controls (n⫽5 for each group) were used. After treatment with K/BxN serum, the clinical course of arthritis was followed by
measuring total joint thickness up to 14 days, at which point the mice were
sacrificed. Total joint RNA from each mouse was obtained for gene
expression analyses by qPCR. Splenic tissue was harvested from each mouse
for gene expression analyses by qPCR, as well as pooled collectively for each
group for immunophenotyping through flow cytometry. The latter was also
done for superficial inguinal and draining popliteal lymph node (LN) tissue.
Statistical analysis was done using the unpaired student’s t-test with p ⬍ 0.05
considered significant.
Results: Preliminary findings showed no significant difference in clinical
phenotype of K/BxN serum-induced arthritis between KO and control mice.
Gene expression profiling of whole joint tissue showed decreases in TNFa,
IL-6, IFN-g expression, as well as selective Notch target gene expression,
while maintaining comparable IL-1, CXCL10, and IL-12p40 levels. Surprisingly, expression levels of FoxP3 in KO mice vs. controls were significantly
decreased in both joint and splenic tissue (p⫽0.0244 and p⫽0.0286, respectively). Immunophenotyping of splenic and LN tissue showed increased
proportions of total CD4⫹ T cells in KO mice vs. controls, but a markedly
lower proportion of the CD4⫹CD25⫹FoxP3⫹ subset. Lower proportions of
F4/80⫹ and Ly6G⫹ cell populations in splenic and draining LN tissue of KO
mice vs controls, but higher populations of Ly6C⫹ cells, were also observed.
Conclusion: Deletion of RBP-J in the myeloid compartment does not lead
to phenotypic differences in K/BxN serum-induced inflammatory arthritis,
though selective modulation of pro-inflammatory cytokine gene expression in
vivo does occur. Decreased gene expression of FoxP3 and fewer
CD4⫹CD25⫹FoxP3⫹ cells in RBP-J deleted mice may contribute to this
selective modulation. The functional significance of these findings, coupled
with differences in myeloid cell composition and trafficking observed, remain
undetermined and will be further studied.
Monday, November 12
expression was significantly upregulated in macrophages differentiated in
M-CSF compared to IL-34, while CXCL7, CXCL9, CXCL10, CXCL11,
CXCL12, LAMA1, and MMP2 were significantly downregulated. M-CSF or
IL-34 had no effect on RA synovial explant IL-6 production, but anti-CSFR1
Ab dose-dependently reduced IL-6 production. Treatment with anti-CSFR1
Ab in CIA significantly reduced paw swelling and joint destruction.
Conclusion: M-CSF and IL-34 are expressed in topographically distinct
regions of inflamed synovial tissue and differentially effect macrophage
capacity to attract inflammatory cells and remodel tissue. Simultaneous
inhibition of CSFR1 interactions with both M-CSF and IL-34 suppresses
inflammatory activation of RA synovial tissue and pathology in CIA,
suggesting a novel therapeutic strategy for the treatment of RA.
Disclosure: S. Garcia, None; L. M. Hartkamp, None; I. E. van Es, None; H. Lin,
Five Prime Therapeutics, Inc., 1, Five Prime Therapeutics, Inc., 3; L. Long, Five
Prime Therapeutics, Inc., 1, Five Prime Therapeutics, Inc., 3; E. L. Masteller, Five
Prime Therapeutics, Inc., 1, Five Prime Therapeutics, Inc., 3; B. R. Wong, Five Prime
Therapeutics, Inc., 1, Five Prime Therapeutics, Inc., 3; P. P. Tak, Five Prime
Therapeutics, Inc., 5; K. A. Reedquist, Five Prime Therapeutics, Inc., 2.
902
Activation of NF-Kb Via Poly(I:C)-Induced Monocyte-Derived Microparticles Decreases TRAIL-Induced Apoptosis of Rheumatoid Arthritis
Synovial Fibroblasts. Mojca Frank Bertoncelj1, Blaz Rozman2, Beat A.
Michel3, Renate E. Gay1, David S. Pisetsky4, Oliver Distler5, Steffen Gay6
and Astrid Juengel1. 1Center of Experimental Rheumatology, University
Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP),
Zurich, Switzerland, 2Department of Rheumatology, University Medical
Centre Ljubljana, Ljubljana, Slovenia, 3Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 4Duke University Medical
Center, Durham, NC, 5Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland,
6
Center of Experimental Rheumatology, University Hospital Zurich and
Zurich Center of Integrative Human Physiology (ZIHP), Zurich, CH-8091,
Switzerland
Background/Purpose: Decreased sensitivity of rheumatoid arthritis
(RA) synovial fibroblasts (SF) to apoptosis leads to synovial hyperplasia and
destruction of joints in RA. Activation of NF-kB was shown to modulate
apoptotic pathways in different target cells. Based on our recent finding that
microparticles (MP) from monocytes, stimulated with Toll-like receptor 3
ligand Poly(I:C) (PIC), increase the resistance of RASF to TRAIL-induced
apoptosis and enhance the production of NF-kB-dependent cytokines IL-6
and IL-8, the aim of the present study was to examine the role of NF-␬B
signaling in the resistance of RASF to TRAIL-induced apoptosis mediated via
MP.
Methods: MP were isolated by differential centrifugation from supernatants of untreated or PIC-stimulated (16h) U937 cells or peripheral blood
mononuclear cells (PBMC) and were analysed by nanoparticle tracking
analysis, flow cytometry and BCA Protein Assay. RASF were treated with
MP⫾TRAIL for 24h. To investigate direct effects of PIC on the apoptosis,
RASF were stimulated with PIC⫾TRAIL for 24h. Apoptosis of RASF was
measured by flow cytometry using Annexin V/propidium iodide staining.
SC-514, a selective inhibitor of I␬B kinase 2, was used to test the role of
NF-kB signaling in MP actions in RASF. NF-␬B activity was determined by
luciferase reporter gene assay in RASF treated with MP for 6h.
Results: PIC-induced MP, but not MP from untreated U937 cells,
significantly decreased TRAIL-induced apoptosis of RASF (9⫾3% vs
TRAIL: 18⫾6%, p⫽0.003, n⫽8), and similar effects were observed with
PIC-induced MP derived from PBMC (18.⫾27% vs 35⫾27%, n⫽3). In
contrast, a direct stimulation with PIC alone significantly increased apoptosis
of RASF (11⫾4% vs 6⫾2% in untreated RASF, p⫽0.03, n⫽6), however it
did not affect TRAIL-induced apoptosis of RASF. Number (MP from
untreated cells: 3.0*1010/mL vs PIC-induced MP: 3.1*1010/mL; n⫽2 each),
size (median diameter 207 vs 199nm, n⫽2 each), surface annexin V binding
(66⫾10% vs 63 ⫾ 9%, n⫽3 each) and total protein content (330⫾50 vs
325⫾83 ng/mL, n⫽3 each) did not differ significantly between MP from
untreated and PIC-stimulated U937 cells. SC-514 significantly increased
TRAIL-induced apoptosis of RASF in the presence of PIC-induced MP
(20⫾3% vs 9⫾3% in the absence of SC-514, p⫽0.002, n⫽8). PIC-induced
MP from U937 cells led to activation of NF-␬B signaling in RASF (median
x-fold change: 13 vs untreated RASF, n⫽4).
Conclusion: Most interestingly, we could show that the activation of
NF-␬B plays a major role in the resistance of RASF to TRAIL-induced
apoptosis mediated via PIC-induced MP. This observed effect may reflect a
specific composition of PIC-induced MP. Alternatively, the effects of MP
could result from small amounts of PIC associated with MP although its
activity would differ from that in the free state.
Disclosure: M. Frank Bertoncelj, Articulum, Masterswitch-FP7, IMI BTcure, IAR, 2;
B. Rozman, None; B. A. Michel, None; R. E. Gay, Masterswitch-PF7, 2; D. S.
Pisetsky, Pfizer Inc, 5, Bio-Rad, 5; O. Distler, Actelion, Pfizer, Ergonex, BMS,
Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science, Bayer, and Active Biotec, 2; S. Gay, IAR, 2; A.
Juengel, IAR, Masterswitch-FP7, IMI-BTCure, 2.
903
NR4A1 Mediates Anti-Inflammatory Effects of Apoptotic Cells. Natacha
Ipseiz1, Stefan Uderhardt1, Georg A. Schett2 and Gerhard Kronke1. 1University of Erlangen, Erlangen, Germany, 2Department of Internal Medicine III
and Institute for Clinical Immunology, University of Erlangen-Nuremberg,
Erlangen, Germany
Background/Purpose: The nuclear receptor NR4A1 has been implicated
as negative feedback regulator of NF kappa B signalling and as key regulator
during the differentiation of Ly6C-low resident monocytes. Apoptotic cells
are known to exert anti-inflammatory effects on macrophages but the
underlying mechanisms are still poorly understood. Here we studied a
potential role of NR4A1 as mediator of the macrophage response to apoptotic
cells.
Methods: We analysed the effect of apoptotic thymocytes on wild type
and NR4A1⫺/⫺ peritoneal resident macrophages, and determined the consequences on intracellular signalling, gene expression and cytokine profile.
Moreover, we examined the consequences of the lack of NR4A1 during
maintenance of self tolerance by using the pristine-induced model of murine
sytemic lupus erythematosus.
Results: Expresion of NR4A1 was rapidly and highly induced in resident
macrophages after incubation with apoptotic thymocytes. NR4A1⫺/⫺ resident macrophages showed an exacerbated pro-inflammatory profile as well as
an increased activity of NF-␬B. Moreover, the anti-inflammatory effects of
apoptotic cells were reduced in NR4A1⫺/⫺ macrophages. In the pristine
model of murine lupus, NR4A1⫺/⫺ mice displayed increased levels of
autoantibodies such as ds-DNA antibodies.
Conclusion: Our data show for the first time that NR4A1 is an important
mediator of the anti-inflammatory effects of apoptotic cells in tissue resident
macrophages and thereby contributes to the maintenance of self-tolerance.
Disclosure: N. Ipseiz, None; S. Uderhardt, None; G. A. Schett, None; G. Kronke,
None.
ACR/ARHP Poster Session B
Epidemiology and Health Services Research:
Epidemiology and Outcomes of Rheumatic Disease II
Monday, November 12, 2012, 9:00 AM–6:00 PM
904
Perinatal Characteristics, Maternal Reproductive History and Juvenile
Idiopathic Arthritis: A Case-Control Study. Samantha W. Bell1, Beth A.
Mueller1, J. Lee Nelson2, Parveen Bhatti1 and Susan Shenoi3. 1University of
Washington, Seattle, WA, 2Fred Hutchinson Cancer Rsch, Seattle, WA,
3
Seattle Children’s Hospital, University of Washington, Seattle, WA
Background/Purpose: Juvenile Idiopathic Arthritis (JIA) is a heterogeneous group of chronic inflammatory arthritis conditions in children with
onset before 16 years of age, and is the leading cause of acquired short and
long-term disability in childhood. The etiology of JIA is largely unknown,
however there is increasing evidence that autoimmune diseases, including
JIA, may be associated with maternal reproductive or early childhood
exposures.
Methods: We conducted a case-control study of JIA cases identified at a
regional children’s hospital in the Seattle-Puget Sound area, using linked birth
certificate data from 1980 – 2009. Potential cases included all children ⬍20
years with relevant ICD codes who had received inpatient or outpatient care.
Their records were linked to Washington State birth records for 1980–2009 to
identify those with a Washington State birth certificate (N⫽1,518). For
comparison, control children were randomly selected in a ratio of 4:1 from the
remaining birth records, frequency matched on year of birth (N⫽6,072).
Review of medical records further refined case ascertainment based on
S392
specific clinical criteria (N⫽1,254) and allowed categorization of cases into
JIA subtypes. Multivariable logistic regression was used to estimate adjusted
odds ratios (OR) and 95% confidence intervals (CI) for the associations of
JIA/JIA subtypes with maternal and early life exposures as measured in the
birth certificates.
Results: Decreased ORs were observed for JIA in relation to greater
maternal parity (2 prior live births, OR 0.70, 95% CI 0.58, 0.85; 4⫹ prior live
births, OR 0.68, 95% CI 0.48, 0.97), a finding also observed for the persistent
oligoarticular JIA subtype. Fewer cases (11.4%) than controls (13.3%) had a
birth weight ⬎4000 g (OR 0.81, 95% CI 0.67, 0.98). Mothers of cases (5.2%)
were slightly more likely than those of controls (4.1%) to have had
preeclampsia during their pregnancy (OR 1.29, 95% CI 0.96, 1.73).
Conclusion: To our knowledge, no studies to date in the United States
have examined these exposures in relation to JIA. Greater maternal parity,
specifically having 2 or more prior live births, was significantly associated
with a decreased OR for JIA, a finding consistent with both the hygiene and
microchimerism hypotheses.
905
The Association Between Lower Body Mass Index and Increased Risk of
Giant Cell Arteritis Is Not Explained by Differences in Physical Activity.
Karin Jakobsson1, Lennart T.H. Jacobsson1, Kenneth J. Warrington2, Eric L.
Matteson2, Kimberly P. Liang3, Olle Melander1 and Carl Turesson1. 1Lund
University, Malmö, Sweden, 2Mayo Clinic, Rochester, MN, 3University of
Pittsburgh, Pittsburgh, PA
Background/Purpose: There is limited data on predictors of giant cell
arteritis (GCA). Low body mass index (BMI), a history of smoking and
several hormonal factors have been associated with GCA in a retrospective
case-control study, and we have confirmed the association with low BMI in
a prospective study. Potential explanations for the association between BMI
and GCA, include a difference in the level of physical activity. To our
knowledge, the impact of physical activity on the risk of GCA has not been
studied previously.
Our purpose was to examine potential influence of physical activity as a
risk factor of GCA in a nested case-control study based on a prospective
health survey.
Methods: Incident cases of GCA among participants in a population
based health survey, in which 30447 subject (12121 men and 18326 women)
were included between 1991 and 1996, were used for the present study. As
part of the health survey, information on medical history and life style factors
was obtained using standard physical examinations and self-administered
questionnaires. Information on physical activity were obtained by asking
participants to estimate the number of minutes per week, for each of the four
seasons, they spent performing 17 different physical activities. The answer
was multiplied by an intensity factor depending on the activity creating a
physical activity score. This method was adapted from the Minnesota
physical activity questionnaire, and has been validated against accelerometermonitoring, an objective measure of physical activity, in a subset of the
present health survey population.
Individuals who developed GCA after inclusion was identified by linking
the health survey database to the local patient administrative register and the
national hospital discharge register. A structured review of the medical
records of all identified cases was performed. Four controls for each validated
case, matched for sex, year of birth and year of screening, who were alive and
free of GCA when the index person was diagnosed with GCA, were selected
from the health survey. The impact of BMI and physical activity as predictors
of GCA was examined in conditional logistic regression models.
Results: Fifty-five cases [mean age 73.6 years; standard deviation (SD
5.21), 43 women (78 %), 31 temporal artery biopsy positive] had a confirmed
diagnosis of GCA after inclusion. The median time from screening to GCA
diagnosis was 9.4 years (range 0.4–16.6). BMI at screening was lower in
GCA cases than in matched controls (mean 24.7 vs 26.1 kg/m2). There was
no association found between level of physical activity and development of
GCA (mean score in cases and controls: 8349 vs 8134; p⫽0.95).The
association between higher BMI and reduced risk of GCA was similar in
bivariate analysis (OR 0.91 per kg/m2; 95 % CI 0.84–0.99) and in multivariate analysis adjusted for physical activity (OR 0.92 per kg/m2; 95 % CI
0.84–1.00).
Conclusion: GCA was predicted by a lower BMI, and this could not be
explained by the level of physical activity at baseline. Physical activity did not
Disclosure: K. Jakobsson, None; L. T. H. Jacobsson, None; K. J. Warrington, None;
E. L. Matteson, None; K. P. Liang, None; O. Melander, None; C. Turesson, None.
906
Patient-Rheumatologist Communication Concerning Medication and
Disease Risks. Susan J. Blalock. University of North Carolina at Chapel
Hill, Chapel Hill, NC
Background/Purpose: Medications play an important role in the management of rheumatoid arthritis.Principles of informed consent, informed and
shared decision-making, and professional ethics highlight the importance of
patients’ understanding both the risks and benefits of different treatment
options. Thus, the work described in this presentation is designed to increase
current understanding of patient-rheumatologist communication about the
risks associated with medications used to manage rheumatoid arthritis
Methods: We are content analyzing approximately 1000 audiotapes of
rheumatoid arthritis patient-rheumatologist office visits that were collected in
a previous study.The current study is guided by fuzzy-trace theory. This
theory suggests that when an individual is exposed to information (e.g., a
statement made by one’s physician) two representations of the information are
encoded in memory, a verbatim representation and a gist representation.
Verbatim representations capture the precise information that was provided;
whereas, gist representations reflect the essential meaning of the information
to the person, including its emotional meaning. A central tenet of fuzzy-trace
theory is that, when making judgments and decisions, people tend to rely on
gist representations that are stored in memory and retrieve verbatim representations only when required by the task at hand. Thus, using fuzzy-trace
theory as a guiding framework, we have developed a detailed 2-level coding
scheme that captures the types of information concerning medication and
disease risks that may be exchanged between patients and rheumatologists
during office visits.
Results: A total of 3588 medication risks were identified in the transcripts. The most common medication risks were: methotrexate-GI problems
(n⫽219); methotrexate-mouth/nose sores (n⫽190); methotrexate-need to
monitor, but labs not specified (n⫽167); methotrexate-liver toxicity (n⫽141);
methotrexate-pulmonary problems (n⫽109); and prednisone-implied risks by
desire to minimize exposure to the medication (n⫽167).An average of 3.87
medication risks were discussed per office visit.Lower patient medication
satisfaction was associated with: discussion of more medication risks (p ⬍
0.03), patient and physician expression of medication safety concerns (p’s ⬍
0.05 and 0.0001, respectively) and lack of patient and physician endorsement
of medication need/efficacy (p’s ⬍ 0.0001 and.03, respectively).
Conclusion: By examining the manner in which medication and disease
risks are discussed in combination, the findings from this study promise to
provide a richer understanding of the risk communication that takes place
during rheumatology office visits.
Disclosure: S. J. Blalock, None;
907
Use of Patient Preferences to Inform the Development of Disease
Modifying Drugs for Osteoarthritis. Liana Fraenkel1, Charles Cunningham2, Gillian A. Hawker3 and Lisa G. Suter4. 1Yale University School of
Medicine, Veterans Affairs Connecticut Healthcare System, New Haven, CT,
2
McMaster University, Hamilton, ON, 3Women’s College Research Institute,
University of Toronto, Toronto, ON, 4Yale University, New Haven, CT
Background/Purpose: Considerable efforts are currently being directed
at developing robust and efficient trial designs to study the efficacy of disease
modifying drugs (DMOADs) for osteoarthritis (OA). As part of this effort, an
understanding of patients’ preferences is needed.
Methods: We administered a conjoint analysis survey to a convenience
sample of 304 patients attending outpatient clinics. The survey was composed
of 4 attributes each having 3 levels: (1) administration (pill, injection (SC),
infusion (IV)), (2) benefit (prevents progression in 40%, 60%, or 80%), (3)
risk (mild: ⬍ 1 week and reversible, moderate: (1–2 weeks and requires
treatment, serious: requires hospitalization), and (4) cost (easy, somewhat,
hard to afford). All subjects were provided with a detailed description of each
attribute before performing the survey. The survey included 12 choice tasks
each with 3 medications and a “None” option (Figure). We performed Latent
Class Segmentation analysis and simulations to estimate preferences for 4
S393
Monday, November 12
Disclosure: S. W. Bell, None; B. A. Mueller, None; J. L. Nelson, None; P. Bhatti,
None; S. Shenoi, None.
influence the risk of GCA. Other factors, such as diet, genetics or hormonal
factors, may explain the association between low BMI and GCA.
Monday, November 12
options: Best Case (pill, prevents progression in 80%, mild side effects, easy
to afford), Worst Case (IV, prevents progression in 40%, serious side effects,
hard to afford), SC (SC, prevents progression in 40%, moderate risk,
somewhat hard to afford), IV (same as previous except IV).
Results: 304 subjects participated; median (range) age⫽57 (34–89); 55%
female; 69% Caucasian, 45% employed; 37% college graduates; 29%
reported knee pain often or very often; 30% reported physician diagnosed
knee arthritis. Segmentation analysis revealed 4 distinct groups of patients.
The relative importances of the attributes are presented in Table 1. Treatment
preferences are described in Table 2. Group 1 (5%) do not want to perform
injections and only consider DMOADs under the Best Case scenario; Group
2 (19.4%) are most influenced by risk and fewer prefer DMOADs under more
realistic scenarios; Group 3 (16.4%) consistently reject DMOADs, and Group
4 (59.2%) strongly prefer DMOADs regardless of risk or cost.
Table 1. Relative Importances of Each Attribute
Attribute
1.
2.
3.
4.
Group 1
(Nⴝ15)
Group 2
(Nⴝ59)
Group 3
(Nⴝ50)
Group 4
(Nⴝ180)
58.5
12.1
14.6
14.8
11.5
22.9
35.7
29.8
11.8
27.5
28.5
32.2
2.9
50.5
24.6
22.1
Administration
Benefit
Risk
Cost
Outcomes Study-Social Support Scale [MOS-SSS]) social support.A hypothetical, Likert-scaled question was also asked: “Would you be willing to
have surgery to replace your knee if your doctor recommended it?”.
Hierarchical logistic regression models were performed to evaluate the
relationship between willingness to undergo TKR and the interaction of
patient race and sex, adjusted for recruitment site, age, income, WOMAC
total score and measures of social support.
Results: Among AA participants, 22.8% were married, as compared with
53.5% of white participants (p⬍0.001).The mean numbers of close friends/
relatives reported by AA and white patients were 7.52 ⫾ 8.88 and 10.31 ⫾
13.13, respectively (p⬍0.001).Half of AA patients reported living alone, as
compared with 33.5% of white patients (p⬍0.001).MOS-SSS scores were
lower in AA (13.44 ⫾ 5.26) as compared with white (15.17 ⫾ 4.79)
participants (p⬍0.001).Compared to white patients with knee OA, AA
patients with knee OA were less willing to undergo TKR surgery (80.0% vs.
62.4%, p⬍0.001).
The odds of willingness to undergo TKR surgery was less in white
females compared to white males when adjusted for recruitment site, age,
income and WOMAC score (OR 0.57, 95% CI 0.34–0.96), but this difference
was no longer significant when further adjusted for marital status, number of
close friends/relatives and MOS-SSS score (OR 0.60, 95% CI 0.35–1.02).The
odds of willingness to undergo TKR surgery was also less in AA females (OR
0.33, 95% CI 0.18–0.60) and AA males (OR 0.26, 95% CI 0.13–0.52)
compared to white males when adjusted for sociodemographic and clinical
factors.These differences in odds remained significant when further adjusted
for all social support measures (OR 0.35, 95% CI 0.19–0.64, in AA females;
OR 0.28, 95% CI 0.14–0.54, in AA males).
Conclusion: We found lower preference for TKR surgery in AA
compared to white patients with knee OA.AA OA patients also reported less
structural and functional social support than white patients.There was a race
and gender interaction in patient preferences for TKR surgery.In white
patients, social support accounted for the gender difference in willingness to
consider TKR.Social support, though, did not seem to mediate the racial
difference in patient preferences for TKR.
Disclosure: E. R. Vina, None; Y. Cloonan, None; S. Ibrahim, None; M. J. Hannon,
None; R. M. Boudreau, None; C. K. Kwoh, AstraZeneca, 2, Beverage Institute, 2.
Table 2. Percent Preferring Each Hypothetical Treatment Option
Scenario
Group 1
(Nⴝ15)
Group 2
(Nⴝ59)
Group 3
(Nⴝ50)
Group 4
(Nⴝ180)
Best case
Worst case
SC
IV
99.4
0.7
5.3
20.2
98.2
4.4
67.2
54.9
18.4
7.6
12.4
11.1
89.8
85.4
86.3
86.1
Conclusion: Almost 60% of patients surveyed are willing to accept
substantial risk in order to prevent progression of OA. These findings should
help inform future drug development.
Disclosure: L. Fraenkel, None; C. Cunningham, None; G. A. Hawker, None; L. G.
Suter, None.
908
Race, Gender and Total Knee Replacement Consideration: The Role of
Social Support. Ernest R. Vina1, Yona Cloonan2, Said Ibrahim3, Michael J.
Hannon4, Robert M. Boudreau2 and C. Kent Kwoh1. 1University of Pittsburgh and VA Healthcare System, Pittsburgh, PA, 2University of Pittsburgh,
Pittsburgh, PA, 3University of Pennsylvania Perelman School of Medicine,
Philadelphia, PA, 4University of Pittsburgh School of Medicine, Pittsburgh,
PA
Background/Purpose: There is marked variation in patient preference
(i.e. willingness) regarding total knee replacement (TKR), an effective
treatment option for end-stage osteoarthritis (OA).Studies have also shown
that higher social support is associated with better patient decision-making.No
study, though, has ever examined the importance of social support on patient
preference.The purpose of this study is to determine whether there are racial
differences in social support among patients with knee OA and whether the
impact of social support on preference for TKR varies by race and gender.
Methods: Our sample consists of 514 white & 285 African-American
(AA) patients with chronic, frequent knee pain and radiographic evidence of
knee osteoarthritis (OA).Structured interviews were conducted to determine
sociodemographic information, clinical characteristics, and extent of structural (marital status, # of close friends/relatives) and functional (Medical
909
Determinants of Patient Preferences for Total Knee Replacement: A
Comparison of Whites and African-Americans. C. Kent Kwoh1, Robert
M. Boudreau2, Yona Cloonan2, Michael J. Hannon3, Ernest R. Vina2 and
Said Ibrahim4. 1University of Pittsburgh and VA Healthcare System, Pittsburgh, PA, 2University of Pittsburgh, Pittsburgh, PA, 3University of Pittsburgh School of Medicine, Pittsburgh, PA, 4University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA
Background/Purpose: TKR is a cost-effective treatment option for
end-stage knee osteoarthritis (OA). Although it is one of the fastest growing
elective surgeries, there are marked racial disparities in the utilization of TKR.
Patient’s preferences have been found to be an important consideration in
TKR disparities. However, determinants of patients’ preference regarding
TKR remain unclear. We sought to identify whether determinants of patients’
preference for TKR differ by race.
Methods: Our sample consisted of 514 whites (59% female) and 285
AAs (73% female) with chronic, frequent knee pain and radiographic
evidence of knee OA. Structured interviews were conducted to collect
sociodemographic information, socio-cultural determinants, disease severity
(i.e, WOMAC), and treatment preferences. We performed hierarchical logistic regression, stratified by race, to identify determinants of patients’ preference for TKR. Clinical and socio-cultural factors were entered simultaneously
into race stratified models. Stepwise selection identified factors for inclusion
in the final models, using a criterion of p⬍0.20. All models were adjusted for
age, sex, income level, disease severity (WOMAC), and study site.
Results: Compared to whites, AA patients were less willing to
undergo TKR (80% vs. 62%, respectively, adjusted OR⫽0.45, 95%CI
0.29 to 0.70). The results of the multivariate modelare summarized in the
table below. Among AA patients, knowledge (p⫽0.031) and expectations
(p⫽0.084) regarding surgical outcomes, religiosity (p⫽0.045), and physician trust (p⫽0.104) were included in the final multivariate model.
Among white patients, expectations regarding surgical outcomes
(p⬍0.001), two items related to physician interaction and referral patterns
(p⫽0.039), and trust in the healthcare system (0.068) were included in the
final multivariate model.
S394
OR for Willingness to Undergo TKR
Whites OR
(95% CI)*
Comparison*
Total Hip
Arthroplasty
THA vs. No Surgery
Improved Implant
(reduced revision
rate, increased cost)
vs. Standard Implant
1.80 (0.97, 3.35)
0.81 (0.58, 1.13)
0.73 (0.39, 1.35)
0.66 (0.37, 1.16)
1.85 (0.76, 4.51)
2.82 (1.30, 6.15)
2.08 (0.91, 4.79)
2.52 (0.93, 6.84)
1.96 (1.05, 3.68)
0.56 (0.32, 0.99)
1.70 (0.86, 3.33)
2.73 (1.32, 5.65)
5.11 (2.31, 11.30)
1.21 (0.43, 3.42)
0.85 (0.32, 2.26)
2.14 (0.89, 5.15)
THA vs. Hip
Resurfacing
Cementless vs. Cement
Total Knee
Arthroplasty
Computer Assisted
Surgery vs. TKA
1.01 (0.46, 2.25)
2.17 (0.90, 5.23)
UKA vs. TKA
2.69 (1.26, 5.76)
TKA vs. UKA
TKA vs. No Surgery
1.94 (0.91, 4.13)
1.58 (0.75, 3.31)
* adjusted for sex, age, income level, WOMAC and site; ** Lowest Quartile is
reference group.
Conclusion: Although expectations regarding surgical outcomes are
associated with preference for TKR in both AA and white patients, they
differed with regard to which other clinical and socio-cultural determinants
impact the preference to undergo TKR. Interventions to reduce or eliminate
racial disparities in the utilization of TKR should consider and target these
factors.
Disclosure: C. K. Kwoh, AstraZeneca, 2, Beverage Institute, 2; R. M. Boudreau,
None; Y. Cloonan, None; M. J. Hannon, None; E. R. Vina, None; S. Ibrahim, None.
Paper
Perspective
ICER
($/QALY;
2011 USD)
Time
Horizon
Chang
Briggs
1996
1998
Societal
Payer
$10,402
$17,671
Lifetime
Lifetime
Briggs
Bozic
McKenzie
2004
2006
2003
Payer
Not clear
Payer
60 yrs
Lifetime
20 yrs
Marinelli
2008
Payer
cost saving
cost saving
THA
dominates
Neither option
clearly
better
Dong
2006
Payer
cost saving
10 yrs
Novak
Slover
Soohoo
Xie
Losina
Dakin
2007
2006
2006
2010
2009
2012
Payer
Payer
Societal
Societal
Societal
Payer
$54,234
cost saving
$458
$71,731
$11,548
$12,566
15 yrs
Lifetime
Lifetime
2 yrs
Lifetime
5 yrs
Lifetime
*The first strategy listed is the primary intervention studied, and the second
strategy is the reference comparator; that is, ICERs refer to the cost-effectiveness
of the first treatment option listed.
Conclusion: THA and TKA have been found to be highly cost-effective
in a number of high-quality studies. Further analyses of the cost-effectiveness
of alternative surgical options, including knee osteotomy, among young
individuals are needed.Future economic evaluations should address the
expanding indications of THA and TKA to younger, more physically active
individuals.
Disclosure: M. E. Daigle, None; A. M. Weinstein, None; J. N. Katz, None; E. Losina,
None.
910
911
The Cost-Effectiveness of Total Joint Arthroplasty: A Systematic Review
of Published Literature. Meghan E. Daigle, Alexander M. Weinstein.
Jeffrey N. Katz and Elena Losina, Brigham and Women’s Hospital, Boston,
MA
Race- and Sex-Specific Estimates of 10-, 20-, 30-Year, and Lifetime Risk
of Diagnosed Symptomatic Knee Osteoarthritis and the Need for TKR in
the US. Elena Losina, Meghan E. Daigle, Sara A. Burbine and Jeffrey N.
Katz. Brigham and Women’s Hospital, Boston, MA
Background/Purpose: Utilization of total hip arthroplasty (THA) and
total knee arthroplasty (TKA) has nearly doubled in the last decade.These
procedures are increasingly performed in younger, more active individuals.
We sought to summarize the state of the literature evaluating the costeffectiveness of these highly efficacious, costly procedures and identify areas
where further work is needed.
Methods: We conducted a systematic review of cost-effectiveness
analyses of elective THA and TKA that were published between January
1980 and February 2012. To limit our search to high-quality publications,
we selected among papers included in the Cost-Effectiveness Analysis
Registry (created by the Center for the Evaluation of Value and Risk in
Health); we augmented our search with papers listed in PubMed.Only
papers reporting incremental cost-effectiveness ratios (ICERs) as the
change in cost over the change in quality-adjusted life expectancy
between alternative treatment strategies were included. We abstracted the
analysis perspective, time horizon, and ICERs (converted to 2011 USD)
from the selected papers.
Results: Seven TKA and six THA studies met the criteria for our
review. All economic evaluations of TKA were published between 2006
and 2012, whereas THA studies spanned 1996 to 2008. Out of the 13
included studies, four assumed the societal perspective, eight the payer
perspective, and in one study the perspective was unclear. Seven studies
spanned the lifetime horizon. Studies of both THA and TKA that have
assumed a societal perspective and lifetime horizon have estimated ICERs
below $50,000/QALY in cohorts withmean age 69 years or older. Hip
resurfacing has been shown to be dominated by THA (more costly, less
effective) in a cohort aged 65 years and younger. Unicondylar knee
arthroplasty (UKA) has been shown to be cost effective or cost-saving
among cohorts of mean age 65–75 years.
Background/Purpose: A growing body of evidence suggests that females are more likely to be diagnosed with knee osteoarthritis (OA) and that
obesity increases the risk of knee OA. Population-based studies suggest that
Black and Hispanic females have a greater likelihood of being obese than
White females. Sex- and race/ethnicity-specific risks of diagnosed symptomatic knee OA and the need for TKR have not been estimated.
Methods: We combined the OAPol Model – a validated state-transition,
computer simulation model – with published data on the incidence of OA,
stratified by sex and obesity. Obesity prevalence, stratified by sex and
race/ethnicity, was derived from published literature and ranged from 19% for
White males to 34% for Black females. The increased risk of symptomatic
knee OA conferred by obesity was derived from published studies (RR ⫽
1.7). Rates of progression of knee OA were derived from the Johnston County
Osteoarthritis Project and calibrated to published data. The annual incidence
of TKR among persons with advanced knee OA (Kellgren-Lawrence grade 3
or 4) was derived using data from two national longitudinal studies of persons
with knee OA (Multicenter Osteoarthritis Study and Osteoarthritis Initiative).
Input parameters related to mortality, obesity, comorbidities, non-surgical OA
treatments, and implant failure were obtained from national survey data and
published literature. Using the OAPol Model we estimated the 10-year,
20-year, 30-year and lifetime risks of diagnosed symptomatic knee OA and
TKR from age 40, stratified by race and sex.
Results: In persons free of knee OA at age 40, the lifetime risk of
diagnosed symptomatic knee OA ranged from 10% among White males to
17% among Black females (Figure). The 20-year risk of diagnosed symptomatic knee OA ranged from about 6% in males (race/ethnicity did not affect
the rate meaningfully) to 8% in Black females. By age 65, 11.3%, 10.5%, and
10% of Black, Hispanic, and White females, free of knee OA at age 40, will
be diagnosed with symptomatic knee OA (Figure). Lifetime need for TKR
ranged from 3.8% for Hispanic males to 6.8% for Black females.
S395
Monday, November 12
Knowledge Regarding TKR
Understands TKR
Prolonged Length of Stay After TKR
Residual Pain After TKR
Residual Difficulty Walking After TKR
Ever Discuss TKR with a physician
Referred to Surgeon
Expectations Regarding TKR**
Second Quartile
Third Quartile
Highest Quartile
Religiosity**
Second Quartile
Third Quartile
Highest Quartile
Physician Trust**
Second Quartile
Third Quartile
Highest Quartile
Trust in Healthcare System**
Second Quartile
Third Quartile
Highest Quartile
AAs OR
(95% CI)*
Table 1. Hazard Ratios for Associations with RKOA Progression
Domain
Knee exam
Medical and family
history
Monday, November 12
Physical
functioning
Self-reported pain/
symptoms
Adjusted covariates
Conclusion: Lifetime risk of diagnosed symptomatic knee OA varies by
age and race/ethnicity. Black females are more likely to be obese, which
corresponds with their having the greatest lifetime risk of being diagnosed
with knee OA and needing TKR. Race- and sex-tailored weight management
programs may reduce the lifetime risk of knee OA.
Disclosure: E. Losina, None; M. E. Daigle, None; S. A. Burbine, None; J. N. Katz,
None.
912
Clinical Features Associated with Progression of Knee Radiographic
Osteoarthritis: Data From the Osteoarthritis Initiative. Michelle S. Yau1,
Laura Yerges-Armstrong1, Braxton D. Mitchell1 and Marc C. Hochberg2.
1
University of Maryland School of Medicine, Baltimore, MD, 2University of
Maryland, Baltimore, MD
Background/Purpose: A better understanding of the factors associated
with structural progression of knee osteoarthritis (OA) may help identify
individuals not only at risk for more rapid OA progression who can benefit
from early intervention, but also help classify high-risk OA patients for
inclusion in clinical trials of new treatments. Using the complete 4-year
follow-up data from the Osteoarthritis Initiative (OAI), we tested baseline
measures from six domains [1) knee examination, 2) anthropometric characteristics, 3) sociodemographic characteristics, 4) medical and family history,
5) physical functioning, and 6) self-reported pain and symptoms] for their
association with radiographic knee OA (RKOA) progression.
Methods: Subjects with evidence of RKOA in one or both knees at
baseline and with at least 1 follow-up exam over the 4-year period (n ⫽
3,204) were eligible for analysis; knees with end-stage disease were excluded
from the analysis. We defined RKOA progression as an increase in KellgrenLawrence (KL) grade or osteophyte score or joint space narrowing score. We
used Cox regression models to test the association of individual level
measures with RKOA progression, adjusting for age, gender, and race. Within
each of the six domains, we performed univariate and multivariable stepwise
analyses. Significant predictors from all domain-level multivariable models
were then included in an overall multivariable analysis with stepwise
selection. We also conducted knee-specific analyses with the same approach,
but included a robust sandwich estimate of the covariance matrix to account
for non-independence of two knees within an individual.
Results: 51% of subjects with baseline RKOA (KL grade 1–3) experienced RKOA progression in one or both knees. Progressors were 58%
female, 19% Black, and had mean (SD) age of 61 (9) years and mean body
mass index of 29 (5) kg/m2. Subjects with no RKOA progression had a
similar profile. In the multivariable model for each domain, the following
baseline factors were found to be significantly associated with RKOA
progression: knee joint effusion, pain on flexion, patellofemoral crepitus,
patellar grind, and flexion contracture; number of hand bony enlargements,
history of knee injury, and use of analgesics; repeated chair stand pace,
400-meter walk pace, and pain during 400-meter walk; KOOS sports and
recreational activities score and KOOS symptoms score. Similar results were
obtained with the knee-specific analyses with the additional significant finding
of KOOS pain score. Final, overall multivariable models for the individual
and knee-specific analyses are presented in Table 1.
Parameter
Knee joint effusion,
bulge sign positive
Patello-femoral crepitus
Knee flexion contracture
Knee flexion pain/
tenderness
Number of bony
enlargements in hands
History of knee injury
Pain during 400-meter
walk
KOOS sports/
recreational activities
score
KOOS Pain Score
Black race
Asian race
Other race
Male gender
Age
Hazard Ratio (95% CI)
Individual-level
Knee-specific
1.34 (1.14–1.58)
1.29 (1.09–1.52)
1.58 (1.36–1.83)
1.02 (1.00–1.04)
–
1.39 (1.22–1.58)
1.02 (1.00–1.04)
1.26 (1.06–1.49)
1.03 (1.00–1.05)
1.04 (1.01–1.06)
–
1.33 (1.12–1.59)
1.27 (1.11–1.46)
–
0.99 (0.99–0.99)
0.99 (0.99–1.00)
–
1.04 (0.86–1.26)
0.74 (0.27–2.00)
0.63 (0.33–1.22)
0.94 (0.81–1.09)
1.00 (0.99–1.01)
0.99 (0.99–1.00)
1.00 (0.84–1.18)
0.75 (0.28–2.00)
0.72 (0.38–1.36)
0.93 (0.81–1.07)
1.00 (0.99–1.01)
Conclusion: Out of the six domains investigated, four domains yielded
significant measures associated with RKOA progression. These measures
may help identify individuals at increased risk of RKOA progression who
may benefit from early intervention.
Disclosure: M. S. Yau, None; L. Yerges-Armstrong, None; B. D. Mitchell, None;
M. C. Hochberg, Abbott Laboratories, Astra-Zeneca, Bioiberica S.A., Eli Lilly Inc.,
Genentech/Roche, Merck Inc., Novartis Pharma A.G., Pfizer Inc., Stryker LLC,
Xoma., 5.
913
Consultation Prevalence of Osteoarthritis in Southern Sweden. Aleksandra Turkiewicz1. Ingemar F. Petersson1, Jonas Björk2, Leif E. Dahlberg1 and
Martin Englund1, 1Department of Orthopedics, Clinical Sciences Lund, Lund
University, Lund, Sweden, 2Division of Occupational and Environmental
Medicine, Lund University, Lund, Sweden, Lund, Sweden
Background/Purpose: To estimate the prevalence of subjects with
osteoarthritis (OA) having led to doctor consultation.
Methods: The Skåne Health Care Register (SHCR) is a legislative,
mandatory register based on physicians’ International Classification of
Diseases (ICD) 10 diagnostic codes. The register covers all in- and outpatient
health care in southern Sweden (total population 1.3 million). We identified
all adult (20 years of age or older) patients having received the diagnosis of
knee OA (ICD-10: M17), hip OA (M16), hand OA (M15.1, M15.2, M18,
M19.0D, M19.1D or M19.2D), spine OA (M47) and OA in other locations,
i.e., elbow, foot, shoulder, or other joints (M19 different from M19.0D,
M19.1D and M19.2D) or polyarthrosis (M15 different from M15.1 and
M15.2) during the years 1999 until 2011. We obtained point estimates of
consultation prevalence by Dec 31st 2011 by cross referencing with the
population register to exclude subjects who had relocated from the county or
were deceased. To obtain valid prevalence estimates and confidence intervals
in presence of missing data on ICD-10 codes (mainly in private care and in
primary care before the year 2004), we used the multiple imputation
technique. The variables included in the imputation model were age, sex and
clinic and their interactions, year, if consulted physiotherapist, if consulted
psychiatrist, residential area, civil status, indicator for in- or outpatient care
and the person as a random effect to account for the correlation between visits
made by the same patient.
Results: The adult consultation prevalence of OA (any location) was
18.6% (95%CI: 18.4%; 18.7%), 15.8% (95%CI: 15.6%; 16.0%) for men and
21.3% (95%CI: 21.0%; 21.5%) for women. The most common location was
knee OA with a prevalence of 9.0%, followed by OA of other joints –7.5%,
OA of the hip –4.0%, hand OA – 2.7% and spine OA with the consultation
prevalence of 1.6%. The consultation prevalence in population aged 65 or
more was 45.5%, 40.5% for men and 49.6% for women. If we considered a
diagnosis of joint pain (ICD-10: M25.5) and age 45 or older as OA, the
consultation prevalence of OA in extremities increased from 29.6% to 38.5%.
The age and sex-specific patterns are displayed in the graph (Figure).
S396
Monday, November 12
Figure. The prevalence of osteoarthritis by location, sex and age. Vertical bars
represent the 95% confidence intervals.
Of subjects who consulted for OA 28% had OA diagnosed in more than
one location, knee OA and other OA being the most common combination
(12.5%).
Conclusion: The high doctor consultation prevalence of OA in extremities, 18.6% of all adults, 45.5% of all above 65 years of age, shed light on the
burden on the health care system and warrants concerns with a steadily ageing
and increasingly obese population. It reinforces the need for improved OA
patient care and preventive strategies as well as an increased need for join
replacement operations.
Disclosure: A. Turkiewicz, None; I. F. Petersson, None; J. Björk, None; L. E.
Dahlberg, None; M. Englund, None.
914
Prognosis for the Year 2030: The Consultation Prevalence of Osteoarthritis in Sweden May Increase by 50%. Aleksandra Turkiewicz1. Ingemar
F. Petersson1, Jonas Björk2, Leif E. Dahlberg1 and Martin Englund1,
1
Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund,
Sweden, 2Division of Occupational and Environmental Medicine, Lund
University, Lund, Sweden, Lund, Sweden
Background/Purpose: To project the future prevalence of knee and
hip osteoarthritis (OA) leading to doctor consultation.
Methods: The Skåne Health Care Register is a legislative, mandatory
register in Skåne County, Sweden (total population 1.3 million), based on
physicians’ International Classification of Diseases (ICD) 10 diagnostic
codes. We used observational data on the consultation prevalence of the
knee (M17) and hip OA (M16) by the 31st Dec 2011 based on the SHCR
data from years 1999–2011. The age-specific (age 20–65 and ⬎65 years)
population structure prognosis and its confidence intervals for Skåne were
provided by Statistics Sweden. We assumed two scenarios. In scenario 1
(conservative) we assumed that the age-specific prevalence would remain
constant. In scenario 2 we assumed that the age-specific prevalence would
increase relatively by 2.6% per year in the first 10 years and by 2% per
year in the next 10 years for those aged ⱕ65 and by 1.6% per year in the
first 10 years and by 1.2% per year in the next 10 years for the population
⬎65. Initial values for that increase are based on the previously published
changes in the prevalence of arthritis between 1994 and 2002 in Canada
(Perrucio et al 2006). The reasons for this observed increase are not fully
understood but the increase in obesity is the main plausible cause.
Results: In the conservative scenario which solely depends on changes
in age distribution of the population, the consultation prevalence of knee
OA in adults (aged 20⫹) will increase from 9.0% in 2011 to 9.9% in 2030.
The hip OA consultation prevalence will increase from 4.0% in 2011 to
4.6% in 2030. Assuming the second scenario, i.e., an increase in
age-specific prevalence, the consultation prevalence of knee and hip OA
in adults will increase to 13.6% and 6.1% in 2030, respectively.
Figure. The prognosis of knee and hip OA consultation prevalence in Swedish
adults (aged 20⫹). Vertical bars represent the confidence intervals of the prognosis
due to uncertainty of the population prognosis.
Conclusion: There is a risk for a 50% increase in OA prevalence in 20
years from now. Results suggest that fighting the negative impact of obesity
will be of primary importance to reduce the occurrence of the OA in the
future.
Disclosure: A. Turkiewicz, None; I. F. Petersson, None; J. Björk, None; L. E.
Dahlberg, None; M. Englund, None.
915
Incidence of Knee, Hip, and Hand Clinical Osteoarthritis: A PopulationBased Cohort Study. Daniel Prieto-Alhambra1, Aina Pagès-Castellà2, M.
Kassim Javaid3, Andrew Judge4. Cyrus Cooper5, Nigel K. Arden3 and
Adolfo Dı́ez-Pérez6, 1URFOA-IMIM, Parc de Salut Mar; Idiap Jordi Gol;
University of Oxford; University of Southampton, Barcelona, Spain, 2IDIAP
Jordi Gol; Institut Català de la Salut, Barcelona, Spain, 3Oxford NIHR
Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford,
UK, Oxford, United Kingdom, 4Oxford University, Oxford, United Kingdom, 5University of Oxford; Southampton General Hospital, Southampton,
United Kingdom, 6Hospital del Mar-IMIM, Universitat Autònoma de Barcelona, Barcelona; and RETICEF, ISCIII Madrid; Spain, Barcelona, Spain
Background/Purpose: Data on age-specific effects of gender, obesity
and previous osteoarthritis (OA) on incident OA at other joints are scarce. We
aimed to calculate age and gender-specific incidence of joint-specific clinical
OA. Secondly, we studied the age-dependent effect of gender, and the excess
risk related to obesity and previous OA on newly diagnosed OA at the knee,
hip and hand.
Methods: We screened computerized medical records in the SIDIAP
Database (www.sidiap.org) to identify those aged 40 years or older with an
incident diagnosis of OA of the knee, hip and hand using ICD-10 codes in the
period 2006–2010. SIDIAP contains the anonymised medical records of
⬎3,100 GPs in Catalonia (North-East Spain) with information on an 80% of
the total population. Age and gender-specific incidence rates (IR), Female:
Male Rate Ratios (RR), and 95%Confidence Intervals (99%CI) were calculated assuming a Poisson distribution. Cox regression was used to compute
adjusted (for age, gender, and body mass index(BMI)) hazard ratios (HR) for
a new diagnosis of OA according to BMI (WHO categories) and to prevalent
joint-specific OA status.
S397
Monday, November 12
Results: We identified 26,381, 12,567 and 10,092 incident cases of knee,
hip and hand OA respectively. Age-specific IRs for knee, hip, and hand OA
are shown [Figure]. Female:Male RRs peaked at age 70–75 years for hip and
knee, and at the age of 50–55 years for hand OA [Figure]. Adjusted HRs for
BMI categories were highest for knee OA (overweight ⫽ HR 2.00 (99%CI
1.94–2.06), obesity 1 ⫽ HR 3.19 (3.09–2.30), obesity 2 ⫽ HR 4.72
(4.56–4.89)), followed by hip OA (HR 1.46 (1.39–1.52); 1.75 (1.66–1.83);
1.93 (1.82–2.05)), and lower for hand OA (HR 1.22 (1.17–1.27), 1.30
(1.25–1.36) and 1.31 (1.24–1.38)).
estimate the annual incidence of clinically diagnosed soft tissue knee-injured
subjects in the entire population.
Methods: In Sweden, in- and outpatient health care is registered using
each individuals’ unique personal identifier. This register includes information on date of visit and the International Classification of Diseases (ICD) 10
diagnostic code(s) as determined by physicians’ clinical examination. For the
calendar years 2004–2011, we studied the population in southern Sweden,
Skåne County (approx. 1.2 million individuals). We identified residents who
had at least one visit to a physician with clinically diagnosed knee contusion
(S80.0) or knee dislocation/distortion (S83 and all subdiagnoses). Consequently, knee fractures were not included. To calculate the annual cumulative
incidence of clinically diagnosed soft tissue knee-injured subjects, stratified
by age- and sex, the number of diagnosed patients during the calendar year
formed the numerator of the rate and the population at risk at the start of the
year, compensated for patients seeking private care (due to missing diagnostic
codes), was the denominator. We then calculated the mean annual cumulative
incidence over the 8-year period. In a second step, we investigated potential
seasonal variations.
Results: The overall incidence of clinically diagnosed soft tissue kneeinjured subjects was 718 per 100,000 per year (672 per 100,000 women and
766 per 100,000 men). The most frequently diagnosed injuries were contusion
of knee (31.3% of subjects) followed by sprain and strain of knee (27.7%),
injury to multiple structures of knee (22.3%), tear of meniscus (11.3%),
collateral ligament injury (10.7%), and cruciate ligament injury (9.9%). The
highest incidence of knee-injured subjects was found in those aged 15 to 19
years for both sexes (1424 per 100,000 women and 1658 per 100,000 men).
After this age, there was a general decline but with an increase again in the
incidence in the most elderly (figure). We found substantial seasonal variations in both genders with peaks in March-May and August-October.
Figure. Age and gender-specific IR (/1,000 person-years) of knee, hip and hand
OA [Top], and unadjusted (solid) and adjusted (dash) Female:Male RR [Below].
Adjusted HR for prevalent knee OA on hip OA was 1.35 (1.28–1.43); HR
for previous hip OA on incident knee OA was 1.15 (1.08–1.23). Hand OA
predicted both knee and hip OA (HR 1.20 (1.14–1.26) and 1.23 (1.13–1.34)
respectively).
Conclusion: Age, gender, BMI and history of OA affecting other joints
are related differently to incident knee, hip and hand OA: both the effect of
age and gender are greatest in the elderly for knee and hip OA, but around
menopause for hand OA. The effect of overweight and obesity is strongest on
knee OA, and weakest but significant on hand OA. Finally, a history of knee
or hip OA predict incidence of each other, and previous hand OA is related
to increased risk of knee and hip OA, all independently of age, gender and
BMI.
Disclosure: D. Prieto-Alhambra, None; A. Pagès-Castellà, None; M. K. Javaid,
None; A. Judge, None; C. Cooper, Amgen, ABBH, Novartis, Pfizer, Merck Sharp and
Dohme, Eli Lilly, Servier, 5; N. K. Arden, None; A. Dı́ez-Pérez, None.
916
Population Incidence of Soft Tissue Knee Injury: Estimates From a
Swedish Health Care Register. Charlotte Bergknut1, George Peat2, Richard
Frobell1 and Martin Englund3. 1Lund University, Lund, Sweden, 2Arthritis
Research UK Primary Care Centre, Keele University, United Kingdom,
3
Department of Orthopedics, Clinical Sciences Lund, Lund University,
Sweden, Sweden
Background/Purpose: Soft tissue knee injury is a well-established and
potent risk factor for development of knee osteoarthritis. However, there is a
paucity of epidemiological data from the general population. Our aim was to
address this gap using data from a large, regional health care register, i.e., to
Conclusion: Clinically diagnosed soft tissue knee injury occurs with
marked age and seasonal variations. The high incidence among young people
warrants further attention as the potential induction point for many cases of
post-traumatic knee osteoarthritis.
Disclosure: C. Bergknut, None; G. Peat, None; R. Frobell, None; M. Englund, None.
917
Feasibility of Remote Activity and Functional Status Monitoring of
Patients with Hip or Knee Pain. Pim Jetanalin1, Hyeon Eui Kim1, Zia
Agha2, Nathaniel Heintzman1, Lucila Ohno-Macado1 and Susan J. Lee1.
1
University of California, San Diego, La Jolla, CA, 2San Diego Veterans
Affairs Medical Center, San Diego, CA
Background/Purpose: The incidence of total hip and knee arthroplasties
has risen over the past decade and by 2030, the demand of these arthroplasties
is estimated to increase by 137% and 601%, respectively. Early ambulation is
critical for timely recovery of functional independence. However, not all
patients have access to rehabilitation due to lack of money, transportation,
and/or time. Accelerometer has been validated in analyzing gait and physical
activities among patients with arthritis. We assessed the feasibility of a
wireless system that remotely monitors patient’s physical activities, functional
status, and pain among patients with hip or knee arthritis. This information
can then provide feedback to patients to facilitate their post-operative
rehabilitation regimen.
S398
Disclosure: P. Jetanalin, None; H. E. Kim, None; Z. Agha, None; N. Heintzman,
None; L. Ohno-Macado, None; S. J. Lee, None.
918
Impact of Comorbidities On Measuring Indirect Utility by the Medical
Outcomes Study Short Form 6D in Lower-Limb Osteoarthritis. Kossar
Hosseini1, Cécile Gaujoux-Viala2, Joel Coste1, Jacques Pouchot1, Bruno
Fautrel3, Anne-Christine Rat1 and Francis Guillemin1. 1Université de Lorraine, Paris Descartes University, APEMAC, EA 4360, F- 54 000, France,
Nancy, France, 2Université de Lorraine, Paris Descartes University,
APEMAC, EA 4360, F- 54 000, Nancy; Paris 6 – Pierre et Marie Curie
University; Rheumatology, Pitié-Salpêtrière Hospital, Paris, France, 3Paris VI
University, Paris, France
Background/Purpose: Comorbidities refer to chronic co-occuring disorders and are inversely and negatively correlated with HRQoL. Because
indirect utility measurement involves HRQoL, comorbidities probably affect
utility assessment. We investigated the impact of comorbidities to assess
indirect utility measured by the Medical Outcomes Study Short Form 6D
(SF-6D) in patients with osteoarthritis (OA).
Methods: The 878 patients of the KHOALA (Knee and Hip OsteoArthritis Long term assessment) cohort were included in the study. KHOALA
cohort is a multiregional population based study of patients aged 45–75 years
with symptomatic knee or/and hip OA. comorbidities were assessed by the
Functional Comorbidity Index (FCI) and grouped in 9 categories. Limitation
in activities and pain was measured by the Western Ontario and McMaster
Universities Osteoarthritis Index (WOMAC).
Two separate linear regression models, using the number of comorbidities
or the different categories of comorbidities of the FCI, were fitted to
determine predictors of utility score.
Results: For the 878 patients included, the mean (SD) utility score was
0.66 (11; range 0.32–1.00) and mean number of comorbidities 2.05 (1.58). In
the first multivariate model, for each additional comorbidity (range 0–9) the
mean utility score decreased of 0.01 point (beta⫽ ⫺0.010, p⬍0.0001). In the
second model, including comorbidities by categories, only psychiatric disease
(beta⫽⫺0.043, p⬍0.0001) and degenerative disc disease (beta⫽⫺0.014,
p⫽0.018) predicted low utility score. In both regression models a worsened
function (increased WOMAC function score) significantly decreased the
utility score. The number of comorbidities explained 2% of the variance in
utility score (partial R-square⫽0.02) and psychiatric and degenerative disc
diseases explained 2% (partial R-square⫽0.025) and 0.7% (partial
R-square⫽0.007), respectively, of the variance in utility score, whereas the
WOMAC function score explained 38% of the variance in both models
(partial R-square ⫽ 0.38).
Conclusion: Compared to greater negative effect of functional impairment, comorbidities have a negative but relatively marginal impact on indirect
utility score. This suggests that clinically, considering the functional severity
of OA remains a first priority.
Disclosure: K. Hosseini, None; C. Gaujoux-Viala, None; J. Coste, None; J. Pouchot,
None; B. Fautrel, None; A. C. Rat, None; F. Guillemin, None.
919
Sedentary Time, Physical Activity, and Concurrent Blood Pressure in
Osteoarthritis Initiative Participants. Min-Woong Sohn1, Rowland W.
Chang1. Grace Ahn1, Linda S. Ehrlich-Jones2, Marc C. Hochberg3, Jungwha
Lee1, Michael C. Nevitt4, Pamela A. Semanik5, Jing Song1, Kai Sun6 and
Dorothy D. Dunlop1, 1Northwestern University, Chicago, IL, 2Rehabilitation
Institute Chicago, Chicago, IL, 3University of Maryland, Baltimore, MD,
4
University of California-San Francisco, San Francisco, CA, 5Northwestern
University, IL, 6Northwestern University, Feinberg School of Medicine,
Chicago, IL
Background/Purpose: The inactivity physiology hypothesis suggests
that sedentarism is a cardiovascular risk factor independent of time spent in
moderate-vigorous activity (MV). Previous research suggests that sedentary
time may be associated with increased blood pressure. But research findings
to date are mixed.
Methods: The Osteoarthritis Initiative accelerometer ancillary study
includes 1760 with objective measures of physical activity, sedentary time,
and blood pressure at the 48 month exam. Participants were classified into
four quartile groups according to accelerometer measures of the percentage of
wear time that was sedentary (⬍100 activity counts per minute).Systolic and
diastolic blood pressures (SBP and DBP) were modeled as a function of
sedentary quartiles, demographic factors (age, gender, race, income), health
behaviors (average daily MV minutes, alcohol use) and general health
(osteoarthritis status,Charlson comorbidity score, BMI, NSAID and antihypertensive medication use during the month preceding the 48⫺month visit).
Results: Of 1,760 adults, 60% had knee OA, 42% used ⱖ1 antihypertensive medications within 30 days prior to the 48 month visit, and 24.4% had
elevated BP (ⱖ 140/90 or 130/80 for diabetic or renal patients). BP values
(see Table) show lowest SBP in the least sedentary group, while DBP is
similar across all groups.Adjusted analyses found the least sedentary group on
average had SBP 1.82 mm Hg lower (95% CI, 0.04 – 3.59) than the other
combined groups. Also, SBP was significantly elevated in adults with OA
(2.3 mm Hg), blacks (5.7 mm Hg), and obesity (3.3 mm Hg).But time spent
in MV activity, NSAID use, and alcohol use were not associated with
SBP.The effect of sedentary time on SBP was primarily observed among
adults not taking antihypertensive medications. Sedentary and MV activity
were not associated with DBP in adjusted analyses.
Relationship of Sedentary Behavior to Blood Pressure
Blood Pressure
(mm Hg)
Quartile 1
(Least Sedentary)
Quartile of Sedentary Behavior
Quartile 2
Quartile 3
Quartile 4
(Most Sedentary)
Unadjusted Analysis
Systolic, mean (SD)
Diastolic, mean (SD)
122.0 (15.8)
74.5 (10.1)
124.9 (16.9)
75.4 (9.8)
124.2 (15.9)
74.5 (9.8)
126.4 (16.5)
73.8 (10.7)
Multiple Regression Analysis
Systolic, Adjusted*
Mean Difference
(95% CI)
Diastolic, Adjusted*
Mean Difference
(95% CI)
Reference
2.44 (0.37–4.51)
1.03 (⫺1.12–3.17)
1.83 (⫺0.48–4.14)
p ⫽ 0.045**
Reference
1.23 (⫺0.05–2.50)
0.42 (⫺0.90–1.73)
0.29 (⫺1.12–1.71)
p ⫽ 0.187**
* Adjusted for demographic factors (age, gender, race, income), health behaviors (average daily
MV minutes, alcohol use) and general health (osteoarthritis status, Charlson comorbidity score,
BMI, NSAID and antihypertensive medication use during the month preceding the 48⫺month
visit).
** Least sedentary Quartile 1 versus more sedentary Quartiles 2–4
Conclusion: Objectively measured sedentary time was significantly
associated with increased SBP, while MV activity was not, in the model
adjusted for all covariates. This finding supports the inactivity physiology
hypothesis that, independent of MV physical activity, sedentary time is
S399
Monday, November 12
Methods: Patients with hip or knee arthritis who had internet access were
asked to complete web-based patient-derived questionnaires and wear the
SenseWear® armband (SWA) for 14 day except during sleep and shower.
SWA collects heat flux, Galvanic Skin Response (GSR), 3-axis accelerometer, and skin temperature. Data on demographics (age, sex, highest level of
education, marital status, and yearly household income) and baseline functional status using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were obtained. The web-based questionnaire comprised of WOMAC, visual analog scale (VAS) for pain, and self-reported
duration of daily exercise. The web-based questionnaire was developed using
a HIPAA compliant commercial survey tool called SurveyGizmo (www.surveygizmo.com).
Results: Convenient sample of 14 patients were recruited with 9 patients
(64%) completing the study. The 2 most common reasons for incompletion
were difficulty downloading the SWA software and inconvenience of
wearing daily SWA. The majority of the completers were Caucasians (56%)
and female (89%) with a mean age and body mass index (BMI) of 52.4 ⫾
12.3 years and 37.5 ⫾ 9.2, respectively. Education level ranged from junior
high to post-graduate levels with 77% having completed at least college.
Majority (77%) had annual household income ⱕ $40,000. Non-completers
were older (70.0 ⫾ 10.9 years) with lower BMI (29.5 ⫾ 5.7). The majority
of patients had significant arthritis with baseline VAS pain of 56.7 ⫹ 26.9 and
WOMAC of 48.7 (out of 97). The paper- and web-based WOMAC score
correlated well with intraclass coefficient (ICC) of 0.885 (p⫽0.0015). Patients
wore SWA for mean 12hrs 25min daily with mean duration of exercise
⬎3MET for 40min daily. The mean self-reported duration of exercise was
higher than actual duration measured by SWA (94min vs 40min). There was
no correlation between the level of pain and the duration of SWA-measured
exercise.
Conclusion: As patients tend to overestimate their levels of physical
activity, a wireless activity-monitoring tool such as SWA serves as a valuable
tool to better assess the level of physical activity. This study demonstrated the
feasibility of our activity and functional status monitoring system, which can
be used to facilitate earlier return to independence after joint arthroplasties by
providing a means to assist patients with home-based rehabilitation program.
associated with deleterious effect on cardiovascular risk. This is the first study
to test this hypothesis using objectively measured sedentary time and
simultaneously controlling for antihypertensive medication use.
Disclosure: M. W. Sohn, None; R. W. Chang, None; G. Ahn, None; L. S.
Ehrlich-Jones, None; M. C. Hochberg, Abbott Laboratories, Astra-Zeneca, Bioiberica
S.A., Eli Lilly Inc., Genentech/Roche, Merck Inc., Novartis Pharma A.G., Pfizer Inc.,
Stryker LLC, Xoma., 5; J. Lee, None; M. C. Nevitt, None; P. A. Semanik, None; J.
Song, None; K. Sun, None; D. D. Dunlop, None.
Monday, November 12
920
A Multimodal Intervention to Improve Osteoporosis Care in Home
Health Settings: Results From a Cluster Randomized Trial. Meredith
Kilgore1, Kenneth G. Saag2, Jeroan Allison3, Elizabeth Kitchin4, Julie L.
Locher1, Amy Mudano4, Ryan C. Outman1 and Jeffrey R. Curtis2. 1University of Alabama at Birmingham, Birmingham, AL, 2Univ of AlabamaBirmingham, Birmingham, AL, 3University of Massachusetts Medical
School, 4Birmingham, AL
Background/Purpose: Although very effective osteoporosis treatments
are available, the rates of use are low, even among individuals who have
already experienced a fracture and are thus at very high risk for a subsequent
fracture. Since many patients commonly receive home health services care
post-fracture, the home health setting is a promising venue for improving
osteoporosis care.To assess the utility of a home health care based strategy for
osteoporosis care improvement, we developed a multimodal intervention for
home health care patients with a fracture history. Our intervention targeted
nurses, physicians, and patients involved in home health care.
Methods: We conducted a cluster randomized trial of a multimodal intervention targeted at patients receiving care in a state-wide home health care agency
in Alabama. The intervention included an educational component and a computerized nursing care plan for nurses, prepared order sheets to facilitate osteoporosis
prescription medications ordering for physicians, and patient education materials
for patients.Offices throughout the state were randomized to receive the intervention or to continue usual care. Following the randomized controlled study, we
delivered the intervention to the offices randomized to the usual care arm. At that
time, we implemented an automatic prompt for nurses in each office that
identified those patients at high risk for a subsequent fracture and required the
nurse to decide to activate the care plan.This allowed us to evaluate the additional
effect of the automatic prompt compared with nurse identification alone.The
primary outcome was the proportion of patients with a fracture history prescribed
osteoporosis medications.
Results: For the randomized trial, among the offices in the intervention
arm the average proportion of eligible patients receiving osteoporosis medications post-intervention was 19.1%, compared with 15.7% in the usual care
arm (difference in proportions 3.4%, 95% CI: ⫺2.6 – 9.5%). The difference
was not statistically significant. Within the intervention arm, a secondary
analysis among the patients who had the care plan activated (27.5%) found
37.7% received osteoporosis medications compared with 11.6% of those who
did not have the care plan activated (p ⬍ 0.0001). The implementation of the
automatic prompt improved overall rates of prescription of osteoporosis
medications (14.8% prior to activation vs. 17.6% after activation), but the
difference was not significant.
Table 1. Enrollment and Drug Treatment Rates in Usual Care & Intervention
Arms of the Home Health Care Osteoporosis Trial
Usual Care Offices
Fracture
Proportion
Cases*
Treated†
Averages
48
42
37
36
36
29
28
25
22
19
15
31
17%
21%
11%
25%
11%
10%
11%
20%
23%
11%
13%
16%
Intervention Offices
Fracture
Proportion
Cases*
Treated†
46
39
38
37
36
31
28
25
21
16
13
30
17%
18%
18%
16%
28%
16%
18%
12%
10%
19%
38%
19%
*Number of patients with fracture diagnoses who were eligible for the
intervention
Proportion of fracture patients receiving prescription osteoporosis medications
during follow up after the intervention
†
Conclusion: The cluster randomized controlled trial conducted in a
state-wide home health care agency did not significantly improve rates of
prescribed osteoporosis medications. This was also the case for the before and
after comparison of rates with respect to the activation of the automated alert
feature in the EMR. Treatment rates did significantly improve when the
nursing care plan was activated.
Disclosure: M. Kilgore, Amgen, 2; K. G. Saag, Amgen, 2, Eli Lilly and Company, 2,
Merck Pharmaceuticals, 2, Amgen, 5, Eli Lilly and Company, 5, Merck Pharmaceuticals, 5; J. Allison, None; E. Kitchin, None; J. L. Locher, Amgen, 2; A. Mudano,
None; R. C. Outman, None; J. R. Curtis, Amgen, 5, Merck Pharmaceuticals, 5, Eli
Lilly and Company, 5, Amgen, 2, Merck Pharmaceuticals, 2, Eli Lilly and Company, 2.
921
Association Between Metabolic Syndrome and Bone Mineral Density in
a Community-Dwelling Older Women: The São Paulo Ageing & Health
Study (SPAH). Luana G. Machado, Diogo S. Domiciano, Jaqueline B.
Lopes, Camille P. Figueiredo, Valéria Caparbo, Liliam Takayama and Rosa
M.R. Pereira. University of São Paulo, São Paulo, Brazil
Background/Purpose: Recent studies have shown a link between metabolic syndrome (MS) and bone mass. However, these results are uncertain
about the positive/negative effect of the components of MS on bone mineral
density (BMD) and risk of fragility fractures. Furthermore, the higher
prevalence of MS among subjects with higher body mass index (BMI) is a
confounding factor, since previous findings have demonstrated that obesity
could be a protective factor against bone loss.In this way, the aim of this study
was to evaluate the prevalence of MS in a community-dwelling older women
with high frequency of overweight/obesity and its association with bone
parameters.
Methods: 343 community-dwelling older women were evaluated by
specific questionnaire (including history of clinical fractures and cardiovascular risk factors). Lumbar spine, femoral neck and total hip BMD were
evaluated by DXA. Laboratory tests, including calcium, phosphorus, creatinine, lipid profile, insulin, glucose and uric acid were also performed.
Thoracolumbar spine X-rays were assessed to identify vertebral fractures.
National Cholesterol Education Program-Adult Treatment Panel III (NCEPATPIII) criteria were used to define MS. Logistic regression models were
used to analyze the relationship between MS and bone parameters.
Results: The prevalence of MS was high (62.1%). Women with MS had
higher BMI (30.7⫾4.9 vs. 27.2⫾4.9kg/m2, P⬍0.001), body fat percentage(37.7⫾5.0 vs. 34.9⫾6.5%, P⬍0.001), serum levels of creatinine (0.9⫾0.2
vs. 0.8⫾0.2mg/dl, P⫽0.003), insulin (12.7⫾10.7vs. 8.7⫾14.2U/mL,
P⫽0.004), uric acid (5.6⫾1.5 vs. 5.1⫾1.3mg/dl, P⫽0.001), lumbar spine
BMD (0.881⫾0.171 vs. 0.837⫾0.178g/cm2, P⫽0.025), femoral neck BMD
(0.684⫾0.120 vs. 0.629⫾0.121g/cm2, P⬍0.001) and total hip BMD
(0.814⫾0.131 vs. 0.743⫾0.140g/cm2, P⬍0.001) compared to women without MS. After adjustments for BMI, logistic regression analyses demonstrated
that hip BMD remained as an independent factor associated with MS
(OR:10.73 95% CI:1.33–86.55, P⫽0.026).No significant difference concerning the prevalence of vertebral or nonvertebral fractures was observed
between the women with and without MS.
Conclusion: A positive association between total hip BMD and MS was
found in our community-dwelling older women, even after adjustment for
BMI. Nevertheless, the frequency of vertebral and nonvertebral fractures was
similar in women with and without MS. Taken together, these results suggest
that higher BMI per se does not explain the positive association between
higher BMD and MS and does not protect against osteoporotic fractures.
Further studies are necessary to elucidate the effect of MS on bone mass and
fracture risk, possibly related to bone quality.
Disclosure: L. G. Machado, None; D. S. Domiciano, None; J. B. Lopes, None; C. P.
Figueiredo, None; V. Caparbo, None; L. Takayama, None; R. M. R. Pereira, None.
922
Risk of Fracture Among Treated and Untreated Men with Osteoporosis.
Karen Tomic1, Joanne Lafleur2, Liisa Palmer1, David M. Smith1, Carly J.
Paoli3, Irene Agodoa3 and Nicole Yurgin3. 1Truven Health Analytics, Washington, DC, 2University of Utah College of Pharmacy, Salt Lake City, UT,
3
Amgen Inc, Thousand Oaks, CA
Background/Purpose: Osteoporosis (OP) affects an estimated 2 million
men in the United States. The relationship between treatment and fracture
outcomes has been reported from clinical trial populations, but little is known
S400
Disclosure: K. Tomic, Amgen, 5; J. Lafleur, Agency for Healthcare Research and
Quality, Amgen, Anolinx, Genentech, United States Centers for Disease Control,
United States Department of Defense, 5, Amgen, 5; L. Palmer, Amgen, 5; D. M.
Smith, Amgen, 5; C. J. Paoli, Amgen, 1, Amgen, 3; I. Agodoa, Amgen, 1, Amgen, 3;
N. Yurgin, Amgen, 1, Amgen, 3.
923
Low Bone Mineral Density and Higher Parathyroid Hormone Levels As
Independent Factors to All-Cause Mortality in Community-Dwelling
Older Adults: the São Paulo Ageing & Health Study (SPAH). Diogo S.
Domiciano, Luana G. Machado, Jaqueline B. Lopes, Camille P. Figueiredo,
Valéria Caparbo, Liliam Takayama, Eloisa Bonfa and Rosa M.R. Pereira.
University of São Paulo, São Paulo, Brazil
Background/Purpose: Previous studies have shown a relationship between osteoporosis and increased risk of death. Moreover, secondary hyperparathyroidism has been linked to mortality amongst frail older hip fractures
patients. However, none of these studies performed a concomitant evaluation
of the parathormone(PTH)-calcium-vitamin D-axis and bone mass, and this is
essential to determine more accurately the contribution of each of these
parameters to survival in community-dwelling older subjects. The aim of this
study was, therefore, to investigate the association between serum PTH status,
calcium, vitamin D and bone mineral density (BMD) and all-cause mortality
during a 5-year period in a community-dwelling older population.
Methods: 739 community-dwelling subjects (446 women and 293 men),
aged over 65 years, were prospectively studied. Clinical data (including
history of non-vertebral fractures and cardiovascular events as previous
myocardial infarction, instable angina, stroke) were assessed by specific
questionnaire. Serum 25(OH)D level, intact PTH, total calcium, phosphorus,
creatinine, and alkaline phosphatase were also measured. BMD of the lumbar
spine and hip were evaluated by DXA. Spine X-ray (T4-L4) was performed
to identify vertebral fractures by the semiquantitative method. All analysis
was done at baseline and after a 5-year period. Mortality was recorded during
5-year follow-up. Multivariate Cox regression analysis was used to compute
hazard ratios for all-cause mortality.
Results: After 5-year follow-up, there were 104 (14.1%) deaths. Comparing with individuals who were alive at the end of follow-up, subjects
who died were older (75.9⫾6.8 vs. 72.6⫾4.8 years, P⬍0.001), had lower
weight (64.4⫾15 vs. 67.6⫾13.1 kg, P⫽0.03), lower glomerular filtration rate
(GFR) (52.3⫾25.3 vs. 59.0 ⫾18.4 ml/min, P⬍0.001), higher PTH level
(45.8⫾23.2 vs. 38.1⫾16.0 pg/dl, P⫽0.003) and lower 25(OH)D level
(17.8⫾10.4 vs. 20.2⫾10.2 ng/ml, P⫽0.005). There was also difference
between the groups (deceased vs. alive) related to frequency of diabetes
mellitus (36.5 vs. 19.1%, P⬍0.001), prevalence of any cardiovascular event
(26.0 vs. 13.1%, P⫽0.001) and low BMD (T-score ⱕ ⫺2: 74.0 vs. 61.3%,
P⫽0.01). After adjustments for age, sex and GFR, low BMD (HR:1.8095%
CI:1.1–2.9, P⫽0.02), PTH level (HR:1.1295% CI:1.01–1.23, P⫽0.003),
diabetes mellitus (HR:2.77 95% CI:1.71–4.50, P⬍0.001) and any cardiovascular event (HR:1.97 95% CI:1.16–3.36, P⫽0.01) remained independently
associated to all-cause mortality.
Conclusion: Low BMD and higher PTH level, but not vitamin D per se,
were significantly associated with mortality in community-dwelling older
adults. These findings support the notion that a careful screening of these bone
parameters might improve the outcomes of elderly population.
Disclosure: D. S. Domiciano, None; L. G. Machado, None; J. B. Lopes, None; C. P.
Figueiredo, None; V. Caparbo, None; L. Takayama, None; E. Bonfa, None;
R. M. R. Pereira, None.
924
Methods to Link a U.S. Arthritis Cohort with Medicare Administrative
Claims Data. Jeffrey R. Curtis1, Lang Chen2, Timothy Beukelman1, Aseem
Bharat2, Fenglong Xie2, Kenneth G. Saag1 and Elizabeth S. Delzell2. 1Univ
of Alabama-Birmingham, Birmingham, AL, 2University of Alabama at
Birmingham, Birmingham, AL
Background/Purpose: Linkages between clinical and administrative data
may provide a valuable resource for pharmacoepidemiologic and health
services research.
Objective: To describe methods and validity of a linkage between a
de-identified national arthritis registry and U.S. Medicare data.
Methods: Data from 2006-9 for rheumatoid arthritis (RA) patients
participating in the Consortium of Rheumatology Researchers of North
America (CORRONA) was linked to Medicare (100% sample selected
using ICD-9 codes). Deterministic linkage was performed using age (in
years), sex, provider identification number, and U.S. state of the CORRONA
site. Medicare data were restricted to rheumatology claims or with an RA
diagnosis occurring in CORRONA provider’s state. Visit dates from
CORRONA were matched to Medicare visit dates. At least 1 visit date was
required to match exactly.
An ‘all-visit match’ was defined when a CORRONA participant had all
CORRONA visits match to all Medicare visits. If a CORRONA participant
had an all-visit match to ⬎1 Medicare beneficiary, unique matches selected to
be the beneficiary with the greatest number of matched CORRONA visits.In
the event of ties, the participant was considered not matched. A fuzzy match
was done for CORRONA participants without any all-visit match allowing
date mismatches of ⫹⫺ 2 week, or ⫹⫺1 digit in month, day or year.
Linkage accuracy was evaluated in a sub-cohort with more complete
information (including full date of birth [DOB]); exact match on full DOB
was used as a gold standard.
Results: CORRONA participants with self-reported Medicare coverage at
any time (n⫽9326) were identified to be matched to 32,788 Medicare
beneficiaries with arthritis treated by CORRONA physicians. A total of 7,441
CORRONA participants matched exactly on at least 1 visit, and 4413 (59%)
had an all-visit match to 1 or more beneficiaries; 4013 (54%) were uniquely
matched with a median (IQR) of 3 (2, 6) matched visits. For those without any
all-visit matches (n⫽3028), only 346 (11.4%) were able to achieve at least 1
all-visit match after fuzzy matching.
For the 837 participants in the validation subcohort with an all-visit match
to a single Medicare beneficiary, match accuracy was 95% for patients with ⬎
2 matched visits, 87% for patients with exactly 2 matched visits, and 73% for
those with exactly 1 matched visit. For additional patients who initially
matched exactly on at least one but not all visit dates and achieved an all-visit
match after fuzzy matching (n⫽162), linkage accuracy was ⬍ 15%. Ongoing
work is refining the linkage strategy for resolution of ties and improvement of
matching validity and to expand the validation sample
Conclusion: A novel linkage between a national, de-identified outpatient
arthritis registry and U.S. Medicare claims data on multiple non-unique
identifiers appears both feasible and valid.
Disclosure: J. R. Curtis, Roche/Genetech, UCB, Centocor, CORRONA, Amgen
Pfizer, BMS, Crescendo, Abbott, 5, Roche/Genetech, UCB, Centocor, CORRONA,
Amgen Pfizer, BMS, Crescendo, Abbott, 2; L. Chen, None; T. Beukelman, Pfizer Inc,
2, Novartis Pharmaceutical Corporation, 5, Genentech and Biogen IDEC Inc., 5; A.
Bharat, None; F. Xie, None; K. G. Saag, None; E. S. Delzell, None.
S401
Monday, November 12
about the impact of treatment on fracture risk among men with OP in the
real-world setting.
Methods: The MarketScan® Medicare Supplemental and Coordination
of Benefits Database was used to identify treated (received an OP medication)
and untreated (had an OP diagnosis or fragility fracture but no OP medication) men with OP between 1/1/04 and 4/30/10 and at least 12 months
pre-period and 3 months post-period follow-up in the database.Patients were
matched on pre-period fracture and age (⫾ 2 years).Follow-up time was
variable and ended with fracture, inpatient death, end of health plan eligibility,
or on 4/30/10, whichever came first.Fracture incidence rates and time to
fracture were reported.A Cox proportional hazards model was used to assess
whether treated men had a lower risk of fracture compared to untreated men
after controlling for demographic and clinical characteristics.
Results: Of the 3,072,696 men ⱖ65 years in the database, a total of
31,696 men met the inclusion and match criteria (15,848 in each cohort).In
both cohorts, the mean age was 78 years and 55% had a pre-period
fracture.1,990 treated men had a follow-up fracture [incidence ⫽ 5.98/100
person-years (p-y)] over 33,274 p-y of follow-up, compared to 2,231
untreated men with a follow-up fracture (incidence ⫽ 8.03/100 p-y) over
27,785 p-y.Treated men also had longer mean time to fracture (588 days, SD
426) than untreated men (401 days, SD 372, p⬍0.001).The adjusted risk of
fracture was lower among treated men compared to untreated men (adjusted
hazards ratio ⫽ 0.83, 95% CI: 0.78 to 0.89).Other pre-period factors
associated with an increased risk of fracture were urban residence, no bone
mineral density test, use of benzodiazepines, and a higher number of
comorbidities and concomitant medications.
Conclusion: The fracture incidence rate was lower and time to fracture
was longer for men with OP who received treatment than for those without
treatment. After controlling for prior fracture and other risk factors, treated
men had a lower adjusted risk of fracture.To better characterize the benefit of
OP treatment, more research is needed into the role of medication adherence
and risk of fracture among men with OP.
925
Monday, November 12
Use of Rheumatology Services for Arthritis: The Role of SES and
Geographic Availability of Rheumatologists and Primary Care Physicians. E. M. Badley1, Mayilee Canizares2 and Aileen M. Davis3. 1Division
of Health Care and Outcomes Research,Toronto Western Research Institute;
Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
2
Division of Health Care and Outcomes Research,Toronto Western Research
Institute, Toronto, ON, Toronto, ON, 3Division of Health Care and Outcomes
Research, Toronto Western Research Institute, Departments of Rehabilitation
Science and Health Policy, Management and Evaluation, University of
Toronto, Toronto, ON
Background/Purpose: Access to rheumatology is critical for timely
treatment of new onset inflammatory arthritis (IA). Barriers to timely care
include patient characteristics, the need for a referral from another physician
(usually a primary care physician (PCP)), and the availability of a rheumatologist to be referred to.Treating patients with IA also needs to be balanced
against the role of rheumatologists as the medical specialist with expertise in
arthritis in general.There is a shortage of rheumatologist as well are large area
variations in their availability. The objectives of this population-based study
is to examine access to rheumatologists for IA and arthritis overall (AO)
taking into account access to PCP, availability of rheumatologists, and
population characteristics.
Methods: A population-based multilevel study of individuals aged 18⫹
living in 105 residential areas in Ontario, Canada (total population about 13
million) which has a publicly funded health care system covering all
physician visits. The physician billing database was used to identify the
number of patients seeing rheumatologists for IA and AO and to derive a
measure of PCP availability by residential area.Census data were used to
calculate indicators of socio-economic status (SES), population age and
rurality. Data from a survey of rheumatologists gave postal code for practice
locations and the number of clinic hours per week.Geographic Information
System analysis was used to calculate a weighted measure of rheumatologist
availability taking into account amount of clinic hours and distance to
rheumatologist locations for each residential area. Multilevel Poisson regression was used to estimate rate ratios for visits to rheumatologists for IA and
AO by rheumatologist availability, PCP access, and SES.
Results: 142,600 patients made at least one visit to rheumatologists (13.4
per 1000 population): only 47.7% of visits were for IA, with a seven-fold
variation across residential areas.Comparing the highest to lowest quintile,
rate of visits for IA were higher in areas of high SES (RR 1.3 95%CI:1.1–1.6)
and areas with high PCP access (RR 1.2 95%CI:1.0–1.5).There was no
association with rheumatologist availability.However higher rheumatologist
availability was associated with visits for AO (RR 1.2: 95% CI 1.0:1.4), as
were high SES (RR 1.4 95%CI:1.2–1.6) and high PCP access (RR 1.4
95%CI:1.2–1.7).
Conclusion: The lack of association with area-level rheumatologist
availability for IA suggests that priority is given to these patients.The
association of higher rheumatologist availability with patients seen with AO,
raises questions of where these patients go for care when no rheumatologist
is available. For both IA and AO, lack of PCP access may be a barrier to
referral.This study also indicates that residents of high SES areas are more
likely to see rheumatologists, suggesting inequalities in access to care. Models
of care that incorporate the location and amount of rheumatologist and PCP
resources are crucial to improve access to care for people with all types of
arthritis particularly in areas of low SES.
patients primarily from rheumatology clinics, which may limit the usefulness
of the results. Our aim was to evaluate the accuracy of administrative data
algorithms to identify RA patients drawn from family physician records.
Methods: We performed a retrospective chart abstraction study using a
random sample of 7500 adult patients, age 20 years and over, from the
primary care Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Our reference standard definition for
classifying patients as RA included physician-reported RA diagnoses and
supporting evidence. RA and non-RA patients were then linked to administrative data to validate different combinations of physician billing (P) and
hospitalization (H) diagnostic codes for RA to estimate sensitivity, specificity,
positive predictive value (PPV) and negative predictive value (NPV).
Results: Based on our reference standard definition, we identified 69
patients with physician-reported RA for an overall RA prevalence of 0.92%.
Most RA cases were female (64%) and the mean (SD) age was 62 (14)
years.Among RA cases, 86% had a documented diagnosis by a specialist and
80% had documentation of a disease-modifying anti-rheumatic drug exposure. Test characteristics of selected RA case definition algorithms tested are
reported in Table 1. All algorithms tested had excellent specificity (97–
100%), however sensitivity varied (75–90%) among physician billing diagnosis algorithms. Despite the low RA prevalence, algorithms for identifying
RA patients had modest PPV, which improved substantially with the
requirement of having musculoskeletal specialist billing codes for RA
(51–83%). Varying the observation window had little impact on the accuracy
of the algorithms tested.
Table 1. Test characteristics of selected algorithms
Algorithm
1
1
2
2
2
3
3
3
1
2
2
2
3
3
3
1
1
1
H ever
P ever
P in 1 year
P in 2 years
P in 3 years
P in 1 year
P in 2 years
P in 3 years
P ever by a specialist
P in 1 year at least 1 P by a specialist
P in 2 years at least 1 P by a specialist
P in 3 years at least 1 P by a specialist
P in 1 year at least 2 P by a specialist
P in 2 years at least 2 P by a specialist
P in 3 years at least 2 P by a specialist
H or 3 P in 1 year at least 1 P by a specialist
H or 3 P in 2 years at least 1 P by a specialist
H or 3 P in 3 years at least 1 P by a specialist
Sensitivity Specificity PPV NPV
(%)
(%)
(%) (%)
22
90
84
84
84
80
80
80
81
78
78
78
75
75
75
78
78
78
100
97
99
99
100
100
100
100
99
100
100
100
100
100
100
100
100
100
88
20
46
45
42
63
60
59
51
65
65
62
83
81
81
77
76
76
99
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
H: Hospitalization code; P⫽physician diagnostic code; Specialist ⫽
rheumatologist, internal medicine, orthopedic surgeon
Conclusion: The RA case definition algorithms that we tested had
excellent specificity. To our knowledge, this is the first study to rigorously
evaluate the accuracy of RA administrative data algorithms in a random
sample from family physician records. We are independently validating these
algorithms in a random sample of patients from rheumatology clinics to
support the findings of this work.
Disclosure: E. M. Badley, None; M. Canizares, None; A. M. Davis, None.
926
Accuracy of Canadian Health Administrative Databases in Identifying
Patients with Rheumatoid Arthritis Using a Random Sample of 7500
Patients Seen in Primary Care. Jessica Widdifield1, Claire Bombardier1,
Sasha Bernatsky2, J. Michael Paterson3, Jacqueline Young3, Diane Green3,
J. Carter Thorne4, Noah Ivers1, Debra Butt3, R. Liisa Jaakkimainen1, Myra
Wang3, Vandana Ahluwalia5. George A. Tomlinson6 and Karen Tu3, 1University of Toronto, Toronto, ON, 2Research Institute of the McGill University
Health Ctre, Montreal, QC, 3Institute for Clinical Evaluative Sciences, Toronto,
ON, 4Southlake Regional Health Centre, Newmarket, ON, 5William Osler Health
Center, Mississauga, ON, 6Toronto General Hospital, Toronto, ON
Background/Purpose: The use of population-based health administrative
databases in rheumatology research is well established, but there are ongoing
concerns about validity. To date, previous validation studies have sampled
Disclosure: J. Widdifield, None; C. Bombardier, None; S. Bernatsky, None; J. M.
Paterson, None; J. Young, None; D. Green, None; J. C. Thorne, None; N. Ivers,
None; D. Butt, None; R. L. Jaakkimainen, None; M. Wang, None; V. Ahluwalia,
None; G. A. Tomlinson, None; K. Tu, None.
927
Shared Decision Making in Secondary Care: Rheumatologic Patient’s
Perspective. Raphael Battisti1, Thiago D. Baumgratz1, Mirella Cuziol2, Ana
Carolina Reiff Janini2, Roger A. Levy Sr.3 and Mirhelen M. Abreu4.
1
Medical Student, São Carlos, Brazil, 2Medical Student at Universidade
Federal de São Carlos, São Carlos, Brazil, 3Hospital Universitário Pedro
Ernesto, Rio de Janeiro, Brazil, 4Universidade Federal de São Carlos, São
Carlos, Brazil
Background/Purpose: This cross-sectional study aimed to analyze the
willingness for shared decision making (SDM) of rheumatologic patients.
S402
Disclosure: R. Battisti, None; T. D. Baumgratz, None; M. Cuziol, None; A. C. R.
Janini, None; R. A. Levy Sr., None; M. M. Abreu, None.
928
Is There an Optimal Treatment Strategy for Disease-ModifyingAntirheumatic-Drug Naı̈ve Patients with Rheumatoid Arthritis?
Roopa Akkineni1 and Daniel A. Albert2. 1Dartmouth Hitchcock Medical
Center, Lebanon, NH, 2Dartmouth-Hitchcock Med Ctr, Lebanon, NH
Background/Purpose: There is a lack of head-to-head clinical trial
data to determine the most effective treatment for rheumatoid arthritis
(RA).However, these trials have had similar patient entry criteria and
outcome measures allowing for meta-analysis.Patients with RA fall into
three therapeutic groups: DMARD naı̈ve (no prior exposure to conventional or biologic disease-modifying-anti rheumatic drugs [DMARD]),
Biologic naı̈ve (prior exposure to conventional DMARDs but not biologic
DMARDs) and Biologic second-line (prior exposure to biologic
DMARDs).
A decision analysis was designed to identify an optimal treatment
strategy for DMARD naı̈ve patients with RA.
Methods: A total of 270 studies were identified on ClinicalTrials.gov
and Medline, of which 193 were eliminated in the abstract review
phase.Seventy-seven studies were screened in full text and seventy were
excluded for reasoning including lack of randomization, uncertain diagnoses, and non-standard treatment.Seven clinical trials were included for
the DMARD naı̈ve group corresponding to twelve treatment options.
The treatment options included placebo, methotrexate, biologic drugs
alone and methotrexate plus biologic drugs.Drug effectiveness was
measured by the ACR 20 and ACR 50 criteria and the rate of serious
adverse events was modeled across different therapeutic options. Sensitivity analyses were conducted for probability of serious adverse drug
reactions and the ACR 20 and ACR 50 effectiveness measures.
Results: In the biologic drugs group alone, treatment with etanercept
25mg bi-weekly resulted in the maximum quality-adjusted-life-year
(QALY) gain of 23.24 years compared to placebo at 21.55 years (1 year
and 8 months) and methotrexate at 22.12 years (1 year and 1 month).In the
methotrexate plus biologic group, treatment with etanercept 50mg plus
methotrexate resulted in 23.20 QALYs. Adalimumab 40mg (21.79
QALYs), Infliximab 3mg plus methotrexate (21.83 QALYs) and triple
therapy (21.76 QALYs) resulted in the lowest QALY gain.
Sensitivity analysis showed at ACR 20 success criteria etanercept
alone is preferred, while at ACR 50 criteria etanercept plus methotrexate
is the preferred treatment option. At base case methotrexate was not a
preferred treatment, however if methotrexate’s ACR50 response rate
exceeds 34% then it would become the optimal treatment strategy if all
other factors were held constant. By contrast, treatment with etanercept
25mg on a bi-weekly basis and etanercept 50mg plus methotrexate are no
longer the favored treatment options if their adverse drug reaction rates
increase from 6% and 12% to 9% and 13% respectively.
Conclusion: Biologic therapy alone and biologic therapy plus methotrexate appear to be the favorable treatment strategies for the DMARD
naı̈ve group. The QALY gains for biologic therapy in rheumatoid arthritis
are similar to that of biologic therapy in psoriasis and interferon therapy
for multiple sclerosis (0.20–3.3 QALYs). The decision depends in part on
the side effect profile and costs.Decision aids to elicit patient preferences
and drug costs may override differences in drug effectiveness.
Disclosure: R. Akkineni, None; D. A. Albert, None.
929
Epidemiology of the US National Burden of Pediatric Lupus Hospitalization From 2000–2009. Andrea Knight1. Pamela Weiss2, Knashawn
Morales3 and Ron Keren1. 1Children’s Hospital of Philadelphia, Philadelphia, PA, 2The Children’s Hospital of Philadelphia, Philadelphia, PA,
3
University of Pennsylvania, Philadelphia, PA
Background/Purpose: Studies indicate that of 11% of adult hospitalizations are related to systemic lupus erythematosus (SLE), with an
average charge of $10,000 US per hospitalization and a 1 in 30 chance of
death (1). There are few studies describing the hospitalization experience
in pediatric SLE, and no national estimates for inpatient healthcare
utilization. We aimed to characterize national US trends in inpatient
healthcare utilization and mortality associated with pediatric SLE.
Methods: We performed a retrospective, serial, cross-sectional analysis of a nationally representative sample of pediatric SLE patients.Using
the Kids’ Inpatient Database (KID) for years 2000, 2003, 2006 and 2009,
we identified patients with SLE by an International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of
710.0 listed as a primary or secondary diagnosis. The main outcome
measures were: SLE hospitalization rate, length of stay (LOS), total
hospitalization charges and mortality. Patient-specific demographic variables included: age, race, sex and insurance status. Hospital-specific
variables included: type (general or children’s), teaching status, location
(urban or rural) and region (Northeast, Midwest, South or West). We used
KID reported sampling weights to calculate national estimates of the main
outcome measures and multivariate regression to evaluate for trends over
time.
Results: An estimated 27,076 (SE 1509) pediatric SLE discharges
were identified in the KID for the years of study, with a hospitalization
rate of 7.9 per 100,000 children (SE 0.5). The median LOS was constant
across years at 2 days (IQR 2,3). The mean total charges per hospitalization (inflated to 2009 USD) were $29,304 for 2000, $36,987 for 2003,
$41,664 for 2006 and $42269 for 2009. (p value for trend ⬍0.001).
Factors associated with increased total charges were: male sex (p⫽0.03);
age⬎⫽18 years (p⫽0.03); Black race (p⫽0.02) and Hispanic ethnicity
(p⫽0.003); urban location (p⬍0.001); and West region (p⬍0.001). The
death rate during hospitalization was 1% for 2000, 1.1% for 2003, 1.2%
for 2006 and 0.6% for 2009, which was statistically different across
years (p⫽0.03). Risk factors associated with death were: male sex
OR⫽1.6 (p⫽0.03), age⬎⫽18 years OR⫽3 (p⫽0.01); Black race OR⫽2.6
(p⫽0.002); other race OR⫽2.5 (p⫽0.01); South region OR⫽2.1
(p⫽0.006) and West region OR⫽1.8 (p⫽0.03).
S403
Monday, November 12
Methods: All rheumatic disease patients assisted at a specialty care
unit were invited to participate in this study. A three parts questionnaire
was applied (demographic, clinical data and 3 scenarios that simulate a
clinical encounter). The scenarios presented the 3 typical steps of a
consultation: 1) Diagnostic statement; 2) treatment options discussion; 3)
decision-making. Each scenario was presented according to SDM process.
For each step, interviewee was argued 3 questions: (a) To identify weather
each part was similar to his/her clinical encounter or not; (b) to define
whether SDM can be a feasible approach and (c) to answer if he/she
wanted to be assisted in SDM process, justifying it. The outcomes were
defined by the justification about the willingness for SDM. Descriptive
and multiple correspondence analysis (MCA) techniques were performed
to explore data.
Results: Demographic data (N⫽160): 89% female, 60% ⬍ 8 years of
school, 76% ⬍ 3 folds the minimum wage (income), 24.3% employed and
10.6%, retired due to the disease; 75% of participants had a rheumatic
diagnosis clearly defined, of which 48.8% had ⬍ 4 years of diagnosis and
30%, ⬎ 8 years of diagnosis. The first scenario showed that 97% would
like to have SDM approach on their real clinical practice. They justified its
desire according to ‘communication empowerment’ (75%) and ‘patients’
right relationship’ (23%). For the scenario two, 98% would like to have
this approach, although 65% declared that it never happen in his/her real
life. They justified according to ‘communication empowerment’ (63%)’.
Decision-making scenario showed that 65% of the participants never took
part in the decision process. However, 98% would like to do it, justifying
according to ‘patients’ right relationship’ (30%), and ‘communication
empowerment’ (28%). Despite these answers, 13% answered that the
whole decision belongs to the physician because they have the technical
knowledge. MCA plot illustrates that diagnostic statement correlates to
‘communication empowerment’, retired because of disease, and low
literacy. To understand treatment option, communication empowerment
and a practice of a patient’s right was correlated with those who had ⬍ 4
years of diagnosis or ⬎ 8 years; ⬎ two rheumatic conditions, and low
literacy. Finally, the desire for SDM was correlated among ‘communication empowerment’ and ‘patient’s right’ with those with ⬍ 4 years of
diagnosis, active working status, and age between 50– 59 years-old.
Conclusion: Communication empowerment and patient’s right were
the most common reasons for the willingness for SDM.
Conclusion: Disease burden for SLE was significantly increased compared with matched population references both for contacts with health care
and loss of productivity, with indirect costs constituting 72 percent. Independent predictors of costs were age, disease activity and organ-damage.
Disclosure: A. Jönsen, None; A. A. Bengtsson, None; F. Hjalte, None; M. Willim,
None; R. Ingvarsson, None; U. Persson, None; I. F. Petersson, None; O. Nived,
None.
Monday, November 12
931
Conclusion: The length of stay for pediatric SLE has remained stable
from 2000 to 2009. Total hospital charges have significantly increased, and
mortality has decreased over time, with estimates differing by age, race, sex,
hospital location and region. Further studies are needed to investigate the
drivers of these differences in healthcare utilization and outcomes.
1. Krishnan E: Hospitalization and mortality of patients with systemic lupus
erythematosus. J Rheumatol 2006, 33(9):1770–1774.
Disclosure: A. Knight, None; P. Weiss, None; K. Morales, None; R. Keren, None.
930
Disease Burden and Cost of Illness in SLE During 8 Years Follow up.
Andreas Jönsen1. Anders A. Bengtsson2, Frida Hjalte3, Minna Willim2,
Ragnar Ingvarsson2, Ulf Persson3, Ingemar F. Petersson4 and Ola Nived5,
1
Section of Rheumatology, Lund, Sweden, 2Department of Clinical Sciences
Lund, Section of Rheumatology, Lund, Sweden, 3Lund, Sweden, 4Musculoskeletal Scienes, Department of Orthopedics, Clinical Sciences, Lund, Sweden, 5University Hospital - Lund, Lund, Sweden
Background/Purpose: To study the annual direct and indirect costs in
SLE in a cohort, from a defined area in southern Sweden, and to find potential
predictors of cost.
Methods: All 127 prevalent and incident cases of clinically confirmed
SLE, all with at least 4 ACR classification criteria, being alive between
January 1st 2003 and December 31st 2010 in a defined area with an adult
population of 175.000, were included.Demographics, date of diagnosis,
follow up period, phenotype, disease activity (SLEDAI), organ-damage
(ACR/SLICC DI) and costs for SLE specific therapy was collected from the
database of the rheumatology unit. From the population registry 508 individuals matched for age and sex constituted a reference group. For both cases and
references the local Health Authorities database provided all costs for
in-patient admissions, out-patient care with all types of health care personnel,
and from the Swedish Social Security Agency data was obtained about sick
leave and disability pensions. The data merge was done within the EpiCentrum in Lund and the cost analysis at the Swedish Institute for Health
Economics.
Results: Eighty-seven percent were females and the mean age in 2003
was 52 years with mean disease duration of 16 years and the total observed
years were 869 for the patients and 4064 for the references.Annual median
inpatient days for cases were 2.91, for subgroup with nephritis 5.68 and for
references 0.70. Annual outpatient physician visits were for cases 6.25, for
subgroup with nephritis 6.25 and for references 2.40. Annual net sick leave
days for cases were 99.9, for subgroup with nephritis 111.6 and for references
35.6. The average total annual costs in SEK 2011, was per SLE patient 180
520 SEK (⫽$ 25 072) of which 72 percent were indirect costs, the
corresponding costs for the subgroup with nephritis was 229 423 SEK(⫽$ 31
864) and for the references 59 985 SEK (⫽$ 8 331) of which 78 percent were
indirect costs. Potential predictors of total costs were age at study year
(p⫽0.001), disease activity measured by SLEDAI (p⬍0.001) and organdamage measured by ACR/SLICC DI (p⬍0.001).
Health Care Utilization Among Medicaid Enrollees with Systemic
Lupus Erythematosus Preceding the Development of End-Stage
Renal Disease: Sociodemographic Variation. Candace H. Feldman1,
Linda T. Hiraki2, Graciela S. Alarcon3, Jinoos Yazdany4, Jun Liu5,
Michael A. Fischer1, Wolfgang C. Winkelmayer6 and Karen H. Costenbader7. 1Brigham and Women’s Hospital, Boston, MA, 2Brigham and
Women’s Hospital/ Harvard School of Public Health, Boston, MA,
3
University of Alabama at Birmingham, Birmingham, AL, 4University of
California San Francisco, San Francisco, CA, 5Brigham and Women’s
Hospital, Harvard Medical School, Boston, Boston, MA, 6Stanford
University School of Medicine, Stanford, CA, 7Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA
Background/Purpose: Extreme sociodemographic disparities exist
among systemic lupus erythematosus (SLE) patients in the development
of end-stage renal disease (ESRD) from lupus nephritis. Better resource
allocation and improved access to care may reduce the incidence of this
adverse outcome. We aimed to understand sociodemographic variation in
health care utilization prior to ESRD development among SLE patients
enrolled in Medicaid, U.S. health insurance for low income individuals.
Methods: From the Medicaid Analytic eXtract (MAX) data containing all U.S. Medicaid billing claims from 2000–2004, we identified adults,
ages 18 to 65 years, diagnosed with SLE (ⱖ3 visits, ICD-9 code 710.0,
⬎30 days apart). To determine progression to ESRD we matched these
individuals with SLE to the U.S. Renal Data System (USRDS), which
contains information on nearly all ESRD patients from 2000–2004. We
assessed duration of Medicaid enrollment prior to ESRD onset, and age,
sex, race/ethnicity and U.S. region for each individual. We determined
residence in a Health Professional Shortage Area, number of rheumatologists per state, and county-level socioeconomic status (SES) using a
previously validated composite score of 7 U.S. Census variables. We
examined 3 outcomes: emergency department (ED), outpatient and
inpatient visits per year. We used multivariate-adjusted general linear
models to understand the relationship between sociodemographic factors
and these health care utilization outcomes.
Results: Of the 34,339 adults with SLE enrolled in Medicaid, 1,475
(4.3%) developed ESRD during the study period. 86% were female, the
mean age of ESRD onset was 30.7 years (SD 11.6), and 58.9% were
African American, 17.4% were White and 16.1% were Hispanic. The
mean number of months in Medicaid prior to ESRD diagnosis was 23.4
(SD 16.4). There were an average of 2.2 (SD 3.2) ED visits, 10 (SD 9.5)
outpatient visits and 2.3 (SD 3.0) inpatient visits per year. In multivariate
models, men had significantly fewer annual outpatient visits than women
(p⬍0.001). Asian patients had nearly 1 less ED visit per year (p⫽0.03)
and 2.4 fewer outpatient visits per year (p⫽0.05), compared to Whites.
There were more annual ED visits in the Midwest (p⫽0.01), and
outpatient visits in the Midwest (p⫽0.001) and West (p⬍0.001), compared to the Northeast. Patients in the lowest county-level SES group had
significantly more ED visits per year than the highest SES group
(p⫽0.02). There were no significant differences in inpatient visits according to the sociodemographic groups examined by multivariate analysis.
Conclusion: In this nationwide cohort of Medicaid enrollees with SLE
who developed ESRD, we observed significant variation in ED and
outpatient visits by sex, race/ethnicity, region, and county-level SES.Increased ED visits in low SES areas may indicate a lack of sustained access
to subspecialty care. Further studies are needed to determine whether
differences in health care utilization, particularly in underserved areas,
contribute to increased rates of progression to ESRD in this high-risk
population.
Disclosure: C. H. Feldman, None; L. T. Hiraki, None; G. S. Alarcon, None; J.
Yazdany, None; J. Liu, None; M. A. Fischer, None; W. C. Winkelmayer, None;
K. H. Costenbader, None.
S404
932
Medical Costs and Health Care Resource Use in Patients with Systemic
Lupus Erythematosus in an Insured Population. Daniel E. Furst1, Ann E.
Clarke2, Ancilla W. Fernandes3. Tim Bancroft4, Kavita Gajria3, Warren
Greth5 and Serban R. Iorga4, 1UCLA Medical School, Los Angeles, CA,
2
McGill University, Montreal, QC, 3MedImmune LLC, Gaithersburg, MD,
4
OptumInsight, Eden Prairie, MN, 5MedImmune, LLC, Gaithersburg, MD
Disclosure: D. E. Furst, Abbott, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis,
Pfizer, Roche/Genentech, UCB, 2, Abbott, Actelion, Amgen, BMS, BiogenIdec,
Centocor, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, 5, Abbott,
Actelion, UCB, 8; A. E. Clarke, MedImmune, HGS/GSK, BMS, 5, GSK, 2, GSK, 8,
HGS, 9; A. W. Fernandes, MedImmune LLC, 3; T. Bancroft, MedImmune, LLC, 9;
K. Gajria, MedImmune LLC, 3; W. Greth, MedImmune LLC, 3; S. R. Iorga,
MedImmune LLC,.
933
Economic Burden of Systemic Lupus Erythematosus by Flare Severity
in a Commercially Insured Population in the United States. Siva Narayanan1, Emily Durden2, Alan Oglesby3, Paul Juneau4 and Kathleen L.
Wilson5. 1Human Genome Sciences, Inc., Rockville, MD, 2Thomson
Reuters, Austin, TX, 3GlaxoSmithKline, Research Triangle Park, NC, 4Truven Health Analytics, Washington, DC, 5Thomson Reuters Healthcare,
Cambridge, MA
Background/Purpose: Systemic Lupus Erythematosus (SLE) is a
chronic autoimmune disease with an unpredictable disease course with
sporadic periods of illness (flares). Little is known about how the severity of
flares impacts the economic burden of SLE. The aim of the current study was
to estimate the economic burden associated with SLE, stratified by flare
severity among SLE patients in a commercially-insured population in the
United States (U.S).
Methods: In this retrospective, observational study, commercially insured
adults (employees or their dependents) ages 18–64 years with at least one
SLE-related inpatient or emergency room (ER) claim or at least two
SLE-related outpatient visits at least 30 days apart with a rheumatologist
Disclosure: S. Narayanan, Human Genome Sciences, Inc., 1, Human Genome
Sciences, Inc., 3; E. Durden, Human Genome Sciences, Inc. and GlaxoSmithKline, 2;
A. Oglesby, GlaxoSmithKline, 1, GlaxoSmithKline, 3; P. Juneau, Human Genome
Sciences, Inc. and GlaxoSmithKline, 2; K. L. Wilson, Human Genome Sciences, Inc.
and GlaxoSmithKline, 2.
934
Direct Medical Cost Associated with Organ System Involvement in a
Commercially Insured Population with Systemic Lupus Erythematosus
in the United States. Alan Oglesby1, Emily Durden2, Siva Narayanan3, Paul
Juneau4 and Kathleen L. Wilson5. 1GlaxoSmithKline, Research Triangle
Park, NC, 2Thomson Reuters, Austin, TX, 3Human Genome Sciences, Inc.,
Rockville, MD, 4Truven Health Analytics, Washington, DC, 5Thomson
Reuters Healthcare, Cambridge, MA
Background/Purpose: Systemic Lupus Erythematosus (SLE) is a
chronic autoimmune disease that affects multiple organs including the heart,
lungs, kidneys, as well as the joints and the nervous system. While the
economic burden has been explored for specific organ systems in SLE with
high associated morbidity (e.g. renal), less is known about the economic
impact of other organ systems associated with SLE, particularly those with
less perceived serious morbidity (e.g. musculoskeletal, etc.)The objective of
this analysis was to describe the annual direct medical costs associated with
select organ system comorbidities among SLE patients in a commerciallyinsured population in the United States (U.S).
Methods: This study employed a retrospective, observational design.
Adults ages 18–64 years with at least one SLE-related inpatient or emergency
department (ED) claim or at least two SLE-related outpatient visits with a
rheumatologist at least 30 days apart between 7/1/2004 and 12/31/2008, and
continuous medical/prescription coverage for at least 6 months prior and 12
months following the index diagnosis of SLE were identified in the MarketScan Commercial Claims and Encounters database. Select comorbid conditions representing SLE-related major organ/system damage were identified
using primary or secondary ICD-9-CM codes and included neuropsychiatric,
renal, pulmonary, cardiovascular, musculoskeletal, and mucocutaneous
manifestations.All-cause healthcare utilization and costs were assessed in the
follow-up period and reported by type of service (e.g. inpatient, outpatient,
pharmacy and total). Total, all-cause healthcare costs, adjusted to 2010 U.S
dollars, are reported as annualized rates per patient to account for variable
follow-up.Costs reflect the paid amounts of adjudicated claims and patient
co-pays.
Results: 13,460 SLE cases (mean age: 45.6 years; female: 91.6% female)
were identified.Mean length of follow-up was 1,054.6 days (SD: 522.9
S405
Monday, November 12
Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic
autoimmune disease that may affect multiple organ systems. The clinical
manifestations of SLE are heterogeneous, and subjects typically experience
periods of disease flares and remission. The objective of this study was to
investigate the economic burden and resource use associated with newly
diagnosed and existing SLE patients in a large national US insurer.
Methods: Subjects at least 18 years of age and with claims-based
evidence of SLE (ICD-9-CM 710.0x) were identified from a health plan
database during 2003–2008. Subjects were divided into two cohorts; newly
diagnosed and existing based on claims history of SLE. Subjects were
matched based on demographic and clinical characteristics at a ratio of 1:3 to
unaffected controls. Health care costs and resource use were captured during
a 12 month post-index period. A generalized linear model (GLM) was used
to predict costs, controlling for demographic and clinical characteristics.
Results: A total of 1,278 newly diagnosed SLE subjects were matched to
3,834 controls, and 10,152 subjects with existing SLE were matched to
30,456 controls. SLE subjects had significantly higher overall mean annual
health care costs than matched controls (newly diagnosed: $19,178 vs.
$4,909; existing: $15,487 vs. $5,156; both p⬍0.001).Inpatient costs were the
largest component of medical costs for newly diagnosed subjects, while
ambulatory costs were the largest component for existing SLE patients.When
adjusting for clinical and demographic characteristics with a GLM model, the
cost ratio of newly diagnosed SLE subjects to controls was 2.15 (95% CI:
1.90–2.42), and the cost ratio of subjects with existing SLE to controls was
2.05 (95% CI: 1.92–2.19).Presence of pharmacy claims for select medications
(including corticosteroids, methotrexate, or cyclophosphamide), and evidence
of specific organ involvement (including renal failure, CNS complications,
and cardiovascular complications) were each associated with increased costs
(all p⬍0.05). Health care resource use was significantly higher among SLE
subjects than matched controls, including average annual numbers of primary
care physician visits, specialist visits (nephrologist, rheumatologist, neurologist or dermatologist), emergency department visits, and inpatient hospital
stays (all p⬍0.001).
Conclusion: Economic burden and resource use were high in both newly
diagnosed and existing SLE patients compared to unaffected controls in this
insured population. Serious complications and immunosuppressant use were
associated with increased costs. These findings highlight the unmet need in
SLE.
between 7/1/2004 and 12/31/2008, and at least 6 months of pre-index and 12
months of post-index continuous medical/prescription coverage were identified in the MarketScan Commercial Claims database. Non-SLE controls were
matched to SLE cases using propensity score matching. Mild, moderate, and
severe flares were identified in the follow-up period for the SLE patients using
a claims-based algorithm and patients were categorized according to their
highest degree of flare. A log transformation was applied to the medical
expenditures to accommodate specific observed data properties (e.g., skewness). A subsequent linear model was used to adjust for any remaining
imbalances from matching and to estimate the incremental annual economic
burden (all-cause direct medical cost, in 2010 U.S dollars) associated with
SLE for different levels of flare severity for SLE patients in comparison to
their matched non-SLE controls.
Results: 13,460 SLE cases (mean age: 45.6 years; 91.6% female; average
length of follow-up: 2.9 years) were matched to 13,460 non-SLE controls
(mean age: 47.1 years; 88.9% female; average length of follow-up: 2.0 years).
During the follow-up period, SLE cases had a significantly higher overall
comorbidity burden, (Charlson Comorbidity Index score 1.5, vs. 1.0;
p⬍0.001) and a higher proportion had hospitalizations (49.7% vs. 27.7%;
p⬍0.001) and ER visits (66.7% vs. 43.7%, p⬍0.001) compared to non-SLE
controls. Among SLE cases with no flares, mild/moderate and severe flares as
highest flare severity, annualized all-cause direct medical costs were $14,945,
$21,606 and $64,578 respectively. In multivariate models comparing nonSLE controls, incremental adjusted annualized direct medical costs for SLE
cases with no flares, mild/moderate and severe flares respectively were $441,
$3,606 (p⬍0.05) and $18,953 (p⬍0.05).
Conclusion: Significantly greater proportions of patients with SLE had a
hospitalization or ER visit over a 1-year follow-up than their matched
non-SLE counterparts. The direct medical costs of patients with SLE were
significantly higher than controls, with costs increasing substantially as the
severity of flares increase.
Monday, November 12
days).During the follow-up period, cardiovascular (49.0%) and musculoskeletal (40.3%) comorbidities were observed most frequently, followed by
neuropsychiatric (16.7%), renal (14.2%), mucocutaneous (5.4%) and pulmonary (3.4%) comorbidities. Total annual, mean all-cause costs were
$30,369 ⫾ $58,344 in the overall SLE population.Among patients with
evidence of SLE-related organ damage, annual mean costs were highest for
pulmonary ($74,433; SD⫽$97,787) and renal ($65,442; SD⫽$111,541)
comorbidities (all p-values⬍0.001). Compared to the overall SLE population,
costs were also higher among SLE patients with cardiovascular ($44,066;
SD⫽$75,161), neuropsychiatric ($43,820; SD⫽$62,646 ), mucocutaneous
($41,841; SD⫽$104,766), and musculoskeletal ($38,986; SD⫽$66,986)
comorbidities (all p-values⬍0.001).
Conclusion: As expected, organ system involvement associated with high
morbidity were associated with highest annual costs on a per diem basis.However, other comorbidities such as cardiovascular and musculoskeletal manifestations, also represent a substantial impact to the health care system,
particularly given their higher prevalence.
Disclosure: A. Oglesby, GlaxoSmithKline, 1, GlaxoSmithKline, 3; E. Durden, Human
Genome Sciences, Inc. and GlaxoSmithKline, 2; S. Narayanan, Human Genome
Sciences, Inc., 1, Human Genome Sciences, Inc., 3; P. Juneau, Human Genome
Sciences, Inc. and GlaxoSmithKline, 2; K. L. Wilson, Human Genome Sciences, Inc.
and GlaxoSmithKline, 2.
935
Primary Care Preventive Services in Patients with Systemic Lupus
Erythematosus Compared to Others in Their Community. Cristina
Drenkard1, Kimberley Rask1, Gaobin Bao1, Gnanesh Patel1, Suparna Bagchi2
and S. Sam Lim1. 1Emory University, Atlanta, GA, 2Georgia Department of
Public Health, Atlanta, GA
Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic
illness frequently complicated by infections, cardiovascular disease (CVD)
and cancer. Primary care preventive services (PCS) are recommended to
prevent these complications among individuals at risk. Yet, the utilization of
PCS in the US may be more challenging for SLE patients, especially given
the worse SLE outcomes among ethnic minorities and those with low
socioeconomic status. We compared the likelihood that a cohort of SLE
patients from a large metropolitan area in Atlanta, GA, US received
recommended PCS relative to the baseline rates of PCS in the same
community from a national population-based survey.
Methods: The Georgians Organized Against Lupus (GOAL) is a cohort
of validated SLE patients predominantly derived from the Georgia Lupus
Registry, a population-based registry of lupus in the Atlanta metropolitan
area. GOAL includes the full sociodemographic spectrum of SLE patients and
collects self-reported measures on health care utilization and health conditions. Eleven self-reported PCS were assessed in 765 SLE GOAL participants
(94% women, 78% blacks,18% uninsured) and 3 representative samples of
individuals (9040 from the same community, 938 of them with diabetes,
and 620 with CVD) derived from the Behavioral Risk Factor Surveillance
System (BRFSS). We compared the proportion of eligible SLE and BRFSS
individuals who received the recommended PCS on (1) immunizations, (2)
cancer screening, (3) cholesterol monitoring, (4) counseling on medications
and lifestyle modifications for high blood pressure (HBP), and (5) all 11
recommended PCS.
Results: Eligible SLE and BRFSS participants who received recommended PCS
PCS
Immunizations (Influenza
and/or Pneumococcal
vaccine)
Cancer Screening (Pap smear
and/or mammogram, and/or
colonoscopy)
Cholesterol Monitoring
Counseling on HBP (Drugs
and/or 4 lifestyle
modifications)
All 11 recommended PCS
SLE%
(95% CI)
Community%
(95% CI)
Diabetes%
(95% CI)
CVD%
(95% CI)
45 (41–49)
19 (18–21)
33 (29–37)
38 (33–43)
78 (74–81)
77 (76–79)
70 (65–75)
70 (64–76)
65 (62–69)
48 (43–53)
81 (79–83)
38 (34–42)
87 (81–92)
50 (43–58)
90 (84–93)
42 (33–51)
19 (17–22)
22 (21–23)
23 (20–27)
26 (22–31)
Conclusion: Although only 45% of eligible SLE participants received the
recommended immunizations, the proportion was higher than in the community or those with diabetes, and similar to CVD. Over 78% of SLE received
complete cancer screening services, which was comparable to the other
BRFSS groups. However, only 65% of SLE participants were adequately
screened for cholesterol, a lower proportion than in the BRFSS samples.
Counseling on hypertension was reported by less than 50% of SLE, similar to
the BRFSS groups. Less than 20% of SLE responders received all recommended PCS. Further research is needed to identify factors associated with
gaps in the utilization of primary care among SLE patients.
Disclosure: C. Drenkard, None; K. Rask, None; G. Bao, None; G. Patel, None; S.
Bagchi, None; S. S. Lim, Human Genome Sciences, Inc., 2, GlaxoSmithKline, 2.
936
Autoimmune Diseases: Declining Mortality Between 1999 and 2008
However Continuing to be a Leading Cause of Death in Children—
A 10-Year Retrospective Review. Eric Y. Yen and Deborah K. McCurdy.
Mattel Children’s Hospital, University of California at Los Angeles, Los
Angeles, CA
Background/Purpose: Autoimmune diseases are chronic illnesses that
cause significant and chronic disability in children and may lead to death.
Using mortality data from 1995, Walsh and Rau showed that autoimmune
disease deaths were the leading causes of death among young women. The
objective of this study is to examine the trends in crude mortality rate in
children for autoimmune diseases in the United States.
Methods: We selected 24 autoimmune diseases (Table 1) chosen by
Jacobson et al using the criteria of Rose and Bona, who defined autoimmune diseases as having direct proof or indirect evidence of autoimmune
pathogenesis. Every autoimmune disease was classified with ICD-10 diagnosis code(s). Using the information provided by the Center for Disease
Control (CDC), we reviewed all mortality data from the period of 1999–
2008 in 3 year intervals. CDC reports that ⬎99% of all deaths in the United
States are registered. Each death certificate that lists an autoimmune disease
as the underlying cause of death was identified and counted. Age groups,
crude mortality rates per 100,000 persons (⫽number of deaths/
population*100,000), and total mortality changes (percent change) between
1998 and 2008 were defined and calculated. We also compared the number of
autoimmune disease deaths to the top ten leading causes of death by age in
2008.
Table 1. Autoimmune Diseases (ICD-10 codes).
Addison’s disease (E27.1, E27.2, E27.4)
Autoimmune hemolytic anemia (D59.1)
Chronic active hepatitis (K73)
Glomerulonephritis (N00, N01, N03,
N05, N18)
Goodpasture’s syndrome (M31.0)
Graves’ disease/hyperthyroidism (E05.0)
Idiopathic thrombocytopenia purpura
(D69.3)
Insulin dependent diabetes (E10)
Multiple sclerosis (G35)
Myasthenia gravis (G70.0)
Myocarditis (I40.1, I40.8, I40.9, I51.4,
I51.8)
Pemphigus vulgaris (L10.0)
Pernicious anemia (D51.0)
Relapsing polychondritis (M94.1)
Polymyositis/dermatomyositis (M33)
Primary biliary cirrhosis (K74.3)
Rheumatic fever and Rheumatic heart
disease
(I00, I01, I02, I05, I06, I07, I08, I09)
Rheumatoid arthritis (M05, M06, M08)
Scleroderma (M34, L94.0, L94.1)
Sjogren’s (M35.0)
Systemic lupus erythematosus (M32)
Thyroiditis (E06.3)
Uveitis (H20.0, H20.1, H20.8, H20.9,
H30)
Vitiligo (L80)
Results: Table 2 presents the crude mortality rates of autoimmune
diseases from 1999, 2002, 2005, and 2008 and the percent change between
1999 and 2008. Mortality rates decreased from 5% to 33% in all age groups
except for children younger than 5 years old. The absolute numbers of
autoimmune disease death did not increase over time. Likewise, mortality
rates for all causes decreased for all age group under 20 years old. Despite a
sharp decline in mortality rates, autoimmune diseases continue to be a leading
cause of death among children (Table 3).
Table 2. Trends in crude mortality rates for autoimmune diseases and all causes
of death. Crude mortality rates are expressed per 100,000 persons.
Age
Autoimmune Diseases
All Causes of Death
S406
1–4
5–9
10–14
15–19
20–24
1–4
5–9
10–14
15–19
20–24
Crude Mortality Rate
(ⴝDeaths/Population*100,000)
1999
2002
2005
2008
0.33
0.19
0.26
0.60
1.05
34.22
16.86
20.39
68.6
90.78
0.22
0.11
0.21
0.56
0.97
31.19
15.17
19.55
67.79
95.15
0.26
0.14
0.21
0.49
1.01
29.36
14.52
18.05
65.13
97.59
0.35
0.18
0.19
0.40
0.93
28.37
12.47
15.7
57.67
93.98
% Change Between
1999 and 2008
6.06%
–5.26%
–26.92%
–33.33%
–11.43%
–17.10%
–26.04%
–23.00%
–15.93%
3.53%
Table 3. Relative ranking of autoimmune disease deaths when compared to the
official 10 leading causes of death in 2008.
Age
Relative Rank
1–4
5–9
10–14
15–19
20–24
#8
#10
#9
#6
#6
Table 1B. Factors Associated with 10 Year Mortality**
Hazard Ratio for Death
(95% Confidence Interval)
SLE Diagnosis in Period 2 vs. Period 1
Increasing Age at Diagnosis, per year
Male Sex
0.47 (0.29–0.75)
1.05 (1.03–1.07)
2.36 (1.32–4.20)
**HR⫽ Hazard Ratio
Cox proportional hazards models adjusted for age at diagnosis, race (White, Black, Hispanic,
Asian, other), sex, hydroxychloroquine use, lupus nephritis.
Conclusion: Although mortality rates from autoimmune diseases appear
to be declining in children 5–20 years of age, autoimmune diseases continue
to rank within the top ten leading causes of death.
Disclosure: E. Y. Yen, None; D. K. McCurdy, None.
Conclusion: Despite changes in patient demographics, survival of patients with immunologically-rich, validated SLE followed in our lupus center
has improved over the past 41 years. This improved survival may be related
to better management of comorbidities and new modalities of treatment.
Disclosure: J. F. Merola, None; B. L. Bermas, None; B. Lu, None; P. H. Tsao, None;
T. Norton, None; C. Iversen, None; E. W. Karlson, None; P. H. Schur, None; K. H.
Costenbader, None.
937
Background/Purpose: Data from other large SLE cohorts have
suggested improving survival among SLE patients in recent years with
protective effects from antimalarial use and less favorable prognoses
among males. We investigated whether a change in survival has occurred
among patients with SLE in our large academic lupus center over the past
41 years.
Methods: Our lupus registry contains data on 5,030 patients seen in
our lupus center for potential SLE (ICD-9 billing code 710.0) since the
1960s.For this study, we included 1,099 patients who had validated SLE
per both treating rheumatologist and an SLE expert, ⱖ 4/11 of the 1997
ACR Criteria for Classification of SLE, date of diagnosis on or after
January 1, 1970, and ⬎ 2 visits to our center.Data ascertained from the
medical record included age at SLE diagnosis, validated history of lupus
nephritis, clinical manifestations, serologies, hematology and renal laboratories, medication use and date of death. Individuals were followed for
ten years, or until death or end of follow-up period (April 30, 2011).
Kaplan Meier curves with log rank tests and multivariable Cox proportional hazards models, adjusted for age at diagnosis, race, sex, nephritis
and hydroxychloroquine use, were used to estimate the risk of death over
time, and to investigate potential predictors of mortality in our cohort.
Results: The 1,009 SLE patients were divided into two periods at a
point where each group contributed equal person-time.Date ranges were
January 1, 1970-August 31, 1993 (54,000 person-months) and September
1, 1993-April 30, 2011 (54,000 person-months). Clinical characteristics of
the patients diagnosed in each period are compared in Table 1A. All
patients were ANA positive and approximately 60% in both periods were
anti-dsDNA positive. More SLE patients in the recent periods were
non-White. They were also older at diagnosis and a higher proportion was
prescribed hydroxychloroquine. Overall mean follow-up of all patients
was 8.8 years (SD⫾2.4). There were 70 deaths in period 1; 28 deaths in
period 2. Ten year survival was 84.5% in period 1 and 95.0% in period 2
(log rank test p⫽0.01). In multivariable Cox proportional hazards model,
the hazard ratio (HR) for 10 year mortality was 0.47 (95% CI 0.29–0.75)
for those diagnosed in the later period, compared to those in the earlier
time period. Older age at diagnosis and male sex were associated with
increased 10 year mortality (Table 1B). There was no significant
association between hydroxychloroquine use, race or nephritis with
survival over this time period among our subjects.
938
Hospitalizations in Systemic Lupus Erythematosus: A Longitudinal
Study. Hong Fang, Jie Xu and Michelle Petri. Johns Hopkins University
School of Medicine, Baltimore, MD
Background/Purpose: Hospitalizations are one of the major direct costs
in SLE.A review of studies looking at the contributions of different medical
components to the economic burden of SLE revealed that hospitalizations
may count for 50% of the direct costs in SLE (Panopalis P, et al. Arthritis
Rheum 2008; 59:1788–1795.).Lupus nephritis has been identified as one of
the significant factors consistent with increased direct costs (Slawsky KA et
al. Arthrit Care Res 2011; 63:1224–1232.).Identification of predictors of
hospitalizations could lead to targeted interventions to reduce costs.
Methods: The medical resource use questionnaire was distributed to SLE
patients in the Hopkins Lupus Cohort that covered the last 3 months before the
baseline visit and then at the following two quarterly clinic visits. 359 patients
(91% female, 55% Caucasian, 36% African-American, 9% other ethnicities,
mean age at baseline 46⫾12 years) were included in the analysis.Exclusion
criteria were diagnosis with lupus less than 6 months ago, age younger than 18 or
older than 75, pregnant at baseline, and active HIV patients.
Results: Univariate analysis identified prednisone, disease activity (mean
Physician’s global assessment, SLEDAI), and renal lupus as predictors of
hospitalization over the next 6 months (Table 1). In the multivariate model for
number of hospitalizations, use of prednisone at baseline and mean SLEDAI were
associated (Table 2).
Table 1. Predictors of hospitalizations (any vs none)—univariate analysis.
Number (%)
hospitalization
during followup
Age at baseline (years)
Gender
Ethnicity
Family income ($)
Education (years)
Use of prednisone at baseline
1
PGA at baseline
Mean PGA over year
SLEDAI at baseline
Mean SLEDAI over year
Table 1A. Comparison of Clinical Characteristics of SLE Patients Diagnosed in
Early vs. Late Periods
C3 or C4 at baseline
Demographics
Period 1 (1970–
1993), nⴝ451
Period 2 (1993–
2011), nⴝ558
p value*
Mean Age at Diagnosis (SD)
Male, (%)
White, (%)
ANA Positive, (%)
Anti-dsDNA Positive, (%)
Lupus Nephritis, (%)
Hydroxychloroquine Use, (%)
29.4 (12.2)
30 (6.7)
283 (62.8)
451 (100)
268 (59.4)
145 (32.2)
338 (75.3)
36.0 (13.6)
53 (9.5)
226 (40.5)
558 (100)
336 (60.2)
167 (29.9)
483 (86.6)
<0.001
0.11
<0.001
0.50
0.85
0.45
<0.001
* t-tests and Fisher exact tests
Anti-dsDNA at baseline
Increased ESR at baseline
Urine Pr:Cr ratio at baseline
Baseline history of
hospitalizations
ⱕ 40 (n⫽134)
⬎ 40 (n⫽225)
Female (n⫽327)
Male (n⫽32)
African-American
(n⫽131)
Caucasian
(n⫽197)
ⱕ 50K (n⫽165)
⬎ 50K (n⫽194)
⬍ 12 (n⫽24)
ⱖ 12 (n⫽335)
No (n⫽224)
Yes (n⫽135)
ⱕ1 (n⫽310)
⬎1 (n⫽49)
ⱕ1 (n⫽304)
⬎1 (n⫽55)
ⱕ2 (n⫽265)
⬎2 (n⫽94)
ⱕ2 (n⫽242)
⬎2 (n⫽117)
Negative (n⫽271)
Positive (n⫽80)
Low (n⫽67)
Normal (n⫽284)
No (n⫽179)
Yes (n⫽167)
ⱕ0.5 (n⫽314)
⬎0.5 (n⫽26)
No (n⫽327)
Yes (n⫽32)
1
PGA: Physician’s global assessment (0–3 scale)
S407
11 (8.2)
28 (12.4)
35 (10.7)
4 (12.5)
19 (14.5)
P-value
0.21
0.77
0.096
17 (8.6)
21 (12.7)
18 (9.3)
2 (8.3)
37 (11.0)
17 (7.6)
22 (16.3)
32 (10.3)
7 (14.3)
28 (9.2)
11 (20.0)
23 (8.7)
16 (17.0)
19 (7.9)
20 (17.1)
28 (10.3)
11 (13.8)
9 (13.4)
30 (10.6)
15 (8.4)
23 (13.8)
31 (9.9)
6 (23.1)
34 (10.4)
5(15.6)
0.30
⬎0.99
0.010
0.41
0.018
0.026
0.0083
0.39
0.50
0.11
0.049
0.37
Monday, November 12
Changes in Ten Year Survival Among SLE Patients At an Academic
Center in North America (1970–2011). Joseph F. Merola, Bonnie L.
Bermas, Bing Lu, Peter Hsun Tsao, Tabatha Norton, Christina Iversen,
Elizabeth W. Karlson, Peter H. Schur and Karen H. Costenbader. Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA
Table 2. Multivariate Linear Regression Model.
Monday, November 12
Age at baseline (per 10 years)
Ethnicity (African-American)
Education (⬍12 years)
Use of prednisone at baseline
Mean SLEDAI (per unit)
Urine Pr:Cr ratio at baseline (per
unit)
Effect on number of
hospitalizations
P-value
0.04 ⫾ 0.02
0.06 ⫾ 0.06
⫺0.05 ⫾ 0.10
0.14 ⫾ 0.06
0.03 ⫾ 0.01
0.01 ⫾ 0.04
0.061
0.25
0.61
0.0091
0.0086
0.73
We next looked at hospitalizations due to lupus. In a multivariate linear
regression model, baseline hospitalizations and mean SLEDAI were predictive.
Conclusion: Total hospitalizations are associated with prednisone use
and disease activity. Hospitalizations due to SLE were also associated
with disease activity captured by SLEDAI. Targeted therapies that reduce
SLEDAI would thus be expected to reduce hospitalizations and direct
costs.
Disclosure: H. Fang, None; J. Xu, None; M. Petri, HGS, 5, GlaxoSmithKline, 5,
Medimmune, 5, UCB, 5, Anthera, 5, Pfizer Inc, 5, TEVA, 5.
939
Shared High Risk of Intensive Care Unit Admission in Three Autoimmune Inflammatory Diseases. Christine Peschken, Carol A. Hitchon, Allan
Garland. Charles N. Bernstein, Randy Fransoo and Ruth Ann Marrie,
University of Manitoba, Winnipeg, MB
Background/Purpose: Little is known about the influence of autoimmune
inflammatory diseases on the risk of critical illness, as defined by Intensive care
unit admissions (ICU). Using a large, population-based dataset we determined the
incidence of ICU admissions in rheumatoid arthritis (RA), multiple sclerosis (MS)
and inflammatory bowel disease (IBD). These conditions are highly prevalent in
Western countries and often managed with immunomodulatory therapies.
Methods: In a stable population of over 900,000 adults, hospital claims
from an administrative database were linked to a population based ICU
database to determine the incidence of ICU admissions from 2000–2010. RA,
MS, and IBD patients were compared to cohorts from the general population,
matched on sex, year of birth and region of residence, with up to 5 controls
per case. Individuals with any diagnostic codes (ICD-9/10) for autoimmune
inflammatory disease were excluded from the control cohorts. We used
previously published and validated definitions for RA, MS, and IBD. Annual
incidence rates were estimated by age group, sex, and geographic region
(number of persons in each cohort with at ⱖ 1ICU admission/ number of
persons alive in that cohort at year-end). Results were age and sex standardized to the general Canadian population. The incidence of ICU admission
between the disease specific cohorts and matched cohorts were compared
using incidence rate ratios (IRR). The 10 year cumulative incidence of ICU
admission for the period 2000–2010 was compared: (number of persons with
disease who had ⱖ 1 episode of critical illness/ person-years at risk).Hazard
ratios for the 10 year period were calculated after adjustment for age, sex,
socioeconomic status and comorbidity.
Results: The annual incidence rates of ICU admission over the 10 year
period were:RA 0.82–1.18%; MS 0.51–1.07%; and IBD 0.55–1.12%, compared to the matched cohorts; 0.32–0.60%. The IRR for the 10 year
cumulative incidence rate was 1.62 (95% CI 1.46–1.80) for RA; 1.54 (95%
CI 1.30–1.77) for MS; 1.52 (95% CI 1.36–1.68) for IBD. Hazard ratios over
the 10 year period for the 3 diseases were: RA HR⫽1.86 (95%CI 1.68–2.05);
MS HR⫽ 1.65 (95%CI 1.36–2.01); IBD HR⫽ 2.02 (95%CI 1.78–2.28).
Conclusion: The risk of ICU admission is significantly increased in RA,
MS and IBD patients compared to the general population. Close to 1% of
adults with these diseases develop critical illness each year; representing a
substantial cost to the healthcare system.The risks between the 3 diseases are
remarkably similar, suggesting shared risks from chronic inflammation and/or
immunomodulatory therapy.
Disclosure: C. Peschken, None; C. A. Hitchon, None; A. Garland, None; C. N.
Bernstein, None; R. Fransoo, None; R. A. Marrie, None.
940
Incidence of Systemic Lupus Erythematosus in England, 1998–2010.
Herve Caspard1, Amy Steffey2, Jie Li2 and Trung N. Tran2. 1MedImmune
LLC, Gaithersburg, MD, 2MedImmune, Gaithersburg, MD
Background/Purpose: Systemic Lupus Erythematosus (SLE) is a
chronic auto-immune disease associated with a wide spectrum of clinical
manifestations and increased mortality. The most recent data about incidence
of SLE in England date back to 1999.
It has been suggested that the incidence of SLE and other auto-immune
diseases has increased over time.
Our purpose was:
* To estimate the incidence of SLE in England from 1998 to 2010 and to
describe the incidence rate distribution by demographic factors.
* To discuss the hypothesis that the incidence of SLE increased from 2001
to 2010.
Methods: We investigated the incidence of SLE among individuals
documented in the Clinical Practice Research Datalink (CPRD) and linked
with the Hospital Episode Statistics (HES) database. CPRD is a database of
anonymized longitudinal medical records from primary care from over 600
practices in the United Kingdom. HES is a database documenting all
admissions to the National Health System hospitals in England that can be
linked with CPRD since 1997. All individuals documented in GPRD and
HES prior to October 1st, 2010 and aged 18 years or older were retained in the
analysis.
Patients with SLE were identified as individuals with at least one relevant
diagnosis code in CPRD or HES (list of codes available upon request).
Incident cases were defined as patients with at least 12 months of
registration in CPRD prior to the date of first diagnosis. Incidence rates were
estimated each calendar year from January 1st 1998 to October 1st 2010.
Results: The incidence rate for the 2001–2010 time period is 5.5 per
100,000 patient*years (table 1): this estimate is very close to the 1998–2000
estimate (5.6 per 100,000 patient*years) and falls within the 95% confidence
interval of each calendar year point estimate from 2001 to 2010.
Table 1. Incidence rate estimates per calendar year
Calendar year
Population exposed
(patient*years)
Incident
cases
1998–2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010 (through September 30)
2001-2010
4,213,018
1,504,620
1,585,560
1,639,386
1,682,720
1,720,965
1,768,140
1,812,779
1,850,292
1,859,559
1,359,960
16,784,884
237
83
89
87
82
88
101
109
111
93
79
922
Incidence rate
(per 100,000
patient*years)
5.6
5.1
5.6
5.3
4.9
5.1
5.7
6.0
6.0
5.0
5.8
5.5
[4.9;6.3]
[4.3;6.7]
[4.4;6.8]
[4.2;6.4]
[3.8;5.9]
[4.0;6.2]
[4.6;6.8]
[4.9;7.1]
[4.9;7.1]
[4.0;6.0]
[4.5;7.1]
[5.1;5.8]
Incidence rate is higher among women than men: 9.4 versus 1.5 per
100,000 patient*years. It reaches a maximum between 45 and 54 years of age
in women (12.2 per 100,000 patient*years) while it keeps growing slightly
with age in men; 25%(294) of the incident cases were documented in the HES
database only.
Conclusion: These incidence rates of SLE in England from 1998 to 2010
are consistent with prior estimates and with estimates in other western
countries.
We did not observe any significant change in the incidence of SLE in
England from 2001 to 2010.
Disclosure: H. Caspard, None; A. Steffey, None; J. Li, None; T. N. Tran, None.
S408
941
Validity and Reliability of the Systemic Lupus Activity Questionnaire
(SLAQ): A Prospective Study. Yuko Okamoto, Yasuhiro Katsumata, Yasushi Kawaguchi, Sayumi Baba, Kae Takagi, Hisae Ichida, Takahisa Gono,
Masanori Hanaoka, Yuko Ota and Hisashi Yamanaka. Tokyo Women’s
Medical University, Tokyo, Japan
Disclosure: Y. Okamoto, None; Y. Katsumata, None; Y. Kawaguchi, None; S. Baba,
None; K. Takagi, None; H. Ichida, None; T. Gono, None; M. Hanaoka, None;
Y. Ota, None; H. Yamanaka, None.
942
Validity and Reliability of the Lupus Damage Index Questionnaire
(LDIQ): A Prospective Study. Yuko Okamoto, Yasuhiro Katsumata, Yasushi Kawaguchi, Sayumi Baba, Kae Takagi, Hisae Ichida, Takahisa Gono,
Masanori Hanaoka, Yuko Ota and Hisashi Yamanaka. Tokyo Women’s
Medical University, Tokyo, Japan
Background/Purpose: The Systemic Lupus International Collaborating
Clinics/American College of Rheumatology (ACR) Damage Index (SDI) is a
validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, thus limiting utility where
this is impossible. A self-administered questionnaire, modeled after the SDI,
the Lupus Damage Index Questionnaire (LDIQ) has been previously developed and validated. It may allow the ascertainment of this construct in SLE
patients followed in the community. The original English version of LDIQ
Disclosure: Y. Okamoto, None; Y. Katsumata, None; Y. Kawaguchi, None; S. Baba,
None; K. Takagi, None; H. Ichida, None; T. Gono, None; M. Hanaoka, None;
Y. Ota, None; H. Yamanaka, None.
943
Impact of Systemic Lupus Erythematosus On Work Productivity and
Income in the United States. Alan Oglesby1, Ellen Sulcs2, Siva Narayanan3,
Mechele Lee2 and Cindy Garris1. 1GlaxoSmithKline, Research Triangle
Park, NC, 2Harris Interactive Inc., Rochester, NY, 3Human Genome Sciences, Inc., Rockville, MD
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disorder characterized by fluctuating periods of
disease activity affecting multiple organ systems. This study was conducted
to evaluate the impact of SLE on patients’ employment and productivity.
Methods: A longitudinal cohort of employed SLE patients in the United
States, recruited through a patient advocacy association and the Harris
Chronic Illness Panel, was surveyed online (IRB approved) between Dec
2010 and Aug 2011. Inclusion criteria were 18 years old, self-reported SLE
diagnosis, and ⱖ1 SLE flare in prior 3 months requiring medical attention
(taking medications, calling or visiting a physician, or going to the ER or
hospital). A control group of employed patients without SLE recruited from
HarrisPollOnline (HPOL) were demographically matched (age, sex, race,
income, and education) to the employed SLE cohort. Controls met the above
inclusion criteria excluding the SLE related criteria and were also surveyed
online. A group of unemployed SLE patients were also recruited for research,
but not included in this analysis of employed cohorts. Both the employed
SLE patients and controls completed baseline and follow-up surveys at the
end of 6 months. Questions for the SLE cohort included perceived SLE
disease activity over the past 3 months using a 10-point scale (mild: 0–3,
moderate: 4–6, severe: 7–10), impact of SLE on work productivity and
absenteeism. The control group answered similar questions about the impact
of any health conditions on work. Employed and unemployed SLE patients
were compared to controls by dependent sample t-tests.
Results: 281 employed SLE patients and 300 employed controls completed
the survey; of the 300 control group respondents, 69% reported having ⱖ1 health
condition(s). The mean age in the employed SLE group and control groups was
39.8 and 41.1 years, respectively (p⬍0.05). Of all surveyed respondents, 96%
S409
Monday, November 12
Background/Purpose: Traditional assessments of systemic lupus erythematosus (SLE) disease activity, such as the SLE Disease Activity Index
2000 (SLEDAI-2K) and the Systemic Lupus Activity Measure (SLAM), rely
on a physician-obtained history, physical examination, and laboratory evaluation and thus may prove impractical and costly especially for large
epidemiologic studies. The Systemic Lupus Activity Questionnaire (SLAQ)
was developed based on the SLAM as a more economical way of following
and tracking large groups of SLE patients who may be at a distance from a
center in epidemiologic studies. The purpose of the present study was to
translate and adapt the SLAQ to Japanese and further investigate its validity
and reliability using a prospective observational cohort of SLE patients
followed at a single university clinic while their physicians score the
SLEDAI-2K.
Methods: The English version of the SLAQ was translated, backtranslated and culturally adapted to Japanese using standard methodology.
Japanese SLE patients who had 4 or more revised American College of
Rheumatology (ACR) criteria for SLE were approached during their outpatient attendance in our university clinic. Some of the hospitalized patients
during the study period were also eligible to the study. Patients were asked to
complete the SLAQ and other related demographic questionnaires such as
Medical Outcomes Study Short Form-36 (SF-36) and physicians were asked
to complete the SLEDAI-2K and the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI). Laboratory items were
omitted from SLEDAI-2K scores in this study and the instrument will be
called SLEDAI-2K-nolab. Patients were prospectively followed for repeat
assessment next year.
Results: A total of 246 patients and 30 physicians (all rheumatologists)
participated. The acceptability of the SLAQ was high, with most of items
having 100% response rate. The distribution of the SLAQ, the SLEDAI-2K,
and the SLEDAI-2K-nolab all skewed to the right. The median SLAQ score
was 5 (range 0–32) and the median SLEDAI-2K score was 2 (range 0–18).
The SLAQ had a weak correlation with the SLEDAI-2K-nolab (Spearman’s
␳ ⫽ 0.18, p ⫽ 0.005) but not with SLEDAI-2K (p ⫽ 0.71). The SLAQ
demonstrated acceptable internal consistency, with a Cronbach’s alpha of
0.78. The SLAQ showed weak correlation with the SDI, and moderate
correlation with physical and mental component summary scores of the SF-36
(Spearman’s ␳ ⫽ 0.17, ⫺0.53, and ⫺0.54, respectively). Twenty-five patients
with stable disease were asked to repeat the SLAQ after 2 weeks and the
intraclass correlation coefficient was 0.85, which means good test–retest
reliability. These figures come from the first year research and the second year
gave similar results. The SLAQ did not demonstrate a good responsiveness by
the longitudinal analyses.
Conclusion: We have successfully translated, adapted and validated the
Japanese version of the SLAQ. There is evidence of acceptable reliability and
validity of the Japanese version of the SLAQ among Japanese patients with SLE.
Our study provides evidence of the cross-cultural validity of this tool and can be
used to assess disease activities among Japanese patients with SLE.
was subsequently translated into Spanish, Portuguese and French. The
purpose of the present study was to translate and adapt the LDIQ to Japanese
and further investigate its validity and reliability using a prospective observational cohort of SLE patients followed at a single university clinic.
Methods: The English version of the LDIQ was translated, back-translated
and culturally adapted to Japanese using standard methodology. Japanese SLE
patients who had 4 or more revised ACR criteria for SLE were approached during
their outpatient attendance in our university clinic. Some of the hospitalized
patients during the study period were also eligible to the study. Patients were
asked to complete the LDIQ and other related demographic questionnaires such
as Medical Outcomes Study Short Form-36 (SF-36) and physicians were asked to
complete the SDI and the SLE Disease Activity Index 2000 (SLEDAI-2K).
Patients were prospectively followed for repeat assessment next year.
Results: A total of 250 patients and 30 physicians (all rheumatologists)
participated. The acceptability of the LDIQ was high, with most of items having
100% response rate. The distribution of the LDIQ and SDI both skewed to the
right. The median LDIQ score was 2 (range 0–12) and the median SDI score was
1 (range 0–9). The LDIQ had a substantial correlation with the SDI (Spearman’s
␳ ⫽ 0.71, p ⬍ 0.001). Cohen’s kappa coefficient, a statistical measure of
agreement for qualitative items, between the individual SDI and LDIQ items
varied between 0.07–1.00. The damage domains of the LDIQ were not associated
with each other, which was reflected in low Cronbach’s alpha (0.53). The LDIQ
showed poor correlation with the SLEDAI-2K, and mental component summary
scores of the SF-36, but had moderate correlation with physical component
summary scores of the SF-36 (Spearman’s ␳ ⫽ ⫺0.08, ⫺0.11, and ⫺0.41,
respectively). Twenty-five patients with stable disease were asked to repeat the
LDIQ after 2 weeks and the intraclass correlation coefficient was 0.85, which
means good test–retest reliability. These figures come from the first year research
and the second year gave similar results. The LDIQ demonstrated a good
responsiveness: standardized response mean ⫽ 0.40 and effect size ⫽ 0.32 in
patients with worsened SDI.
Conclusion: We have successfully translated, adapted and validated the
Japanese version of the LDIQ. There is evidence of acceptable reliability and
validity of the Japanese version of the LDIQ among Japanese patients with SLE.
Our study provides evidence of the cross-cultural validity of this tool and can be
used to assess SLE-related damage among Japanese patients with SLE.
Monday, November 12
were female and 79% were Caucasian (no significant differences across groups).
The employed SLE cohort reported fewer overall hours worked per week (25.3
vs 32.8) and more lost work hours per week due to SLE (6.9 hours) than the
employed control group due to any health condition (1.6 hours) (all
p-values⬍0.05). While at work, patients reported significantly greater impact on
productivity due to SLE (45%) compared to controls for any health reason (13%,
p⬍0.05). In the SLE employed group, the number of work hours missed
increased as self-reported disease severity worsened from mild, moderate, to
severe (2.0, 4.2, and 7.9 hours, respectively (p⬍0.05). Hourly employees with
SLE (52.3% of SLE cohort) reported losing an average of $346 per week due to
their lupus. Similarly, lost income per week increased as SLE activity increased
($49 in mild to $522 in severe, p⬍0.05).
Conclusion: Patients with SLE reported significantly reduced ability to
work compounded by worsening disease activity. For hourly employees with
SLE, increased disease activity may have significant detrimental impacts to
their earning potential.
Disclosure: A. Oglesby, GlaxoSmithKline, 1, GlaxoSmithKline, 3; E. Sulcs, Harris
Interactive, 3; S. Narayanan, Human Genome Sciences, Inc, 1, Human Genome
Sciences, Inc., 3; M. Lee, Harris Interactive, 3; C. Garris, GlaxoSmithKline, 1,
GlaxoSmithKline, 3.
944
Job-Related Burden and Effort-Reward Imbalance in Patients with
Systemic Lupus Erythematosus. Jutta G. Richter, Thomas Muth, Ralph
Brinks, Tobias Koch, Johannes Siegrist, Nicole Hoffmann, Peter Angerer and
Matthias Schneider. Heinrich-Heine-University, Duesseldorf, Germany
Background/Purpose: Working life factors influence patients’ (life)
satisfaction and well being. Effort at work is part of a social contract that
reciprocates effort by adequate reward. Components of work-related rewards
matter for health. Research on effort-reward imbalance (ERI) might contribute to the understanding of factors related to the well-being of patients (pts)
with systemic lupus erythematosus (SLE). We studied pts’ job-tasks-related
burdens and stress levels measured by the ERI model.
Methods: In a cross-sectional nationwide study a set of standardized
self-administered questionnaires was applied to SLE pts. ERI was assessed by
the corresponding questionnaire in pts capable for work. Effort reward ratio
(ERR) scores ⬎ 1 and upper tertile scores of overcommitment (OCS) reflect
relevant values. Based on pts’ reported occupations, occupational physicians
categorized tasks-related burden into a developed, standardized coding
system that included ‘working environment burden’, ‘physical burden’,
‘mental burden’, and ‘other burden’. Ethical approval was obtained.
Results: 252 pts (95.2% female) contributed data. Mean age was
40.1⫾9.4 years, mean disease duration 10.5⫾7.3 years, mean HAQ 0.8⫾0.4.
86.0% self-reported at least one comorbidity (range 1–10). 77.4% took at least
one immunosuppressive drug (DMARD, range 1–3), 40.5% steroids
ⱕ7.5mg, 16.3% steroids ⬎7.5mg, 34.0% NSAIDS.
For ERI results see table 1. 79.5% showed relevant effort-reward
imbalance (ERR⬎1). ERR⬎1 pts scored significantly lower in the esteem,
job security and the job promotion/salary scales (p-values⬍0.05). Above
mentioned personal and disease related factors, pts’ self-categorized occupation groups, working environment burden, physical burden, mental burden
and other burden did not differ significantly in ERR⬎1 and ERRⱕ1 pts.
39.0% had relevant OCS, see table 1. Except HAQ above mentioned
personal and disease related factors, working environment burden, physical
burden, mental burden and other burden did not differ significantly in pts with
OCS in the lower tertiles compared to pts with relevant OCS.
945
Work Loss in Systemic Lupus Erythematosus, the General Public, and
Other Chronic Conditions. S. Sam Lim1, Greg Dennis2, Hong Kan3, Priti
M. Jhingran4, Charles T. Molta5, Gaobin Bao1 and Cristina Drenkard1.
1
Emory University, Atlanta, GA, 2Human Genome Sciences, Inc., Rockville,
MD, 3GlaxoSmithKline, Research Triangle Park, NC, 4GlaxoSmithKline
R&D, Research Triangle Park, NC, 5GlaxoSmithKline, Philadelphia, PA
Background/Purpose: Systemic lupus erythematosus (SLE) predominantly develops in young groups, when many are establishing themselves in
the workforce and can have a devastating impact on employment. We studied
the impact of sociodemographic factors on work loss in SLE, the general
public, and other major chronic conditions.
Methods: The Georgians Organized Against Lupus (GOAL) cohort is
derived predominantly from the population-based Georgia Lupus Registry and
collects annually self-reported measures from validated patients with SLE. The
Behavioral Risk Factor Surveillance System (BRFSS) survey samples representative individuals from the general population on self-reported health conditions
and behaviors. We studied GOAL SLE participants who lived in the Atlanta
metropolitan area surveyed between August 2011 and April 2012, and 4 BRFSS
samples (general population and self-reported diabetes, asthma, and cardiovascular disease [CVD]) from the same geographic area, surveyed between 2005-10.
The effect of sociodemographic factors on being unemployed/disabled at survey
completion in SLE and BRFSS participants aged ⬎18 and ⬍65 was analyzed
with logistic regression. We reported the adjusted odds ratios (OR) of being
unemployed/disabled for each sociodemographic variable within SLE and 4
BRFSS samples.
Results:
Age, mean
SLE
nⴝ630
General
nⴝ6339
Diabetes
nⴝ473
Asthma
nⴝ783
45
41
49
38
CVD nⴝ244
51
Females %
94
52
51
57
49
Whites %
19
59
51
61
46
Blacks %
Education ⱕhigh school %
81
35
42
23
49
30
39
28
54
34
Unemployed/disabled% (95% CI)
47 (43–50)
OR (95% CI) of unemployed/disabled1
Age (Per 5 year increase)
1.1 (1.0–1.2)
12 (11–13)
23 (18–28)
19 (14–23)
33 (25–42)
1.1 (1.1–1.2)
1.1 (1.0–1.3)
1.2 (1.1–1.3)
0.9 (0.7–1.2)
Gender (Male vs Female)
1.2 (0.6–2.4)
1.2 (0.9–1.5)
0.9 (0.5–1.7)
2.0 (1.0–3.9)
1.0 (0.5–2.2)
Race (Black vs White)
2.7 (1.7–4.3)
1.9 (1.4–2.5)
1.0 (0.6–2.0)
1.7 (0.9–3.2)
1.5 (0.7–3.1)
Marital Status (Married vs other2)
0.5 (0.4–0.7)
2.1 (1.5–3.0)
0.5 (0.4–0.6)
3.0 (2.3–3.9)
0.4 (0.2–0.7)
4.0 (2.2–7.3)
0.3 (0.2–0.7)
2.9 (1.5–5.7)
0.2 (0.1–0.4)
2.5 (1.1–5.8)
Education (ⱕHigh School vs
⬎High School)
1Adjusted by the other sociodemographics
2never married, separated, divorced, widowed
Conclusion: The burden of unemployment/disability was significantly
higher in SLE than in other chronic diseases, even when the mean age of
SLE and the education level were similar across groups. Less than 1/3 of
individuals with diabetes, asthma and CVD were unemployed, as compared
to almost 50% of SLE. Black race was associated with unemployment/
disability in SLE and the general population, but not in other chronic diseases.
Lower education and not being married increased the risk of unemployment/
disability in all groups. Important factors, such as disease severity, treatment
response, or access to care in black patients with SLE must be further
explored in order to reduce the burden of work loss in SLE.
Disclosure: S. S. Lim, Human Genome Sciences, Inc., 2, GlaxoSmithKline, 2; G.
Dennis, Human Genome Sciences, Inc., 1, Human Genome Sciences, Inc., 3; H. Kan,
GlaxoSmithKline, 1; P. M. Jhingran, GlaxoSmithKline, 3; C. T. Molta, GlaxoSmithKline, 1, GlaxoSmithKline, 3; G. Bao, None; C. Drenkard, GlaxoSmithKline, 2,
Human Genome Sciences, Inc., 2.
Table 1. ERI and overcommittment scores
Effort
mean ⴞ SD
Reward
mean ⴞ SD
15.6 ⫾ 4.9
21.6 ⫾ 9.2
946
ERR>1 %
Esteem
mean ⴞ SD
Job
Security
mean ⴞ SD
Job
Promotion/
Salary
mean ⴞ SD
Overcommittment
mean ⴞ SD
79.5
9.6 ⫾ 4.9
3.9 ⫾ 2.6
8.2 ⫾ 3.7
14.3 ⫾ 4.0
Conclusion: In this first study investigating the ERI in SLE pts a high
proportion had effort reward imbalance (ERR⬎1). Analysis on mechanisms
potentially involved in the relation between ERI and SLE showed that job-tasksrelated burden scored by occupational physicians and most disease related factors
did not differ in ERI and OCS subgroups. Further study data analysis will address
pts’ perceptions of their job-related burden to develop appropriate support
strategies.
Disclosure: J. G. Richter, None; T. Muth, None; R. Brinks, None; T. Koch, None;
J. Siegrist, None; N. Hoffmann, None; P. Angerer, None; M. Schneider, None.
Self-Reported Disease Activity and Health-Related Quality of Life in a
Longitudinal Cohort of Patients with Systemic Lupus Erythematosus.
Siva Narayanan1, Ellen Sulcs2, Alan Oglesby3, Cindy Garris4 and Mechele
Lee2. 1Human Genome Sciences, Inc., Rockville, MD, 2Harris Interactive
Inc., Rochester, NY, 3GlaxoSmithKline, Research Triangle Park, NC,
4
GlaxoSmithKline R&D, Research Triangle Park, NC
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disease with variable clinical manifestations
and an unpredictable waxing and waning disease course impacting patient
health-related quality of life (HRQoL). The objective of this analysis is to
portray the self-perceived burden of illness by assessing patterns of selfreported disease activity and HRQoL over the course of 6 months.
S410
Disclosure: S. Narayanan, Human Genome Sciences, Inc., 1, Human Genome
Sciences, Inc., 3; E. Sulcs, Harris Interactive, 3; A. Oglesby, GlaxoSmithKline, 1,
GlaxoSmithKline, 3; C. Garris, GlaxoSmithKline, 1, GlaxoSmithKline, 3; M. Lee,
Harris Interactive, 3.
947
The Impact of Dyspigmentation and Scarring in Cutaneous Lupus On
Quality of Life. Saroj M. Verma1, Joyce Okawa2, Kathleen Propert1 and
Victoria P. Werth3. 1University of Pennsylvania, Philadelphia, PA, 2Perelman School of Medicine at the University of Pennsylvania and Philadelphia
V.A. Medical Center, Philadelphia, PA, 3University of Pennsylvania and
Philadelphia V.A. Medical Center, Philadelphia, PA
Background/Purpose: Patients with more severe cutaneous lupus activity have poorer quality of life. The main objective of the current study was to
evaluate the impact that lupus-related disease damage had on skin-specific
quality of life and the differences observed within a population of CLE
patients from different racial backgrounds with respect to disease damage and
its impact on quality of life.
Methods: Patients were enrolled into our prospective database and
evaluated with a validated cutaneous lupus-scoring tool (CLASI). Data
collected included sex, race, diagnosis, Cutaneous Lupus Area Activity and
Severity Index (CLASI) scores, and Skindex-29 QoL scores. These parameters were analyzed at the initial and last visits. CLASI damage scores
(dyspigmentation and scarring) and CLASI activity scores were collected,
grouped by race, and correlated with Skindex-29 domains.
Results: 223 patients were analyzed at baseline, with 141 of these patients
completing more than one study visit. The majority of patients were
Caucasians (63.7%), followed by African Americans (29.1%) and Asian
Americans (4.0%). African Americans accounted for a disproportionate
percentage of both localized (50% of cases) and generalized (48.9% of cases)
DLE. Median CLASI damage scores significantly differed between African
Americans, Caucasians, and Asian Americans, at both first (8.5, 4.0, 7.0)
(Kruskal-Wallis p⬍0.0001) and last visit (10.0, 6.0, 8.5) (Kruskal-Wallis
p⬍0.01), (Dunn’s Multiple Comparison p⬍0.0001, p⬍0.01). CLASI damage
scores in African Americans correlated with CLASI activity scores (Spear-
man’s r⫽0.45, p⫽0.0003). There was no significant correlation between
CLASI damage scores and Skindex domains overall. Individually, dyspigmentation and scarring also did not have a significant effect on Quality of
Life.
Conclusion: In conclusion, disease damage does not affect quality of life,
as measured by the Skindex-29.Differences were found in CLE patients of
different races: African American patients with CLE, do exhibit a high rate of
DLE, experience damage early in their disease course, frequently in conjunction with disease activity
Disclosure: S. M. Verma, None; J. Okawa, None; K. Propert, None; V. P. Werth,
None.
948
Antibody-Based Prediction Rules for Connective Tissue Disease: Analysis of 12,555 Patients with Antinuclear Antibody Testing. Ryo Rokutanda1. Mitsumasa Kishimoto1, Yasuharu Tokuda2, Ken-ichi Yamaguchi1,
Hisanori Shimizu1, Yasuhiro Suyama1, Yuri Ohara1, Yoichiro Haji1, Chisun
Min1, Akira Takeda1, Yukio Matsui1 and Masato Okada1, 1St. Luke’s
International Hospital, Tokyo, Japan, 2University of Tsukuba, Ibaraki, Japan
Background/Purpose: Antinuclear antibody (ANA) is widely used as
a screening test for connective tissue diseases (CTDs). The sensitivity of
this test is high in 3 CTDs--systemic lupus erythematosus (SLE), systemic
sclerosis (SSc), and mixed connective tissue disease (MCTD). ANAassociated specific autoantibodies are also identifiable in 3 additional CTDs
including polymyositis and dermatomyositis (PM/DM), as well as primary
Sjögren syndrome (SS).However, appropriate cutoff points for ANA titers or
in combination with other CTD-specific antibodies remains unclear.
Methods: We reviewed records for all patients (n⫽12,555) with ANA
immunofluorescence assay testing from January 2003 to June 2012. Among
3302 patients with positive ANA (ⱖa40), 94 were excluded due to lack of
information about ANA titers. Data collection also included specific CTD
diagnoses, ANA titers, and results of specific antibody tests for DNA, Sm,
U1RNP, Ro, La, centromere, Scl-70, and RNA polymerase III. We calculated
sensitivity, specificity, and positive (PPV) and negative (NPV) predictive
values for diagnosing each CTD at different ANA cutoffs. We then performed
classification and regression tree (CART) analysis to develop prediction rules
for each CTD. Potential predictors included ANA titers, ANA staining
patterns, and specific antibody test results.
Results: Of 12,461 patients with ANA testing, 665 patients (5.3%) were
diagnosed as having at least one of the 6 CTDs of interest. Area under the
ROC curves of ANA testing were 0.943, 0.977, 0.926, 0.840, and 0.740 for
SLE, MCTD, SSc, SS, and PM/DM, respectively. The sensitivities of ANA
(ⱖa40) for SLE, SSC, MCTD, SS, PM/DM were 98.6%, 95.9%, 100%,
83.0%, and 69.6%, while PPV was 6.7%, 5.1%, 0.7%, 6.3, and 1.7%,
respectively. Prediction rules developed by CART were as follows: (1) ANA
(ⱖa40) with anti-DNA antibody (PPV: 70.3% for SLE), (2) ANA (ⱖa40)
with anti-U1RNP antibody (PPV: 26.8% for MCTD), (3) ANA (ⱖa320) with
anti-centromere antibody (PPV: 44.7% for SSc), and (4) ANA (ⱖa320) and
anti-Ro without anti-DNA (PPV: 49% for SS).
Conclusion: ANA testing demonstrates substantial sensitivity, but has
low PPV for CTDs. Nonetheless, in combination with other antibody testing,
our prediction rules reveal a high specificity and PPV for diagnosing CTDs.
Disclosure: R. Rokutanda, None; M. Kishimoto, None; Y. Tokuda, None; K. I.
Yamaguchi, None; H. Shimizu, None; Y. Suyama, None; Y. Ohara, None; Y. Haji,
None; C. Min, None; A. Takeda, None; Y. Matsui, None; M. Okada, None.
949
The Inverse Association Between Obesity and Anti-Nuclear Antibodies
Is Modified by Systemic Inflammation and Maybe Associated with Body
Composition. Irene Blanco, Monalyn Labitigan and Matthew Abramowitz.
Albert Einstein College of Medicine, Bronx, NY
Background/Purpose: Obesity and abdominal adiposity have been
frequently associated with inflammation. However, an association of obesity
with a decreased likelihood of anti-nuclear antibodies (ANAs) was recently
reported in the general population. We used data from adult participants ⱖ20
years of age in the National Health and Nutrition and Examination Survey
1999–2004 to further explore this association.
Methods: To rule out a possible previous history of autoimmune disease,
participants were excluded if they reported a history of arthritis other than
osteoarthritis, thyroid or liver disease, or steroid use. ANAs were screened
S411
Monday, November 12
Methods: A longitudinal cohort of employed SLE patients in the U.S
meeting the following inclusion criteria were recruited between Dec 2010
and March 2011 through a patient advocacy association and the Harris
Chronic Illness Panel: ⱖ18 years old, self-reported SLE diagnosis, and ⱖ1
SLE flare in prior 3 months requiring medical attention (physician/ER/
hospital encounter or taking SLE medications). SLE patients completed a
baseline (BL) and six monthly follow-up (FU) surveys online. Monthly
surveys included assessments of self-perceived SLE disease activity (scale: 0
(no activity) to 10 (most activity); mild: 0–3, moderate: 4–6 & severe: 7–10),
Lupus Impact Tracker (LIT; scale: 0 (low) to 100 (high); a 10-item HRQoL
tool assessing disease impact on pain, fatigue, ability to perform daily
activities, etc), self-reported flares & symptoms and work/productivity (data
not shown).
Results: 272 SLE patients (mean age: 40.9 yrs; female: 96%; Caucasian:
78%; had at least college education: 63%) who completed the BL and ⬎⫽1
FU survey during the 6-month follow-up period were included in the analysis.
Time since first onset of SLE symptoms and time since SLE diagnosis were
12.5yrs and 7.8yrs respectively. At BL, mean disease activity score was 5.9;
patients reporting different levels of severity of lupus disease activity at BL
and each of the monthly FUs were clustered consistently over time as follows
- Mild: 15–16%, moderate: 40–42%, severe: 43–45%. For all patients, at BL,
mean LIT score was 49.3, and monthly FUs ranged between 44.3 & 48.7.
Fatigue, pain, and difficulty concentrating were identified by over 55%, 55%,
and 30% of patients respectively as occurring at least ‘most or all of the time’
at every evaluation period. LIT scores for patients reporting mild, moderate
and severe disease activity across the individual surveys were in the range of:
30.2–40.9, 49.7–59.7 and 56.8–75.2 respectively. Mean LIT scores statistically significantly (p⬍.001) correlated to disease activity scores at BL and
monthly assessments (pearson correlation coefficients range: 0.57–0.67).
Conclusion: Overwhelming majority of SLE patients in the study
consistently rated their disease activity to be moderate-to-severe over the
course of 6-months, and it significantly correlated with HRQoL measured by
LIT. While patient self-assessment of disease activity may differ from
physician’s clinical assessment, consistently high patient disease severity
reported by the study cohort highlights the perceived disease burden.
Incorporating patient perspective in clinical decision making may be important to consider in managing patients optimally and alleviate their burden of
illness.
Monday, November 12
using indirect immunofluorescence (IF). Titers were done on samples with
IFⱖ 3⫹. We subsequently strictly defined positive ANA as an ANA titer ’
1:160. Overweight and obesity were classified by traditional BMI criteria.
High and low C-reactive protein (CRP) were defined using the 75th percentile
cutpoint as ⱖ0.42 and ⬍0.42 mg/dL, respectively. Dual-energy X-ray
absorptiometry (DEXA) was used to determine body composition. Logistic
regression models were created to examine associations with ANA status and
were adjusted for demographics, comorbidities, smoking status, and total
cholesterol.
Results: 2552 participants were included in our analyses. Obese participants were older (p⬍0.001), more likely to be men (p⫽0.004) and to have
comorbidities, and had higher levels of CRP (⬍0.001).After multivariable
adjustment, obesity was associated with a decreased odds of having ANAs
(OR 0.78, 95%CI 0.62–0.99). However when adding log-transformed CRP
into our model, this association was no longer significant (OR 0.85, 95%CI
0.62–1.15), and there was evidence of effect modification by CRP (p⫽0.12).
To study the effect of systemic inflammation, as measured by CRP, we then
stratified our models based on the CRP cutpoint.Among participants with low
CRP (⬍0.42), obesity was again associated with a reduced likelihood of
ANA positivity (OR 0.69, 95%CI 0.48–0.99), but a trend was seen in the
opposite direction among those with high CRP (ⱖ0.42) (OR 1.77, 95%CI
0.81–3.88).When looking specifically at the 1143 obese and overweight
participants with low CRP, ANA positivity was associated with a higher
prevalence of cardiovascular disease (p⫽0.02) and higher % total body fat
(p⫽0.007), trunk fat (p⫽0.02), and non-trunk fat (p⫽0.004). This association,
however, was not found in the high CRP group.
Conclusion: In the general population the association of obesity with
ANA is modified by the presence of systemic inflammation as measured by
CRP, where the inverse association previously found is eliminated when
controlling for CRP. While this inverse relationship remains among obese
participants with low CRP, when these obese and overweight participants are
ANA positive, it is associated with greater total body and trunk fat. Therefore
it is possible that body composition, particularly fat distribution, is driving
autoimmunity in the general population even in the absence of systemic
inflammation. Further studies are needed to determine if in fact this is the
case.
Disclosure: I. Blanco, None; M. Labitigan, None; M. Abramowitz, None.
950
Performance of Various Anti-Nuclear Antibody Methodologies in the
Assessment of Autoimmune Connective Tissue Diseases. Xiaoli Deng,
Cynthia S. Crowson, Helen Khun, Melissa R. Snyder and Kevin G. Moder.
Mayo Clinic, Rochester, MN
Background/Purpose: The anti-nuclear antibody (ANA) is the classic
biomarker associated with autoimmune connective tissue diseases (CTDs).
ANA testing is often ordered as part of the evaluation of patients with
suspected CTD. Different methods, including indirect immunofluorescence
assays (IFAs), enzyme immunoassays (EIAs), and multiplex immunoassays
(MIAs) are currently used by clinical labs for general ANA screening.
However, because the methodologies are very different, discordance between
results may be observed, leading to challenges in interpretation. The purpose
of this study is to analyze the performance of these methods in a subset of
patients referred for rheumatology consultation.
Methods: A cohort of patients who had an ANA ordered for clinical
assessment and a rheumatology consultation at our institution in 2010– 2011
were enrolled. ANA testing was performed by IFA (Zeus Scientific), EIA
(BioRad), and MIA (BioRad). A titer of ⱖ1:40 for the IFA and a value ⬎1.0
for the EIA were identified as positive. Autoantibodies to dsDNA, chromatin,
ribosome P, SS-A, SS-B, Sm, Sm/RNP, RNP, Scl-70, Jo-1 and centromere B
were detected by MIA; positivity for at least 1 specific autoantibody identified
the ANA as positive. Sensitivities and specificities were computed and were
compared using McNemar’s test.
Results: In the study cohort (n⫽327; 81% female; mean age 52 [sd: 16]
years), a subset had no identifiable autoimmune disease (non-auto; n⫽87) and
the remaining patients had a diagnosed autoimmune CTD (auto CTD;
n⫽240), including systemic lupus erythematosus (SLE; n⫽51), Sjogren
syndrome (SS; n⫽34), mixed CTD/undifferentiated CTD (MCTD/UCTD;
n⫽51), rheumatoid arthritis (RA; n⫽33), and various other miscellaneous
CTDs (n⫽71). Sensitivities and specificities of the IFA, EIA and MIA within
these groups are shown in the table.
Auto CTD
(nⴝ240)
IFA
EIA
MIA
92%
92%
75%
Sensitivity
SLE
SS
(nⴝ51)
(nⴝ34)
100%
98%
92%
100%
100%
100%
MCTD/UCTD
(nⴝ51)
Specificity
Non-Auto
(nⴝ87)
100%
100%
82%
25%
28%
62%
In the auto CTD group overall, IFA and EIA had similar sensitivities
(p⫽0.83), both of which were significantly higher than MIA (p⬍0.001).
However, in the non-auto group, the MIA demonstrated significantly improved specificity compared to both the IFA and EIA (p⬍0.001). In specific
CTD groups, all SS patients were ANA positive by all 3 methods. In SLE
patients, the EIA and IFA had similar sensitivities (p⫽0.32); the sensitivity of
the MIA was significantly lower than the IFA (p⫽0.046), and marginally
lower than the EIA (p⫽0.08). In the MCTD/UCTD group, the EIA and IFA
were positive in all patients, and the MIA had significantly lower sensitivity
(p⫽0.003).
Conclusion: The sensitivities of IFA, EIA, and MIA vary significantly
depending on the specific diagnostic category. Although the sensitivities of
IFA and EIA tend to be improved over the MIA, the specificities of these
methods are a significant issue. Further comparisons of methods used for
ANA screening can provide valuable information that could lead to improved
interpretation and utilization of lab testing.
Disclosure: X. Deng, None; C. S. Crowson, None; H. Khun, None; M. R. Snyder,
Bio-Rad Laboratories, 5, Inova Diagnostics, Inc., 5; K. G. Moder, None.
951
A Systematic Review of Quality of Prognosis Studies in Systemic Lupus
Erythematosus. Lily Siok Hoon Lim1, Senq-J Lee1, Brian M. Feldman2,
D. D. Gladman3, Eleanor Pullenayegum4 and Earl D. Silverman5. 1Hospital
for Sick Children, Toronto, ON, 2The Hospital for Sick Children, Toronto,
ON, 3Toronto Western Hospital and University of Toronto, Toronto, ON,
4
McMaster University, Hamilton, ON, 5Pediatric Rheumatology Collaborative Study Group (PRSCG), Toronto, ON
Background/Purpose: Prognosis studies study future outcomes and/or
seek to identify predictive or associative factors associated with outcomes.
Strong and consistent prognostic factors can be used to individualize management and better outcomes of patients. Many prognostic factors have been
identified in SLE but few have been consistent. We hypothesize that this is
due to flawed study design. We aim to systematically assess methodological
quality of prognosis studies in SLE.
Methods: A systematic search of prognosis studies in SLE was performed
in MEDLINE and EMBASE, from January 1990 to June 2011. Non-English
literature, non-original research, non- full length reports and animal studies
were excluded. Of 5419 articles subjected to a title and abstract screen, 1039
articles were found. A representative sample of 150 articles was selected
using a random number generator and assessed by 2 reviewers. Studies were
classified according to design and the clarity of research question was
assessed. Each study was assessed by a risk-of-bias tool “QUality In
Prognosis Studies” (QUIPS) in 6 domains: study participation, study attrition,
measurement of prognostic factors, measurement of outcomes, measurement/
adjustment for confounders and appropriateness of statistical analysis. Information on missing data was also collected.
Results: Of 150 articles, 15 were pediatric studies, 3 made comparisons
of pediatric and adult patients and the remainder were adult studies. The
majority were published in rheumatology journals (69%). Cohort design was
used in 67% of studies; the remainder used cross-sectional (21%), casecontrol (5%) and other designs (7%). The research question clearly included
study population in 92%, prognostic factor in 54% and outcome in 61% of
studies. High risk of bias (QUIPS) was noted in 57% of studies for study
participation, 57% for attrition, 20% for prognostic factor, 18% for outcome,
65% for confounders and 36% for statistical analyses. Confounders were
named in the methods section in only 12% of studies. Some consideration for
confounding was built into the design of 21% of studies. The amount of
missing data could not be assessed in 39% of studies.
Conclusion: Inadequate articulation of research questions for prognostic
factors, poor design addressing confounding, study participation and attrition
and inadequately reported information on missing data limited the quality of
prognosis studies in SLE. Future prognosis studies should be designed with
better consideration to the above factors to improve methodological rigor.
Disclosure: L. S. H. Lim, None; S. J. Lee, None; B. M. Feldman, None; D. D.
Gladman, None; E. Pullenayegum, None; E. D. Silverman, None.
S412
953
ACR/ARHP Poster Session B
Comparative Symptom Severity of Patients Satisfying Chronic Widespread
Pain and Fibromyalgia Criteria. Frederick Wolfe1, Brian Wallitt2, Robert S.
Katz3 and Winfried Häuser4. 1National Data Bank for Rheumatic Diseases,
Wichita, KS, 2Washington Hospital Center, Baltimore, MD, 3Rush University
Medical Center, Chicago, IL, 4Klinikum Saarbrücken, Saarbrücken, Germany
Cognitive Behavioral Therapy and Milnacipran in Combination
Appears to Be More Efficacious Than Either Therapy Alone. Dennis
C. Ang1, Mark P. Jensen2, Jennifer L. Steiner3, Janna Hilligoss1, Richard
Gracely4 and Chandan Saha5. 1Indiana University, Indianapolis, IN,
2
Seattle, WA, 3Indianapolis, IN, 4Chapel Hill, NC, 5Indiana University
Background/Purpose: Chronic widespread pain (CWP) is often used as a
surrogate for fibromyalgia in epidemiological research, particularly in Europe and
in whiplash-related injuries. This CWP substitution occurred because it was
operationally impossible to perform tender point examinations in epidemiological
and survey research. CWP is a requirement for fibromyalgia diagnosis when the
American College of Rheumatology (ACR) 1990 criteria are used. 20–35% of
patients with CWP will also satisfy fibromyalgia criteria. Despite the common use
of CWP, it is not clear how closely CWP positive patients resemble those with
fibromyalgia, and whether CWP is a valid substitution for fibromyalgia. In this
report we determined the relative severity of patients satisfying the CWP and
fibromyalgia criteria.
Methods: We studied 6,583 rheumatic disease patients who completed a
research questionnaire that contained assessments of criteria and severity variables. Fibromyalgia was diagnosed using the 2010 American College of Rheumatology (ACR) criteria for fibromyalgia, as modified for survey research.
Widespread pain used the 1990 ACR definition: pain above and below the waist,
on the left and right sides of the body, and involving the axial skeleton. Severity
measures included the Polysymptomatic Distress Scale (PSD) and the Symptom
Severity (SS) scale from the 2010 criteria. In addition, we employed other
standard assessments of severity, including measures of pain, sleep, fatigue and
quality of life. We categorized patients as a) without CWP, b) with fibromyalgia,
c) with CWP assuming 20% of CWP cases had FM, and d) with CWP assuming
33% of CWP cases had fibromyalgia (Table 1).
952
Background/Purpose: The two treatment options that have received the
significant attention in fibromyalgia (FM) management are cognitive behavioral therapy (CBT) and medications. Given the fact that either therapy alone
appears to only produce modest improvements in clinical symptoms, we
completed a 3-arm randomized attention-controlled trial whose primary aim
was to obtain preliminary estimates of the effects of combined CBT and
milnacipran on primary clinical endpoints: changes in weekly average pain
intensity (daily electronic recording of pain scores) and physical function
(SF-36 physical component summary score).
Methods: Fifty eight patients with FM were randomized to one of the 3
treatment arms: (1) combination therapy (n⫽20), (2) drug ⫹ education
attention (n⫽19), and (3) placebo ⫹ CBT (n⫽19). Throughout the 21-week
study, subjects received either milnacipran (50 mg BID) or placebo (BID).
Subjects also received 8 sessions of telephone-delivered CBT or educational
instructions, but only from baseline to week 9. Assessments were conducted
at baseline, week 9 and 21. Secondary clinical endpoints included changes in
PHQ-8 depression severity (0–24), and evoked (thumb) pressure pain scores
(0–20), a measure of pain sensitivity.
Results: Characteristics of the 58 FM subjects: mean age⫽ 46.6 (10.4)
years; female⫽93%; whites⫽ 81%; high school graduates⫽71%; concomitant opioid analgesics⫽43%; PHQ-8 depression⫽10.55 (4.79); evoked pressure pain⫽ 8.8 (0.59); weekly average pain intensity ⫽ 6.31 (1.27); and
SF-36 physical function⫽ 45.26 (22.4).
Compared to drug alone, combination therapy demonstrated a medium
effect on reducing weekly average pain intensity (effect size/ES⫽0.67) and in
improving SF-36 physical function (ES⫽0.60). The magnitude of change in
the pain intensity score in the combination group was more than twice the
magnitude of change in the drug monotherapy group.Compared to drug alone,
CBT alone was marginally efficacious in improving SF-36 physical function.
No significant between group differences were seen in improvement in
depression severity and change in evoked pain scores. Interestingly, subjects
in the drug groups (i.e., combination and drug alone) became less sensitive to
pressure stimuli compared to subjects in the CBT monotherapy group, albeit
this difference was not statistically significant.
Table 1.
Combination
therapy
Nⴝ17
Drug
monotherapy
Nⴝ17
CBT
monotherapy
Nⴝ15
P values Combo vs.
drug Combo vs.
CBT Drug vs. CBT
Cohen’s d
(Effect
sizes)
⫺2.15 (0.43)†
⫺0.97 (0.43)†
⫺1.67 (0.45)†
0.067
0.67
Primary Outcomes
⌬ Weekly average¶
pain intensity
score
⌬ SF-38 physical
component
13.47 (3.74)†
4.05 (3.84)
summary score
Secondary Outcomes
⌬ PHQ-8 depression
15.04 (4.01)†
0.058
⫺2.65 (1.06)†
⫺2.93 (1.07)†
⫺3.19 (1.11)†
score
0.441
0.27
0.286
0.40
0.092
0.775
0.60
0.10
Table 1. Severity status of patients with fibromyalgia or chronic widespread pain
Variable
VAS Pain (0–10)
VAS Fatigue (0–10)
VAS Sleep problem
(0–10)
Mood (0–10)
HAQ (0–3)
VAS Pt. Global
(0–10)
SS Scale (0–12)
WS Pain Index
(0–19)
PSD scale (0–31)
EQ-5D (0–1)
PCS
MCS
VAS QOL (0–100)
0.70
0.860
0.727
⫺0.76 (1.20)
⫺0.41 (1.22)
0.78 (1.27)
FMS Mean
(95% C.I.)
Widespread
Pain At 20%
FM Prevalence
Widespread
Pain At 33%
FM Prevalence
2.8 (2.7, 2.9)
3.2 (3.1, 3.3)
3.1 (3.0, 3.2)
6.1 (6.0, 6.3)
7.0 (6.9, 7.1)
6.5 (6.3, 6.6)
4.3 (4.2, 4.4)
4.4 (4.3, 4.5)
4.3 (4.2, 4.5)
4.6 (4.5, 4.7)
4.8 (4.7, 5.0)
4.7 (4.6, 4.8)
2.4 (2.3, 2.4)
0.7 (0.6, 0.7)
2.8 (2.8, 2.9)
4.1 (4.0, 4.2)
1.5 (1.4, 1.5)
5.8 (5.7, 5.9)
2.9 (2.8, 2.9)
1.1 (1.0, 1.1)
4.1 (4.0, 4.2)
3.1 (3.0, 3.2)
1.1 (1.1, 1.2)
4.3 (4.2, 4.4)
3.3 (3.2, 3.4)
2.1 (2.0, 2.3)
7.7, (7.6, 7.8)
12.3 (12.1, 12.4)
4.3 (4.2, 4.4)
8.2 (8.0, 8.4)
4.9 (4.8, 5.0)
8.9 (8.7, 9.1)
6.0 (5.8, 6.2)
0.80 (0.79, 0.80)
41.8 (41.4, 42.1)
50.5 (50.1, 50.9)
71.2 (70.5, 71.9)
20.6
0.56
29.3
39.5
52.6
13.5 (13.2, 13.8)
0.7 (0.7, 0.7)
34.8 (34.3, 35.2)
47.6 (47.1, 48.2)
63.4 (62.5, 64.3)
14.7 (14.5, 15.0)
0.7 (0.7, 0.7)
33.9 (33.6, 34.3)
46.3 (45.8, 46.8)
61.8 (61.0, 62.7)
(20.4,
(0.55,
(28.9,
(39.0,
(51.7,
20.9)
0.57)
29.8)
40.0)
53.5)
Results: Figure 1 shows the relation of both measures to PSD in the overall
sample.X and y lines cross when probability of diagnosis is ⬎⫽ 0.5. This occurs
at 9.3 and 13.3 on the PSD scale for CWP and FM, respectively. Table 1, adjusted
for age and sex, demonstrates that patients with fibromyalgia have more severe
symptoms than those with CWP at 20% and 33% prevalence levels. For the 3
clinical VAS scales, fibromyalgia patients are approximately 30% more severe
than those with CWP.
0.865
⌬ Evoked pain scores
Not
Widespread
pain Mean
(95% C.I.)
0.838
0.379
0.504
⌬: Baseline to week 21 change in the specified variable; Values represent means and standard error
†Significant within group difference (p⬍0.04)
Conclusion: Based on the observed effect sizes, our preliminary data
justifies pursuing a larger definitive trial to test the superiority of combination
therapy vs. monotherapy.Additionally, a direct comparison of CBT vs. drug
monotherapy is warranted to inform future health care decisions.
Disclosure: D. C. Ang, None; M. P. Jensen, None; J. L. Steiner, None; J. Hilligoss,
None; R. Gracely, None; C. Saha, None.
S413
Monday, November 12
Fibromyalgia and Soft Tissue Disorders
Monday, November 12, 2012, 9:00 AM–6:00 PM
Conclusion: Patients satisfying fibromyalgia criteria have a more severe
illness than those with CWP. The use of CWP as a surrogate measure of
fibromyalgia substantially underestimates fibromyalgia severity, but still
identifies a group of severe patients.
Disclosure: F. Wolfe, None; B. Wallitt, None; R. S. Katz, None; W. Häuser,
None.
954
WITHDRAWN
Monday, November 12
955
Post–Surgical Outcome Is Correlated with Pre–Surgical Symptoms of
Fibromyalgia in Patients Undergoing Spinal Surgery. Jacob N. Ablin1,
Mark Berman1, Eyal Behrbalk2, Dan Buskila3, Gilad Regev2 and Zvi Lidar2.
1
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, 2Department of
Neurosurgery and Orthopedic, Tel Aviv Sourasky Medical Center, Tel Aviv,
Israel, 3Beer-Sheva, Israel
Background/Purpose: Chronic pain is a major symptom for which
patients undergo spinal surgery. At the same time, chronic pain is considered
an entity in and of itself, often constituting part of the clinical spectrum of
central sensitization (e.g. fatigue, cognitive impairment etc) thus overlapping
with the fibromyalgia syndrome (FMS).
The impact of surgical intervention on chronic pain is not well known.
While such interventions may remove a local “pain generator” they may
simultaneously constitute a form of physical trauma, as well as entailing
prolonged immobilazion, both potentially detrimental for fibromyalgia patients.
The aim of this study was to evaluate patients who undergo spinal surgery
for presence of central pain and central sensitization symptoms and evaluate
the correlation between these symptoms and the surgical outcomes.
Methods: Participants were patients scheduled for spinal surgery. Presurgical evaluation included physical examination and manual dolorimetry,
documenting the 1990 ACR FMS classification criteria. In addition, patients
filled out the widespread pain index (WPI) and the Symptom Severity Scale
(SSS) which are part of the suggested 2010 diagnostic criteria of fibromyalgia, as well as the fibromyalgia-Impact Questionnaire (FIQ) and SF-36.
Eight weeks after surgery, patients underwent follow-up evaluation.
Statistics: Spearman correlations were calculated between the pre-surgery
parameters (WPI and SSS) and the change in SF-36 items. P values under
0.05 were considered significant.
Results: Twenty eight patients (18 male, 10 female) were recruited. The
average age was 56.3 (23–85). The average BMI was 26.7 kg. Three patients
fulfilled ACR 1990 fibromyalgia criteria (10.7%), whereas 8 patients fulfilled
the 2010 diagnostic criteria (28.6%).Thirteen patients were available for post–
surgical evaluation.
Table 1 presents the correlations calculated between the pre–surgical WPI
and SSS and the change in the SF-36 domains: Physical Functioning (PF),
Role–Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT),
Social Functioning (SF), Role Emotional (RE), Mental Health (MH) as well
as the Mental Component Score (MCS) and Physical Component Score
(PCS). A significant negative correlation was observed between the WPI and
the delta RP item; a significant negative correlation was also observed
between the SSS and the delta of the GH and RE items.
WPI-correlation
⌬TP
⌬PF
⌬RP
⌬BP
⌬GH
0.03
⫺0.04
ⴚ0.72
0.15
⫺0.33
0.63
⫺0.41
0.27
ⴚ0.69
WPI-P value
SSS–correlation
0.95
0.25
0.88
0.20
0.006
⫺0.32
SSS-P value
0.58
0.51
0.28
0.16
0.008
⌬VT
⌬SF
⌬RE
⌬MH
⌬PCS
⌬MCS
0.09
0.15
⫺0.31
⫺0.01
⫺0.28
0.06
0.77
0.51
0.62
0.31
0.30
ⴚ0.56
0.96
0.04
0.34
⫺0.31
0.84
⫺0.18
0.077
0.31
0.90
0.30
0.55
0.047
Conclusion: FMS symptoms were highly prevalent among patients
scheduled for spinal surgery (28.6%). A negative correlation was observed
between pre-surgical severity of FMS symptoms and components of the
post-surgical SF-36. Patients with symptoms of FMS may have a poor
outcome after spinal surgery. The clinical utility of surgical intervention in
such patients should be carefully evaluated and treatment specific for FMS
considered, before embarking on a surgical course.
Disclosure: J. N. Ablin, Pfizer Inc, 5, MSD, 5; M. Berman, None; E. Behrbalk, None;
D. Buskila, None; G. Regev, None; Z. Lidar, None.
956
Learning Disability in Fibromyalgia Patients: FMS Patients Report
More Language and Spatial Difficulties. Robert S. Katz1, Alexandra
Small2. Carlen Katz3 and Susan Shott1, 1Rush University Medical Center,
Chicago, IL, 2University of Illinois Medical School, 3Rheumatology Associates, Chicago, IL
Background/Purpose: Fibromyalgia patients are reported to have central
sensitization and abnormal central processing of sensory input. Fibromyalgia
patients alsohave more neurocognitive complaints and abnormalities on
certain types of neurocognitive testing, especially the Stroop test for naming
speed and a distraction test, the Auditory Consonant Trigram.To evaluate
other possible central nervous system dysfunction, we asked fibromyalgia
patients and patients with other rheumatic diseases in a questionnaire whether
or not they had symptoms and features of a learning disability.
Methods: Office patients and controls were asked to complete a questionnaire about difficulties in reading, writing, body awareness/spatial relationships, and oral expressive language. A score consisting of the percentage
of items for which the respondent reported difficulty was obtained for each of
these areas. Four diagnosis groups were compared with respect to questionnaire responses: 85 FMS patients, 39 RA patients, 21 SLE patients, and 14
controls without rheumatic diseases. The Kruskal-Wallis and Mann-Whitney
tests were used to compare scores and the chi-square test of association was
used to compare percentages, with a 0.05 significance level.
Results: Compared to controls, FMS patients had significantly worse
reading and oral expressive language scores (p ⫽ 0.001). FMS patients had
significantly worse scores for all four areas than the RA and SLE groups (p ⬍
0.001–0.007). There were no statistically significant differences between the
RA, SLE, and control groups with respect to any of the scores. FMS patients
were significantly more likely to report the following difficulties: making
mistakes when reading like skipping words or lines (FMS 43%, controls 0%,
RA 3%, SLE 5%, p ⬍ 0.001); reading the same line twice (FMS 57%,
controls 14%, RA 15%, SLE 19%, p ⬍ 0.001); problems remembering what
was read (FMS 59%, controls 0%, RA 11%, SLE 24%, p ⬍ 0.001); difficulty
understanding the main idea or identifying the important details from a story
(FMS 27%, controls 0%, RA 5%, SLE 14%, p ⫽ 0.007); problems with
grammar or punctuation (FMS 28%, controls 14%, RA 8%, SLE 0%, p ⫽
0.004); tendency to be clumsy or uncoordinated (FMS 41%, controls 7%, RA
10%, SLE 10%, p ⬍ 0.001); difficulty with eye-hand coordination (FMS
27%, controls 7%, RA 5%, SLE 5%, p ⫽ 0.004); difficulty expressing self in
words (FMS 42%, controls 7%, RA 8%, SLE 5%, p ⬍ 0.001); trouble finding
the right words to say in a conversation (FMS 57%, controls 8%, RA 11%,
SLE 24%, p ⬍ 0.001); and trouble talking about a subject or getting to the
point of a conversation (FMS 43%, controls 7%, RA 5%, SLE 5%, p ⬍
0.001).
Conclusion: Fibromyalgia patients, compared to rheumatic disease controls, are found to haveproblems in reading, writing, body awareness, and
spatial relationships and problems in oral expressive language.Fibromyalgia
patient responses suggested frequent symptoms of a learning disability.
Learning disability may be another part of central nervous system
dysfunction in fibromyalgia patients.Patients, practitioners and educators
should be made aware of the association between fibromyalgia and learning
disabilities.
Disclosure: R. S. Katz, None; A. Small, None; C. Katz, None; S. Shott, None.
957
Key Psychological Processes Associated with the Fibromyalgia Phenotype Exist On a Continuous Spectrum with Asymptomatic People.
Katrina Malin1 and Geoffrey O. Littlejohn2. 1Monash University, Clayton,
Australia, 2Monash Medical Centre and Monash University, Clayton, Victoria, Australia
Background/Purpose: The core features of the fibromyalgia phenotype,
the widespread pain and widespread tenderness, represent one extreme of a
continuous spectrum with asymptomatic people at one end and those meeting
criteria for fibromyalgia at the other. A number of key central processes
associate with fibromyalgia, such as personality [neuroticism and Type A]
and psychological characteristics, including attitude, control, coping, catastrophizing and stress-reactivity.We hypothesized that these psychologically
linked processes also exist on a single continuous spectrum from normal in
asymptomatic people to abnormal in fibromyalgia, and that increasing the
“gain” of these processes will increase the features contributing to the
fibromyalgia phenotype.
S414
Disclosure: K. Malin, None; G. O. Littlejohn, None.
958
Prevelance of Spondyloarthropathy in Fibromyalgia Patients. A.Eftal
Yucel, Derya Kaskari and Muhtesem Agýldere. Baskent University, Ankara,
Turkey
Background/Purpose: Most of the tender points typical for fibromyalgia
syndrome (FMS) are also entesis points. Besides, FMS and spondyloartropathy (SpA) can co-exist. Both disease groups have negative effects on the life
quality of patients. Our aim is to document the prevalence of SpA in patients
diagnosed as FMS by physical therapy specialists and to emphasize evaluation of spondyloartropathy before diagnosing with FMS.
Methods: he patients diagnosed to have FMS in the department of
Physical Therapy and Rehabilition at our center between 2006 and 2011 were
involved. Patients were called by phone and asked 3 questions about their
inflammatory back pain. Questions were about the presence of 1.Nontraumatic pain, swelling and stiffness in any joint 2.Low back pain or back
stiffness on awakening, which lasted over a period of at least 3 months and
which improved with exercise 3.Heel pain more in the morning which lasted
over a period of at least 3 months and improved with activity. The patients
who answered positive to at least one of these three questions were invited for
further evaluation and to be involved in this study. The study included 71
patients (70 female and 1 male).In all patients, comparative sacroiliac
radiographies were taken for sacroiliitis and lateral radiographies of both feet
were taken for enthesitis. Patients with stage 1 and stage 1–2 sacroiliitis on
direct radiography, were examined with sacroiliac MR. In order to diagnose
FMS, 1990 and 2010 ACR Classification were applied while ESSG Criteria
were applied to diagnose SpA.
Results: According to 1990 ACR criteria, 23 patients out of 71(32.3%)
were diagnosed as FMS however 33 patients (46.4%) were diagnosed as FMS
according to 2010 ACR criteria.Fifteeen (21.1%) patients were diagnosed
according to both 1990 and 2010 ACR criteria; however 41(57.7%) patients
were diagnosed with either 1990 ACR criteria or 2010 ACR criteria.Of our 71
patients, 20 (28.1%) were diagnosed as SpA according to ESSG criteria.Ten
(43.4%) FMS patients out of 23 who were diagnosed according to 1990 ACR
criteria were rediagnosed as SpA according to ESSG criteria. Eleven (33.3%)
patients out of 33 who were diagnosed as FMS with 2010 ACR criteriawere
rediagnosed as SpA according to ESSG criteria. We determined 9(39.1%)
patients out of 23 patients diagnosed with 1990 ACR criteria and 13 (39.3%)
patients out of 33 diagnosed with 2010 ACR criteria were found to have stage
2 and higher sacroiliitis. According to sacroiliac MR examinations of 10
patients, 3 (30.0%) patients had sacroiliitis on MR who had stage 1 and stage
1–2 sacroiliitis on direct radiography who were diagnosed with SpA according to ESSG criteria Twelve (60.0%) out of 20 patients diagnosed as SpA
according to ESSG criteria were found to have 2nd stage and higher
sacroiliitis. We determined that 14 (60.8%) out of 23 patients diagnosed with
ACR’s 1990 and 17 (51.5%) out of 33 patients diagnosed with ACR’s 2010
found to have enthesopathy.
Conclusion: There is a meaningful percentage of patients who have
clinically insidiously progressive SpA among the patients who were thought
to be diagnosed as FMS or the patients who were diagnosed as FMS
according to ACR’s criteria
Disclosure: A. E. Yucel, None; D. Kaskari, None; M. Agýldere, None.
959
Treatment of Lateral Epicondylitis with Injection of Platelet-Rich
Plasma or Corticosteroid Versus Saline: A Randomized, Double-Blind,
Placebo-Controlled Trial. Thoger Krogh1, Ulrich Fredberg1, Kristian
Stengaard-Pedersen2, Pia Jensen1, Robin Christensen3 and Torkell Ellingsen1.
1
Diagnostic Centre Region Hospital Silkeborg Denmark, Silkeborg, Denmark, 2Arhus University Hospital, Aarhus, Denmark, 3Copenhagen University Hospital at Frederiksberg, Copenhagen, Denmark
Background/Purpose: Lateral epicondylitis (LE) is a common musculoskeletal disorder for which an effective treatment strategy still remains
absent. The objective is to examine whether one injection with Platelet-rich
plasma (PRP) is more effective than saline and corticosteroid (CS) in reducing
pain in adults with LE.
Methods: A block randomized, double-blind, placebo-controlled trial
with primary outcome assessed at 3 months, and with a 12 months follow-up,
conducted between January 2009, and June 2011. Patients who did not
achieve a satisfying treatment response (assessment made by patient and
doctor) at 3 month had the option to discontinue the study and receive other
treatment. In total, 60 patients with chronic LE were randomized (1:1:1) to
receive either a blinded injection of PRP, saline or CS. The primary outcome
was change in pain compared to baseline using the Patient Rated Tennis
Elbow Evaluation (PRTEE) questionnaire at 3 months. Secondary endpoints
were all assessed at 1 month, plus ultrasonographic changes in tendon
thickness and color Doppler activity at 3 months.
Results: The 60 enrolled patients in the intention to treat population had
an average PRTEE pain score at baseline of 26.8 (SD 7.6). All randomized
patients completed the study. At endpoint 3 months from baseline pain
reduction was observed in all three groups, with no statistical significant
difference between the groups. CS vs. saline ⫺3.76 (95% CI ⫺9.94 to 2.42),
PRP vs. saline ⫺2.64 (95% CI ⫺8.80 to 3.52) and CS vs. PRP ⫺1.12 (95%
CI ⫺7.23 to 4.99). However, at one month CS reduced pain more efficiently
than both saline and PRP. The mean difference at one month between CS and
saline was ⫺8.11 (95% CI ⫺14.29 to ⫺1.93), between CS and PRP ⫺9.27
(95% CI ⫺15.38 to ⫺3.16). CS was more efficient than PRP and saline in
reducing both color Doppler activity and tendon thickness at three months.
Only 16 of 60 patients completed the entire 12 months follow-up. The huge
attrition rate was due to lack of treatment efficacy.
Figure. Changes in pain from baseline at 1 and 3 months using the PRTEE
(Patient-Rated Tennis Elbow Evaluation) in patients treated with 1 injection of PRP
(platelet-rich plasma), glucocorticoid, or saline. Values are Least Squares Means ⫾
Standard Error.
S415
Monday, November 12
Methods: We identified 98 women with fibromyalgia diagnosed according to standard ACR criteria. Applied questionnaires included the Big 5
Personality Inventory, Type A scale, Fibromyalgia Impact Questionnaire,
Perceived Control of Internal States, Mastery scale, the Coping Scale and
Perceived Stress scale and the depression, anxiety, confusion and optimism
scales of the Profile of Mood States questionnaire. Normallity assessment
using Shapiro-Wilk test and correlations and regression modelling and
comparisons between smallest and largest tertileswere used to explore the
relationships between personality and psychological variables in both the
healthy controls and in the patients with fibromyalgia.
Results: There was a significant relationship between lower and higher
tertiles of neuroticism, internal and external control, attitude, coping and stress
and the characteristic fibromyalgia phenotype features of fatigue, sleep and
confusion, in both the healthy control and the fibromyalgia groups [p all
⬍0.001]. Pain was also significantly different in the healthy controls
[p⬍0.001] but showed a non-significant ceiling effect between lowest and
highest tertiles in the fibromyalgia group. Personality and psychological
variables also correlated significantly in both healthy controls and fibromyalgia with depression and anxiety [p⬍0.001]. The absolute levels of all
characteristics in healthy controls and fibromyalgia patients differed significantly [p⬍0.001].Normality plots indicated that the psychological characteristics examined existed on a spectrum with healthy controls at one end and
fibromyalgia patients at the other.
Conclusion: The personality and psychological variables that associate
with fibromyalgia exist on a continuous spectrum, linking normal asymptomatic persons to the fibromyalgia phenotype.Increasing certain centrally important psychological variables will increase fibromyalgia clinical features.
This is suggestive of a key role for central psychological factors in the
pathogenesis of fibromyalgia.
Conclusion: This RCT showed no superiority of either PRP or CS
compared to saline in pain reduction in LE at primary endpoint. However,
anticipating immediate relief, CS had a short term pain reducing effect at one
month in contrast to the other therapies. At 6 and 12 months the attrition rates
in all treatment arms were too high for any meaningful conclusions to be
made.
Disclosure: T. Krogh, None; U. Fredberg, None; K. Stengaard-Pedersen, None;
P. Jensen, None; R. Christensen, None; T. Ellingsen, None.
Monday, November 12
960
Cyclobenzaprine (CBP) and Its Major Metabolite Norcyclobenzaprine
(nCBP) Are Potent Antagonists of Human Serotonin Receptor 2a
(5HT2a), Histamine Receptor H-1 and á-Adrenergic Receptors: Mechanistic and Safety Implications for Treating Fibromyalgia Syndrome by
Improving Sleep Quality. Bruce Daugherty, Leland Gershell and Seth
Lederman. Tonix Pharmaceuticals, Inc., New York, NY
Background/Purpose: Bedtime cyclobenzaprine (CBP) improves fibromyalgia symptoms (pain, fatigue, tenderness, and mood) and improves sleep
quality (decreases Cyclic Alternating Pattern Type A2 ⫹ A3) (1).CBP is
metabolized by the hepatic P450 isoforms CYP1A1/2 and CYP3A4 into
desmethyl, or norcyclobenzaprine (nCBP)(2), but plasma nCBP has only
been detected in cases of overdose (3–5). Although CBP has been shown to
interact with both the serotonergic (6,7) and noradrenergic (8,9) receptor
systems, the functional interactions of CBP with isolated receptors are not
fully characterized and those of nCBP are unknown. Therefore, plasma nCBP
was measured in healthy subjects after ingesting CBP and the binding and
functional activity of CBP and nCBP was studied on a set of CNS targets with
potential relevance to CBP actions.
Methods: Plasma CBP and nCBP were measured over 168 hr in ten
healthy, fasting subjects who received 5 mg po immediate release CBP
HCl.Equilibrium receptor binding assays were performed on cell lines
expressing select recombinant human serotonin, adrenergic, histamine, and
muscarinic receptors. Select receptors were analyzed in ligand-induced
intracellular Ca⫹mobilization.
Results: The oral bioavailability of CBP was similar to published
results (Cmax ⫽ 4.12 ng mL⫺1, tmax ⫽ 3.5 h, T ⁄ ⫽ 31.0 h, AUC0-⬁ ⫽
103.1 ng hr mL⫺1), but plasma nCBP was unexpectedly high and
persistent (Cmax ⫽ 1.27ng mL⫺1, tmax ⫽ 24.0 h, T ⁄ ⫽ 72.8 h, AUC0-⬁ ⫽
169.5 ng hr mL⫺1).Unlike CBP, nCBP does not form a stable N⫹glucuronide, which may affect its clearance.In vitro, CBP and nCBP
exhibited high affinity binding (Ki) to receptors: 5HT2a (5.2 and 13 nM,
respectively) and 5HT2c (5.2 and 43 nM), adrenergic ␣-1A (5.6 and 34
nM), ␣-2B (Ki ⫽ 21 and 150 nM) and ␣-2C (Ki ⫽ 21 and 48 nM,); H1
(1.3 and 5.6 nM); and M1 (7.9 and 30 nM). Like CBP, nCBP is a
functional antagonist at 5HT2a (IC50 ⫽ 92 nM) by Ca⫹ mobilization.CBP
is also an antagonist on 5HT2b (IC50 ⫽ 100 nM). CBP and nCBP are
functional antagonists on 5HT2c (IC50 ⫽ 0.44 and 1.22 ␮M) and on ␣-2A
(IC50 ⫽ 4.3 and 6.4 ␮M). In contrast, both CBP and nCBP are functional
agonists on 5HT1a (EC50⫽ 5.3 and 3.2 ␮M).
Conclusion: CBP is metabolized to nCBP which persists in plasma at
biologically relevant concentrations after oral CBP in healthy subjects.CPB and nCBP are potent antagonists of 5HT2a, 5HT2b, H-1,
adrenergic ␣-1A, ␣-2B and ␣-2C receptors.CBP’s antagonist activity on
5HT2b is consistent with the lack of any association with heart valve
pathology.Antagonists of 5HT2a and H-1 are known to have effects on
sleep and sleep maintenance.Adrenergic antagonists may have effects on
autonomic dysfunction.The accumulation of biologically active nCBP
without N⫹-glucuronidation may affect responses to CBP therapy in a
chronic bedtime dosing regimen.
12
12
References
(1) Moldofsky H et al, (2011) J Rheum 38: 2653–2663, (2) Wang R et al,
(1996) Drug Metab Dispos 24: 786–791, (3) Hucker HB, et al, (1978) Drug Metab
Dispos. 6:659-72 (4) Hucker HB, et al (1977) J Clin Pharmacol. 17:719-27, (5)
Wong EC et al, (1995) J Anal Toxicol. 19:218-24, (6) Kobayashi H et al, (1996) Eur
J Pharm 311: 29–35, (7) Honda M et al, (2003) Eur J Pharm 458: 91–99, (8) Barnes
C et al, (1980) Neuropharm 19: 221–224, (9) Commissiong JW, et al. (1981), Can
J Physiol Pharmacol. 59:37–44.
Disclosure: B. Daugherty, Tonix Pharmaceuticals Holding Corp., 3; L. Gershell,
Tonix Pharmaceuticals Holding Corp., 3; S. Lederman, Tonix Pharmaceuticals
Holding Corp., 1, Tonix Pharmaceuticals Holding Corp., 6.
961
Cerebral Grey and White Matter Changes in Fibromyalgia Depend On
Patients’ Age. Marta Ceko, Mary-Ann Fitzcharles, M. Catherine Bushnell
and Petra Schweinhardt. McGill University, Montreal, QC
Background/Purpose: Fibromyalgia (FM) patients show accelerated agerelated decrease of grey matter (GM). Similarly, brain imaging studies in other
chronic pain populations suggest interaction between age and GM changes. We
investigated the relationship between age and GM alterations in FM patients
categorized according to age.
Methods: This female study cohort comprised 29 FM patients and 29
controls matched for handedness, education, physical activity, and socioeconomic
status. The sample was split at median age (50 yrs) into younger and older groups
[mean age (SD)], FM vs. controls 42.4 (5.9), vs. 43.1 (5.3), p⫽0.7, and 54.9 (2.8)
vs.55.7 (3.7), p⫽0.5. FM age groups were similar for disease duration, pain
intensity, and medication use.All subjects underwent magnetic resonance imaging
(MRI) in a 3T Siemens Trio scanner. T1-weighted images were obtained for GM
analysis and diffusion-weighted images for interrogation of white matter.GM was
analyzed using voxel-based morphometry (VBM)(SPM8, Wellcome Trust for
Neuroimaging, London, UK), as well as cortical thickness analysis [CIVET 1.9.9.
and Surfstat (MNI, Montreal, Canada)]. Diffusion data were analysed with FSL
(FMRIB, Oxford, UK). For all analyses, voxel-wise differences between groups
were examined using independent sample t-tests controling for age.
Results: The GM in the medial prefrontal cortex (MPFC), left superior frontal
gyrus (SFG), and premotor cortex (PMC) was reduced in FM patients compared
to controls.Total GM was negatively correlated with age in FM (p⫽0.009), but
not in controls (p⫽0.6). Similar relationships with age were observed for the
clusters in MPFC (FM p⫽0.02, controls p⫽0.9) and SFG (FM p⫽0.02, controls
p⫽0.4). Older FM patients compared to controls showed pronounced GM
decreases:patients had less GM in the MPFC/anterior cingulate cortex, right
PMC, left inferior frontal gyrus (IFG), right posterior cingulate cortex, and right
temporo-occipital gyrus. There were no regions where older FM patients had
more grey matter. White matter adjacent to the posterior cingulate showed
decreased fractional anisotropy (FA) in older FM patients. In contrast, younger
FM patients showed exclusively grey matter increases compared to matched
controls in the left putamen/insula, right putamen/globus pallidum, and IFG, with
no region showing decreased GM. White matter adjacent to the left putamen
showed increased FA.
Conclusion: FM-related brain changes depend on age with findings driven
predominantly by older, postmenopausal patients. Younger, premenopausal
patients showed regions of increased GM compared to age-matched controls, in
line with previous findings in younger pain patients (Schweinhardt et al., 2008).
Furthermore, GM alterations were partly paralleled by alterations of the adjacent
white matter, with integrity compromised in older and increased in younger FM
patients respectively.These findings highlight the interaction between age and
cerebral changes in chronic pain states.
Schweinhardt P, Kuchinad A, Pukall CF, Bushnell MC (2008) Increased gray
matter density in young women with chronic vulvar pain. Pain 140:411–419.
Disclosure: M. Ceko, None; M. A. Fitzcharles, Pfizer Inc, Lilly, Purdue, Valeant, 5;
M. C. Bushnell, None; P. Schweinhardt, None.
962
Pain, Sleep Disturbance, and Depression Mediate the Association Between Body Mass Index and Fatigue in Fibromyalgia. Mary O. Whipple1,
Loren L. Toussaint2, Daniel J. Clauw3, David A. Williams4, Terry H. Oh1,
Jeffrey M. Thompson1, Connie A. Luedtke1 and Ann Vincent1. 1Mayo
Clinic, Rochester, MN, 2Luther College, Decorah, IA, 3University of Michigan, Ann Arbor, MI, 4Univ of MI Hlth System-Lobby M, Ann Arbor, MI
Background/Purpose: Previous research and clinical observation suggest
that patients with chronic disease who are obese report significant fatigue. Our
objective was to explore similar relationships in patients with fibromyalgia and the
extent to which pain, sleep disturbance, and depression mediated this relationship.
Methods: 3917 patients who consented to be part of a fibromyalgia registry
were included in this analysis. Registry measures included demographics, body
mass index (BMI), the modified 2010 American College of Rheumatology Fibromyalgia Survey Criteria, and selected items from the Multidimensional
Assessment of Fatigue. Data were analyzed using the INDIRECT macro for
SPSS which allows multiple mediator models to be specified. All analyses controlled for age and sex. INDIRECT provides unstandardized regression coefficients (reported below as “B”) which are the preferred metric in mediation models.
Results: BMI was positively associated with fatigue (B ⫽.03, p ⬍.0001).
BMI was also positively associated with pain (B ⫽.06, p ⬍.0001), sleep
S416
disturbance (B ⫽.004, p ⬍.05), and depression (B ⫽.003, p ⬍.01). After
controlling for pain, sleep disturbance, and depression, the relationship between
BMI and fatigue (B ⫽ 02, p ⬍.0001) was reduced by over 33% (.02/.03). In spite
of this, pain, sleep disturbance, and depression remained statistically significant
(all p’s ⬍.0001). Hence, we examined the partial mediating effects of these
variables.Results indicated that pain, sleep disturbance, and depression combined
mediate the association between BMI and fatigue (B ⫽.01, p ⬍.05). Additionally,
pain (B ⫽.01, p ⬍.05), sleep disturbance (B ⫽.01, p ⬍.05), and depression (B
⫽.002, p ⬍.05) also had unique indirect effects on fatigue.
Conclusion: Statistically significant total and direct effects were present for
the association between BMI and fatigue in patients with fibromyalgia.Hence, the
association between BMI and fatigue was only partially explained by pain, sleep
disturbance, and depression. While these data provide insight into a potential
relationship between obesity and fatigue and possible mechanisms, these are
cross-sectional results and do not offer insight into causality. These types of
analyses should also be examined through longitudinal research.
963
Efficacy of Long-Term Milnacipran Treatment in Patients Meeting Different Thresholds of Clinically Relevant Pain Relief: Subgroup Analysis of a
Double-Blind, Placebo-Controlled Discontinuation Study. Daniel J. Clauw1,
Philip Mease2, Robert H. Palmer3, Joel M. Trugman3 and Yimin Ma3. 1University of Michigan, Ann Arbor, MI, 2Swedish Medical Center and University of
Washington, Seattle, WA, 3Forest Research Institute, Jersey City, NJ
Background/Purpose: Patients with fibromyalgia (FM) who received up to
3.25 years of milnacipran (MLN) in a flexible-dose (ⱕ200 mg/d) open-label (OL)
study were eligible to continue into this randomized, double-blind (DB), placebo
(PBO)-controlled discontinuation study, which demonstrated loss of therapeutic
effect after withdrawal of long-term MLN treatment in patients who had achieved
ⱖ50% pain improvement. The present analysis was conducted to determine
whether patients from this study who met lower thresholds of pain improvement
also experienced loss of therapeutic effect after discontinuing long-term MLN
treatment.
Methods: After 4 weeks (OL) of continuing MLN treatment at the dose
received in the prior long-term study, patients were evaluated for pain response
and randomized (2:1) to continue MLN or discontinue treatment (ie, switch to
PBO) for the 12-week DB withdrawal period. In patients who had received MLN
ⱖ100 mg/d, 3 subgroups were identified based on percent of pain reduction from
pre-MLN exposure: 1) ⱖ50%, n⫽150; 2) 30 to ⬍50%, n⫽61; and 3) ⬍30%,
n⫽110. Efficacy assessments included visual analog scale pain (VAS, 0–100
mm), SF-36 Physical Component Summary (SF-36 PCS), Fibromyalgia Impact
Questionnaire Revised (FIQR), and Beck Depression Inventory (BDI).
Results: In both subgroups of patients with clinically meaningful pain relief
(ⱖ50% and 30 to ⬍50% subgroups), mean worsening of VAS pain scores from
randomization to end of the DB withdrawal period was significantly greater
(P⬍.05) in patients switched to PBO (ⱖ50%, ⫹17.7 mm; 30% to ⬍50%, ⫹8.5
mm) than in patients continuing MLN (ⱖ50%, ⫹8.3 mm; 30% to ⬍50%, ⫺0.5
mm). The absolute difference between treatment arms was similar in both
subgroups (ⱖ50%, ⫺9.4 mm; 30 to ⬍50%, ⫺9.0 mm), as was the percentage of
lost treatment effect after withdrawal (ⱖ50%, 37.7%; 30 to ⬍50%, 31.2%).
Patients with ⱖ50% pain response also experienced notable worsening in SF-36
PCS and FIQR total scores after treatment withdrawal (P⬍.01, MLN vs PBO;
both measures). In the subgroup with ⬍30% pain improvement, no worsening in
pain was observed in either treatment arm at endpoint (PBO, ⫺1.1 mm; MLN,
⫺5.3 mm; P⫽.14). However, patients in this subgroup experienced significant
worsening in FIQR scores after withdrawal from MLN relative to those who
continued treatment (P⬍.001). Additionally, patients in this subgroup who were
withdrawn from MLN had worsened SF-36 PCS and BDI scores while patients
continuing MLN experienced no worsening in these domains.
Conclusion: Significant worsening in pain after drug withdrawal was found
in both subgroups of FM patients that had shown clinically meaningful responses
to long-term MLN therapy (ⱖ50%, 30 to ⬍50% pain improvement), suggesting
that the traditional ⱖ30% pain responder cutoff may be adequate to demonstrate
efficacy in randomized withdrawal studies. Patients with ⬍30% pain response did
not experience worsening in pain following withdrawal, but did experience
worsening in other symptoms, suggesting that these patients may have received
long-term benefit from milnacipran treatment for some FM symptom domains
despite only modest improvements in pain.
964
High-Energy Extracorporeal Shock Wave Therapy Is Effective for
Treating Chronic Calcific Tendonitis of the Shoulder: A Meta-Analysis.
Nina E. Flavin, Raveendhara R. Bannuru, William F. Harvey and Timothy E.
McAlindon. Tufts Medical Center, Boston, MA
Background/Purpose: Calcific tendonitis (CT) and noncalcific tendonitis
(NCT) of the shoulder is a common cause of shoulder pain and can be
unresponsive to conventional therapies. Based on several randomized controlled
studies (RCTs), extracorporeal shock wave therapy (ESWT) has been considered
an effective alternative treatment. We performed an updated meta-analysis using
all available data to analyze the efficacy of ESWT on CT and NCT.
Methods: We searched Medline, Cochrane database, and Google Scholar
from inception to May 2012 for human RCTs comparing ESWT versus placebo
for shoulder pain due to CT or NCT. We hand searched review articles,
manuscripts, and medical journal supplements for additional references. Inclusion
criteria were outcome measures of pain (VAS score; low score ⫽ less pain),
functional assessment (Constant score; high score ⫽ better function), and resolution of calcifications (for CT trials). Two reviewers independently determined
eligibility, assessed the quality of each trial, and extracted means and variances for
these outcome measures. We computed effect sizes for mean change from baseline to 6 months or 3 months if not reported, using Hedges’ g statistic. Effect sizes
were pooled using random effects model. We assessed heterogeneity and performed sensitivity analyses removing the outlier trials. Subgroup analyses for CT
and NCT, and high energy (HE) and low energy (LE) trials were also performed.
Results: Fifteen trials met inclusion criteria; 11 for CT, 4 for NCT. Overall
there were 1221 participants with mean age of 51 years (range 46–56). The
proportion of women was 56% (range 39%–76%). Among all trials, the effect
size (ES) for VAS pain favored HE (⫺2.17; 95%CI [⫺2.85, ⫺1.49]; I2 51%,
p⫽0.15) and LE showed no effect (⫺1.15; [⫺2.63, 0.32]; I2 96%, p⫽0.00) and
the ES for Constant score favored HE (1.77; [1.41, 2.14]; I2 29%, p⫽0.24) and
LE (0.53; [0.16, 0.89]; I2 28%, p⫽0.24). In CT trials, any level of ESWT
improved VAS scores (⫺2.18; [⫺3.55, ⫺0.8]; I2 95%, p⫽0.00) and Constant
scores (1.39, [0.81, 1.97]; I2 84%, p⫽0.00). In NCT trials, any level of ESWT had
no effect on VAS scores (⫺0.15; [⫺0.57, 0.27]; I2 0%, p⫽0.35) or Constant
scores (0.65; [⫺0.51, 1.82], I2 75%, p⫽0.04). Among CT, effect sizes for VAS,
Constant scores and resolution of calcifications favored HE over LE (VAS:
⫺0.57; [⫺1.10,⫺0.03]; I2 74%, p⫽0.01; Constant: 0.57; [0.28, 0.87]; I2 56%,
p⫽0.03; Resolution of calcifications: 3.95; [1.55, 10.03]; I2 70%, p ⬍0.01).
Sensitivity analysis removing outlier trials yielded comparable results. The overall
trial quality was moderate.
Table 1. Characteristics of included studies
Study
Age (Mean,
Years)
Female
(%)
Treatment 1
Treatment 2
N
0.28 mJ/mm2, 1500 pulses,
1 dose
0.3 mJ/mm2, 2000 pulses,
1 dose
0.28 mJ/mm2, 1200 pulses,
4 doses weekly
0.32 mJ/mm2, 1500 pulses,
2 doses, 2 weeks apart
0.42 mJ/mm2, 2000 pulses,
2 doses, 3 weeks apart
0.44 mJ/mm2, 1500 pulses,
up to 5 doses, 6 weeks
apart
0.28 mJ/mm2, 2000 pulses,
2 doses, 2 weeks apart
100
48
56
80
n/a
n/a
0.55 mJ/mm2, 1000 pulses,
2 doses, 2 weeks apart
0.3 mJ/mm2, 3200 pulses,
1 dose
0.06 mJ/mm2, 1500 pulses,
1 dose
0.1 mJ/mm2, 2000 pulses,
1 dose
0 mJ/mm2, 1200 pulses, 4
doses weekly
0.08 mJ/mm2, 6000 pulses,
2 doses, 2 weeks apart
0.23 mJ/mm2, 2000 pulses,
2 doses, 3 weeks apart
0.15 mJ/mm2, 1500 pulses,
up to 5 doses, 6 weeks
apart
⬍0.07 mJ/mm2, 2000
pulses, 2 doses, 2 weeks
apart
0.1 mJ/mm2, 25 pulses, 4
doses weekly
0.02–0.06 mJ/mm2, 2500
pulses, 2 doses, 2 weeks
apart
0 mJ/mm2, 0 pulses, 2
doses 2 weeks apart
0.2 mJ/mm2, 1600 pulses,
2 doses, weekly
Noncalcific Tendonitis
Schmitt, 2001‡
0.11 mJ/mm2, 2000 pulses,
3 doses weekly
Speed, 2002‡
0.12 mJ/mm2, 1500 pulses,
3 doses, 4 weeks apart
Schofer, 2009
0.35 mJ/mm2, 2000 pulses,
3 doses weekly
Galasso, 2012‡
0.068 mJ/mm2, 3000
pulses, 2 doses weekly
0 mJ/mm2, 2000 pulses, 3
doses weekly
0.04 mJ/mm2, 1500 pulses,
3 doses, 4 weeks apart
0.11 mJ/mm2, 2000 pulses,
3 doses weekly
0 mJ/mm2, 3000 pulses, 2
doses weekly
Calcific Tendonitis
Rompe, 1998
Loew, 1999*
Cosentino, 2003
Gerdesmeyer, 2003*
Perlick, 2003
Peters, 2004*
Pleiner, 2004
Cacchio, 2006 ‡
Albert, 2007
Hsu, 2008
Farr, 2011
0.1 mJ/mm2, 2500 pulses,
4 doses weekly
0.45 mJ/mm2, 2500 pulses,
2 doses, 2 weeks apart
70
52
61
144
50
60
80
48
55
90
52
61
43
52
72
90
56
39
80
47
76
46
56
51
30
49
47
39
52
50
74
52
58
40
53
53
20
51
45
*Trial also included placebo group: Energy level 0 mJ/mm2, pulses and dosing equivalent to treatment 1 group.
‡Low Energy: ⱕ 0.27 mJ/mm2
Conclusion: High energy shock wave therapy is effective for improving
pain and shoulder function in patients with chronic calcific shoulder tendonitis, and can result in complete resolution of calcifications. Limitations include
S417
Monday, November 12
Disclosure: M. O. Whipple, None; L. L. Toussaint, None; D. J. Clauw, None; D. A.
Williams, None; T. H. Oh, None; J. M. Thompson, None; C. A. Luedtke, None; A.
Vincent, None.
Disclosure: D. J. Clauw, Forest Laboratories, 5, Forest Laboratories, 2; P. Mease, Forest
Laboratories, 2, Forest Laboratories, 5, Forest Laboratories, 8; R. H. Palmer, Forest
Laboratories, 3; J. M. Trugman, Forest Laboratories, 3; Y. Ma, Forest Laboratories, 3.
the heterogeneous nature of the included studies. Despite this, ESWT may be
an underutilized therapy for a condition that is difficult to manage otherwise.
Disclosure: N. E. Flavin, None; R. R. Bannuru, None; W. F. Harvey, None; T. E.
McAlindon, None.
965
Monday, November 12
Increased Number of Painful Body Sites Is Associated with Worse Pain
and Disability-Associated Outcomes Among Returning Operations Enduring Freedom/Operation Iraqi Freedom Service Members. Dennis C.
Ang1, Jingwei Wu2, Samantha Outcalt2, Zhangsheng Yu2 and Matthew Bair2.
1
Indiana University, Indianapolis, IN, 2Indiana University School of Medicine
Background/Purpose: Chronic pain is a critical health problem among
Operations Enduring Freedom/Operation Iraqi Freedom service members. The
deleterious impact of chronic pain on quality of life and function are well
described in the literature. However, little is known about the relationship between
the number of chronically painful body sites and pain severity and disabilityassociated outcomes. In this secondary data analysis of a randomized clinical trial
of a stepped-care intervention for OEF/OIF veterans with chronic musculoskeletal
pain, we evaluated the association between the number of chronically painful
body sites with long term pain-related outcomes.
Methods: We analyzed 222 subjects (92% of the original cohort) with
available data at baseline and at the last follow-up visit (i.e., month 9). Consistent
with the 2010 ACR criteria for fibromyalgia*, we dichotomized the number of
chronically painful body sites (primary independent variable) as ⱖ3 (yes or
no).We measured baseline to month 9 changes on our two primary outcomes: 1)
pain intensity (as measured by Graded Chronic Pain Scale/GCPS), and 2)
pain-related disability (as measured by Brief Pain Interference (BPI). Secondary
outcomes included changes in SF-36 Physical Component Summary (SF-36
PCS), depression (PHQ-9) and anxiety (GAD-7) measures. We used multiple
linear regression analyses to determine the relationships of the number of painful
body sites with the outcome measures.
Results: Characteristics of the 222 subjects at study entry: mean age
(SD)⫽37.3 (10.2) years; male⫽88%; whites⫽ 78%; married⫽57%; # comorbidity⫽1.0 (1.0); GCPS pain intensity⫽65.6 (13.7); BPI pain interference⫽5.3
(2.2); SF-36 PCS⫽37.6 (7.2); PHQ-9⫽10.8 (5.8); GAD-7⫽8.5 (5.2); # of
pain-related medications⫽1.7 (1.2); # of physical symptoms⫽2.0 (1.8); and 69%
(n⫽154) had ⱖ 3 painful body sites.
Table 1.
Baseline Predictors
Number of painful sites
ⱖ3 (reference group: ⬍3)
Treatment group
Stepped care (vs. usual care)
Number of comorbidity
Response variable at study entry
OUTCOMES Parameter estimate
(standard error/SE), p values
Improvement in Improvement in
GCPS pain
BPI pain
Improvement in
intensity
interference
SF-36 PCS
⫺4.9 (2.4),
p⫽0.0396
⫺1.0 (0.3),
p⫽0.0016
4.2 (1.0),
p⬍0.0001
6.9 (2.2),
p⫽0.0017
⫺2.2 (1.2),
p⫽0.0636
0.2 (0.1),
p⫽0.0172
0.9 (0.3),
p⫽0.0034
⫺0.3 (0.2),
p⫽0.0911
0.4 (0.1),
p⬍0.0001
⫺1.9 (0.9),
p⫽0.0362
⫺0.04 (0.5),
p⫽0.9364
0.3 (0.1),
p⬍0.0001
Background/Purpose: Approximately one-quarter of the UK population uses complementary or alternative treatments (CAM) each year, and
this is higher among persons with pain, or musculoskeletal conditions
such as arthritis.A recent review has summarised the evidence relating to
the use of CAM medicines (anything taken orally or applied topically) in
the treatment of fibromyalgia.The aim of the current study was to review
the evidence relating to CAM therapies (treatments delivered by a
practitioner).
Methods: Randomised controlled trials (RCTs), published in English
up to May 2011, were identified using systematic searches of bibliographic databases and searching of reference lists.Data were extracted by
a single reviewer, and checked by a second, and the Jadad (J) score was
used to assess methodological quality of the RCTs (0⫽poor; 5⫽high
quality).All outcomes were considered but with a focus on patient global
assessment and pain reporting.
Results: From 525 articles, 25 RCTs were identified, examining 14
therapies.The effectiveness of biofeedback has been tested in five RCTs
(median J ⫽ 3), ranging from 30 to 143 patients.One RCT that compared
biofeedback against anti-depression medication reported positive findings
in terms of pain and fatigue.However, four RCTs comparing biofeedback
with sham biofeedback, usual care or fitness training found no significant
difference in the same outcomes.Three RCTs examined progressive
muscle relaxation (median J ⫽ 3) ranging from 24 to 45 patients.In two
RCTs, no significant benefit was observed, compared to hydro-galvanic
bath therapy or hypnotherapy, and one RCT demonstrated progressive
muscle relaxation to be inferior to massage therapy in terms of pain,
stiffness, fatigue and a number of other outcomes.
Aromatherapy, chiropractic, healing therapy, hypnotherapy, imagery
and qigong were each examined in two RCTs (median J ⫽ 4.5; 2.5; 3.5;
1.5; 2.0 and 3.5 respectively).With the exception of hypnotherapy, there
was generally no improvement in outcome in the intervention group,
compared to various control treatments.In hypnotherapy, in one RCT
patients receiving hypnotherapy reported significantly greater improvements in pain, fatigue, sleep and general health compared to those
receiving in physical therapy; and in the second RCT, patients receiving
hypnotherapy with analgesia suggestions reported improvements in pain
intensity compared to those receiving hypnotherapy with relaxation
suggestions, or relaxation alone.
Finally, one RCT each examined the effectiveness of autogenic
training (J⫽3), craniosacral therapy (J⫽5), music therapy (J⫽3), static
magnet therapy (J⫽4), meditation (J⫽5) and Tai-chi (J⫽4).Only in Tai
chi was there evidence of positive effect of treatment: patients in this
group reported significantly greater improvements in health, disease
impact, mental health and sleep compared to a control group who received
wellness education and stretching exercises.
Conclusion: The major limitation in reviewing the evidence for
practitioner-based CAM therapies in the treatment of FM is the paucity of
RCTs.The available studies provide no consistent evidence that these
treatments are effective, but the lack of RCTs means that it is hard to reach
firm conclusions.
Disclosure: G. T. Jones, None; P. Paudyal, None; G. J. Macfarlane, None;
967
Age, gender, race, and marital status were included on each of the multivariate models
but were all non-significant (p⬎0.10)
Neither the number of painful sites nor the treatment group assignment was significantly
associated with changes in PHQ-depression and GAD-7 anxiety. Only the number of
comorbid medical conditions was associated with changes in depression (estimate (SE)
⫽⫺0.9 (0.4), p⫽0.0184) and anxiety (estimate (SE) ⫽⫺0.7 (0.3), p⫽0.0179).
Conclusion: Compared to veterans with ⬍3 painful body sites, veterans with
ⱖ3 painful body sites improved significantly less during the 9 months of the trial.
Our findings suggest more aggressive treatment interventions are needed in this
population of veterans with multiple pain sites.
Disclosure: D. C. Ang, None; J. Wu, None; S. Outcalt, None; Z. Yu, None; M. Bair,
None.
966
A Systematic Review of Evidence for the Effectiveness of Practitioner-Based
Complementary and Alternative Therapies in the Management of Fibromyalgia. Gareth T. Jones1, Priya Paudyal2, Gary J. Macfarlane1 and the Arthritis
Research UK Working Group on Complementary and3, 1 University of
Aberdeen, Aberdeen, United Kingdom, 2University of Plymouth, Plymouth,
United Kingdom, 3Aberdeen
Haplotypes of GTP Cyclophydrolase Gene Polymorphisms Are Protective in the Susceptibility of Fibromyalgia Syndrome. Hwajeong Lee1,
Shin-Seok Lee2, Seong-Kyu Kim3, Jung-Yoon Choe1, Seong-Ho Kim KIM4,
Seong-Su Nah5, Ji Hyun Lee6, Seung-Jae Hong7, Hyun-Sook Kim8, HyeSoon Lee9, Hyun Ah Kim10 and Chung-Il Joung11. 1Catholic University of
Daegu School of Medicine, Daegu, South Korea, 2Chonnam National
University Medical School, Gwangju, South Korea, 3and Autoimmunity
Research Center, Catholic University of Daegu School of Medicine, Daegu,
South Korea, 4Inje University Haeundae Paik Hospital, Busan, South Korea,
5
Soonchunhyang University, College of Medicine, Cheonan, South Korea,
6
Maryknoll Medical Center, Busan, South Korea, 7Kyung Hee University,
Seoul, South Korea, 8Internal Medicine, Chosun University Hospital,
Gwangju, South Korea, 9Hanyang University Guri Hospital, Guri, South
Korea, 10Hallym university sacred heart hospital, Kyunggi, South Korea,
11
Konyang University Medical School, Daejeon, South Korea
Background/Purpose: Guanosine triphosphate cyclohydrolase 1
(GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin,
which is an essential co-factor in nitric oxide (NO) production. Polymorphisms in the GCH1 gene have been implicated in protection against pain
S418
Disclosure: H. Lee, None; S. S. Lee, None; S. K. Kim, None; J. Y. Choe, None;
S. H. K. KIM, None; S. S. Nah, None; J. H. Lee, None; S. J. Hong, None; H. S.
Kim, None; H. S. Lee, None; H. A. Kim, None; C. I. Joung, None.
968
Sympathetic Nervous System Dysfunction in Fibromyalgia and in
Overlapping Central Sensitivity Syndromes. A Systematic Review of
Controlled Studies. Laura Aline Martinez, Tania Mora, Angelica Vargas, Mario Fuentes and Manuel Martinez-Lavin. National Institute of
Cardiology, Mexico City, Mexico
Background/Purpose: Fibromyalgia often coexists and overlaps with
other common painful syndromes such as chronic fatigue, irritable bowel
and interstitial cystitis. Yunus proposed the label “central sensitivity
syndromes” as an umbrella term for these related maladies. Sympathetic
nervous system dysfunction has been reported in these central sensitivity
syndromes raising the possibility that such dysautonomia could be the
common underlying pathogenesis that cluster fibromyalgia with these
interrelated clinical entities.
Our objective: To carry out a systematic review of all published
comparative case-control studies investigating sympathetic nervous system
performance in fibromyalgia, chronic fatigue syndrome, irritable bowel
syndrome and interstitial cystitis.
Methods: PubMed and Embase were accessed using the following key
words: autonomic (OR) sympathetic (AND) fibromyalgia, chronic fatigue
syndrome, irritable bowel syndrome and interstitial cystitis. All entries up
to April 30 2012 were reviewed by three investigators searching for
case-control studies in humans. The Method for Evaluating Research and
Guidelines Evidence (MERGE) adapted to the Scottish Intercollegiate
Guidelines Network (SIGN 50) was used to rank the level of evidence
contained in the selected articles. “Sympathetic predominance” was
defined as statistically significant data suggesting higher sympathetic
activity, decreased parasympathetic activity or both. Reverse definition
applied for “parasympathetic predominance”.
Results: See table. Heart rate variability analysis (36%) was the most
often used method to assess sympathetic system performance. Other less
frequently used methods were: Tilt table testing (9%), sympathetic skin
response (9%) and genetic studies (5%).
Selected articles
Fibromyalgia n ⫽ 58
34.9%
Chronic fatigue n ⫽ 49
29.5%
Irritable bowel n ⫽ 50
30.1%
Overall assessment
MERGE - SIGN 50
Quality
n
%
High
Medium
Low
High
Medium
Low
High
Medium
Low
18
38
2
22
25
2
9
33
7
31.03
65.52
3.45
44.90
51.02
4.08
18.37
67.35
14.29
Participants average
age (years)
43.6
33.4
36.0
Interstitial cystitis
n⫽9
5.4%
High
3
33.33
Medium
Low
5
1
55.56
11.11
49.3
Total ⫽ 166
Source: PubMed only ⫽24.09 %, Embase only ⫽ 21.08 %, both databases ⫽ 54.81%
The overwhelming majority of case-control studies described sympathetic predominance in these painful syndromes (figure). Heart rate variability
analyses and tilt table testing disclosed a clear pattern of sympathetic
dysfunction; basal sympathetic hyperactivity accompanied by sympathetic
hypo-reactivity to stress.
Conclusion: This systematic review suggests that sympathetic nervous system predominance is very common in these overlapping central
sensitivity syndromes. This concordance raises the possibility that these
syndromes may share similar clinical and pathogenic mechanisms.
Disclosure: L. A. Martinez, None; T. Mora, None; A. Vargas, None; M. Fuentes,
None; M. Martinez-Lavin, None.
969
Presence of Small Fiber Neuropathy in a Cohort of Patients with
Fibromyalgia. Todd Levine1, Victoria Lawson2, Aidan Levine1, Kevin V.
Hackshaw3 and David Saperstein1. 1Phoenix Neurological Associates, Phoenix, AZ, 2Ohio State University, Columbus, OH, 3Ohio State Univ/Wm Davis
Res, Columbus, OH
Background/Purpose: The pain associated with fibromyalgia is
classically described as deep, muscular, aching and flu-like; however, a
significant percentage of patients with fibromyalgia also describe neuropathic symptoms. The pain in these patients can be categorized and
burning, tingling or stabbing.These clinical descriptors may raise the
concern for a coexistent neuropathy. Yet, EMG/NCS in fibromyalgia
patients are typically unrevealing. The constellation of neuropathic pain
with normal nerve conduction studies, raises the possibility of a neuropathy confined purely to the small unmyelinated nerve fibers: a small fiber
neuropathy. These small fiber neuropathies can be diagnosed through a
3-mm punch biopsy and may offer insight into the pathogenesis of some
cases of fibromyalgia.
Methods: We retrospectively examined 56 patients referred for
neurological evaluation who met diagnostic criteria for fibromyalgia. The
patients were seen in neuromuscular consultation atthe Ohio State
University or at Phoenix Neurological Associates. Patients were included
if they met either the ACR criteria or the revised criteria of 2010
forfibromyalgia. Patients underwent 3 mm punch biopsies at a proximal
and a distal site of one lower limb.PGP 9.5 immunolabelling was
performed and the epidermal nerve fiber density was counted on 50
micron sections. The patients who were found to have reduced epidermal
nerve fiber density underwent a standard serologic evaluation looking for
identifiable causes for their neuropathy.
Results: 34/56 (61%) of the cases were diagnosed with small fiber
neuropathy on the basis of reduced epidermal nerve fiber density. Of these
34 patients only 5 had evidence for neuropathy on EMG/Nerve conduction
studies. Further, this evidence was subtle enough as to be inconclusive for
diagnosis.24/34, 71%, of the patients with fibromyalgia and small fiber
neuropathy had serologic evidence of an underlying etiology for their
neuropathy that had not been detected prior to identification of the
neuropathy: errors of glucose metabolism (n⫽11), vitamin D deficiency
(n⫽5), elevated ESR (n⫽2), B6 deficiency (n⫽1), B12 deficiency (n⫽1),
Sjogrens (n⫽2), elevated ANA (n⫽1), mutation in alpha galactosidase
(Fabry’s Disease) (n⫽1).
Conclusion: In this retrospective series, 61% of patients with fibromyalgia and neuropathic pain were found to have small fiber neuropathy based on
S419
Monday, November 12
sensitivity. Our study was to determine whether single nucleotide polymorphisms (SNPs) in the GCH1 gene affect susceptibility and/or pain sensitivity
in fibromyalgia syndrome (FMS).
Methods: A total of 409 FMS patients and 422 controls were enrolled.
The alleles and genotypes at four positions, rs3783641(T⬎A), rs841(C⬎T),
rs752688(C⬎T), and rs4411417(T⬎C), in the GCH1 gene were analyzed.
The associations of the GCH1 SNPs with susceptibility and clinical parameters in FMS patients were assessed.
Results: The frequencies of alleles and genotypes of the four SNPs did
not differ between FMS patients and healthy controls. Among 13 constructed
haplotypes, we further examined four (CCTT, TTCT, TTCA, and CCTA)
with ⬎1% frequency in both FMS and controls. No associations of GCH1
polymorphisms with FMS-related activity or severity indexes were found,
although the number and total score of tender points in FMS patients differed
among the four haplotypes (p ⫽ 0.03 and p ⫽ 0.01, respectively). The CCTA
haplotype of GCH1 was associated with significantly lower pain sensitivity
and occurred less frequently than the CCTT haplotype in FMS patients
(OR ⫽ 0.45; 95% CI, 0.21–0.96).
Conclusion: This study provides evidence that certain GCH1 haplotypes
may be protective against susceptibility and pain sensitivity in FMS. Our data
also suggest that NO is responsible for pain sensitivity in the pathogenesis of
FMS.
reduced epidermal nerve fiber density on a standard 3-mm punch biopsy. In
71% of these patients, a diagnosis was made based on serologic evaluation.
These results suggest that testing for small fiber neuropathy in patients with
fibromyalgiawill allow for earlier diagnosis of underlying conditions such as
glucose dysmetabolism, toxicities, connective tissue disorders, and others.
Further, identification of patients who have both fibromyalgia and small fiber
neuropathy may suggest earlier therapeutic trials of neuropathic agents in
treating the pain in these patients. It is unclear whether our patients had two
separate disorders or whether patients had small fiber neuropathy and not
fibromyalgia as the cause of their symptoms. A larger, prospective study is
needed to answer this question.
Monday, November 12
Disclosure: T. Levine, Dr Levine has a financial interest in Corinthian Reference
Labs. A lab that performs small fiber testing, 4; V. Lawson, None; A. Levine, None;
K. V. Hackshaw, None; D. Saperstein, Corinthian Reference Labs, 4.
ACR/ARHP Poster Session B
Genetics and Genomics of Rheumatic Diseases
Monday, November 12, 2012, 9:00 AM–6:00 PM
970
Genetic Interactions Between SNP Variants in C3 Receptor Subunits in Patients with SLE. Jeffrey C. Edberg1, Christine W. Duarte2,
Amit Patki2, Elizabeth E. Brown MPH2, Kenneth M. Kaufman3, Jennifer A. Kelly4, Mary E. Comeau5, Marta E. Alarcon-Riquelme on behalf of BIOLUPUS and GENLES6. Sang-Cheol Bae7, Lindsey A.
Criswell8, Barry I. Freedman9, Patrick M. Gaffney10, Gary S. Gilkeson11,
Chaim O. Jacob12, Judith A. James13, Diane L. Kamen14, Kathy Moser
Sivils4, Timothy B. Niewold15, Robert H. Scofield16, Betty P. Tsao17,
Timothy J. Vyse18, John B. Harley19, Carl D. Langefeld20, Hemant
Tiwari2 and Robert P. Kimberly2, 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 2University of Alabama at Birmingham, Birmingham, AL, 3Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, 4Oklahoma Medical Research Foundation, Oklahoma City, OK, 5Wake Forest University Health Sciences,
Winston-Salem, NC, 6Oklahoma Medical Research Foundation, Center
for Genomics and Oncological Research Pfizer-University of GranadaJunta de Andalucia, Oklahoma City, OK, 7Hanyang University Hospital
for Rheumatic Disease, Clinical Research Center for Rheumatoid Arthritis
(CRCRA), Seoul, 8University of California San Francisco, San Francisco, CA, 9Department of Internal Medicine, Wake Forest School of
Medicine, Winston-Salem, NC, 10Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK,
11
Medical University of South Carolina, Charleston, SC, 12Department of
Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 13Oklahoma Medical Research Foundation
and Oklahoma University Health Sciences Center, Oklahoma City, OK,
14
Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Charleston, SC, 15University of Chicago, Chicago, IL,
16
Arthritis & Clinical Immunology Program, Oklahoma Medical Research
Foundation; Department of Medicine, University of Oklahoma Health
Sciences Center; US Department of Veterans Affairs Medical Center,
Oklahoma City, OK, 17UCLA School of Medicine, Los Angeles, CA,
18
Divisions of Genetics and Molecular Medicine and Immunology, King’s
College London, London, United Kingdom, 19Cincinnati Children’s
Hospital Medical Center; US Department of Veterans Affairs Medical
Center, Cincinnati, OH, 20Wake Forest School of Medicine, WinstonSalem, NC
Background/Purpose: Genome-wide and candidate gene studies
have supported a role for genes involved in immune complex processing
as being important contributors to development of SLE.The association
of ITGAM variants and SLE highlights the importance of complement
and complement receptors in the SLE diathesis.We hypothesized that
there may also be statistical interactions between variants in genes that
encode proteins in the complement system.We have developed a genebased analysis strategy and present data that support a role for genetic
interactions between variants in genes involved in the complement
system.
Methods: A newly developed variation of the Rank Truncated Product
(RTP) statistic was used to assess the combined genetic contribution of
loci involved in complement component 3 (C3), C3 activation (C2, C3,
C4, CFH, CRP, MBL2), and C3 recognition (CR1, CR2, CR3 (ITGAM/
ITGB2), CR4 (ITGAX/ITGB2)).The significance of the RTP statistic for
each gene pair was assessed using a parametric bootstrap procedure.The
study population included 16,105 unrelated SLE affecteds and controls
from four different ancestry backgrounds (European (EA), African (AA),
Hispanic (Hisp), Asian). All participants were of self-reported sex and
race/ethnicity. Affecteds met 1997 American College of Rheumatology
revised criteria for the classification of SLE.347 SNPs in these loci were
genotyped on an Illumina iSelect custom array as part of the Large Lupus
Association Study 2 (LLAS2).
Results: We identify new SNP associations across multiple race/
ethnicities in the C2 locus with SLE (p⬍10⫺11/ ⬍10⫺7, OR⫽1.8/1.7 in
EA/AA) and confirm trans-racial associations of ITGAM and SLE (P⬍10⫺27/
10⫺11/10⫺12OR⫽1.7/1.6/2.1 in EA/AA/Hisp respectively).
We hypothesized that there are genetic interactions between variants in
genes encoding proteins in the C3 pathway that are known to functionally
and/or physically interact.Indeed, significant gene-by-gene genetic interactions were identified between receptor-ligand, between C3 and complement
regulators and between C3 receptor loci.Specific interactions included C3ITGAM (p⬍0.001 in AA), C3-ITGB2 (p⫽0.002 in Hisp), C3-CRP
(p⫽0.003 in AA), C3-CFH (p⫽0.009 in AA), ITGAM-ITGB2 ( p⬍0.001 in
Hisp) and ITGAX-ITGB2 (with trans-racial association in both Hisp and EA,
p⫽0.02/0.045).
Conclusion: We demonstrate significant and replicated genetic association of genes in the C3 pathway with SLE.These associations extend
beyond the ITGAM locus to include other C3 receptor genes and
regulators of C3 activation.The elucidation of genetic interactions between genes in this pathway demonstrates that the contribution of variants
in the C3 pathway act both independently and jointly.
Disclosure: J. C. Edberg, None; C. W. Duarte, None; A. Patki, None; E. E.
Brown MPH, None; K. M. Kaufman, None; J. A. Kelly, None; M. E. Comeau,
None; M. E. Alarcon-Riquelme on behalf of BIOLUPUS and GENLES, None;
S. C. Bae, None; L. A. Criswell, None; B. I. Freedman, None; P. M. Gaffney,
None; G. S. Gilkeson, None; C. O. Jacob, None; J. A. James, None; D. L. Kamen,
None; K. Moser Sivils, None; T. B. Niewold, None; R. H. Scofield, None; B. P.
Tsao, None; T. J. Vyse, None; J. B. Harley, ERBA Diagnostics, 7, ERBA
Diagnostics, 5, ERBA DIagnostics, 1; C. D. Langefeld, None; H. Tiwari, None;
R. P. Kimberly, None.
971
Association of adam33 Polymorphisms with Systemic Lupus Erythematosus. Seung Cheol Shim, Mi Kyoung Lim, Donghyuk Sheen and
Hyo Park. Eulji University Hospital, Daejeon, South Korea
Background/Purpose: A Disintegrin and Metalloprotease 33
(ADAM33) is a member of a family of genes that encode membraneanchored proteins with a disintegrin and a metalloprotease domain,
and is located on chromosome 20p13. Recently, the polymorphisms in
Adam33 have been found to be associated with asthma. Among the
rheumatic diseases, systemic lupus erythematosus (SLE) is a prototypic
Th2-mediated autoimmune disease like allergic disorders. To assess
whether genetic functional variants of ADAM33 are associated with
susceptibility to SLE or development of specific phenotypes in patients
with SLE.
Methods: We have identified 48 SNPs, and nine SNPs were selected
with regard to the LD pattern. Genotyping for g.10918G⬎C,
g.12433T⬎C and g.13506C⬎G in the ADAM33 gene was conducted
with PCR-RFLP methods, and genotyping for g.-330C⬎T, g.517 A⬎G,
g.8227 G⬎A, g.9511 G⬎T, g.12462 C⬎T, g.12988 C⬎A polymorphisms
was performed by single-base extension (SBE), using the ABI PrismR
SNaPshot™ Multiplex kit (Applied Biosystems). We conducted an association study for ADAM33 polymorphisms in 190 SLE patients, 469
healthy controls, and 390 rheumatoid arthritis (RA) patients as a disease control. Haplotype analyses of related variants were performed as
well.
Results: Significant associations of ADAM33 polymorphisms with
susceptibility to SLE were found at g.8227 G⬎A, g.12988 C⬎A, and
g.13506 C⬎G (P value were all below 0.001) (Table 1). Polymorphisms
at g.8227 G⬎A was associated with the ANA titers among SLE patients
(P ⫽ 0.012). In addition, we analysed the haplotype, and found a positive
association of susceptibility to SLE with the major haplotype CGCG (P ⫽
3.5E-11) (Table 2). There was no association between ADAM33 polymorphisms and RA as expected.
S420
Table 1. Genotype and allele analyses of the polymorphisms of Adam33 gene in
SLE patients and healthy controls
Positiona
g.-330C⬎T
g.517 A⬎G
g.8227 G⬎A
g.10918 G⬎C
g.12433 T⬎C
g.12462 C⬎T
g.12988 C⬎A
g.13506 C⬎G
Control n
(%)
SLE
n (%)
Odds ratiob
(95% CI)
CC
CT
TT
C
T
AA
AG
GG
A
G
GG
GA
AA
G
A
GG
GT
TT
G
T
GG
GC
CC
G
C
TT
TC
CC
T
C
CC
CT
TT
C
T
CC
CA
AA
C
A
CC
CG
GG
C
G
426 (90.8)
43 (9.2)
0 (0.0)
895 (95.4)
43 (4.6)
165 (38.4)
201 (46.7)
64 (14.9)
531 (61.7)
329 (38.3)
300 (64.1)
168 (35.9)
0 (0.0)
768 (82.1)
168 (17.9)
390 (84.2)
71 (15.4)
2 (0.4)
851 (91.9)
75 (8.1)
275 (59.4)
172 (37.1)
17 (3.7)
722 (77.8)
206 (22.2)
391 (85.2)
66 (14.4)
2 (0.4)
848 (92.4)
70 (7.6)
380 (84.5)
68 (15.1)
2 (0.4)
828 (92.0)
72 (8.0)
327 (70.2)
134 (28.8)
5 (1.0)
788 (84.5)
144 (15.5)
193 (43.3)
207 (46.4)
46 (10.3)
593 (66.5)
299 (33.5)
168 (88.4)
22 (11.6)
0 (0.0)
358 (94.2)
22 (5.8)
62 (32.6)
97 (51.1)
31 (16.3)
221 (58.2)
159 (41.8)
122 (65.2)
59 (31.6)
6 (3.2)
303 (81.0)
71 (19.0)
156 (87.6)
19 (10.7)
3 (1.7)
331 (93.0)
25 (7.0)
98 (61.3)
52 (2.5)
10 (6.2)
248 (77.5)
72 (22.5)
178 (92.7)
13 (6.8)
1 (0.5)
369 (96.1)
15 (3.9)
177 (93.2)
12 (6.3)
1 (0.5)
366 (96.3)
14 (3.7)
170 (92.4)
14 (7.6)
0 (0.0)
354 (96.2)
14 (3.8)
91 (49.5)
48 (26.1)
45 (24.4)
230 (62.5)
138 (37.5)
1.00
1.30 (0.75–2.24)
–
1.00
1.28 (0.75–2.17)
1.00
1.29 (0.88–1.88)
1.29 (0.77–2.17)
1.00
1.16(0.91–1.49)
1.00
0.86(0.60–1.24)
1.00
1.07 (0.79–1.46)
1.00
0.67 (0.39–1.15)
3.75 (0.62–22.66)
1.00
0.86 (0.54–1.37)
1.00
0.85 (0.58–1.25)
1.65 (0.73–3.23)
1.00
1.02(0.75–1.38)
1.00
0.43 (0.23–0.81)
1.10 (0.10–12.19)
1.00
0.49 (0.28–0.87)
1.00
0.38 (0.20–0.72)
1.07 (0.10–11.92)
1.00
0.44 (0.25–0.79)
1.00
0.20 (0.11–0.36)
1.00
0.22(0.12–0.38)
1.00
0.49 (0.33–0.73)
2.08 (1.28–3.36)
1.00
1.19 (0.92–1.53)
P
0.347
0.399
0.392
0.256
>0.0001
0.692
0.093
0.563
0.271
0.938
0.025
0.013
0.009
0.005
>0.0001
Disclosure: C. H. Huang, None; J. Y. Zhan, None; K. J. Yeo, None; J. C. Wei, None;
C. S. Chuang, None; R. H. Wong, None.
>0.0001
>0.0001
0.193
a
Calculated
b
from the translation start site.
Logistic regression analyses were used for calculating OR (95% CI; confidence interval)
Table 2. The haplotype frequencies by Adam33 polymorphisms in both SLE
patients and controls
Haplotype
Ht 1
Ht 2
Ht 3
Ht 4
Ht 5
Ht 6
others
Frequencya
g.-330 g.8227 g.12988 g.13506
C>G G>A
C>A
C>G Control SLE
C
C
C
C
G
C
-
G
G
A
A
G
G
-
C
C
A
C
C
A
-
G
C
G
G
C
G
-
0.482
0.259
0.088
0.057
0.030
0.027
0.057
0.272
0.484
0.014
0.043
0.022
0.003
Chisquare
Pb
43.88
56.53
21.21
0.915
0.517
6.655
-
3.5E-11
5.5E-14
4.1E-6
0.339
0.472
0.010
-
Conclusion: ADAM33 polymorphisms were strongly associated with
susceptibility to SLE and the development of specific clinical manifestations.
Disclosure: S. C. Shim, None; M. K. Lim, None; D. Sheen, None; H. Park, None.
972
Associations of Genetic Polymorphisms of Microrna-146a and Its
Target Interleukin-1-Receptor-Associated Kinase 1 with Ankylosing
Spondylitis. Chun-Huang Huang1, Jia-Yan Zhan1, Kai-Jieh Yeo2, James
C. Wei3, Chih-Shien Chuang1 and Ruey-Hong Wong1. 1Chung Shan
Medical University, Taichung, Taiwan, 2Chung Shan Medical University
Hospital, Taichung, Taiwan, 3Chung Shan Med Univ Hospital, Taichung,
Taiwan
973
New Genetic Risk Loci for the Radiographic Severity of Rheumatoid
Arthritis. Diederik P.C. de Rooy1, Sacha Zhernakova1, Roula Tsonaka2,
Fina Kurreeman1, René E.M. Toes1, Tom W. J. Huizinga1, Jeanine
Houwing-Duistermaat2, Peter K. Gregersen3 and Annette H.M. van der
Helm-van Mil1. 1Rheumatology, Leiden University Medical Center,
Leiden, Netherlands, 2Statistics, Leiden University Medical Center,
Leiden, Netherlands, 3Feinstein Institute Medical Research and North
Shore-Long Island Jewish Health System, Manhasset, NY
Background/Purpose: The severity of joint destruction is highly
variable between Rheumatoid Arthritis (RA) patients; approximately 54%
of this variance is explained by genetic factors. Many of the genetic
factors responsible for the severity of joint destruction are unknown. We
aimed to identify new genetic risk factors by studying genetic susceptibility loci of several auto-immune diseases.
Methods: In the first phase, 646 Dutch RA-patients with yearly X-rays
of hands and feet over 7 years of follow-up were studied. These patients
were genotyped for 148,880 SNPs by Immunochip which contains 186
loci previously associated with autoimmune diseases. Following quality
control, association of SNPs with MAF ⬎0.01 (130,841 SNPS) with
joint destruction was analyzed using a marginal regression model. Correction for multiple testing was done using the Bonferroni correction for
the number of uncorrelated SNPs (threshold p⬍1.1 ⫻ 10⫺6). In the
second phase, 686 North American RA-patients with repeated hands
X-rays over 15 years of follow-up, for which Immunochip genotyping
data were also available, were studied. SNPs that were significantly
associated in phase 1 were selected and evaluated. All X-rays were scored
by the Sharp van der Heijde score (ICC 0.91 and 0.98 for phase 1 and 2
respectively).
Results: In phase 1, 109 SNPs were significantly associated with joint
destruction in Dutch RA-patients (threshold p⬍1.1 ⫻ 10⫺6). Of these, 76
were located in the HLA-region in chromosome 6; since the association of
this region with joint damage is already known, these SNPs were not
analyzed in phase 2. The other 33 non-HLA genetic variants, though
several were in high LD, were studied in the North-American RA-patients.
S421
Monday, November 12
g.9511 G⬎T
Genotype/
Allele
Background/Purpose: Tumor necrosis factor-␣ (TNF-␣) and
interleukin-1 (IL-1) were important mediators of inflammation response in
the development of ankylosing spondylitis (AS). Especially, microRNA
(miR)-146a targets TNF-receptor-associated-factor-6 (TRAF-6) and
interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress nuclear
factor kB (NF-kB) activity and lipopolysaccharide (LPS)-induced inflammatory response. Here, we evaluated the effects of miR-146a rs2910164
G/C, IRAK1 rs3027898 A/C, and IRAK1 rs1059703 T/C genetic polymorphisms on the development of AS and clinical characteristics.
Methods: A total of 450 AS patients and 438 healthy controls were
included, miR-146a genotypes were identified by polymerase chain
reaction-restriction fragment length polymorphism, and IRAK1 genetic
polymorphisms were determined by the Taqman system.
Results: Our results showed that subjects possessing miR-146a
rs2910164 GG genotype had 1.71-fold (95% confidence interval [C.I.] ⫽
1.15–2.56) risk for AS development than those with GC/CC genotypes.
Subjects with IRAK1 rs3027898 A allele (odds ratio [OR] ⫽ 1.54, 95% C.I.
⫽ 1.20–1.99) also had a significantly increased risk of AS than those with C
allele. Further, subjects carrying both of miR-146a rs2910164 GG genotype
and IRAK1 rs3027898 A allele had the highest risk (OR ⫽ 2.63, 95% C.I. ⫽
1.25–5.55) for AS development than those with rs2910164 GC/CC genotypes
and rs3027898 C allele, followed by subjects with rs2910164 GG genotype
and rs3027898 C allele (OR ⫽ 1.75, 95% C.I. ⫽ 1.29–2.37) and subjects with
rs2910164 GC/CC genotypes and rs3027898 A allele (OR ⫽ 1.57, 95% C.I.
⫽ 1.20–2.06). These results were also observed in males, but not in females.
In addition, IRAK1 rs3027898 A/C and IRAK1 rs1059703 T/C polymorphisms were significantly associated with the abnormal erythrocyte sedimentation rate (ESR) level of AS patients, respectively. AS patients with both of
miR-146a rs2910164 GG genotype and IRAK1 rs3027898 A allele had a
6.68-fold (95% C.I. ⫽ 2.83–15.73) risk for uveitis development than patients
without.
Conclusion: MiR-146a rs2910164 G/C and IRAK1 rs3027898 A/C
polymorphisms might be associated with the development of AS, as well
as its clinical manifestations.
Monday, November 12
After correction for the number of number of uncorrelated SNPs (threshold p⬍0.0036), two variants were associated with the severity of joint
destruction. These were rs451066 on chromosome 14 (puncorrected⫽0.002,
MAF⫽0.20)) and rs11908352 on chromosome 20 (puncorrected⫽0.002,
MAF⫽0.21). In the presence of a risk allele of rs451066 and rs11908352
respectively Dutch RA-patients had a 3.7% and 2.7% higher rate of joint
destruction per year, which equals 29% and 20% more joint destruction
over a seven years period.
Conclusion: Two new risk loci for progressive joint destruction in RA
were identified. The region of rs451066 on chromosome 14 has previously
been linked to susceptibility to type-1 diabetes. The other SNP is located
at chromosome 20 and in low LD with rs4810485 (R2 0.062), a variant
that has previously been identified as RA risk locus. Altogether, the
current data indicate that two loci that confer risk to other autoimmune
disease may also affect the severity of RA.
Disclosure: D. P. C. de Rooy, None; S. Zhernakova, None; R. Tsonaka, None; F.
Kurreeman, None; R. E. M. Toes, None; T. W. J. Huizinga, None; J.
Houwing-Duistermaat, None; P. K. Gregersen, None; A. H. M. van der
Helm-van Mil, None.
974
Identification of Susceptibility Loci for Inflammatory Arthritis.
K. J. A. Steel1, Anne Hinks1, John Bowes1, Joanna Cobb1, Edward
Flynn2, Carl D. Langefeld3, Sampath Prahalad4, Johannes Peter Haas5,
John F. Bohnsack6, Stephen Guthery6, Anne Barton1, Susan D. Thompson7 and Wendy Thomson1. 1Arthritis Research UK Epidemiology Unit,
University of Manchester, Manchester, United Kingdom, 2University of
Manchester, Manchester Academy of Health Sciences, Manchester,
United Kingdom, 3Wake Forest School of Medicine, Winston-Salem, NC,
4
Emory Children’s Center, Atlanta, GA, 5Childrens Hospital, Erlangen,
Germany, 6University of Utah, Salt Lake City, 7Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH
Background/Purpose: One of the principal findings of genome wide
association studies in autoimmune diseases has been the substantial
overlap of genetic susceptibility loci identified. This has underpinned
fine mapping initiatives such as the Immunochip (IC) project in which
custom chips were designed to fine-map regions of associations common
to a number of autoimmune diseases. Samples from patients with
rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic
arthritis (PsA) have been genotyped using IC; given that all are types of
inflammatory arthritis (IA) which exhibit common pathology and some
overlap of associated loci, the data emerging from IC provides a unique
opportunity to identify novel overlapping regions and determine whether
the causal variants within overlapping loci are the same or different for
each disease.
Methods: As part of the IC project, genotyping, quality control and
association analysis was performed for RA (11475 cases and 15870
controls), JIA (2816 polygoarticular and oligoarticular JIA cases and
13056 controls) and PsA (929 cases and 4537 controls). Some controls
were shared between cohorts.For this analysis all SNPs with a minor allele
frequency ⬎1% which reached p⬍10⫺3 in any of the 3 diseases were first
selected. IC regions were defined as including all SNPs from the 1000
Genomes Project CEU population (September 2009 release) that were in
0.1-cM (HapMap3 CEU) recombination blocks around each GWAS
region lead marker. IC Regions which contained SNPs associated with
more than one type of IA were considered overlapping.
Results: 49 regions showed association at p⬍10⫺3 with more than one
type of IA, of these, in RA and JIA 4 loci (PTPN22 STAT4, ANKRD55 and
TYK2) reached genome wide significance (5 ⫻ 10⫺8), with a further 7
associated at p⬍10⫺5 in both diseases. Interestingly 4 of these loci are
also associated with PsA at p⬍10⫺3 (TNFAIP3, PTPN2. RUNX1 and
TYK2). 6 of these loci have been previously associated with both RA and
JIA (PTPN22, STAT4, AFF3, TNFAIP3, PTPN2 and IL2RA) whilst 5 are
novel overlapping regions (DNASE1L3, ANKRD55, TYK2, RUNX1 and
IL2RB). For the PTPN22, STAT4, DNASE1L3, ANKRD55, TYK2 and
RUNX1 regions the RA and JIA associated SNPs are either identical or
highly correlated (r2⬎0.8), the direction of effect is the same in both
diseases and odds ratios similar. For AFF3, TNFAIP3 and PTPN2 the
associated SNPs are different and weakly correlated (r2⬎0.4⬍0.8) but the
direction of effect is similar for each disease. An interesting finding is that
for IL2RA and IL2RB the pattern of association in the region is completely
different.
Conclusion: These findings add to the body of evidence that there are
shared susceptibility genes for inflammatory arthritis. Further investigation is
required to fully explore whether the regions contain the same or different
causal effect, including functional studies to determine whether, in overlapping loci with the same causal variant, the variant predisposes to disease by
the same mechanism.
Acknowledgements: Rheumatoid Arthritis Consortium for Immunochip (RACI),
Juvenile Arthritis Consortium for Immunochip (JACI), UK Psoriatic Arthritis Consortium
Disclosure: K. J. A. Steel, None; A. Hinks, None; J. Bowes, None; J. Cobb, None; E.
Flynn, None; C. D. Langefeld, None; S. Prahalad, None; J. P. Haas, None; J. F.
Bohnsack, None; S. Guthery, None; A. Barton, None; S. D. Thompson, None; W.
Thomson, None.
975
Dense Genotyping of Risk Loci in Black South Africans with
Rheumatoid Arthritis: An Association Study. Nimmisha Govind1,
Ananyo Choudhury2, Bridget Hodkinson1, Claudia Ickinger1, Jacqueline
Frost3, Annette T. Lee4, Peter K. Gregersen4, Richard J. Reynolds5,
S. Louis Bridges Jr.5, Scott Hazelhurst2, Michèle Ramsay3 and Mohammed Tikly1. 1Division of Rheumatology, University of the Witwatersrand, Johannesburg, South Africa, 2Wits Bioinformatics Department,
University of the Witwatersrand, Johannesburg, South Africa, 3Division of Human Genetics, National Health Laboratory Service, University of the Witwatersrand, Johannesburg, South Africa, 4Feinstein Institute
for Medical Research, Manhasset, NY, 5Division of Clinical Immunology
and Rheumatology, University of Alabama at Birmingham, Birmingham,
AL
Background/Purpose: Genome wide association studies (GWAS)
have identified numerous rheumatoid arthritis (RA) risk loci in patients of
European and Asian ancestry but the causal variants have rarely been
identified. These studies have also identified susceptibility loci that are
common to various autoimmune diseases. The need to identify casual
variants prompted the design of the Immunochip, a custom Illumina
Infinium high density genotyping array, with 196 000 single nucleotide
polymorphisms (SNPs) from 186 loci previously associated with 12
autoimmune diseases. Little is known about the genetics of RA in black
South Africans. We aimed to test associations with known genetic loci and
to identify novel risk loci in black South Africans with RA.
Methods: Consenting black RA patients fulfilling the 1987 ACR
criteria for RA, ⬎18 years at disease onset, and seen at a single centre in
Johannesburg, South Africa were studied and compared to ethnically and
geographically matched controls. Genotyping of 716 samples was performed using the Immunochip. Only samples with ⱖ94% call rate and
individual SNPs with ⱖ95% call rate, were polymorphic, in HardyWeinberg equilibrium (pⱖ5 ⫻ 10⫺7) and with a minor allele frequency
of ⱖ0.02 were analyzed. The cohort was further pruned for relatedness
and ancestral outliers. After quality control, 117 353 SNPs were tested
for association in 263 cases and 365 controls. The statistical analysis
was performed using PLINK vers1.07. A p value ⫽ ⬍5 ⫻ 10⫺8
was considered significant based on previous genome wide association
studies.
Results: The strongest associations were found in the MHC region
with 64 SNPs reaching statistical significance. The most significant
associations were in the intergenic region of the HLA DRB1- HLA DQA1
alleles (rs3104413, OR⫽3.88, p⫽5.49 ⫻ 10⫺21; rs3129769, OR⫽3.91,
p⫽4.60 ⫻ 10⫺21; rs6931277, OR⫽3.97, p⫽1.03 ⫻ 10⫺21). There were 2
non HLA SNPs that reached genome wide significance, rs9283487
(OR⫽3.25, p⫽7.96 ⫻ 10⫺18) in the PRKRA gene, and rs35198051
(OR⫽0.34, p⫽2.94 ⫻ 10⫺8) in the intergenic region of C11orf76
andLOC100133306. In addition there were suggestive associations of 2
SNPs on chromosome 1, rs12739262 (OR⫽0.36, p⫽1.36 ⫻ 10⫺7) in the
PPP1R12B gene and rs12738883 (OR⫽0.36, p⫽1.69 ⫻ 10⫺7) in the
intergenic region of PLD5 and LOC400723, both SNPs reached statistical
significance in the rheumatoid factor (RF) positive subgroup (n⫽240/254)
(rs12739262, OR⫽0.33, p⫽9.10 ⫻ 10⫺8 and rs12738883, OR⫽ 0.33,
p⫽9.10 ⫻ 10⫺8).
Conclusion: In keeping with previous studies the HLA class II region
confers the strongest genetic risk for RA in black South Africans. We also
found 2 novel SNPs in the overall cohort and a further 2 SNPs in the RF
positive subgroup. The association of the PRKRA gene with RA is of interest
S422
because of its recent association with Sjogren’s Syndrome. Further studies in
larger cohorts of African patients are required to validate these findings and
to better understand the functional role of these novel loci in the pathogenesis
of RA in black South Africans.
Disclosure: N. Govind, None; A. Choudhury, None; B. Hodkinson, None; C.
Ickinger, None; J. Frost, None; A. T. Lee, None; P. K. Gregersen, None; R. J.
Reynolds, None; S. L. Bridges Jr., None; S. Hazelhurst, None; M. Ramsay, None;
M. Tikly, None.
976
Background/Purpose: Studies have shown associations between
environmental factors and rheumatoid arthritis (RA) risk. Also, genomewide association studies (GWAS) have identified genetic markers associated with RA risk. We examined additive and multiplicative geneenvironment interactions between 44 RA genetic markers and smoking,
parity/breast-feeding, body mass index (BMI), and BMI at age 18 in
determining RA risk.
Methods: We used a pooled nested case-control sample of 541 RA
cases, including 303 seropositive (CCP⫹ and/or RF⫹) cases, and 549
matched controls from the Nurses’ Health Study and Nurses’ Health
Study II. Controls were matched on age, menopausal status, and postmenopausal hormone use. All participants were Caucasian. We genotyped 36 single nucleotide polymorphisms identified in previous GWAS
and meta-analysis, and 8 HLA-DBR1 shared epitope (SE) genotypes
at 4 digit resolution. The information on cumulative pack-years of
smoking, parity and months of breast-feeding prior and BMI variables
determined prior to RA diagnosis, and BMI at age 18 was extracted from
questionnaires. We examined the main effects of the genetic and environmental factors. We tested for additive interactions using the attributable proportion (AP) due to interaction and tested for multiplicative
interactions using a 1 d.f. test. We used unconditional logistic regression
models, adjusted for matching factors. Bonferroni correction was used to
adjust for multiple comparisons. We further stratified the cases into
seropositive RA and seronegative RA phenotypes and tested for interactions separately.
Results: We found significant main effects of HLA-DBR1*0401
(OR⫽1.77, 95% CI⫽1.32–2.38), any HLA-DBR1 SE (OR⫽1.80, 95%
CI⫽1.41–2.29), and smoking (OR⫽1.55, 95% CI⫽1.21–1.99) on RA
risk. For the interaction analyses, combined HLA-DRB1 SE and HLADBR1*0401 showed significant interaction with smoking in all RA and
seropositive RA. Also, PTPN22 showed significant interaction with
smoking in all RA (Table). The effect of interaction between BMI
prior to RA diagnosis and PXK on RA risk was significant in all RA
(AP⫽0.74, p⬍0.005) and seropositive RA (AP⫽0.80, p⬍0.005).
We also found significant interaction effects on RA risk between
BMI at age 18 and HLA-DBR1*0401 in all RA (AP⫽0.66, p⫽0.013)
and seropositive RA (AP⫽0.67, p⫽0.031). However, we did not
find any significant interaction between genetic factors and parity/
breast-feeding. Also, there was no significant interaction found in the
seronegative RA phenotype. Several multiplicative interactions were
significant, but none remained significant after multiple comparisons
correction.
Table 1. Summary of significant additive interactions for 44 RA risk alleles after
multiple comparison adjustment and corresponding stratified analyses
All cases
Genetic factors
HLA-DRB1*0401
None
None
Any
Any
Environmental
factors
OR (95% CI)
Smoking prior to
diagnosis1
⬍ 10 pack-years
ⱖ 10 pack-years
⬍ 10 pack-years
ⱖ 10 pack-years
Ref
1.33 (1.01–1.75)
1.32 (0.89–1.95)
3.23 (2.03–5.15)
AP
(corrected
p-value3)
0.49 (0.031)
Seropositive cases
AP
(corrected
p-value4)
OR (95% CI)
Ref
1.37 (0.99–1.90)
1.16 (0.72–1.88)
3.46 (2.07–5.81)
0.56 (0.004)
Ref
1.14 (0.82–1.59)
1.35 (0.99–1.86)
2.90 (2.03–4.16)
0.48 (⬍0.005)
Ref
1.31 (1.00–1.72)
1.03 (0.68–1.54)
2.84 (1.75–4.60)
0.53 (0.009)
Ref
0.64 (0.45–0.91)
0.96 (0.65–1.43)
2.32 (1.00–5.42)
0.74 (⬍0.005)
Ref
0.66 (0.013)
0.97 (0.59–1.58)
1.60 (1.16–2.21)
4.66 (1.73–12.57)
Ref
1.08 (0.71–1.65)
1.62 (1.11–2.37)
3.91 (2.59–5.90)
0.56 (⬍0.005)
Ref
0.54 (0.35–0.83)
0.98 (0.62–1.57)
2.65 (1.05–6.68)
0.80 (⬍0.005)
Ref
0.67 (0.031)
0.96 (0.54–1.73)
0.55 (1.07–2.27)
4.60 (1.59–13.34)
1
cumulative pack-years of smoking none ⫺10 vs. ⱖ10
2⬍30 vs. ⱖ30 kg/m2 defined as obese by World Health Organization
3
⬍25 vs. ⱖ25 kg/m2 defined as overweight by World Health Organization
4
P-values were corrected for multiple comparisons. We used unconditional logistic regression model with
3 indicator variables for genetic factor, environmental factor, and interaction, adjusting for age,
menopausal status, and postmenopausal hormone use.
RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; AP: attributable proportion due to
interaction; SE: shared epitope; BMI: body mass index
Conclusion: We found significant gene-environment interaction
effects on RA risk with stronger associations for the seropositive
RA phenotype. We also found HLA-DBR1*0401 had different AP
when interacting with different environmental factors, which suggests
different mechanisms for these interactions. C:⶿data⶿abstract⶿acr⶿
2012⶿Paper_28425_abstract_29444_0.jpg
Disclosure: C. Y. Chen, None; L. T. Hiraki, None; S. Malspeis, None; J. Cui,
None; B. Lu, None; R. M. Plenge, None; K. H. Costenbader, None; E. W.
Karlson, None.
977
14-3-3 Eta Is a Novel Citrullination Target in Rheumatoid Arthritis
That Enhances Diagnostic Utility in Anti-CCP Negative Patients.
Walter P. Maksymowych1, Vivian P. Bykerk2, Désirée van der Heijde3, R.
Landewe4 and Anthony Marotta5. 1University of Alberta, Edmonton, AB,
2
Hospital for Special Surgery, New York, NY, 3Leiden University
Medical Center, Leiden, Netherlands, 4Academic Medical Center/
University of Amsterdam, Amsterdam, Netherlands, 5Augurex Life Sciences Corp, North Vancouver, BC
Background/Purpose: 14-3-3 eta is normally an intracellular protein
and only in the disease state is it released into the extracellular space. We
have previously presented data describing serum 14-3-3 eta’s diagnostic
utility as a marker that complements RF and anti-CCP in early and
established RA and is associated with joint damage in RA and PsA.
Circulating autoantibodies directed to citrullinated proteins are highly
specific for RA, but a significant percentage of patients are or remain
sero-negative for anti-CCP. Given that 14-3-3 eta is liberated into the
synovial space where PAD enzymes are present, we investigated whether
14-3-3 eta represents a novel citrullination target that could identify
anti-CCP negative RA patients.
Methods: Assays to measure the autoantibody levels to either noncitrullinated (non-cit) or citrullinated (cit) 14-3-3 eta were developed
using full-length recombinant human 14-3-3 eta. Full-length cit-14-3-3 eta
was generated by citrullinating the protein with purified PAD. Reactivity
to non-cit and cit-14-3-3 eta was evaluated in 3 anti-CCP positive RA
patients to confirm the presence of autoantibodies to cit-14-3-3 eta. To
evaluate whether these novel autoantibodies are detectable in anti-CCP
negative RA patients and differentially expressed compared to healthy
controls, reactivity to both non-cit and cit-14-3-3 eta was measured in 30
anti-CCP negative RA patients and 30 confirmed anti-CCP negative
healthy controls.Mean and median fluroescence intensity [1 MFI ⫽ 1 unit
(U)] was evaluated and corresponding t-tests and Mann-Whitney U-tests
were used to determine differences within and between groups. The area
under the ROC curve (AUC) was generated for diagnostic utility estimates
and to determine likelihood ratios (LR) for various anti-cit-14-3-3 eta
cut-offs.
S423
Monday, November 12
Effect of Interactions Between Validated Rheumatoid Arthritis
Genetic Factors and Environmental Factors On Rheumatoid Arthritis Risk. Chia-Yen Chen1, Linda T. Hiraki2, Susan Malspeis3, Jing Cui4,
Bing Lu4, Robert M. Plenge3, Karen H. Costenbader4 and Elizabeth W.
Karlson4. 1Harvard School of Public Health, Boston, MA, 2Brigham and
Women’s Hospital, Harvard School of Public Health, Boston, MA,
3
Brigham and Women’s Hospital, Boston, MA, 4Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA
Any HLA-DRB1 SE Smoking prior to
diagnosis1
None
⬍ 10 pack-years
None
ⱖ 10 pack-years
Any
⬍ 10 pack-years
Any
ⱖ 10 pack-years
PTPN22
Smoking prior to
diagnosis1
None
⬍ 10 pack-years
None
ⱖ 10 pack-years
Any
⬍ 10 pack-years
Any
ⱖ 10 pack-years
PXK
BMI prior to
diagnosis2
None
⬍ 30 kg/m2
None
ⱖ30 kg/m2
Any
⬍ 30 kg/m2
Any
ⱖ 30 kg/m2
HLA-DRB1*0401
BMI at age 182
None
⬍ 25 kg/m2
None
ⱖ 25 kg/m2
Any
⬍ 25 kg/m2
Any
ⱖ 25 kg/m2
Monday, November 12
Results: Compared to non-cit 14-3-3 eta, up to 25X higher reactivity
was observed to cit-14-3-3 eta in 2 of the 3 anti-CCP positive RA patients,
revealing the novel expression of autoantibodies to the citrullinated form
of 14-3-3 eta in RA. Within the anti-CCP negative RA group, significantly
higher reactivity was observed to cit versus non-cit-14-3-3 eta at 1943U
versus 395U, p⫽0.01. No significant differences in reactivity were
observed within the healthy group. Anti-cit-14-3-3 eta expression was
significantly higher in anti-CCP negative RA patients with means (SD)
and medians (min-max) of 1943U (3045U) and 306U (68–8982U)
compared to 155U (122U) and 100U (45–564U) for healthy controls,
p⬍0.002.The corresponding ROC AUC for anti-cit-14-3-3 eta differential
expression in anti-CCP negative RA patients compared to healthy controls
was 0.79 (95% CI 0.68–0.91; p⬍0.0001). At a cut-off of 320U, the
specificity and sensitivity were 90% and 50% delivering an LR positive of
5 increasing to 14 at 439U with a corresponding specificity of 97% and
sensitivity of 47%.
Conclusion: Extracellular 14-3-3 eta protein has been described as an RA
diagnostic biomarker with prognostic and therapy monitoring applications.
14-3-3 eta also represents a novel citrullination target that is differentially
expressed in anti-CCP negative RA patients versus healthy controls, indicating that anti-cit-14-3-3 eta may improve RA diagnosis.
Disclosure: W. P. Maksymowych, Augurex Life Sciences Corp., 7, 9; V. P. Bykerk,
Augurex Life Sciences Corp., 5; D. van der Heijde, Augurex Life Sciences Corp., 5;
R. Landewe, Augurex Life Sciences Corp., 5; A. Marotta, Augurex Life Sciences
Corp, 3.
978
A Genome-Wide Interaction Study with Smoking Suggests New Risk
Loci for Two Different Subsets of Rheumatoid Arthritis; Results
From Swedish Epidemiological Investigation of Rheumatoid Arthritis
Study. Xia Jiang1, Henrik Källberg1, Leonid Padyukov2, Lars Klareskog2
and Lars Alfredsson1. 1Karolinska Institutet, Stockholm, Sweden, 2Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
Background/Purpose: Rheumatoid arthritis (RA) is believed to have
a multifactorial etiology, involving both genetic and environmental
components, and can be divided into two major subsets according to the
presence/absence of anti-citrullinated protein/peptide antibodies (ACPA).
Smoking is the most established environmental risk factor. Despite
progress from genome-wide association studies (GWAS), identified genetic variants only explain a small proportion of RA occurrence. Hypothetically, gene-environment interaction could add etiologic understanding of the disease. The aim of current study was to investigate geneenvironment interaction between smoking and SNPs from an
Immunochip, with selected SNPs of interest from an inflammatory point
of view, for each of the two major RA subsets.
Methods: Data from Swedish EIRA case-control study was analyzed
by means of logistic regression models. Smoking history was collected
through questionnaires. Heavy smoking was defined as more than 10
pack-years. Genetic information was obtained from an Immunochip scan.
Interaction between smoking intensity and 133648 genetic markers that
passed quality control were examined for the two RA subsets (1590
ACPA positive cases, 891 ACPA negative cases; compared with 1856
matched controls). Attributable proportion due to interaction together with
95% confidence interval was evaluated for each smoking-SNP pair.
Results: For ACPA positive RA, 390 SNPs were found to significantly
interact with heavy smoking after Bonferroni correction, with a majority
located in the HLA region (328 out of 390, 84.10%), all of which
displayed high linkage disequilibrium (LD); for ACPA negative RA, 56
SNPs passed threshold for significance, most located outside the HLA
region (51 out of 56, 91.07%). After adjusting for HLA-DRB1 shared
epitope (SE), 37 SNPs remained significant for ACPA positive RA, with
17 (45.95%) confined to HLA region and the rest spread across 9 other
chromosomes; for ACPA negative RA, 19 SNPs stood out, all of them
outside the HLA region. Through functional prediction and pathway
annotation, 24 candidate genes/regions were identified for ACPA positive
RA, several of them (C6orf10, GRB10, HCG9, TAP2, PPT2, HLA-E,
SMAD3) together with HLA-DR presented a network of antigen presentation pathways; for ACPA negative RA, 13 genes were demonstrated, 6
of them (GP1BA, AFF3, ICOSLG, NOTCH2, TGS1, LYN) constitute T
helper cell differentiation pathways. For ACPA positive RA, besides those
SNPs in LD with known susceptibility variant at HLA-DRB1, none of the
others have previously been identified.
Conclusion: Our study presents the most explicit picture to date,
with regard to the patterns of gene-smoking interaction in ACPA
positive/negative RA, suggesting fairly contrasting etiology of the two
subsets. Our findings support the, by far, greatest influence from HLAregion on ACPA positive RA; while for ACPA negative RA, more
genes outside HLA-region contribute to the etiology. Noticeably, for
both RA subsets, new SNPs that are not significant in association analyses stand out in interaction analyses, indicating that genetic factors
should be considered together with environmental factors in studies of RA
etiology.
Disclosure: X. Jiang, None; H. Källberg, None; L. Padyukov, None; L. Klareskog,
None; L. Alfredsson, None.
979
Cell-Type Specific Type I Interferon Signatures in Systemic Lupus
Erythematosus and Viral Infection: What Makes the Difference?
Chieko Kyogoku1, Joachim R. Grün1, Tobias Alexander2. Robert Biesen2,
Falk Hiepe2, Thomas Häupl2, Andreas Radbruch1 and Andreas Grützkau1,
1
German Rheumatism Research Centre Berlin (DRFZ), an institute of the
Leibniz Association, Berlin, Germany, 2Charité University Hospital Berlin,
Berlin, Germany
Background/Purpose: Gene expression profiling experiments using
peripheral blood mononuclear cells (PBMCs) revealed a crucial role of type
I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE).
However, it is almost unknown how particular leukocyte subsets contribute to
the overall type I IFN signature described for PBMCs. Furthermore, a detailed
analysis of how IFN signatures differ in autoimmune disease from that
observed after viral infection is missing so far. Therefore, we compared
expression levels of 2442 IFN signature genes in peripheral CD4⫹ T helper
cells, CD16-negative inflammatory and CD16-positive resident monocytes
(Mo) isolated from patients with SLE, healthy donors (ND) and ND
vaccinated against yellow fever by global gene expression profiling.
Methods: Peripheral blood from 6 patients with SLE and 4 ND for CD4⫹
T cells, 4 patients with SLE and 4 ND for CD16-negative Mo, and 4 patients
with SLE and 3 ND for CD16-positive Mo were recruited. Same ND were
examined before and after immunization by yellow fever vaccine. After
sorting cells, isolated RNA were applied to Affymetrix Human Genome
U133 Plus 2.0 Array. Data analysis was done using BioRetis database,
Genesis Software and Ingenuity Pathway Analysis (IPA). A reference list of
2442 IFN-related genes was obtained from recent publications and used to
estimate IFN imprints.
Results: When compared total significantly differentially expressed probe
sets, 9/3/2 (CD4⫹ T cells/CD16-negative Mo/CD16-positive Mo, respectively) times more number of probes were detected in patients with SLE
compared to immunized ND. The contribution of IFN signature to total gene
signature was 20.7/23.3/23.3 % in patients with SLE, whereas 48.6/35.2/30.5
% in immunized ND. 98/165/173 probe sets (fold change⬎⫽2, ⬍⫽⫺2) were
detected as a “common” IFN signature observed both in autoimmunity and in
immunized ND. 111/164/120 probe sets were detected as an “autoimmunespecific” IFN signature, whereas only 0/8/5 probe sets were detected to be
specific for the “virus-induced” IFN signature. Expression pattern of these
IFN signature genes clearly distinguished patients with SLE from immunized
ND by hierarchical cluster analysis. Although major IFN signature genes
were commonly expressed in CD4⫹ T cells and Mo of patients with SLE and
immunized ND, expression magnitudes of them were higher in patients with
SLE compared to immunized ND. In SLE, in addition to the typical
“viral-induced” IFN signature, genes that are involved in apoptosis signaling,
antiviral PKR signaling, Fc␥ receptor-mediated phagocytosis and IL-10-/
IL-9-/ IL-15-mediated JAK/Stat signaling pathways were identified by IPA.
Conclusion: This study demonstrated that IFN signature in autoimmunity
and that in viral infection are quite different in the number of IFN-related
genes activated and their expression magnitudes. Autoimmunity is characterized by a much stronger expression of IFN signature genes and is obviously
modulated by a separate set of co-regulated genes defining the “autoimmunespecific” IFN signature. “Common” and “autoimmune-specific” IFN signature genes can be applied as a clinical biomarker to diagnose SLE flare
discriminating from viral infection.
Disclosure: C. Kyogoku, None; J. R. Grün, None; T. Alexander, None; R.
Biesen, None; F. Hiepe, None; T. Häupl, None; A. Radbruch, None; A.
Grützkau, None.
S424
980
Background/Purpose: Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with an estimated prevalence of 40:100,000 cases in
European populations. SLE has a strong genetic risk component (sibling
relative risk 30). Positional candidate studies have identified the association of
HLADRB1, STAT4 and IRF5 loci with SLE risk. However, Genome-Wide
Association Studies (GWAS) have allowed to expand the number of SLE risk
loci to more than 20. In order to identify additional risk loci we have
performed a GWAS in a Southern European population.
Methods: 510 SLE cases and 1,540 controls of Spanish origin were
genotyped for more than 550,000 SNPs using Illumina Quad-610 platform.
Only SNPs having ⬎95% call rate and individuals having 95% of SNPs
genotyped were included. Principal Component Analysis was used to identify
the main axis of variation and discard any population outlier. After QCfiltering 489 SLE cases and 1490 Controls were included to test for
association. In order to evaluate the association of all previously known
SLE-risk loci all GWASs published from 2,008 to 2,012 where evaluated.
Loci associated at a nominal P-value ⬍ 5e-5 were included. Within each SLE
risk locus (n⫽43), the SNP having the highest statistical evidence was
selected. For those SNPs not directly genotyped (n⫽3) genotype was imputed
using MACH v1.0 software.
Results: From the 24 loci previously showing Genome-Wide level of
association (P⬍5e-8) with SLE risk, loci HLA-DRB1, ITGAM, STAT4 and
MSH5 were also replicated at Genome-Wide level. Four additional loci were
also replicated at nominal (P⬍0.05) level of significance. From the remaining
19 loci still requiring additional evidence (5e-8 ⬍ P ⬍ 5 e-5) we were able to
nominally replicate three loci. 20 SNPs within genomic regions previously
not associated with SLE were also identified (P⬍5e-5).
Conclusion: The present study has validated previous SLE risk loci in an
independent population and gives additional support to loci with suggestive
association. The association of the new candidate risk loci for SLE identified
in this GWAS is currently being tested for validation.
Disclosure: A. Fernandez-Nebro, None; P. E. Carreira, None; R. Blanco, None;
V. M. Martinez-Taboada, None; L. Carreño, None; A. Olive, None; J. L. Andreu,
None; M. A. Aguirre, None; P. Vela, None; J. J. Pérez Venegas, None; J. L.
Marenco, None; J. M. Nolla, None; A. Zea, None; J. M. Pego-Reigosa, None; M.
Freire González, None; G. Ávila, None; M. A. López-Lasanta, None; R. Tortosa,
None; A. Julià, None; S. Marsal, None.
981
Aggregated Genetic Information Explains Variations On Hand Radiographic Scores in Rheumatoid Arthritis Patient. Jing Cui1, Nancy A.
Shadick2, Katherine P. Liao1, Michael Weinblatt3, Robert M. Plenge1 and
Elizabeth W. Karlson4. 1Brigham and Women’s Hospital, Boston, MA,
2
Department of Medicine, Division of Rheumatology, Immunology and
Allergy, Brigham and Women’s Hospital, Boston, MA, 3Rheumatology &
Immunology, Brigham & Women’s Hospital, Boston, MA, 4Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA
Background/Purpose: Rheumatoid arthritis (RA) has an estimated heritability of approximately 60%. Joint destruction as a severity measure of RA is
influenced by genetic factors, however the heritability of this trait remains unclear.
Our objective was to determine the genetic heritability of joint destruction,
Table. Top 10 SNPs associated with Sharp/van der Heijde Hand Score
chr
rs
gene
Base pair
Allele A
Minor allele
frequency
beta
P value
9
21
5
8
9
4
19
4
8
1
rs16925520
rs2832760
rs10079663
rs13256240
rs10901313
rs1980037
rs4801371
rs10024454
rs1471705
rs6674099
JMJD2C
CLDN8
VDAC1
FUBP3
GYPB
ZNF71
IGFBP7
ZFHX4
DISC2
7162354
30584023
133384433
83633555
132275229
145136964
61926872
57942964
77880207
230033485
C
G
C
A
C
A
A
C
A
A
0.01
0.30
0.41
0.01
0.02
0.02
0.04
0.32
0.01
0.45
3.52
0.31
0.28
-3.38
-2.13
2.73
-1.28
-0.27
-2.79
0.23
4.3E-09
3.3E-08
1.1E-07
2.2E-07
1.1E-06
1.2E-06
1.8E-06
2.2E-06
2.7E-06
3.2E-06
Conclusion: Our study suggests that joint damage in RA (as measured by
SHS) is a heritable trait where genetic factors explain 22% of the phenotypic
variance.These findings corroborate with a previous study where heritability
was estimated to be higher at 45%-58%. Although several SNPs were
associated with SHS at genome-wide significance, none were known RA risk
alleles.These findings require confirmation in an independent sample.
Disclosure: J. Cui, None; N. A. Shadick, Amgen, 2, Abbott Immunology Pharmaceuticals, 2, Genentech and Biogen IDEC Inc., 2, Crescendo Bioscience, 2, Medimmune,
2; K. P. Liao, None; M. Weinblatt, MedImmune, 2, Crescendo Bioscience, 2,
MedImmune, 5, Crescendo Bioscience, 5; R. M. Plenge, None; E. W. Karlson, None.
982
Genetic Variants near Insulin-Like Growth Factor Binding Protein 3
(IGFBP3) Are Associated with Hip Osteoarthritis. Daniel S. Evans1,
Neeta Parimi1, Ana M. Valdes2, Hanneke J.M Kerkhof3, Frederic Cailotto4,
Michael C. Nevitt5, Steven R. Cummings1, Rik J. Lories4, Timothy D.
Spector2, Nigel K. Arden6, Joyce B. van Meurs3 and Nancy E. Lane7.
1
California Pacific Medical Center Research Institute, San Francisco, CA,
2
Dept of Twin Research and Genetic Epidemiology, St. Thomas’ Hospital,
King’s College London, London, United Kingdom, 3Department of Internal
Medicine, Erasmus Medical Center and The Netherlands Genomics InitiativeSponsored Netherlands Consortium for Healthy Aging, Rotterdam, Netherlands, 4Laboratory for Skeletal Development and Joint Disorders, Department
of Development and Regeneration, KU Leuven, Leuven, Belgium, 5University of California-San Francisco, San Francisco, CA, 6Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK,
Oxford, United Kingdom, 7UC Davis School of Medicine, Sacramento, CA
Background/Purpose: Hip osteoarthritis (HOA) is one of the most
common joint disorders and can result in pain and disability.HOA is heritable,
S425
Monday, November 12
Genomewide Association Study in Systemic Lupus Erythematosus:
Known Loci. Antonio Fernandez-Nebro1. Patricia E. Carreira2, Ricardo
Blanco3, Victor M. Martinez-Taboada4, Luis Carreño5, Alejandro Olive6,
José Luis Andreu7, Ma Angeles Aguirre8, Paloma Vela9, Jose Javier Pérez
Venegas10, Jose Luı́s Marenco7, Joan Miquel Nolla11, Antonio Zea12, José M.
Pego-Reigosa13, Mercedes Freire González14, Gabriela Ávila15, Marı́a
América López-Lasanta15, Raül Tortosa15, Antonio Julià15 and Sara Marsal15, 1Hospital Regional Universitario Carlos Haya, Málaga, Spain, 2Instituto
de Investigación Hospital 12 de Octubre, Madrid, Spain, 3Hospital Universitario Marques De Valdecilla, Santander, Spain, 4Hospital Universitario
Marques de Valdecilla. IFIMAV, Santander, Spain, 5Gregorio Marañón
Hospital, Madrid, Spain, 6Germans Trias Pujol Hospital, Barcelona, Spain,
7
HU Puerta de Hierro Majadahonda, Madrid, Spain, 8IMIBIC-Reina Sofia
Hospital, Cordoba, Spain, 9Hospital General Universitario de Alicante,
Alicante, Spain, 10Hospital del SAS de Jerez de la Frontera, Jerez De La
Frontera, Spain, 11Hospital Universitari de Bellvitge, Barcelona, Spain,
12
Hospital Universitario Ramon y Cajal, Madrid, Spain, 13Hospital do
Meixoeiro, Vigo, Spain, 14Complejo Hospitalario Universitario de La
Coruña, La Coruña, Spain, 15Vall d’Hebron Hospital Research Institute,
Barcelona, Spain
quantified as Sharp/van der Heijde scores (SHS), and to conduct a genome wide
association study (GWAS) to identify SNPs associated with quantitative joint
damage in RA patients.
Methods: We studied 422 anti-CCP⫹ RA subjects in a prospective observational RA cohort at an academic hospital with baseline bilateral hand radiographs and blood samples. Using the SHS method, 4 radiologists assigned an
erosion score (0–5) for 16 joints, and a joint space narrowing score (0–4) for 15
joints in each hand (total SHS range 0–280). The inter-rater reliability for the SHS
in our study was 0.93. SHS measures were normalized by taking the inverse
normal of the rank. Samples were genotyped on the Affymetrix 6.0 platform. We
applied standard quality control procedures, followed by imputation to 2.5M
SNPs using IMPUTE with HapMap2 CEU. Clinical predictors of SHS such as
age. gender, disease duration were studied using general linear regression.We
applied mixed linear model analysis to estimate the proportion of variance
explained by genotyped SNPs from the whole genome to determine heritability.
We studied the association between each SNP and SHS using linear regression
assuming a genetic additive model adjusting for the first three principal component values from Eigenvector analysis and RA disease duration.
Results: The 422 RA cases had mean age of 59 yrs, mean disease duration of
17 yrs, and 81% were female. The SHS range was 0–270 with median of 40.
Clinical predictors including age and disease duration were significant in univariate analyses, and only disease duration was significant (P ⬍0.0001) in multivariate analyses. Heritability analysis adjusted for disease duration and 3 principal
components estimated 22% (p⫽0.39) of SHS variation was attributable to genetic
variants using all genotyped SNP information. From the GWAS, we found 2
SNPs that exceeded the genome-wide significance threshold of 5E-8 (rs16925520
p⫽4E-9, rs2832760 p⫽3E-8) for association with SHS. The independent top 10
findings are shown in the table. The MHC region was not significantly associated
with SHS. No known RA risk alleles (50 loci) were associated with SHS.
Monday, November 12
but the particular genes contributing to the development of HOA are not well
defined.To identify genetic associations with HOA, we conducted a two-stage
genome-wide association study (GWAS).
Methods: All analyses were restricted to individuals of European ancestry.The discovery phase was performed using radiographically determined
HOA cases and controls selected from the Osteoporotic Fractures in Men
(MrOS) Study and the Study of Osteoporotic Fractures (SOF) (combined
cases ⫽ 662).HOA cases were defined as Croft grade ⱖ 2 or total hip
replacement (THR).HOA controls were defined as Croft grade ⱕ 1, maximum joint space narrowing (JSN) ⱕ 1, maximum osteophytes ⱕ 1, and no
THR.SNPs were genotyped using the Illumina Omni1-Quad array and
approximately 2.5 million SNPs were imputed using the HapMap reference
panel.Logistic regression was performed, and MrOS and SOF results were
combined using inverse variance weighted fixed effect meta-analysis.SNP
associations with P-values ⱕ 5 ⫻ 10⫺8were examined for replication in the
Rotterdam cohorts (RSI ⫽ original cohort, RSII ⫽ second recruitment cycle),
Twins UK, and Chingford cohorts.Publicly available eQTL data from
HapMap CEU lymphoblastoid cell lines were used.
Results: On average, MrOS participants (100% male) were older than
SOF participants (100% female) at the clinic visits when HOA was assessed
(MrOS: mean⫾SD ⫽ 77.5⫾5.4 years, range ⫽ 69–97; SOF: mean⫾SD ⫽
70.9⫾5.0 years, range ⫽ 65–91).In the discovery meta-analysis, the rs788748
A allele and the rs879966 G allele were associated with decreased odds for
HOA (Table 1).The two directly genotyped SNPs were 23 kb apart and were
in moderate LD (HapMap CEU r2⫽ 0.54).Neither SNP remained nominally
significant in conditional analysis, indicating dependence.The SNP rs788748
replicated in the RSI cohort, but not the RSII cohort or the Chingford
cohort.In the Twins UK cohort, the association between the rs788748 A allele
and HOA was significant and in the opposite direction relative to the
discovery samples (Table 1).The SNP rs879966 did not replicate (Table 1).
Table 1. SNP association results in discovery and replication cohorts.
SNP
Effect
allele
(Freq)
MrOS/SOF
(discovery)
cases/
controls
OR
(P)
rs788748 A (0.49) 662/4750 0.71
(3⫻10⫺8)
rs879966 G (0.39) 662/4750 0.70
(2⫻10⫺8)
RSI
cases/
controls
RSII
OR
(P)
cases/
controls
OR
(P)
Twins UK
cases/
controls
OR
(P)
Chingford
cases/
controls
OR
(P)
462/3428 0.86 (0.03)
149/
1430
1.02 (0.86) 73/366 1.48(0.03) 83/492 1.11 (0.54)
462/3428 0.92 (0.24)
149/
1430
1.12 (0.38) 73/366 1.34(0.10) 83/492 1.00 (0.99)
From eQTL data, rs788748 and rs879966 were marginally associated with
IGFBP3 expression (P-value ⫽ 0.07 and 0.06, respectively), but not IGFBP1
expression (P-value ⫽ 0.74 and 0.34, respectively).SNP associations with
circulating IGFBP3 levels and results from IGFBP3 knockdown experiments
in the ATDC5 chondrogenesis model system will be presented.
Conclusion: Our genetic association and eQTL results provide suggestive
evidence for a link between IGFBP3 and HOA, but further replication is
required for the association results to be considered robust.IGFBP3 is known
to be expressed in human chondrocytes and might be an attractive candidate
for follow-up studies.
Disclosure: D. S. Evans, None; N. Parimi, None; A. M. Valdes, None; H. J.M
Kerkhof, None; F. Cailotto, None; M. C. Nevitt, None; S. R. Cummings, None; R. J.
Lories, None; T. D. Spector, None; N. K. Arden, None; J. B. van Meurs, None; N. E.
Lane, None.
983
Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 As a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis. Jing Cui1 and International RA Consortium on Therapy
(InteRACT)2. 1Brigham and Women’s Hospital, Boston, MA, 2Boston, MA
Background/Purpose: There are no biomarkers that predict response to
anti-TNF therapy in rheumatoid arthritis (RA).Here, we conduct a genomewide association study (GWAS) to identify genetic variants that influence
response to anti-TNF therapy.
Methods: GWAS data were aggregated on 2,743 RA patients as part of
an international collaboration. Clinical data and Disease Activity Score
(DAS28) were available for RA patients treated with three anti-TNF medications: etanercept (N⫽773), infliximab (N⫽894) or adalimumab
(N⫽1,071). GWAS data were quality controlled by genotype batch, and all
data were imputed to 2.5M SNPs using IMPUTE with HapMap2 CEU.
Change in DAS28 (delta-DAS) was used as the primary phenotype in linear
regression association tests of all samples combined and subset by anti-TNF
drug.We adjusted for baseline DAS28 and three ancestry-derived principal
component eigenvectors. Expression quantitative trait locus (eQTL) data for
the CD84 locus were available for peripheral blood mononuclear cells
(PBMCs, N⫽228). Replication samples from the Portuguese Reuma.pt
registry (n⫽405), and the Japanese IORRA and Kyoto University Hospital
registries (n⫽374), were genotyped using Sequenom and/or TaqMan and
analyzed as in our GWAS.
Results: While no single SNP was genome-wide significant for association with delta-DAS in an analysis of all samples combined, a SNP at the
1q23/CD84 locus was highly significant in the etanercept subset of patients
(rs6427528, P⫽7 ⫻ 10⫺8).This same SNP was not associated with deltaDAS in the infliximab or adalimumab subsets (P⬎0.05). The allele associated
with a better response, which is in the 3’ UTR of an immune-related gene
CD84, is also associated with higher CD84 gene expression in PBMCs
(P⬍10⫺12). In a subset of RA patients with gene expression data, CD84 gene
expression correlates with baseline DAS (n⫽210, P⫽0.02), and demonstrates
a non-signficant trend toward predicting response to etanercept therapy.In a
small replication study, the SNP was not associated with response to
etanercept therapy among European (n⫽139, P⫽0.4) or Japanese (n⫽151,
P⫽0.8) RA patients.
Conclusion: GWAS in etanercept-treated RA patients revealed a highly
suggestive association with the CD84 locus.Further, CD84 gene expression is
under genetic control and influenced by disease activity. These findings
provide support that CD84 genotypes and/or expression may serve as a useful
biomarker for response to etanercept treatment in RA, although larger
replication studies are required.
Disclosure: J. Cui, None;
984
Association of Elevated C5a Levels, but Not the Presence of Anti-Cfh
IgG Autoantibodies, with the Deletion of CFHR3 and CFHR1 in SLE.
Jian Zhao, Seema Kamble, Yun Deng, Magdangal Erika, Daisuke Sakurai,
Rongqun Li, Weiling Chen, Jennifer M. Grossman, Bevra H. Hahn and Betty
P. Tsao. Division of Rheumatology, David Geffen School of Medicine,
University of California Los Angeles, Los Angeles, CA
Background/Purpose: We previously reported association of the deletion of complement regulator factor H related CFHR3 and CFHR1 genes
(CFHR3-1⌬), rather than CFH exonic SNPs, with SLE in 15,864 case-control
subjects of multiple ancestries (P⫽2.9⫻10⫺7, OR⫽1.17). Both CFHR3 and
CFHR1 suppress C5a generation, and CFHR3-1⌬ has been associated with
the presence of anti-CFH IgG autoantibodies that block CFH C-terminal
binding in patients with atypical hemolytic uremic syndrome. To investigate
possible functional consequences of CFHR3-1⌬ in SLE, we tested its
association with 1) the presence of anti-CFH IgG autoantibodies, and 2)
elevated C5a levels.
Methods: CFHR3-1⌬ was either directly genotyped by multiplex
ligation-dependent probe amplification or deduced by its tag SNP rs6677604
2
(r ⫽1).Levels of plasma C5a and anti-CFH IgG autoantibodies were measured by ELISA. The presence of anti-CFH IgG autoantibodies (anti-CFH⫹)
was defined as higher levels than the mean ⫹ 3 SD of those from healthy
controls carrying no deletion.
Results: Plasma anti-CFH IgG autoantibodies levels showed no difference between SLE cases and controls (Mean⫾SEM: 5.46⫾0.074 RU/ml in
75 cases vs. 5.47⫾0.063 RU/ml in 45 controls, P⫽0.91), no difference
between men and women (P⫽0.71 in cases [9 men and 66 women]; P⫽0.23
in controls [22 men and 23 women]) and no correlation with age (r2⫽0.00042
in cases [mean: 43 years old, range: 18–72], P⫽0.91; r2⫽0.0010 in controls,
P⫽0.79 [mean: 39, range: 20–77]). Anti-CFH⫹ was only identified in 4 of
the 75 studied SLE cases (7%): two of them carried two copies of CFHR3-1⌬
and the other two had zero copies, showing no association of anti-CFH⫹ with
CFHR3-1⌬ (P⫽1.00). Although none of the 45 controlswas classified as
anti-CFH⫹, the presence of anti-CFH was not significantly associated with
SLE (P⫽0.30) at the current sample size.
Preliminary results of plasma C5a levels were significantly higher in 15
SLE cases carrying two copies of CFHR3-1⌬ than in 84 cases carrying one
or zero copy (Mean⫾SEM: 5.23⫾0.13 ng/ml vs. 4.86⫾0.06 ng/ml,
P⫽0.018). We observed no significant difference in plasma C5a levels
between 5 controls carrying two copies of CFHR3-1⌬ and 57 controls
carrying one or zero copy (Mean⫾SEM: 4.57⫾0.29 ng/ml vs. 4.76⫾0.09
ng/ml, P⫽0.55), which might be due to the small sample size.
Conclusion: Our preliminary data showed that homozygous deletion of
CFHR3-1⌬, which predisposes to SLE, was associated with elevated C5a
levels in SLE cases, suggesting that this deletion might confer SLE risk by
uninhibited production of C5a leading to neutrophil chemotaxis and inflammatory injuries. In contrast, the deletion was not associated with IgG
S426
antibodies to CFH. Further investigation of these association in additional
samples is ongoing.
Disclosure: J. Zhao, None; S. Kamble, None; Y. Deng, None; M. Erika, None; D.
Sakurai, None; R. Li, None; W. Chen, None; J. M. Grossman, None; B. H. Hahn,
None; B. P. Tsao, None.
985
Inverse Relation Between the tumor Necrosis Factor Promoter Methylation and Trascript Leveles in Leukocytes From Patients with Rheumatoid Arthritis. James R. Maxwell1, Lyndsey H. Taylor2, Richardo A.
Pachecho2, Neil Lawrence2, Gordon W. Duff3, M. Dawn. Teare2 and
Anthony G. Wilson4. 1University of Sheffield, Sheffield, United Kingdom,
2
University of Sheffield, United Kingdom, 3Royal Hallamshire Hospital,
Sheffield, United Kingdom, 4Section of Musculoskeletal Sciences, University
of Sheffield, Sheffield, United Kingdom
Disclosure: J. R. Maxwell, None; L. H. Taylor, None; R. A. Pachecho, None; N.
Lawrence, None; G. W. Duff, None; M. D. Teare, None; A. G. Wilson, None.
986
Genome Wide Association Studies of Knee Osteoarthritis in 2 Large
North American Cohorts: A Meta-Analysis with 2667 Cases. Marc C.
Hochberg1, Laura Yerges-Armstrong2, Changwan (Larry) Lu2, Michelle S.
Yau1, Braxton D. Mitchell2, Joanne M. Jordan3, Youfang Liu4, Jordan B.
Renner5, T. McSherry6, D.M. Taverna6, David Duggan6, W.J. Mysiw7 and
Rebecca D. Jackson8. 1University of Maryland, Baltimore, MD, 2University
of Maryland School of Medicine, Baltimore, MD, 3University of North
Carolina Thurston Arthritis Research Center, Chapel Hill, NC, 4University of
North Carolina, Chapel Hill, NC, 5University of North Carolina at Chapel
Hill Dept of Radiology, Chapel Hill, NC, 6TGen, Pheonix, AZ, 7Ohio State
University, Columbus, 8Ohio State University, Columbus, OH
Background/Purpose: A strong genetic contribution to knee osteoarthritis (OA) is widely recognized although few loci have been robustly associated
with knee OA susceptibility. To identify genes associated with knee OA, we
performed a meta-analysis of genome wide association (GWA) results from
two large studies of knee OA: the Genetic Components of Knee OA
(GeCKO) Study, an ancillary study from the Osteoarthritis Initiative (OAI),
and the Johnston County (JoCo) Osteoarthritis Project.In addition, we
Disclosure: M. C. Hochberg, Abbott Laboratories, Astra-Zeneca, Bioiberica S.A., Eli
Lilly Inc., Genentech/Roche, Merck Inc., Novartis Pharma A.G., Pfizer Inc., Stryker
LLC, Xoma., 5; L. Yerges-Armstrong, None; C. Lu, None; M. S. Yau, None; B. D.
Mitchell, None; J. M. Jordan, Algynomics, Inc., 1, Johnson and Johnson, 5, Johnson
& Johnson, 2, Interleukin Genetics, Inc., 5, Eli Lilly and Company, 5, Mutual
Pharmaceutical Company, 5; Y. Liu, None; J. B. Renner, None; T. McSherry, TGen,
3; D. M. Taverna, TGen, 3; D. Duggan, TGen, 3; W. J. Mysiw, None; R. D. Jackson,
None.
987
Autoimmune Susceptibility Genes Are Regulators of Gene Expression
Response to ER Stress. William E. Bernal1, Michael P. Morley2 and Vivian
G. Cheung3. 1The Children’s Hospital of Philadelphia, Philadelphia, PA,
2
University of Pennsylvania, Philadelphia, PA, 3Howard Hughes Medical
Institute, Chevy Chase, MD; University of Pennsylvania, Philadelphia, PA
Background/Purpose: Endoplasmic reticulum (ER) stress is caused by
excessive demands on the protein-processing capacity of the ER; inefficiencies in response to ER stress lead to human diseases such as ankylosing
spondylitis (AS). ER stress has been linked to inflammatory pathways. To
study the role of ER stress in disease susceptibility, we identified the genes
and pathways involved in ER stress response in human cells, assessed
individual variation in these pathways, and mapped DNA sequence variants
that influence ER stress response.
Methods: To study ER stress response in B-cells, we exposed the cells
from 131 normal unrelated individuals to tunicamycin, a chemical inducer of
ER stress, and measured changes in gene expression before and following ER
stress. Then, to determine the genetic basis of variation in gene expression
response to ER stress, we carried out genetic mapping using B-cells from
members of 15 extended families.
Results: We identified 1,523 ER stress-responsive genes which showed at
least 1.5 fold changes in gene expression following ER stress.The results
showed extensive individual variation in gene expression response to ER
stress.For instance, TNFSF13B (BAFF/Blys), a potent activator of B cells,
has a mean induction of 1.6-fold but there is a 2.4-fold difference in its level
between the individuals with the lowest and highest induction of this
gene.XBP1 and DDIT3 (CHOP), which encode key ER stress transcription
factors, vary by 5-fold and 9-fold. From our linkage and association studies,
we focused our analysis on 778 ER stress-responsive genes and identified
DNA sequence variants that regulate the response of 497 of the genes,
including TNFSF13B.Regulators of gene expression response to ER stress
include susceptibility genes for autoimmune diseases: BLK (systemic lupus
erythematosus, rheumatoid arthritis, Kawasaki disease); SVIL (multiple
S427
Monday, November 12
Background/Purpose: The importance of the epigenetic signature in RA
is unclear but levels of methylation of CpG motifs in the TNF promoter are
known to be important determinants of transcriptional activity.In view of the
central importance of this cytokine in RA we hypothesised that methylation
of the TNF gene in peripheral blood cells might differ between RA patients
and controls.The primary objectives were to determine if CpG motifs in the
TNF gene promoter were differentially methylated in RA compared with
controls and if TNF mRNA levels correlated with DNA methylation.We also
determined whether methotrexate was associated with alterations in genomic
or TNF promoter DNA methylation levels.
Methods: A cross-sectional RA population (n⫽218) and healthy controls
(n⫽312) was used to investigate the primary objective.A second population
of RA patients starting MTX were recruited (n⫽33) and DNA and DAS28
scores were obtained prior to treatment and at 3 months.Methylation of seven
TNF 5’ CpG motifs (⫺349 to ⫺78) and LINE-1, an assay of genomic
mehtylation, in peripheral blood leucocytes were assessed by pyrosequencing
and levels of TNF mRNA were measured using quantitative PCR.
Results: Levels of methylation of 4 TNF CpGs (⫺170, ⫺239, ⫺245,
⫺304) were higher in RA compared with controls (p⫽7.1 ⫻ 10⫺5 to 1.3 ⫻
10⫺10) and TNF mRNA was 58% lower in RA cases (p⫽1.5 ⫻ 10⫺10).In
both RA and controls negative correlations of TNF-245 methylation with
TNF mRNA levels were detected (p⫽0.02 and 0.04 respectively). There was
no difference in LINE-1 or TNF methylation in MTX treated patients and no
correlation between change in methylation with DAS28 response after 3
months.
Conclusion: Higher levels of methylation of the TNF promoter are
present in RA leukocytes compared with controls, and levels of TNF mRNA
were lower in the patients.Methylation levels of TNF-245 were inversely
correlated with TNF mRNA levels in both groups.Treatment with MTX was
not associated with changes in genomic or TNF methylation levels.These
results suggest that methylation of the TNF promoter is higher in RA
compared with controls and that methylation of TNF-245 is an important
regulatory mark for TNF expression.
attempted replication of 18 single nucleotide polymorphisms (SNPs) previously reported in the literature to be associated with hip or knee OA by the
TREAT-OA Consortium, arcOGEN Study and others.
Methods: Cases with knee OA were Caucasians who had at least one
knee with definite radiographic OA (Kellgren-Lawrence [KL] grade ⬎⫽2) at
any available visit.Controls were Caucasians who were free of definite
radiographic OA in both knees (KL grade ⬍⫽1) at all available study visits.In
total, data from 2014 cases and 953 controls from the OAI and 653 cases and
823 controls from the JoCo Study were included in the analysis. The OAI and
JoCo DNA samples were genotyped using the Illumina 2.5M and Illumina
1M genotyping chip, respectively.In both studies imputation was performed
using the 1000 genomes reference panel (June 2011 release) and statistical
analysis was performed assuming an additive genetic model and adjusting for
participant age and sex. Fixed-effects meta-analysis was conducted using
METAL.
Results: Over 5.8 million SNP variants present in both the OAI and JoCo
datasets and having both high quality 1000 genomes imputation (r2⬎0.3) and
minor allele frequency of at least 5% were included in the meta-analysis.Ten
variants had a meta-analysis P-value ⬍ 1 ⫻ 10⫺6 with Odds Ratios ranging
from 1.27–1.54.The 10 variants were located in three loci: one on chromosome 11p15.4 upstream of the TRIM21 gene (encodes for tripartite motifcontaining protein 21, an intracellular antibody effector in the proteolysis
pathway), and two in non-genic regions of chromosome 11p15.3and chromosome 2q35; the closest genes to the latter region being MREG and FN1
(FN1 encodes for fibronectin, a glycoprotein that binds to chondrocytes and
is involved in cell adhesion and migration).Similar to previously reported
findings (Osteoarthritis Cart 2012;20[Suppl 1]:S46), only the rs143383 SNP
in GDF5 (Growth and Differentiation Factor 5) was modestly associated with
knee OA (P ⫽ 0.006) in the current analysis.
Conclusion: These data support the polygenic nature of the genetic
contribution to knee OA. Further analyses will consist of both de novo and in
silico replication in other datasets and populations.
sclerosis); ANTXR2, RUNX3 and ERAP1 (AS). Genes associated with
neurodegenerative diseases in which ER stress is known to play a role in
disease pathology–amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease–are also represented among the regulators.
Conclusion: These results allowed us to identify genes and their regulators involved in ER stress response in human B-cells. The presence of
susceptibility genes for autoimmune diseases among the regulators identified
in our study implicates ER stress in disease pathology. Identification of
TNFSF13B as an ER stress-responsive gene in human B-cells provides
further evidence of a link between ER stress and inflammation.
Disclosure: W. E. Bernal, None; M. P. Morley, None; V. G. Cheung, None.
Monday, November 12
988
Zone-Specific Protein Profiles in Human Cartilage Unraveled by a
Quantitative Proteomic Approach. Patricia Fernandez-Puente1. Lucia
Lourido2, Valentina Calamia2, Jesus Mateos2, Cristina Ruiz-Romero2, Martin
K. Lotz3 and Francisco J. Blanco2, 1Osteoarticular and Aging Research
Group. Rheumatology Division, Biomedical Research Center (INIBIC).
Hospital Universitario A Coruña, As Xubias de Arriba 84, 15006, A Coruña,
Spain, 2Rheumatology Division, Proteomics Group/ProteoRed-ISCIII,
INIBIC-C. Hospitalario, A Coruña, Spain, 3Department of Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla, CA
Background/Purpose: Articular cartilage consists of a single type of
cells called chondrocytes, which comprise 2–5% of total tissue mass and an
extracellular matrix (ECM) mainly composed of water, proteoglycans and
collagens. The tissue function is dependent on the molecular composition of
this ECM. Articular cartilage is characterized by a zonal architecture with
unique cell phenotypes and ECM properties in the superficial, middle and
deep zone. In osteoarthritis (OA), cartilage is thinned, eventually completely
degraded, resulting in joint dysfunction and pain. OA is also associated with
hypertrophic bone changes with osteophyte formation, subchondral bone
remodeling, and, chronic inflammation of the synovial membrane. The final
common pathway of cartilage destruction results from a failure of chondrocytes to maintain a homeostatic balance between matrix synthesis and
degradation. There is a considerable interest pointed in the characterization of
new cartilage specific OA biomarkers for diagnosis and disease progression
studies in OA. The aim of this work was to identify and localize proteins in
normal cartilage, and compare them to the osteoarthritic tissue in a quantitative way.
Methods: Cartilage samples were obtained from OA patients undergoing
joint replacement and normal donors without history of joint disease (n⫽3).
For the localization studies, independent normal cartilage samples (n⫽3)
were sectioned into three layers (superficial, middle and deep). Cartilage
proteins were extracted, quantified, digested with trypsin and differentially
labelled with iTRAQ isobaric tags.The peptide mixture was separated by
two-dimensional LC coupled to MALDI-TOF/TOF mass spectrometry.
Identification and relative quantification of the proteins were performed using
ProteinPilot 3.0 software.
Results: We identified 220 different proteins in normal articular cartilage.
An increased abundance of type VI collagen and small proteoglycans
(mimecan, lumican or PRG4) was detected in the superficial layer of cartilage.
Several proteins involved in cell adhesion processes were also increased in
this layer (gelsolin, vitronectin, tenascins). The middle layer was characterized by a high presence of type II, V, IX and XXVIII collagens, cartilage
intermediate layer proteins (CILPs), COMP, vitrin and decorin. Finally, the
deep layer exhibited an increased abundance of type I and XI collagens,
aggrecan and bone-related proteins (bone sialoprotein 2, osteomodulin, and
bone morphogenetic protein 3). Comparison of this normal cartilage proteome with that from OA tissue led to the identification of 281 proteins: 23
were increased in the pathologic tissue (including aggrecan, COMP, complement factors or thrombospondin 1), whereas 36 were decreased in OA
cartilage, such as type I, II and VI collagens, proteoglycans (biglycan, PRG4),
tenascins or actin.
Conclusion: In summary, more than 300 different human articular
cartilage proteins have been mapped according to their presence in the three
different tissue layers. 59 of them were altered in OA cartilage when
compared to normal tissue. This information would be of high relevance in
the search of tissue-specific OA biomarkers.
Disclosure: P. Fernandez-Puente, None; L. Lourido, None; V. Calamia, None; J.
Mateos, None; C. Ruiz-Romero, None; M. K. Lotz, None; F. J. Blanco, None.
989
Genome-Wide Analysis Reveals a Recessive Association of ERAP1
Variants with Behçet’s Disease and Epistasis Between ERAP1 and
HLA-B*51. Elaine F. Remmers1, Yohei Kirino1, George Bertsias1, Yoshiaki
Ishigatsubo2, Yoonhee Kim3, Michael J. Ombrello1, Ilknur Tugal-Tutkun4,
Emire Seyahi5, Yilmaz Ozyazgan5, F. Sevgi Sacli5, Burak Erer4, Zeliha
Emrence6, Atilla Cakar6, Neslihan Abaci6, Duran Ustek6, Colleen Satorius1,
Mitsuhiro Takeno2, Ahmet Gül4 and Daniel L. Kastner1. 1National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD,
2
Yokohama City University Graduate School of Medicine, Yokohama,
Japan, 3National Human Genome Research Institute, National Institutes
of Health, Baltimore, MD, 4Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, 5Cerrahpasa Faculty of Medicine, Istanbul University,
Istanbul, Turkey, 6Institute of Experimental Medicine, Istanbul University,
Istanbul, Turkey
Background/Purpose: We recently performed a genome-wide association study in 1215 patients with Behçet’s disease (BD) and 1278 controls
from Turkey and found disease-associated variants within the class I region of
the MHC, and in the IL10 and IL23R loci. However, the combined effects of
these loci account for less than 10% of the estimated disease heritability,
suggesting other loci are yet to be identified.
Methods: To limit disease heterogeneity, we performed an analysis of
the subset of patients with uveitis. In this subset we expanded the association
analysis to include 3 genetic models, additive, dominant, and recessive,
correcting the threshold for genome-wide significance for the 3 models
examined.Confirmatory studies were conducted in our combined GWAS and
replication sets of 2017 BD cases and 1875 controls, and in this sample an
interaction between two loci was evaluated with a logistic likelihood ratio test
comparing a full model (including a multiplicative interaction term) with a
reduced model (without the interaction term).
Results: A genome-wide analysis, applying a recessive model, in 420 BD
patients with uveitis and 1278 controls revealed one variant located 5⬘ of
ERAP1, with near genome-wide significance (rs2927615, p ⫽ 1.02 ⫻
10⫺7).This effect was not observed with an additive or dominant model.ERAP1 encodes an endoplasmic reticulum expressed aminopeptidase that
plays an important role in trimming and loading intracellular peptides for
class I MHC presentation. Fine-mapping with the same samples and replication in an independent collection of 370 Turkish BD cases with uveitis and
630 controls identified two disease-associated non-synonymous variants in
ERAP1, with the most significant combined p value for rs17482078
(R725Q) ⫽ 4.73 ⫻ 10⫺11, OR ⫽ 4.56, 95%CI: 2.88–7.22). Focusing solely
on the recessive model, the effect of the variant was corroborated by
meta-analysis of the combined 2017 BD cases (including those with and
without uveitis) and 1875 controls (p ⫽ 4.35 ⫻ 10⫺8). Furthermore, we
identified a genetic interaction between the BD-associated MHC class I allele,
HLA-B*51, and ERAP1 (p ⬍ 0.0009) in the combined Turkish GWAS and
replication samples. ERAP1 R725Q homozygosity compared with nonhomozygosity was associated with an OR for BD of 3.78 (95% CI ⫽
1.94–7.35) in HLA-B*51 positive individuals versus an OR of 1.48 (95% CI
⫽0.78–2.80) in HLA-B*51 negative individuals.
Conclusion: A coding variant of ERAP1, encoding endoplasmic reticulum expressed amino peptidase 1, recessively confers risk for BD preferentially to individuals carrying the disease-associated HLA-B*51 allele. Genetic
similarity with two other MHC class I associated diseases, ankylosing
spondylitis and psoriasis (shared loci include MHC class I, IL23R, ERAP1
and the MHC-ERAP1 interaction), suggest shared pathogenic pathways
among these diseases.
Disclosure: E. F. Remmers, None; Y. Kirino, None; G. Bertsias, None; Y.
Ishigatsubo, None; Y. Kim, None; M. J. Ombrello, None; I. Tugal-Tutkun, None; E.
Seyahi, None; Y. Ozyazgan, None; F. S. Sacli, None; B. Erer, None; Z. Emrence,
None; A. Cakar, None; N. Abaci, None; D. Ustek, None; C. Satorius, None; M.
Takeno, None; A. Gül, None; D. L. Kastner, None.
990
Proteomic Shotgun Analysis of Mesenchymal Stem Cells Reveals an
Alterated Regulation of Proteosomal Proteins in Osteoarthritis Patients.
Jose Ramon Lamas. Hospital clinico San Carlos, Madrid, Spain
Background/Purpose: To describe proteins with a potential role in OA
pathogenesis, in this study we have followed a proteomic approach based on
a shotgun comparative analysis of Mesenchymal Stem Cells (MSCs) isolated
from OA patients and healthy donors.
S428
Disclosure: J. R. Lamas, None;
991
MTHFR Polymorphisms in Systemic Lupus Erythematosus and
Rheumatoid Arthritis: Associations with Intima Media Thickness
Scores. Clio P. Mavragani1, Maira Giannelou2, Ioanna Papadaki3, Eleni
Antypa4, Dimitrios Ioakeimidis5, Haralampos M. Moutsopoulos2 and
Michael Koutsilieris1. 1School of Medicine, University of Athens, Athens, Greece, Athens, Greece, 2School of Medicine, University of Athens,
Athens, Greece, 3General Hospital of Athens “G. Gennimatas”, Athens,
Greece, 4General Hospital of Athens, Greece, 5General Hospital, Greece
Background/Purpose: Previous studies identified polymorphisms in
the gene coding for the Methylenetetrahydrofolatereductase (MTHFR)
enzyme as genetic contributors for cardiovascular disease in the general
population. The purpose of the present study was to determine the
prevalence of the MTHFR polymorphisms for either 677 or 1298 allele in
patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and to investigate whether they associate with carotid and femoral
intima media thickness scores and plaque formation.
Methods: 77 consecutive SLE patients, according to the American/
European classification criteria, 101 RA patientsand 137 healthy controls
were enrolled. All study groups were assessed for MTHFR 677CT or
1298AC genotype. Furthermore, all patients underwent ultrasound determination of intima-media thickness score (IMT) and plaque formation in
the carotid and femoral arteries.Data regarding clinical, hematological,
serological, immunological information and therapeutic regimens were
recorded in all patients. Classical risk factors for cardiovascular disease
were also assessed.
Results: The prevalence of MTHFR TT and CC genotypes in the SLE
group was 25% (19 of 77 patients) for the 677 allelle and 10.5% (8 of 77
patients) for the 1298 allele, respectively. The corresponding figures for
the RA group were 9% (12 of 133) and 9.8% (13 of 133) and the healthy
controls 13.13% (18 of 137) and 9.48% (13 of 137), respectively. A
significantly higher prevalence for the MTHFR homozygous 677TT
mutation was observed in patients with SLE compared to both RA patients
and healthy controls (p-values 0.004 and 0.038, respectively). No differences were detected in the prevalence of the different MTHFR genotypes
between RA and healthy controls.
Among the 77 SLE patients evaluated for subclinical atherosclerosis,
25 (32.46%) had increased IMT scores (defined as ⬎0.90mm) and 44
(57.14%) had plaque. IMT score was found positively associated with the
presence of either the MTHFR 677 or 1298 homozygous mutation
(p⫽0.026). A trend of increased IMT scores was detected in RA patients
sharing the heterozygous MTHFR 1298 AC genotype compared to the
other groups.No correlation was found between the development of
plaque and the presence of any MTHFR mutation in SLE and RA
populations.
Conclusion: The prevalence of MTHFR homozygous mutation for
677 allelle was significantly higher in SLE compared to RA and controls.
Furthermore, IMT score was found positively associated to homozygocity
for either MTHFR 677TT or 1298CC, suggesting the effect of genetic risk
factors in the accelerated atherosclerotic disease characterizing SLE
patients.
Disclosure: C. P. Mavragani, None; M. Giannelou, None; I. Papadaki, None; E.
Antypa, None; D. Ioakeimidis, None; H. M. Moutsopoulos, None; M. Koutsilieris,
None.
992
Functional Genomics of the Human ITGAM Locus. Yebin Zhou1, Dan C.
Bullard1, Alexander Szalai2. Jianming Wu3 and Jeffrey C. Edberg4, 1University of Alabama at Birmingham, Birmingham, AL, 2University of alabama
at birmingham, Birmingham, AL, 3University of minnesota, St. Paul, MN,
4
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
Background/Purpose: ITGAM encodes CD11b, the ␣M subunit of
the Mac-1-␣M␤2 integrin. Mac-1 has many functions on leukocytes
including its role as an adhesion molecule and complement receptor.Genome wide association studies (GWAS) have demonstrated that a nonsynonymous SNP in the ITGAM locus, rs1143679 encoding an Arg/His in
the extracellular domain, is associated with SLE susceptibility. This
variant is in strong linkage disequilibrium with another common nonsynonymous SNP (rs1143678 encoding a Ser/Lys in the cytoplasmic
domain). We have explored possible functional changes due to these
ITGAM variants through analysis of expression level, activation and cell
function using ex vivo approach with neutrophils from genotyped healthy
donors.
Methods: Neutrophils from healthy control donors genotyped at both
rs1142679 and rs1143678 were isolated for ex-vivo functional studies.The
phagocytic potential of CD11b variants was probed with complement
coated erythrocytes (EAC) and serum treated zymosan (STZ).The adhesion potential of ITGAM variants was assessed in a flow chamber
analyzing neutrophil adhesion to both ligand (ICAM-1) and endothelial
cells.Total neutrophil CD11b expression and expression of the activation
dependent I-domain was assessed by flow cytometry.
Results: In 2424 healthy control donors, we confirmed strong LD
between SNP rs1134678 and rs1143679 (D’⫽0.97, r⫽0.82).We assessed
the functional potential of neutrophils from donors heterozygous for each
SNP alone using STZ to determine complement dependent binding and
phagocytosis.Variation at either SNP results in a quantitative decrease in
STZ phagocytosis and that donors heterozygous for both variants had
even lower phagocytosis (repeated measures ANOVA, p⬍0.04,
n⫽3).Quantitative complement dependent phagocytosis was also significantly decreased in donors homozygous for the variant alleles (39%
decrease for STZ, n⫽3 pairs, p⬍0.02/38% decrease for EAC, n⫽3 pairs,
p⬍0.02).In a flow chamber based assay of neutrophil adherence, cells
from donors homozygous for the variant alleles of rs1134678 and
rs1143679 adhered significantly less than neutrophils for donors homozygous for the common alleles (adherence to ICAM-1/endothelial cells:42%
decrease, n⫽3 pairs, p⬍0.002/46% decrease, n⫽4 pairs, p⬍0.001).
These functional changes in neutrophil Mac-1 function were not attributable to differences in total CD11b expression nor to difference in expression
of the activation induced I-domain in donors homozygous for the common vs.
variant alleles of ITGAM.
Conclusion: We demonstrate that ITGAM variants rs1143678 and
rs1143679 SNP each make separate contributions to alterations in Mac-1
function on human neutrophils.These functional alterations are not caused by
differences in quantitative total receptor expression or expression of the
I-domain.The study of the functional consequences of allelic variants associated with disease in primary human cells is necessary to fully understand the
role of disease associated genetic variants.
Disclosure: Y. Zhou, None; D. C. Bullard, None; A. Szalai, None; J. Wu, None; J. C.
Edberg, None.
S429
Monday, November 12
Methods: MSCs were obtained from bone marrow aspirates at the
time of joint replacement surgery of three OA patients (mean age 76.7
years) and three hip fracture subjects without OA (mean age 73.3). Cells
were cultured and expanded. Confluent cells at the third passage (approximately 2 ⫻ 106) were used for the experiments. After Protein extraction,
solubilization and digestion, samples were subjected to a LC-MS shotgun
analysis. For protein identification the MS/MS spectra were extracted
using the Proteome Discoverer 1.0 software and searched against the
MSIPI human database (version 091510) using the Mascot 2.1 program.
GeneCodis 2.0 software was used for functional classification of differential proteins.
Results: A total of 1748 proteins were identified. The statistical
analysis revealed 123 differentially expressed proteins between OA-MSCs
and control MSCs with foldchange values ⬎ 2 times at the p ⬍ 0.05 level
of significance, of which 76 (62%) were upregulated and 47 (38%) were
downregulated in OA-MSCs as compared with control cells. Interestingly,
five proteosomal proteins, pertaining to the regulation of ubiquitin-protein
ligase activity biological function: PSMD2 (2.52), PSMA1 (3.36),
PSMB3 (4.56), PSMA3 (7.08) and PSMA4 (13.26) were clearly upregulated.
Conclusion: Given that proteasomal-dependent degradation has a
critical role in regulating activities of key osteoblastogenic transcription
factors (e.g., RUNX2, ATF4) and signaling pathways (e.g., Hedgehog,
BMP, Wnt/␤-catenin), upregulation of proteasome subunits and increased
activity in MSCs from OA patients might be related to reduced bone mass
and/or poor bone tissue quality in OA patients.
Monday, November 12
993
994
A Genome-Wide DNA Methylation Analysis Reveals Different Methylation
Patterns in the OA Disease. Ignacio Rego-Pérez1, Juan Fernandez-Tajes1.
Mercedes Fernandez-Moreno1, Maria Tamayo Novas2, Alejandro Mosquera
Rey2, Natividad Oreiro1, Carlos Fernandez-Lopez1, Jose Luis Fernandez Garcia2
and Francisco J. Blanco1. 1INIBIC-Hospital Universitario A Coruña. Rheumatology Division. Genomic Group, A Coruña, Spain, 2INIBIC-Hospital Universitario A Coruña. Genetic Deparment., A Coruña, Spain
The Genome-Wide Expression of Human Osteoarthritic Cartilage
Shows A Differential Pattern Between Two Subgroups of OA Patients.
Ignacio Rego-Perez, Juan Fernandez-Tajes. Angel Soto-Hermida, Mercedes
Fernandez Moreno, Maria Eugenia Vazquez Mosquera, Natividad Oreiro,
Carlos Fernandez-Lopez, Estefania Cortes Pereira, Sara Relaño-Fernandez
and Francisco J. Blanco, INIBIC-Hospital Universitario A Coruña. Genomic
Group. Rheumatology Division., A Coruña, Spain
Background/Purpose: DNA methylation is a basic mechanism involved in
epigenetic regulation that affects gene transcription by the addition of a methyl
group to the cytosine residue within a CpG dinucleotide to form methylated
cytosine. The objective of this work is to identify and analyze the genome-wide
DNA methylation profiles of human articular chondrocytes from a populationbased case-control study of OA.
Methods: DNA methylation profiling was performed using the Infinium
HumanMethylation27 beadchip (Illumina Inc.), which allows interrogation of
27,578 highly informative CpG loci. Previously, cartilage isolated DNA from
23 OA patients and 19 healthy controls was bisulfite-modified, using the EZ
DNA methylation kit (Zymo Research) and hybridized according to the
manufacturerxs instructions. DNA methylation b-values were normalized
using GenomeStudio v3.0 (Illumina Inc.). Appropriate bioinformatics analyses were carried out using both R bioconductor software packages and
Babelomics suite v4.2 (babelomics.bioinfo.cipf.es).
Results: A first approach based on an unsupervised clustering method for the
most variable CpG loci (n⫽508) showed three distinct groups of samples called
cluster 1, cluster 2 and cluster 3. Specifically, cluster 2 formed a particularly tight
cluster with a characteristic DNA methylation profile (Figure 1). The analyses of
the biological relevance of the differentially methylated genes in cluster 2
compared with non-cluster 2 by means of a gene set enrichment approach,
showed that some of the biological processes significantly altered were those
related to cellular adhesion, morphogenesis/angiogenesis and regulation of cell
proliferation, all of them hypermethylated in cluster 2; on the contrary, those
genes related to cytokine secretion/production as well as immune response and
inflammation appeared significantly hypomethylated in cluster 2.
Background/Purpose: Many genes, many of them still unknown, are
involved in the etiology and development of OA. Today, different tools are
available to try to identify some of the key genes related to the OA process.
Therefore, the objective of this work is to perform a genome-wide expression
assay in order to identify different expression profiles in the OA disease
Methods: Total RNA from OA cartilage samples was isolated with
RNeasy Kit (Qiagen, Madrin, Spain) following manufacturerxs instructions.
RNA was checked for integrity and purity with the Agilent Bioanalyzer
(Agilent Technologies) and NanoDrop spectrophotometer (Thermo Scientific). 150 nanograms of total RNA were used for cDNA synthesis using the
Ambion WT Expression kit (Ambion). The fragmented cDNA was hybridized against the Human Gene 1.1 ST array strip (Affymetrix) and scanned
using the GeneTitan system (Affymetrix). Quality controls, normalization,
pre-processing, differential gene expression and functional analyses were
carried out with Bioconductor packages using R software.
Results: Human Gene 1.1 ST Array, which interrogates more than 28,000
well-annotated genes of 33,297 probes, was used for studying the genome wide
expression profile of 23 OA-patients cartilage samples. A non-specific filtering
was previously applied for removing those probes with non-annotation information and with low intra-array variation. An unsupervised machine learning
approach revealed a group of samples highly different (Figure 1). The differential
expression analysis between this cluster, comprising a total of six OA-patients,
and the rest of the samples allowed for the identification of 176 differentially
expressed probes with an adjusted p value below 0.0001. The analysis of the
biological processes related to these differentially expressed genes showed that
inflammation and immune processes were the main pathways found to be altered
when a gene set enrichment analysis was applied.
Figure 1. Heatmap showing the three distinct clusters. Cluster 2 shows a
characteristic DNA methylation profile clearly different from the other two clusters.
Conclusion: The genome-wide methylation analysis shows a clearly distinct
epigenetic profile for OA patients. The DNA methylation profile could be one of
the reasons of the existence of different forms OA and could also be related to
both the prevalence and progression of this disease.
Disclosure: I. Rego-Pérez, None; J. Fernandez-Tajes, None; M. FernandezMoreno, None; M. Tamayo Novas, None; A. Mosquera Rey, None; N. Oreiro, None;
C. Fernandez-Lopez, None; J. L. Fernandez Garcia, None; F. J. Blanco, None.
Figure 1. Dendrogram showing the two different groups of OA patients. Cluster
2 shows a characteristic expression profile among OA patients.
Conclusion: The genome-wide expression analysis shows a clearly
distinct profile for a group of OA patients. Both inflammation and immune
response processes appeared to be significantly altered and revealed as key
factors in the development of the OA disease.
Disclosure: I. Rego-Perez, None; J. Fernandez-Tajes, None; A. Soto-Hermida,
None; M. Fernandez Moreno, None; M. E. Vazquez Mosquera, None; N. Oreiro,
None; C. Fernandez-Lopez, None; E. Cortes Pereira, None; S. Relaño-Fernandez,
None; F. J. Blanco, None.
S430
995
996
Genetic Effects of HLA-DRB1, IL4R, and Fc␥RIIb On Long-Term
Treatment Responses in Patients with Early Rheumatoid Arthritis:
78-Week Results of a Phase 4 Study. Alla Skapenko1, Josef S. Smolen2,
Arthur Kavanaugh3, Vipin Arora4, Hartmut Kupper5 and Hendrik SchulzeKoops1. 1University of Munich, Munich, Germany, 2Medical University of
Vienna and Hietzing Hospital, Vienna, Austria, 3UCSD School of Medicine,
La Jolla, CA, 4Abbott, Abbott Park, IL, 5Abbott GmbH and Co. KG,
Ludwigshafen, Germany
Genetic Predictors of Methotrexate Efficacy and Toxicity in Early
Rheumatoid Arthritis: Results From the Treatment of Early Aggressive
Rheumatoid Arthritis Trial. Stella Aslibekyan1, Elizabeth Brown2, Richard
J. Reynolds1, David T. Redden1, Sarah L. Morgan3, Joseph Baggott1, Jin
Sha1, Larry W. Moreland4. James R. O’Dell5, Jeffrey R. Curtis6, S. Louis
Bridges Jr.7 and Donna K. Arnett1, 1University of Alabama at Birmingham,
Birmingham, AL, 2Univ of Alabama at Birmingham, Birmingham, AL,
Birmingham, AL, 3University of Alabama Birmingham, Birmingham, AL,
4
University of Pittsburgh, Pittsburgh, PA, 5Univ of Nebraska Med Ctr,
Omaha, NE, 6Univ of Alabama-Birmingham, Birmingham, AL, 7Marguerite
Jones Harbert-Gene V. Ball, MD Professor of Medicine, and Director,
Division of Clinical Immunology and Rheumatology, University of Alabama
at Birmingham, Birmingham, AL
Table. Percentage of Pts with DAS28 ⬍3.2 at Week 78, n/N (%), non-responder
imputation
Treatment
0x
HLA-DRB1 SE
1x
2x
AA
IL4R
AG
GG
TT
Fc␥RIIb
TC
CC
ADA WITHDRAWAL
21/28
(75.0)
25/36
(69.4)
17/22
(77.3)
23/31
(74.2)
33/44
(75.0)
7/11
(63.6)
43/63
(68.3)
17/20
(85.0)
3/3
(100)
ADA CONTINUATION
16/22
(72.7)
36/45
(80.0)
18/20
(90.0)
23/31
(74.2)
33/39
(84.6)
14/17
(82.4)
54/67
(80.6)
14/18
(77.8)
2/2
(100)
OL ADA CARRY ON
29/81
(35.8)
49/
113
(43.4)
18/36
(50.0)
28/68
(41.2)
49/
109
(45.0)
19/53
(35.8)
87/
200
(43.5)
8/29
(27.6)
1/1
(100)
MTX CONTINUATION
30/40
(75.0)
59/
115
(51.3)
25/38
(65.8)
10/15
(66.7)
18/24
(75.0)
31/44
(70.5)
16/25
(64.0)
47/69
(68.1)
18/24
(75.0)
80/
148
(54.1)
19/42
(45.2)
49/93
(52.7)
83/
164
(50.6)
26/48
(54.2)
117/
225
(52.0)
40/76
(52.6)
0/0
(0)
1/4
(25.0)
RESCUE ADA
Background/Purpose: Methotrexate (MTX) has emerged as first-line
therapy for early moderate to severe rheumatoid arthritis (RA), but individual
variation in treatment efficacy and toxicity remains unexplained. We test the
hypothesis that genetic markers in genes involved in drug metabolism,
excretion, and transport are associated with MTX response in early RA.
Methods: Treatment of Early Aggressive Rheumatoid Arthritis Trial
participants (n⫽471) were analyzed for 863 markers spanning 224 genes
from key pharmacogenetic pathways. Multiple regression models were fit
with efficacy (Disease Activity Score on 28 joints at 24 weeks) and toxicity
(self-report of any side effects or infections) as outcomes, adjusted for age,
sex, race, and treatment, and single markers as predictors. Penalized regression models were used to test joint associations of markers and/or covariates
with the outcomes.
Results: The strongest genetic associations with efficacy were in the
CHST11 gene (five markers with P ⬍0.0024), encoding carbohydrate
(chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 superfamily genes CYP20A1 and
CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2 (P⬍0.004). Results from the
penalized regression models included only genetic markers for the toxicity
outcome, while clinical covariates were stronger predictors of MTX efficacy.
The selected markers explained more variance in toxicity (9%) than efficacy
(4%).
Conclusion: We identified several novel and biologically relevant genetic
markers associated with MTX response in early RA. These preliminary
findings could inform future development of personalized therapeutic approaches.
Disclosure: S. Aslibekyan, None; E. Brown, None; R. J. Reynolds, None; D. T.
Redden, None; S. L. Morgan, None; J. Baggott, None; J. Sha, None; L. W.
Moreland, None; J. R. O’Dell, None; J. R. Curtis, Roche/Genetech, UCB, Centocor,
CORRONA, Amgen Pfizer, BMS, Crescendo, Abbott, 5, Roche/Genetech, UCB,
Centocor, CORRONA, Amgen Pfizer, BMS, Crescendo, Abbott, 2; S. L. Bridges Jr.,
None; D. K. Arnett, None.
997
Conclusion: Regardless of genetic background, wk 78 responses were
generally higher for pts who achieved the stable LDA target at wks 22 & 26.
The positive effects of HLA-DRB1 SE and Fc␥RIIb-CC in response to
ADA⫹MTX previously noted at wk 26 were less apparent at wk 78, but
noticeable in pts who failed to achieve the target. Further, while SE predicted
clinical response to ADA⫹MTX, particularly when combined with IL4R
alleles, it had no influence on the ability to withdraw ADA in pts who
achieved LDA. These findings may indicate that genetic factors have a
stronger influence on initial treatment response than on sustained disease
control.
Reference
1. Skapenko A, et al. EULAR 2011 [THU0309].
Disclosure: A. Skapenko, None; J. S. Smolen, Abbott, Amgen, AstraZeneca, BMS,
Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough),
Novo-Nordisk, Roche, Sandoz, and UCB, 2, Abbott, Amgen, AstraZeneca, BMS,
Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough),
Novo-Nordisk, Roche, Sandoz, and UCB, 5; A. Kavanaugh, Abbott, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, 2, Abbott, Amgen,
Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, 5; V. Arora,
Abbott Laboratories, 1, Abbott Laboratories, 3; H. Kupper, Abbott Laboratories, 1,
Abbott Laboratories, 3; H. Schulze-Koops, Abbott Laboratories, 5.
Evidence of Novel Genetic Predictors of Methotrexate Efficacy in
Rheumatoid Arthritis. Stella Aslibekyan1, Maria I. Danila2, Jin Sha1, David
T. Redden1, Richard J. Reynolds1, Elizabeth Brown3, Laura B. Hughes1,
Molly S. Bray1, Sarah L. Morgan4, Larry W. Moreland5. James R. O’Dell6,
Jeffrey R. Curtis2, Robert P. Kimberly1, Lindsey A. Criswell7, Robert M.
Plenge8, S. Louis Bridges Jr.9 and Donna K. Arnett1, 1University of Alabama
at Birmingham, Birmingham, AL, 2Univ of Alabama-Birmingham, Birmingham, AL, 3Univ of Alabama at Birmingham, Birmingham, AL, Birmingham,
AL, 4University of Alabama Birmingham, Birmingham, AL, 5University of
Pittsburgh, Pittsburgh, PA, 6Univ of Nebraska Med Ctr, Omaha, NE,
7
University of California San Francisco, San Francisco, CA, 8Brigham and
Women’s Hospital, Boston, MA, 9Marguerite Jones Harbert-Gene V. Ball,
MD Professor of Medicine, and Director, Division of Clinical Immunology
and Rheumatology, University of Alabama at Birmingham, Birmingham, AL
Background/Purpose: Methotrexate (MTX), a disease-modifying
anti-rheumatic drug used as first-line therapy in rheumatoid arthritis (RA),
is characterized by considerable heterogeneity in individual treatment
response. We tested the hypothesis that polymorphisms in RA susceptibility genes and MTX metabolism pathways are associated with MTX
efficacy and toxicity.
S431
Monday, November 12
Background/Purpose: Previous analyses suggested that the HLA-DRB1
shared epitope (SE), and the IL4R V50I and the Fc␥RIIb I232T single
nucleotide polymorphisms (SNPs) affected response to adalimumab (ADA)
plus methotrexate (MTX) at 26 weeks.1 Their effect on long-term responses
is unclear. To examine 78-wk clinical responses according to 3 candidate loci:
HLA-DRB1 SE, and IL4R I50V and Fc␥RIIb I232T SNPs.
Methods: MTX-naı̈ve patients (pts) ⱖ18 yrs with RA ⬍1 yr, active
disease [DAS28(CRP)⬎3.2, ESRⱖ28 mm/hr or CRPⱖ1.5 mg/dL], and ⬎1
erosion, RF⫹, or anti-CCP⫹ were randomized to ADA⫹MTX or placebo
(PBO)⫹MTX for 26 wks (Period 1, P1). Pts who achieved a stable LDA
target (DAS28⬍3.2 at wks 22 & 26) with ADA⫹MTX were re-randomized
to continue ADA⫹MTX (ADA Continuation arm) or have ADA blindly
withdrawn (ADA Withdrawal arm) for 52 wks (P2). Pts who achieved the
stable LDA target with PBO⫹MTX continued blinded therapy (MTX
Continuation arm). Pts who did not achieve the stable LDA target with initial
combination therapy or MTX monotherapy were offered open-label (OL)
ADA⫹MTX (OL ADA Carry On and Rescue ADA arms, respectively).
Results: Baseline demographics were similar across alleles. The Table
shows the percentage of pts achieving DAS28⬍3.2 at wk 78. There were no
consistent patterns for the IL4R alleles in any group. While limited by small
sample sizes, pts with Fc␥RIIb-CC appeared to have higher responses at wk
78 among groups initially exposed to ADA⫹MTX during P1. The positive
influence of SE was apparent at wk 78 in groups originally exposed to
ADA⫹MTX, particularly in pts who did not achieve the stable LDA target at
wks 22 & 26 but continued ADA⫹MTX. However, this pattern was not
observed in pts who failed to achieve the target with MTX and were
subsequently treated with ADA⫹MTX.
Monday, November 12
Methods: Data from a combined population of three MTX trials
(Treatment of Early Aggressive RA Trial; Immunex Early RA Trial; UAB
Folic Acid Supplementation Trial, total subjects ⫽ 633) were analyzed for
3,127 genetic markers previously linked to RA risk or MTX metabolism
pathways, with MTX efficacy (defined as the change joint count scores
over 24 weeks of MTX therapy) and toxicity (defined as self-report of any
adverse events) as outcomes. Gene-based tests were conducted to complement single marker analyses. All statistical models were adjusted for
age, sex, race, and treatment as fixed effects, and for study as a random
effect; the efficacy models were additionally adjusted for baseline disease
activity.
Results: In the MTX efficacy models, the strongest signals were observed
with variation in genes encoding efflux transporters (ABCC1; gene-based P⫽
1.4 ⫻ 10–4), B cell surface antigen (CD40, gene-based P⫽3.8 ⫻ 10–4), and
immunoglobulin receptors (FCGR2A, FCGR3A; gene-based P⫽ 1.5 ⫻ 10–5
and P⫽ 1.6 ⫻ 10–5 respectively). Although no genetic variants reached
statistical significance in the models of adverse effects associated with MTX
therapy, the top hits included markers near GFRA2 (rs12549890, P⫽ 2.8 ⫻
10–3), the ABCA12 transporter (rs4673907, P⫽ 4.6 ⫻ 10–3), and multiple
SNPs in ADK included in the adenosine pathway.
Conclusion: This study provides preliminary identification of several
novel targets relevant to MTX metabolism in RA. These findings will inform
future studies aimed at developing pharmacogenetic tools to predict response
to MTX therapy.
Disclosure: S. Aslibekyan, None; M. I. Danila, None; J. Sha, None; D. T. Redden,
None; R. J. Reynolds, None; E. Brown, None; L. B. Hughes, None; M. S. Bray,
None; S. L. Morgan, None; L. W. Moreland, None; J. R. O’Dell, None; J. R. Curtis,
Roche/Genetech, UCB, Centocor, CORRONA, Amgen Pfizer, BMS, Crescendo,
Abbott, 5, Roche/Genetech, UCB, Centocor, CORRONA, Amgen Pfizer, BMS,
Crescendo, Abbott, 2; R. P. Kimberly, None; L. A. Criswell, None; R. M. Plenge,
None; S. L. Bridges Jr., None; D. K. Arnett, None.
998
Association Study of Genetic Risk Variants for Psoriasis in a Large
Cohort of Psoriatic Arthritis, Psoriasis and Controls of the Spanish
Population and Association with Relevant Clinical Subphenotypes. J. D.
Cañete1, Jose Luis Fernandez-Sueiro2. Raimon Sanmarti3, Jesus Rodriguez4,
Jordi Gratacós5, Rubén Queiro6, Juan Carlos Torre-Alonso7, Jose Perez
Venegas8, Santiago Muñoz-Fernandez9, Carlos Gonzalez10, Carlos Montilla11, Daniel Roig12, Alba Erra13, Isabel Acosta14, Antonio FernándezNebro15, Pedro Zarco16, Arnald Alonso17, Marı́a América López-Lasanta17,
Antonio Julià17, Raül Tortosa17 and Sara Marsal18, 1Hospital Clı́nic de
Barcelona, Barcelona, Spain, 2Complejo Hospitalario Universitario La
Coruña, La Coruña, Spain, 3Hospital Clı́nic of Barcelona, Barcelona, Spain,
4
Hospital Universitari de Bellvitge, Barcelona, Spain, 5Hospital Parc Taulı́,
Sabadell (Barcelona), 6Hospital Universitario Central de Asturias, Oviedo,
Spain, 7Hospital Monte Naranco, Oviedo, Spain, 8Hospital del SAS de Jerez
de la Frontera, Jerez De La Frontera, Spain, 9Hospital Infanta Sofı́a, Madrid,
Spain, 10Hospital Gregorio Marañon, Madrid, Spain, 11Hospital Universitario
de Salamanca, Salamanca, Spain, 12Hospital Universitari de Bellvitge, Hospitalet de Llobregat- Barcelona, Spain, 13Hospital San Rafael, Barcelona,
Spain, 14Hospital Universitari Vall d’Hebron, Barcelona, Spain, 15Hospital
Regional Universitario Carlos Haya, Málaga, Spain, 16Fundación Hospital
Alcorcon, Alcorcon, Madrid, Spain, 17Vall d’Hebron Hospital Research
Institute, Barcelona, Spain, 18University Hospital Vall d’Hebron, Barcelona,
Spain
Background/Purpose: Psoriatic Arthritis (PsA) is a complex disease
with a substantial genetic risk component (first-degree relative risk 55).
Recently, Genomewide Association Studies (GWAS) have expanded the
number of risk loci for Psoriasis (Ps) in ⬎20 new loci.We have studied the
association of Ps risk loci in PsA and purely cutaneous Ps (PsC). We have
also analyzed the genetic association with several subphenotypes of clinical
relevance.
Methods: Loci showing the strongest statistical evidence of association to
Ps were selected (n⫽32). For each locus, the SNP having the highest
statistical evidence was genotyped using Taqman technology in a cohort of
n ⫽ 955 PsA, 1,050 PsC and 1,497 hypernormal controls of the Spanish
population. According to each subphenotype variable, the genetic association
was performed using the chi-square test, logistic regression or linear regression.
Results: We have replicated the association to COG6 and SERPINB8 loci
with Ps for the first time in a Caucasian population. We have identified, for the
first time, an association of PsA with variation at IFIH1, DPP6 and COG6.
Analyzing the association with other clinically relevant subphenotypes we
have identified a strong association of LCE3D locus with the severity of
cutaneous affection (P⬍ 2e-5). We have also found a significant association
of IL1RN gene with nail disease (P ⬍ 3e-4).
Conclusion: Our findings show that common genetic variants associated
to a complex phenotype like PsV influence PsA as well as different
subphenotypes of high clinical relevance.
Disclosure: J. D. Cañete, None; J. L. Fernandez-Sueiro, None; R. Sanmarti, None;
J. Rodriguez, None; J. Gratacós, None; R. Queiro, None; J. C. Torre-Alonso, None;
J. Perez Venegas, None; S. Muñoz-Fernandez, None; C. Gonzalez, None; C.
Montilla, None; D. Roig, None; A. Erra, None; I. Acosta, None; A. FernándezNebro, None; P. Zarco, None; A. Alonso, None; M. A. López-Lasanta, None; A.
Julià, None; R. Tortosa, None; S. Marsal, None.
999
Identification of New Epistatic Interactions with the HLA Region in the
Genetic Etiology of Psoriasis and Psoriatic Arthritis. Sara Marsal1, Juan
D. Cañete2, Jose Luis Fernandez-Sueiro3. Raimon Sanmarti2, Jesus Rodriguez Moreno4, Jordi Gratacós5, Rubén Queiro6, Carlos Montilla7, Juan Carlos
Torre-Alonso8, Jose Perez Venegas9, Santiago Muñoz-Fernández10, Carlos
M. Gonzalez11, Daniel Roig12, Alba Erra13, Isabel Acosta1, Antonio
Fernández-Nebro14, Pedro Zarco15, Arnald Alonso16, Marı́a América LópezLasanta16, Raül Tortosa16 and Antonio Julià16, 1Hospital Universitari Vall
d’Hebron, Barcelona, Spain, 2Hospital Clı́nic of Barcelona, Barcelona, Spain,
3
Complejo Hospitalario Universitario La Coruña, La Coruña, Spain, 4Hospital Universitario de Bellvitge., Barcelona, Spain, 5Hospital Parc Taulı́,
Sabadell (Barcelona), 6Hospital Universitario Central de Asturias, Oviedo,
Spain, 7Hospital Universitario de Salamanca, Salamanca, Spain, 8Hospital
Monte Naranco, Oviedo, Spain, 9Hospital del SAS de Jerez de la Frontera,
Jerez De La Frontera, Spain, 10Hospital Universitario Infanta Sofı́a, San
Sebastián de los Reyes (Madrid), Spain, 11Hospital Gregorio Maranon,
Madrid, Spain, 12Hospital Universitari de Bellvitge, Hospitalet de LlobregatBarcelona, Spain, 13Hospital San Rafael, Barcelona, Spain, 14Hospital Regional Universitario Carlos Haya, Málaga, Spain, 15Fundación Hospital
Alcorcon, Alcorcon, Madrid, Spain, 16Vall d’Hebron Hospital Research
Institute, Barcelona, Spain
Background/Purpose: Psoriatic Arthritis (PsA) is a complex disease and
is present in 11% in patients with Psoriasis (Ps). Recently, Genomewide
Association Studies (GWAS) have expanded the number of risk loci for Ps in
⬎20 new loci. Two of these genes, ERAP-1 and HLA-C, have been shown to
interact epistatically in the risk to develop Ps. We have studied the presence
of new genetic interactions between Ps risk lci with the HLA region in Purely
cutaneous Psoriasis (PsC) and PsA.
Methods: Within each Ps risk locus (n⫽31), the SNP having the highest
statistical evidence was selected. The 31 SNPs were genotyped using Taqman
technology in a cohort of n ⫽ 955 PsA, 1,050 PsC and 1,497 hypernormal
controls of the Spanish population. The presence of statistically significant
gene-gene interactions was performed using a logistic regression model with
three parameters to determine the presence of interaction at the allelic level.
Results:: We replicated the previously described interaction of HLA-C
and ERAP1 in the PsC cohort but not in the PsA cohort. We identified, for the
first time, a significative epistatic association between HLA-C and SERPINB8.
Microarray gene expression studies on cutaneous biopsies corroborate the
presence of this interaction at a functional level. In PsA, no statistically
significant interactions where identified with variation at HLA-C. However, 6
of the studied genes showed a significant (P⬍0.05) association with HLA-B27
positivity.
Conclusion: The present study has identified new genetic interactions
associated with the risk to develop PsC and PsA. The functional study of these
interactions will improve our knowledge of the biological basis of these
complex diseases.
Disclosure: S. Marsal, None; J. D. Cañete, None; J. L. Fernandez-Sueiro, None; R.
Sanmarti, None; J. Rodriguez Moreno, None; J. Gratacós, None; R. Queiro, None;
C. Montilla, None; J. C. Torre-Alonso, None; J. Perez Venegas, None; S. MuñozFernández, None; C. M. Gonzalez, None; D. Roig, None; A. Erra, None; I. Acosta,
None; A. Fernández-Nebro, None; P. Zarco, None; A. Alonso, None; M. A.
López-Lasanta, None; R. Tortosa, None; A. Julià, None.
S432
1000
Background/Purpose: BANK1 and BLK belong to pleiotropic genes and
recently a genetic and physical interaction between BANK1 and BLK has been
detected in systemic lupus erythematosus. Although BLK has been reproducibly identified as a RA risk factor, conflicting results have been reported
regarding the contribution of BANK1 in RA susceptibility. To ascertain the
real impact of BANK1 on RA genetic susceptibility we performed a large
meta-analysis. In addition, we tested for an epistatic interaction between BLK
and BANK1 in RA susceptibility.
Methods: We performed a large trans-ethnic meta-analysis including data
from 8,898 RA patients and 15,479 controls genotyped for BANK1
rs10516487 and data from 3,641 RA cases and 3,710 controls genotyped for
BANK1 rs3733197. BLK rs13277113 and BANK1 genotypes available from
1,901 RA patients and 1,898 ethnically matched controls coming from
France, Spain and Japan were used to test for epistasis by logistic regression
analysis.
Results: The meta-analysis provided evidence for an association between
RA and BANK1 rs3733197 G risk allele (OR⫽1.11 95% CI[1.02–1.21],
P⫽0.012). An epistatic interaction between BLK rs13277113 and BANK1
rs3733197 was detected (Pep⫽0.037). The association between the BANK1
rs3733197 G risk allele and RA was restricted to individuals carrying the BLK
rs13277113 GG genotype:OR⫽1.21 95%CI[1.04–1.41], P⫽0.015
Conclusion: This study confirms BANK1 as a RA susceptibility gene and
provides for the first time, evidence for epistasis between BLK and BANK1.
Our results illustrate the concept of pleiotropic epistatic interaction suggesting
that BLK and BANK1 might play a role in RA pathogenesis.
Disclosure: E. Genin, None; B. Coustet, None; Y. Allanore, None; M. Teruel, None;
A. L. Constantin, None; S. Tohma, Pfizer Japan, 2, Eisai, 2, Chugai Pharmaceutical,
2; O. Vittecoq, None; H. Furukawa, The work was supported by Research Grants from
Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation
for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research
Grants from Takeda Science Foundation., 2; A. Balsa, None; T. Schaeverbeke, None;
M. A. González-Gay, None; G. Chiocchia, None; N. Tsuchiya, None; J. Martin,
None; P. Dieude, None.
ACR/ARHP Poster Session B
Biology and Pathology of Bone and Joint
Monday, November 12, 2012, 9:00 AM–6:00 PM
1001
CNstream2: Improved SNP and CNV Genotyping Reveals New Loci
Associated with Rheumatic Diseases. Arnald Alonso, Antonio Julià,
Raül Tortosa and Sara Marsal. Vall d’Hebron Hospital Research Institute,
Barcelona, Spain
Background/Purpose: In Genome-Wide Association Studies (GWAS),
the performance of the genotyping algorithm is crucial to identify new
SNPs associated to disease risk. Recently, new methods have been developed
to exploit SNP-oriented microarrays in order to genotype Copy Number
Variations (CNVs), albeit with a reduced performance compared to SNPs. In
this study we present CNstream2, a method for both SNP and CNV
Disclosure: A. Alonso, None; A. Julià, None; R. Tortosa, None; S. Marsal, None.
1002
Microrna Expression Profiles in Peripheral Blood Mononuclear Cells of
Early Onset Psoriatic Arthritis. G. Ciancio1, Manuela Ferracin2, Barbara
Zagatti2, Elena Saccenti2, Valentina Bagnari1, Ilaria Farina1, Matteo Colina3,
Marco Seri4, Francesco Trotta1, Massimo Negrini2 and Marcello Govoni1.
1
Rheumatology Unit-Azienda Ospedaliera-Universitaria Sant’Anna, Ferrara,
Italy, 2Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy, 3Section of Internal Medicine A.Ospedale
Maggiore, Bologna, Italy, 4Medical Genetics Unit, Bologna, Italy
Background/Purpose: Micro-RNAs (miRNAs) are small non-coding
RNAs that negatively regulate gene expression. It is known that an altered
miRNA expression plays an important role in cancer. A new emerging role
for miRNAs has been evidenced in the pathogenesis of autoimmune diseases
such as rheumatoid arthritis (RA), in which miR-146a has gained increasing
relevance, psoriasis and systemic lupus erithematosus. No data about the
miRNA expression profile in psoriatic arthritis (PsA) are available to date. In
a preliminary study, we identified 16 miRNAs (9 up- and 7 down-regulated)
differentially expressed in a sample of 13 early PsA vs 7 healthy controls
(submitted data). Now, our main purpose is to validate the identified miRNA
signature in a larger series of patients and controls.
Methods: Blood samples from 21 consecutive patients with early, active
and naı̈ve from treatment PsA (disease duration ⬍ 6 months; M:9; W:12;
mean age:39,3⫾8,1; DAS 44: 4,12 ⫾ 0,29; SPARCC Enthesitis Index score:
2 ⫾ 0.5) were collected. As controls, 12 random healthy volunteers (M:4;
W:8; mean age 34 ⫾ 11) were recruited. The expression levels of 723 mature
miRNAs in peripheral blood mononuclear cells (PMBC) were investigated in
all patients and controls by using an Agilent miRNA microarray. Differentially expressed genes were identified by applying a two-tailed unpaired t-test
(Graph-Pad).
Results: We identified 3 microRNAs (miR-21,miR-34a and miR-21*),
S433
Monday, November 12
Epistatic Interaction Between BANK1 and BLK in Rheumatoid Arthritis: Results From a Large Trans-Ethnic Meta-Analysis. Emmanuelle
Genin1, Baptiste Coustet2, Yannick Allanore3, Maria Teruel4, Arnaud L.
Constantin5, Shigeto Tohma6, O. Vittecoq7, Hiroshi Furukawa8, Alejandro
Balsa9. Thierry Schaeverbeke10, Miguel Angel González-Gay11, Gilles
Chiocchia12, Naoyuki Tsuchiya13, Javier Martin14 and Philippe Dieude15,
1
INSERM UMR-S946, Paris, France, 2Université Paris Descartes, Hopital
Cochin, Paris, France, 3Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 4Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain, 5Purpan University Hospital,
Toulouse Cedex 9, France, 6Sagamihara National Hospital, Sagamihara City,
Japan, 7University Hospital, Rouen, France, 8Clinical Research Center for
Allergy and Rheumatology, Sagamihara National Hospital, National Hospital
Organization, Sagamihara, Japan, 9La Paz Hospital. IdiPaz, Madrid, Spain,
10
Groupe Hospitalier Pellegrin, Bordeaux, France, 11Hospital Universitario
Marqués de Valdecilla. IFIMAV, Santander, Spain, 12Institut Cochin INSERM U1016 - CNRS (UMR 8104), Paris, France, 13Molecular and
Genetic Epidemiology Laboratory, University of Tsukuba, Tsukuba, Japan,
14
Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada,
Spain, 15APHP, Hopital Bichat, Paris, France
genotyping that achieves a superior accuracy compared to other established
methods. In addition, we have identified several new CNV loci that are in
high linkage disequilibrium (LD) with SNPs previously associated to rheumatic diseases.
Methods: CNstream2 is a substantially improved version of our previous
CNstream software which achieves a superior accuracy in both SNP and
CNV genotyping compared to other well-established methods (i.e. GenoSNP/
GenCall for SNP genotyping and PennCNV/QuantiSNP for CNV genotyping). All these improvements have been assessed in different Illumina
platforms using public microarray data from HapMap samples. SNP genotypes from the 1000 Genomes Project (1KGP) and CNV genotypes from
recent studies using CNV-oriented technologies have been used as golden
standards for performance comparisons. In order to show the power of
CNstream2, we performed a correlation analysis between SNPs associated
with rheumatic diseases reported by the GWAS catalog and the CNVs
identified by CNstream2 over the same HapMap samples using HumanOmni1 data. All the CNV loci that obtained an r2⬎0.7 (N⫽16) were
reported in this study.
Results: CNstream2 obtained a high performance both on SNP and CNV
genotyping. When assessing SNP genotyping accuracy, CNstream2 obtained
an average gain of 0.20% with respect to GenoSNP and GenCall (representing a gain of 1,000–2000 genotyped SNPs per GWAS). On the other hand,
when comparing CNV calls obtained by CNstream2, PennCNV and QuantiSNP within previously characterized CNV loci, CNstream2 exceeded by an
average of 20% the number of correctly captured loci compared to its
competitors. The LD analysis between SNPs associated to rheumatic diseases
and CNVs detected by CNstream2 revealed 16 highly correlated SNP-CNV
pairs. From these, 11 pairs were located in the HLA region and were
associated to several rheumatic diseases. Given the strong correlation of the
CNV with the disease risk SNP, additional functional studies exploring its
relevance are warranted. Outside the HLA region, 5 new CNVs from loci
associated with rheumatological diseases were identified. From these, a
previously unidentified intronic deletion in Rheumatoid Arthritis risk gene
PADI4, showed a strong association.
Conclusion: After an exhaustive evaluation of CNstream2 performance
we can conclude that this new software tool provides an unprecedented
accuracy both in SNP and CNV genotyping. Using CNStream2 on publicly
available data, we have identified new CNVs on loci previously associated to
rheumatological diseases which could likely explain the observed disease risk
association.
previously described as upregulated in PsA as significantly upregulated also
in this new cohort of patients (p 0.01-0.001) compared to controls.
Conclusion: A 3-miRNA signature was identified in patients with early
active PsA. The upregulated miR-21, miR-34a and miR-21* appear of great
interest to understand the underlying pathogenic processes of PsA. Moreover,
their expression in patients with active disease makes them attractive as
potential biomarkers.
1004
Disclosure: G. Ciancio, None; M. Ferracin, None; B. Zagatti, None; E. Saccenti,
None; V. Bagnari, None; I. Farina, None; M. Colina, None; M. Seri, None; F. Trotta,
None; M. Negrini, None; M. Govoni, None.
Background/Purpose: Due to the wide range of highly specific and
effective biologic response modifiers that are available today for the treatment
of RA it has become of great importance to identify biomarkers for the
prediction of therapy outcome, supporting an individualized therapy. Most
studies in this field analysed potential markers for a single biological or
substance group, respectively. In this study we analysed the association of
genotypes of the single nucleotide polymorphism (SNP) rs10414216 in the 3’
UTR of the MED29 gene with the outcome of two biologic response
modifiers, targeting different pathways.
Methods: We studied 275 RA patients treated first with the TNF-blocker
etanercept (ETN) and a subgroup of 62 patients treated later in the course of
the disease with a B-cell directed therapy, with rituximab (RTX). The
frequency of the SNP rs10414216 MED29 C/T was analysed using a
validated TaqMan™ genotyping assay containing sequence-specific primers
and fluorescence-labelled allele-specific probes. Disease activity and therapy
response were assessed according to the EULAR improvement criteria
(http://www.das-score.nl). The primary response of the ETN therapy was
assessed 3–4 months after initiation of therapy, the outcome of rituximab after
4–6 months after the first infusion of RTX.
Results: The genotype distribution of the SNP rs10414216 MED29 C/T
in 275 RA patients was comparable with a cohort of non-affected controls.
There were no differences in the genotype frequencies in subgroups of
ACPA- positive and -negative RA patients. There was no association of
genotypes with disease activity observed. The DAS28 at baseline before start
of ETN or RTX treatment was comparable for all genotypes. After 3–4
months of ETN treatment the DAS28 decreased by 1.670⫾1.377,
2.083⫾1.348 and 2.382⫾1.286 (mean⫾SD) for the C/C, C/T and T/T
genotypes, respectively. The improvement of the DAS28 was significantly
better for the T/T genotype compared to C/C (p⫽0.003). 58% of T/T carriers
but only 27.2 % of the C/C carriers were identified as good responders to
ETN. However, in RTX treated patients the carriers of the C/C genotype were
identified as better responders, after 4–6 months the DAS28 decreased by
2.277⫾1.558 for the C/C genotype compared to 1.310⫾1.347 for the C/T
genotype (p⫽0,025). 46.2% of C/C and only 27.3% of C/T carriers were
good responders to RTX. The T/T carriers were underrepresented in the RTX
subgroup, probably as a result of a better outcome of the TNF-blocker therapy
in these patients.
Conclusion: Our data clearly indicate that a single SNP has the potential
to predict the outcome to different therapeutic approaches. The functional
importance of this genetic variation has not yet been characterized. However,
this SNP is located in the gene region of MED29, a subunit of the mediator
complex which plays a substantial role in the regulation of gene expression.
Further analysis of this SNP and the respective gene locus could provide
further insight into the mechanisms which determine the outcome of different
targeted therapies.
Monday, November 12
1003
Role of Particular Class I MHC Haplotypes in Determining Different
Traits within the Psoriatic Arthritis Phenotypes. Muhammad Haroon1,
Jon T. Giles2, Robert Winchester3 and Oliver M. FitzGerald1. 1Dublin
Academic Medical Center, St. Vincent’s University Hospital, Dublin, Ireland,
2
Columbia University Medical Center, New York, NY, 3Columbia University, New York, NY
Background/Purpose: A rigorously ascertained psoriatic arthritis (PsA)
cohort demonstrated considerable genetic heterogeneity and provided preliminary evidence that MHC genes determine quantitative traits within the PsA
phenotype with different patterns of MHC effect.
Methods: We now extend these findings by performing detailed clinical
phenotyping of PsA cases to better characterize the clinical features associated with particular HLA class I alleles and their haplotypes.
Results: A total of 150 PsA patients [mean age 52⫾12 years; 46% male;
mean PsA duration⫽25⫾12 years; 45% with axial involvement; 25% with
sacroiliitis; 41% with radiographic erosions; median PASI⫽1.2] were studied. In univariate analysis, the inheritance of B*27:05 was apparently
associated with a more severe joint disease phenotype including: joint
erosions, the requirement for TNF therapy and axial disease manifestations
such as spine involvement and sacroiliitis that were temporally preceded by or
coincident with skin disease. In striking contrast, the presence of HLA-C*06,
whether on a B*57-C*06 or B*37-C*06 haplotype, was associated with a
considerable delay in the development of arthritis, and conferred a reciprocal
phenotype of significant negative associations with arthritis severity, including the presence of erosions, the requirement for TNF inhibitor therapy,
and axial disease. B*08 and B*08-C*07 (EH8.1) were correlated with joint
deformities, erosions, TNF inhibitor requirement, osteolysis, and dactylitis,
developing after the appearance of psoriasis, suggesting this haplotype
denotes a more severe but delayed arthritic phenotype.
Surprisingly, in contrast to the uniform association of disease susceptibility
with B*27, the association with phenotypic features was not uniform across all
B*27 alleles, and was mainly accounted for by the B*27-C*01 (EH27.1)
haplotype and not B*27-C*02 (EH27.2), suggesting the influence of additional
genetic effects on EH27.1. The predictive value of these haplotypes was
confirmed by logistic regression, which after adjustment for confounders showed,
for example, the probability of developing sacroiliitis was almost completely
determined by the inheritance of EH27.1, EH8.1 or C*05, figure A. Similarly, the
probability of developing peripheral joint erosions was strongly associated with
the presence of EH27.1, EH8.1 or C*03, figure B.
A Unique Single Nucleotide Polymorphism in the 3’ UTR of the MED29
Gene On Chromosome 19 Is Associated with the Clinical Outcome of
Different Biologic Response Modifiers. Susanne Drynda, David Leesch,
Marietta Gloetzner and Joern Kekow. Univ of Magdeburg, VogelsangGommern, Germany
Disclosure: S. Drynda, None; D. Leesch, None; M. Gloetzner, None; J. Kekow,
None.
1005
Conclusion: Certain HLA alleles, and, most strikingly particular haplotypes, contribute importantly to the magnitude of traits comprising the diverse
phenotypes of PsA, but this contribution does not completely parallel the role
of these alleles or haplotypes in determining susceptibility.
Disclosure: M. Haroon, None; J. T. Giles, Roche/Genentech, 5; R. Winchester, None;
O. M. FitzGerald, Abbott Immunology Pharmaceuticals, Bristol-Myers Squibb, 2, Abbott
Immunology Pharmaceuticals, UCB, 5, Abbott Immunology Pharmaceuticals, 8.
The Identification of Pathway Markers in Behcet’s Disease Using
Genomewide Association Data From Two Different Populations. Burcu
Bakir-Gungor1, Elaine Remmers2, Daniel L. Kastner3, Akira Meguro4,
Nobuhisa Mizuki4, Ahmet Gul5 and Osman Ugur Sezerman6. 1Bahcesehir
University, Istanbul, Turkey, 2National Institutes of Health, National Human
Genome Research Institute, Bethesda, MD, 3National Human Genome
Research Institute, National Institutes of Health, Bethesda, MD, 4Yokohama
City University Graduate School of Medicine, Yokohama, Japan, 5Istanbul
University, Istanbul Faculty of Medicine, Istanbul, Turkey, 6Sabancı University, Istanbul, Turkey
Background/Purpose: Behcet’s disease (BD) is a multi-system inflammatory disease, characterized by recurrent exacerbations affecting several
organs including orogenital mucosa, eyes and skin. Two recent genome-wide
association study (GWAS) of BD in Turkish and Japanese populations both
confirmed the strong association of MHC Class I region and identified two
non-HLA common genetic variations with a mild effect on BD. In complex
S434
Disclosure: B. Bakir-Gungor, None; E. Remmers, None; D. L. Kastner, None; A.
Meguro, None; N. Mizuki, None; A. Gul, None; O. U. Sezerman, None.
1006
Dynamic Gene Expression of Wnt Signaling Pathway During Osteogenic
Stimulation in Vitro of Osteoarthritis Mesenchymal Stem Cells. A.
Peralta-Sastre1, M. Hernandez-Molinero2, P. Tornero-Esteban2, E. Villafuertes2, B. Fernandez-Gutierrez3 and Jose Ramon Lamas4. 11UGC de
Reumatologı́a, Hospital Clı́nico San Carlos, Instituto de Investigación Sanitaria del Hospital Clı́nico San Carlos (IdISSC), Madrid, Spain., 2Hospital
Clinico San Carlos, Madrid, Spain, 3Department of Rheumatology, Hospital
Clinico San Carlos, Madrid, Spain, 4Hospital clinico San Carlos, Madrid,
Spain
Background/Purpose: The role of Wnt signalling in Mesenchymal
Stem Cell (MSC) fate is still unclarified. Both, canonical and noncanonical pathways have been implicated in differentiation and proliferation resulting from specific Wnt ligands, receptors, inhibitors and
downstream molecules responsible for the signalling and/or the developmental commitment. Although osteogenesis is a well-studied process,
molecular details remain unknown. Te aim of the study was to delineate
the changes in gene expression of Wnt related occurring during osteogenesis in OA and control patients.
Methods: MSCs were obtained from bone marrow aspirates at the
time of joint replacement surgery of five OA patients (mean 76 years) and
three control subjects without OA signs (mean 80 years). Cells were
cultured and expanded under osteogenic stimuli. Confluent cells in
passage 6 were collected at days 1, 10 and 21. RNA was purified and
retrotranscribed prior quantitative PCR analysis. Simultaneous gene expression of 84 Wnt related genes was analysed using the Human Wnt PCR
Array PAHS-043A, from SABiosciences according. The resulting expression raw data was analyzed using the SABiosciences web-based PCR
Array Data Analysis tool. ⌬⌬Ct values relative to the RPL13A housekeeping gene were used to calculate the expression changes. Two-fold
changes with p⬍0.05 were considered significative.
Results: MSCs from OA patients undergoing osteogenesis progressively increases the number of downregulated genes related to the Wnt
signaling. While at basal conditions only two genes were downregulated,
at days 10 and 21, twelve and sixteen genes were downregulated
respectively. Among downregulated genes, some encode for essential
proteins participating both in canonical and non-canonical Wnt pathway
and including several ligands, co-rreceptors, inhibitors, kinases and
transcription factors.
Conclusion: Our data demosnstrate a clear alteration during osteogenesis
of MSCs biology from OA patients. We hypothesized that a possible cause of
OA may lie in these intrinsic alterations of MSCs preventing proper
differentiation into fully functional adult tissues.
Disclosure: A. Peralta-Sastre, None; M. Hernandez-Molinero, None; P. TorneroEsteban, None; E. Villafuertes, None; B. Fernandez-Gutierrez, None; J. R. Lamas,
None.
ACR/ARHP Poster Session B
Imaging of Rheumatic Diseases:
Magnetic Resonance Imaging, Computed Tomography and X-ray
Monday, November 12, 2012, 9:00 AM–6:00 PM
1007
High Resolution Peripheral Quantitative CT Detects Marked Differences in Metacarpal Head and Shaft and Ultra-Ultra-Distal Radius
Bone Volumetric Density and Microstructure in Early Rheumatoid
Arthritis. Lynne M. Feehan1, Helen R. Buie2, Linda C. Li1, Kamran
Shojania3, Cheryl Barnabe2 and Heather A. McKay3. 1Arthritis Research
Centre of Canada and University of British Columbia, Vancouver, BC,
2
University of Calgary, Calgary, AB, 3University of British Columbia,
Vancouver, BC
Background/Purpose: Despite improvements in clinical management of rheumatoid arthritis (RA), many with early disease are still at high
risk for developing periarticular erosions and osteopenia, as well as,
generalized systemic bone loss. It is essential to develop new approaches
to assess changes in bone microstructure in people with early RA before
permanent macro structural bone damage occurs. High Resolution Peripheral Quantitative CT (HR-pQCT) [XtremeCT, Scanco Medical AG]
provides a solution; it is a novel imaging system that images bone
microstructure at the thickness of a human hair. The purpose of this study
was to determine if HR-pQCT could identify and characterize early
volumetric density or microstructural differences in people with early RA
relative to controls.
Methods: Thirty individuals with early RA and 30 age and gender
matched controls consented to participate. Five regions of interest (ROI)
of the dominant side were imaged with HR-pQCT (82 ␮m, 60 kVp, 900
␮A, 100 ms): ultra-ultra-distal radius (UUDr) [9 mm, starting 3 mm
proximal to the medial tip distal radius]; metacarpal heads (MH) of the 2nd
and 3rd digits [18 mm, starting 2 mm distal to tip of most distal 2nd or 3rd
MH]; and metacarpal shafts (MS) of the 2nd and 3rd digits [9 mm, starting
4.5 mm distal to 3rd MS mid-shaft].
Standard manufacturer protocols were used for segmentation of the
bone from the soft tissue. Cortical and trabecular regions were extracted
using direct transformation methods with modified boundary conditions
for the MH. Primary outcome variables included: 1) whole, trabecular and
cortical region apparent volumetric bone density (vBMD) and bone
volume fraction (BV/TV), 2) trabecular region structural model index
(SMI), 3) cortical region thickness (CtTh) and material vBMD, and 4) MS
marrow space diameter (MSd). Paired Student T-test statistical analyses
were used to compare all variables.
Results: Participants: Both groups ⫽ Sex (Females 24, Males 6);
age (mean 53 years, range 21 to 73). RA group ⫽ 73% Rheumatoid
Factor &/or anti-CCP positive; mean 8 (SD 5) months since diagnosis
and 13 (SD8) months since symptom onset and a Health Assessment
Questionairre - Disability Index mean of 0.6 (SD 0.6). Imaging: HRpQCT identified marked differences in whole, trabecular and cortical
bone volumetric density and microstructure in the periarticular UUDr
and MH regions, as well as, the extra-articular MS regions between RA
subjects and controls. All density and microstructural outcome variables were lower in early RA participants with the exception of UUDr
and MH trabecular bone SMI and MSd, which were higher (Table 1).
S435
Monday, November 12
diseases such as BD, multiple factors [e.g. single nucleotide polymorphisms
(SNPs), miRNAs, metabolic and epigenetic factors] may target different sets
of genes in the same pathway crippling its function and thus causing the
disease development. In this regard, we hypothesized that the pathways
critical to the mechanisms underlying BD will be conserved within and across
populations.
Methods: To identify these disease-associated pathways, we previously developed a novel methodology that combines nominally significant
evidence of genetic association with current knowledge of biochemical
pathways, protein-protein interaction networks, and functional information of selected SNPs. Using this methodology, we herein searched for the
disease related pathways on two BD GWAS in Turkish and Japanese
case-control cohorts by using the list of SNPs providing a P value ⬍0,05.
Results: Even though there were a few significantly conserved
SNPs/genes within and between populations, five of the top ten affected
pathways were found to be significant in both populations. The probability
of random occurrence of such an event is 5.13E-36. These shared
pathways were Notch signaling pathway, focal adhesion, Jak-STAT
signaling pathway, long-term potentiation and pathways in cancer. Considering some differences in the clinical manifestations such as more
frequent involvement of major vessels in Turkish patients, we observed
some correlating rankings in the pathways. The complement and coagulation cascades pathway was identified in 5th and 33rd rankings with
P⫽2.47E-20, P⫽2.6E-12 in Turkish and Japanese populations, respectively.
Conclusion: By applying our method on two BD GWAS dataset, here
we have shown that while the total number of genome-wide significant
genetic associations is limited, identification of the shared pathways
between the Turkish and the Japanese populations may help further
explaining the general mechanisms of BD pathogenesis. Even though each
individual has a unique combination of factors involved in disease
development mechanism, most of the targeted pathways that need to be
altered by these factors are expected to be conserved. The pathways that
are identified by population specific GWAS need to be examined to gain
a more comprehensive understanding of BD pathogenesis and their
potential to be used as biomarkers and/or drug targets.
Table 1. Comparison of Volumetric Density and Microstructural Outcomes for
UUD, MH3 and MS2 ROIs
Ultra-Ultra-Distal Radius ROI
(nⴝ54, 27 Pairs)
Non-RA
[Mean (SD)]
Difference
(%)
Whole Bone
262.26 (53.27)
281.52 (44.41)
-7%
Trabecular
Region
* Apparent vBMD (mgHA/cm3)
167.30 (34.74)
187.70 (36.26)
-11%
Cortical Region
Apparent vBMD (mgHA/cm3)
760.25 (93.2)
785.52 (74.9)
-3%
Whole Bone
aterial vBMD (mgHA/cm3)
Bone Volume Fraction - BV/TV (%)
942.28 (41.83)
36.70 (4.9)
949.81 (35.29)
38.33 (4.5)
-0.8%
-6%
Trabecular
Region
* Bone Volume Fraction - BV/TV
(%)
26.88 (0.9)
29.39 (0.9)
-9%
Cortical Region
* Structural Model Index -SMI
Bone Volume Fraction - BV/TV (%)
Thickness - CtTh (mm)
1.87 (0.38)
90.49 (5.3)
0.56 (0.14)
1.60 (0.37)
91.47 (5.3)
0.58 (0.11)
17%
-1%
-1%
3rd Metacarpal Head ROI
(nⴝ54, 27 Pairs)
Monday, November 12
RA [Mean
(SD)]
Apparent vBMD (mgHA/cm3)
RA [Mean
(SD)]
Non-RA
[Mean (SD)]
Difference
(%)
Whole Bone
* Apparent vBMD (mgHA/cm3)
290.28 (47.16)
316.96 (40.72)
-9%
Trabecular
Region
Cortical Region
* Apparent vBMD (mgHA/cm3)
241.78 (31.32)
262.56 (33.02)
-8%
* Apparent vBMD (mgHA/cm3)
542.42 (73.31)
592.91 (72.49)
-8%
* Material vBMD (mgHA/cm3)
817.34 (72.49)
843.87 (45.04)
-3%
42.32 (4.6)
35.74 (4.4)
44.91 (3.7)
37.99 (3.2)
-7%
-6%
Whole Bone
Trabecular
Region
* Bone Volume Fraction - BV/TV (%)
* Bone Volume Fraction - BV/TV (%)
* Structural Model Index -SMI
Cortical Bone
* Bone Volume Fraction - BV/TV (%)
* Thickness - CtTh (mm)
2nd Metacarpal Shaft ROI
(nⴝ52, 26 Pairs)
0.88 (0.45)
42.32 (4.6)
0.35 (0.09)
0.60 (0.42)
44.91 (3.7)
0.39 (0.07)
47%
-7%
-13%
RA [Mean
(SD)]
Non-RA
[Mean (SD)]
Difference
(%)
1033.79 (34.57)
1079.82 (27.78)
1050.48 (21.78)
1091.87 (18.30)
-2%
-1%
Cortical Bone
* Apparent vBMD (mgHA/cm3)
* Material vBMD (mgHA/cm3)
Whole Bone
* Apparent vBMD (mgHA/cm3)
843.17 (79.35)
-5%
Cortical Region
* Bone Volume Fraction - BV/TV (%)
97.96 (1.2)
98.48 (0.61)
-1%
Whole Bone
* Thickness - CtTh (mm)
* Bone Volume Fraction - BV/TV (%)
1.93 (0.36)
72.68 (9.7)
2.08 (0.29)
76.63 (6.9)
-7%
-5%
Marrow Space Diameter ⫽ MSd (mm)
2.79 (0.61)
2.67 (0.51)
4%
796.84 (112.32)
Figure 1. a) Metacarpal bone with periosteal segmentation and segmented
erosion. b) Manual measurement of cortical break and maximum depth.
Bold Difference (%) & * ⫽ p ⬍ 0.05 (Paired T-Test, no adjustment for multiple comparisons). NOTE: MH2 and
MS3 similar results, not shown
Conclusion: HR-pQCT is a promising new imaging technology that can
identify and quantify very early changes in hand and distal forearm bone
volumetric density and microstructure in people with early RA. Participants
in this study will be evaluated again at 1 year.
Disclosure: L. M. Feehan, None; H. R. Buie, None; L. C. Li, None; K. Shojania,
None; C. Barnabe, None; H. A. McKay, None.
1008
Segmentation and Quantification of Bone Erosions in the Hands of
Patients with Rheumatoid Arthritis Using High Resolution Computed
Tomography. Dominique Toepfer1, Stephanie Finzel1, Oleg Museyko1,
Klaus Engelke1 and Georg A. Schett2. 1University of Erlangen-Nuremberg,
Erlangen, Germany, 2Department of Internal Medicine III and Institute for
Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Background/Purpose: Bone erosions are important for diagnosis and
monitoring of disease activity in RA. However, semi-quantitative scoring
schemes may be inadequate for a true 3D quantification of size and shape.
Recently high-resolution peripheral quantitative CT (HR-pQCT) with an
isotropic spatial resolution of about 120␮m has been used for a semiquantitative assessment of erosion volume in the metacarpophalangeal (MCP)
joints. Here we developed a highly automated 3D analysis technique to more
accurately quantify volume, shape and surface of erosions and to increase
precision.
Methods: In the MCP joints of the second to forth digit of 18 patients 80
slices distally and 242 slices proximally to the surface of the third metacarpal
head were scanned (XtremeCT, Scanco Switzerland; isotropic voxel size
82␮m). Erosions were quantified as follows: After segmenting the periosteal
surface the user identified each erosion by manually placing a seed point. The
erosions were then automatically segmented by a 3D level-set algorithm (Fig.
1a) with the option of operator corrections. Erosion volume (Vol), surface
area (SA), and sphericity (SP), a parameter describing the shape deviation
from a perfect sphere, were determined. In addition manual measurements
were carried out. Here the erosion volume was approximated by a halfellipsoid constructed from the surface area of the cortical break and the
maximum erosion depth perpendicular to it (Fig. 1b). In order to compare
both methods the lengths measurements obtained from the manual technique
were also determined during the automated 3D analysis.
Results: 32 erosions were assessed in the 18 datasets with a mean/min/max
Vol of 9.66mmⱖ/0.37mmⱖ/54.7mmⱖ (automated 3D analysis). Inter-operator
precision errors (3 operators, root mean squares coefficients of variation
(RMSCV)/RMS standard deviation (RMSSD)) were 7.8%/0.8 mmⱖ, 10.4%/3.8
mm2 and 4.9%/0.02 for Vol, SA and SP, respectively. Excluding 18 erosions, in
which operator interactions were performed, decreased the errors by about a factor
of 3. Correlation between the manual analysis and the length measurements
obtained from the automated 3D analysis was r ⫽ 0.87, however, correlation with
the Vol obtained from the full 3D analysis was r ⫽ 0.39, indicating that a
simplistic approximation of erosion volume may not capture the full shape
information.
Conclusion: We developed a new precise full 3D characterization of bone
erosions that may help improving the assessment of disease activity and treatment
efficacy. Precision errors depend on the degree of user interaction that may be
necessary to correct the automated segmentation, which is more frequent in
erosions with large cortical breaks. Manual measurements are less impacted by
image quality, such as motion artifacts; however, the approximation of erosion
volume by a half-ellipsoid underestimates the true erosion volume. The clinical
evaluation of this method is currently being performed.
Disclosure: D. Toepfer, None; S. Finzel, None; O. Museyko, None; K. Engelke,
None; G. A. Schett, None.
1009
A New Approach for Detecting Progressive Joint Damage Using 3D Imaging
From High-Resolution Peripheral Quantitative Computed Tomography:
Measuring Reproducibility. Cheryl Barnabe, Helen R. Buie, Michelle Kan,
Susan G. Barr, Liam Martin and Steven K. Boyd. University of Calgary,
Calgary, AB
Background/Purpose: Joint space narrowing is an important feature of
progressive joint damage and functional impairment in rheumatoid arthritis (RA).
Methodology to provide longitudinal and sensitive 3D measurements of joint
space width have not yet been developed for research or clinical applications.
High-resolution peripheral quantitative computed tomography (HR-pQCT)
(Scanco Medical AG, Switzerland) has recently become available to accurately
and reproducibly measure bone microstructure at a nominal isotropic voxel
dimension of 82 ␮m. Given the ability of HR-pQCT to detect bone margins with
high precision, we developed a methodology to measure the 3D metacarpophalangeal (MCP) joint space width. This work determines the reproducibility of the
scan protocol with hand repositioning for application for early detection and
longitudinal monitoring of RA.
Methods: Two repeated HR-pQCT scans of the 2nd and 3rd MCP joints of ten
subjects with early RA (70% female, mean age 45 years) withrepositioning
between scans were obtained. The periosteal edges of the metacarpal head
S436
and proximal phalanx base were detected and segmented, and from these
images the joint space width and distribution of joint space thickness were
measured using a custom analysis implemented for the HR-pQCT based
on direct measurements from the high resolution image data.
Results: In this population, the mean joint space width of the 2nd MCP was
1.82 mm (SD 0.20) and of the 3rd MCP 1.84 mm (SD 0.23). Reproducibility with
repositioning was excellent, with overlapping filtered histograms and a root
square mean coefficient of variance of 4.8%.
Conclusion: We have established a highly reproducible methodology for
evaluating the joint space width, applied here to the MCP joints. Currently, we
combine this assessment with measures of joint erosions and periarticular bone
density. Together, these measures from HR-pQCT show great promise for a new
approach for early RA detection, and monitoring of disease activity and/or
treatment.
Table 1. Descriptive Statistics for mTSS by Week 36 Clinical Disease Response
Category
Disclosure: C. Barnabe, None; H. R. Buie, None; M. Kan, None; S. G. Barr, None;
L. Martin, None; S. K. Boyd, None.
Week 36
Response
1010
Bone Loss Before Clinical Onset of Rheumatoid Arthritis o Subjects with
Anti-Citrullinated Protein Antibodies. Stephanie Finzel1, Veronika Lang2,
Arnd Kleyer1, Juergen Rech1, Bernhard Manger1, Elizabeth Araujo1, Axel J.
Hueber1, Ulrike Harre3 and Georg Schett3. 1University of Erlangen-Nuremberg,
Erlangen, Germany, 2University of Erlangen-Nuremberg, Germany, 3Institute for
Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Background/Purpose: Anti-citrullinated protein antibodies (ACPA) are a
major risk factor for rapid disease progression in rheumatoid arthritis (RA). We
have recently shown that ACPA directly induce bone loss by stimulating
osteoclast differentiation (Harre et al, J Clin Invest 2012;122:1791). As ACPA
precede the clinical onset of RA we hypothesized that ACPA positive healthy
individuals may shows skeletal changes.
Methods: performed a comparative micro computed tomography analysis of
the bone microstructure in the metacarpophalangeal joints (MCPJ) of ACPA
positive and -negative healthy individuals without signs of arthritis.
Results: ACPA positive (N⫽ 10) and -negative (N⫽ 10) healthy individuals
were not different in age (48.2 ⫾ 4.1 vs. 51.4 ⫾ 3.8 years, p ⫽ 0.57) and gender
(each 8 females and 2 males). Bone minaral density was significantly reduced in
ACPA-positive individuals (mean ⫾ SEM: 280 ⫾ 11 mg/ccm) as compared to
controls (327 ⫾ 6 mg/ccm). Bone loss was based on cortical bone changes with
significant (p ⫽ 0.044) reduction in cortical thickness in the ACPA-positive group
(mean ⫾ SEM: 0.22 ⫾ 0.03 mm) as compared to controls (0.32 ⫾ 0.03 mm).
Conclusion: Structural bone damage starts before the clinical onset of arthritis
in subjects with ACPA. These findings revise the concept of bone damage as an
exclusive consequence of synovitis in ACPA positive individuals.
CDAI Remission
(ⱕ2.8)
CDAI LDA (⬎2.8
ⱕ10)
CDAI NR (⬎10)
DAS28 Remission
(ⱕ2.6)
DAS28 LDA
(⬎2.6ⱕ3.2)
DAS28 NR
(⬎3.2)
n
ETN ⴙ MTX mTSS
Final Time
Point,†
Baseline,
Units
Units
Mean
Mean
(Median)
(Median)
Progression
Rate, Units/Yr
Mean
(95% CI)
195
36.5 (14.5)*
36.6 (14.5)*
0.1 (⫺0.1, 0.4)*
415
39.3 (17.5)
39.7 (19.5)
0.4 (0.2, 0.6)
94
487
44.4 (22.3)
37.9 (16.5)
45.0 (22.3)
38.2 (18.0)
0.6 (⫺0.3, 1.4)
0.3 (0.2, 0.5)*
135
41.9 (19.4)
42.1 (19.5)
0.2 (⫺0.1, 0.6)
82
42.6 (16.0)
43.3 (17.0)
0.7 (⫺0.2, 1.6)
*P ⬍ 0.05, Kruskal Walis test for differences in distributions. †Final time point
defined as the sum of baseline and progression rate. DAS28 ⫽ 28-joint Disease
Activity Score; CDAI ⫽ Clinical Disease Activity Index; LDA ⫽ low disease
activity; NR ⫽ no response.
Conclusion: Inhibition of radiographic progression was more robust with
ETN ⫹ MTX therapy compared with MTX, regardless of week 24 disease
activity. Overall, patients who achieved remission at week 24 had less radiographic progression at year 2 than those with LDA or NR, and less progression
with remission defined by CDAI than DAS28. These results may be the first to
indicate that achievement of clinical remission within 6 months may predict
longer term inhibition of structural damage.
Reference
1. Combe B. Best Pract Res Clin Rheumatol. 2007;21:1;27-42.
Disclosure: P. Emery, Abbott, Merck, Pfizer, UCB, Roche, and BMS, 5; V. Strand, Pfizer
Inc, 5; A. S. Koenig, Pfizer Inc, 3, Pfizer Inc, 1; R. Pedersen, Pfizer Inc, 3, Pfizer Inc, 1; E.
Bananis, Pfizer Inc, 1, Pfizer Inc, 3.
Disclosure: S. Finzel, None; V. Lang, None; A. Kleyer, None; J. Rech, None; B. Manger,
None; E. Araujo, None; A. J. Hueber, None; U. Harre, None; G. Schett, None.
1012
1011
Radiographic Deformity of the Foot Is Starting From the Early Stage of
Rheumatoid Arthritis. Kenji Mamoto, Tatsuya Koike, Tadashi Okano,
Atsuko Kamiyama, Yuko Sugioka, Masahiro Tada and Hiroaki Nakamura.
Osaka City University Graduate School of Medicine, Osaka, Japan
Structural Damage Is Reduced by Early Achievement of Clinical Remission.
Paul Emery1, Vibeke Strand2, Andrew S. Koenig3, Ronald Pedersen3 and
Eustratios Bananis3. 1Leeds Musculoskeletal Biomedical Research Unit, Leeds,
United Kingdom, 2Stanford University, Portola Valley, CA, 3Pfizer Inc., Collegeville, PA
Background/Purpose: Foot deformities frequently arise in patients with
rheumatoid arthritis (RA). It might cause gait dysfunction and lead to disability.
However, the precise mechanism of progression of foot deformity is still unclear.
S437
Monday, November 12
Figure 1. Cross-sectional views (left) and three-dimensional views (middle) of the
third metacarpal joint for repeat scans showing consistent repositioning and highly
reproducible joint space distribution measurements (right).
Background/Purpose: The importance of early, intensive treatment of
rheumatoid arthritis (RA) to decrease disease activity and prevent structural
damage is established.1 The objective of this analysis was to examine the
relationship between disease activity measured by CDAI and DAS28 at week 24,
and inhibition of radiographic progression by mean mTSS change from baseline
at year 2 in patients treated with etanercept (ETN) ⫹ methotrexate (MTX) or
MTX monotherapy.
Methods: Randomized subjects from TEMPO (moderate-severe RA, 6.6
years mean disease duration) and COMET (moderate-severe RA, 9 months mean
disease duration) who received ETN 50 mg weekly ⫹ MTX or MTX alone for
2 years with available X-rays were included in this analysis. Stratified and
multivariate regression analyses (observed data) were performed to determine the
relationship between variables.
Results: There were a total of 182 patients in COMET and 296 in TEMPO
included in this analysis. Patients receiving ETN ⫹ MTX had less radiographic
progression after 2 years of treatment than MTX monotherapy, independent of
disease activity at week 24. In COMET, the percentage of patients achieving
CDAI and DAS28 remission in the ETN ⫹ MTX group were 17.0% and 46.5%
vs 8.8% and 27.7% in the MTX group, respectively. Results were similar in
TEMPO with 18.6% and 35.5% of patients in ETN ⫹ MTX group and 6.4% and
20.2% in the MTX group achieving remission. Mean change (SD) in annualized
mTSS were lower in patients who achieved remission at week 24 compared with
those with low disease activity or non-responders, which were significant
(P⬍0.05) in the ETN ⫹ MTX group (Table). In the ETN ⫹ MTX groups, the
majority of patients who achieved CDAI or DAS28 remission were nonprogressors by mTSS change scores ⱕ0.5 (TEMPO 100% and 86.9%; COMET
87.5% and 87.0%) with similar observations in the MTX group (TEMPO 100%
and 72.0%; COMET 71.4% and 78.3%).
Monday, November 12
The aim of this study is to clarify the relationship between disease progression and
the deformity of feet in patients with RA.
Methods: The prospective cohort TOMORROW (TOtal Management Of
Risk factors in Rheumatoid arthritis patients to lOWer morbidity and mortality;
clinical trial registration number, UMIN000003876) study was started in 2010.
We examined antero-posterior and lateral radiographs obtained from 416 weightbearing feet of 208 patients with RA from this cohort. The stage of articular
destruction was classified from the hand radiographs based on Steinbrocker’s
classification. We measured the hallux valgus angle (HVA), the intermetatarsal
angle between the first and second metatarsals (M1M2) and the first and fifth
metatarsals (M1M5) on antero-posterior radiographs, and calcaneal pitch (CP) on
lateral radiographs. Each deformity was defined as hallux valgus: HVA⬎15
degree, spread foot: M1M5⬎30 degree and flat foot:CP⬍20 degree.
Results: We finally analyzed 387 feet of 196 patients excluding those that had
been surgically treated. The mean age and mean disease duration were 58.2 years
old and 12.7 years, respectively. Steinbrocker’s stages 1, 2, 3 and 4 were identified
39, 48, 44 and 65 patients, respectively (Table 1). We identified any of hallux
valgus, spread foot and flat foot in Steinbrocker’s stage 1. Moreover HVA and CP
had progressed according to the progression of stage and disease duration.
However, M1M2 and M1M5 had been progressed from the early stage. These
findings indicate that foot deformities started from the early stage of RA and
progressed with advancing stages.
Table 1. Development of foot deformities in patients with rheumatoid arthritis
according to Steinbrocker’s stage.
Steinbrocker’s stage
Disease duration (y)
DAS28-ESR
HVA (°)
M1/M2 angle (°)
M1/M5 angle (°)
Calcaneal pitch (°)
Hallux valgus (%)
Spread foot (%)
Flat foot (%)
1 (n ⴝ 39)
2 (n ⴝ 48)
3 (n ⴝ 44)
4 (n ⴝ 65)
6.9
2.8
15.6
9.5
29.5
19.3
47.4
41.6
52.6
7.6
3.2
18.9
10.5
29.4
18.2
59.4
40.6
58.3
14.5
3.8
17.4
9.7
30.3
16.9
50.6
44.8
67.8
21.8
3.9
24.9
9.4
29.2
15.5
63.5
42.1
73.8
Conclusion: Foot deformities started from an early stage of RA, and
correlated with disease stage and duration in patients with RA. This result
suggests that the disease activity may be underestimated without the assessment
of feet in routine clinical care. It is necessary to consider joint destruction and
deformity of the foot from the early stage of RA.
Disclosure: K. Mamoto, None; T. Koike, Chugai Pharmaceutical, 2, Eli Lilly Japan, 8,
Novartis Pharmaceutical Corporation, 2, Teijin Pharma, 8, Bristol-Myers Squibb, 5, Ono
Pharmaceutical, 8, Santen Pharmaceutical, 8, Eisai, 8, Abbott Japan, 8, Mitsubishi Tanabe
Pharma Corporation, 2, Takeda Pharmaceutical, 8, Astellas Pharma Inc., 8, Pfizer Japan Inc.,
8, Janssen Pharmaceutical, 2, Asahi Kasei Pharma Corporation, 8, Daiichi Sankyo Company, 2; T. Okano, None; A. Kamiyama, None; Y. Sugioka, None; M. Tada, None; H.
Nakamura, None.
1013
The Influence of Vertebral Fractures On the Functional Disability of
Patients with Rheumatoid Arthritis. Soo-Kyung Cho1, Joo-Hyun Lee2, MinKyung Han3, Seunghun Lee4, Ji Young Kim4, Jeong Ah Ryu4, Yun Young
Choi4, Sang-Cheol Bae5 and Yoon-Kyoung Sung5. 1Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, 2Ilsan Paik Hospital, Inje
University, Goyang, South Korea, 3Hanyang University Hospital for Rheumatic
Disease, Seoul, South Korea, 4Hanyang University College of Medicine, Seoul,
South Korea, 5Hanyang University Hospital for Rheumatic Diseases, Clinical
Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
Background/Purpose: Rheumatoid arthritis (RA) is a chronic, painful, and
disabling disease associated with reduced health-related quality of life (HRQOL)
compared to the general population. Higher levels of comorbidity can make the
physical disability of RA patients even worse. Osteoporosis leading to bone
fracture is one of the main co-morbidities of RA, and approximately one-third of
women with RA report a fracture within 5 years of follow-up. Few studies have
examined the influence of vertebral fracture (VF) on the outcome of patients with
RA. The aim of the present study was to compare functional disability between
RA patients with and without VF.
Methods: All female RA patients aged 50 years or older who visited our
hospital for periodic examination between April 2011 and August 2011 were
asked to participate in this study. Of these 169 patients, 100 were consecutively
enrolled after excluding 69 patients who either did not wish to participate or
recently had a routine examination for osteoporosis. Participants completed
questionnaires via interview regarding demographic and lifestyle characteristics.
Functional disability as a primary outcome was evaluated with the Health
Assessment Questionnaire Disability Index (HAQ-DI). Each participant underwent thoracolumbar radiography, and the results were evaluated by two radiologists. We used multivariable-adjusted logistic regression analysis to test for
associations between functional disability and the presence of VF, the severity of
VF, and the number of VFs.
Results: Among the 100 RA patients, 47 had at least one VF, but 34 of these
patients were unaware that they had experienced a fracture. The presence of two
or more VFs (OR 3.0, CI 1.18.1) and moderate or severe VF (OR 3.4, CI 1.39.0)
were related to disability in univariate analyses, but these effects were no longer
significant after adjusting for age, disease duration, current steroid use, disease
activity, and no previous history of VF. Among those RA patients with higher
disease activity (n⫽51), the presence of VF (OR 5.1, CI 1.221.7) and moderate
or severe VF (OR 7.1, CI 1.339.4) were associated with disability.
Table 1. Factors influencing functional disability in patients with RA (n⫽100)
Unadjusted
analysis
Age 50-60
61-70
71 ⱕ
Disease duration (years) 10 ⱕ
BMI Normal or low (ⱕ22.9)
Over weight (23.0⬃24.9)
Obesity (25.0⬍)
Current steroid use
DAS28 Remission and low (⬍3.2)
Moderate and high (ⱖ3.2)
No previous history of VF
Presence of VF
Number of VFs 0
1
ⱖ2
Severity of VF None
Mild
Moderate or severe
1
2.3 (0.9⬃5.8)
2.0 (0.7⬃6.1)
1.8 (0.7⬃4.3)
1
1.3 (0.5⬃3.2)
0.9 (0.3⬃2.4)
1.3 (0.6⬃2.8)
1
4.7 (2.0⬃10.9)
0.7 (0.2⬃1.8)
2.2 (1.0⬃4.9)
1
1.6 (0.6⬃4.4)
3.0 (1.1⬃8.1)
1
1.3 (0.5⬃3.8)
3.4 (1.3⬃9.0)
Adjusted
analysis
1
5.4 (2.2⬃13.2)
0.4 (0.1⬃1.3)
Table 2. Influence of vertebral fracture on disability in RA patients with
moderate or high disease activity
Regression model
Model 1
Model 2
Model 3
Details of VF
OR (95% CI)
Moderate or high
disease activity
(nⴝ51)
Presence of VF
Number of VFs 0
1
2ⱕ
Severity of VF Normal
Mild
Moderate or sever
5.1 (1.2⬃21.7)
1
3.2 (0.5⬃23.2)
4.8 (0.9⬃24.7)
1
3.3 (0.6⬃18.6)
7.1 (1.3⬃39.4)
Conclusion: Many patients with RA have occult VF. Among RA patients
with higher disease activity, the presence and severity of VF may affect functional
disability.
Disclosure: S. K. Cho, None; J. H. Lee, None; M. K. Han, None; S. Lee, None; J. Y.
Kim, None; J. A. Ryu, None; Y. Y. Choi, None; S. C. Bae, None; Y. K. Sung, None.
1014
Trimmed Analyses, a New Approach to the Analysis of Sharp Score Data in
the Assessment of Progression in Patients with Rheumatoid Arthritis. Robert
B. M. Landewé1Désirée van der Heijde2, Carol Connell3, John Bradley3, David
Gruben3 and Michael Brown3. 1Academic Medical Center/University of Amsterdam & Atrium Medical Center, Amsterdam, Netherlands, 2Leiden University
Medical Center, Leiden, Netherlands, 3Pfizer Inc., Groton, CT
Background/Purpose: Tofacitinib is a novel oral Janus kinase inhibitor
being investigated as a targeted immunomodulator and disease-modifying therapy
for RA. In the Phase 3 ORAL Scan study [NCT00847613], progression in
radiographic scores (mean change from baseline [BL] in modified Total Sharp
Scores [mTSS] at Month 6) was a primary analysis using an Analysis of
Covariance (ANCOVA). ANCOVA demonstrated statistically significant inhibition in structural damage progression for tofacitinib 10 mg but not 5 mg twice
daily (BID) doses, compared with placebo (PBO).1 There has been a general trend
towards less PBO progression in recent radiographic studies;2 the PBO period is
generally shorter (ⱕ3 months) and most patients receiving PBO are rescued. It is
therefore important to confirm that efficacy detected in a primary analysis is
robust. Rank analysis of ORAL Scan data demonstrated borderline evidence of
inhibition by both doses. Rank analyses are used to show results are not driven
primarily through extreme values, as ranking down weights extreme values
S438
relative to ANCOVA, but analyses of ranks do not yield intuitively interpretable
values representing the magnitude of damage inhibition. A conceptual bridge
between rank analyses and ANCOVA is the trimmed-analysis approach, where
extreme values are systematically removed from the data set.
Methods: In this analysis, mTSS data were trimmed in 1% increments up to
10%, eg 2% trimming deletes observations ⬍1st percentile and ⬎99th percentile.
In the ORAL Scan study this resulted in approximately 2–3 observations
symmetrically removed per group per 1% trimming. ANCOVA was then applied
to each resulting trimmed set (0% was the primary analysis).
Results: At 1% trimming, nominal statistical significance was achieved for
both tofacitinib doses (CI less than 0) and was maintained with further trimming
(Figure). As expected, the mean difference from PBO diminished slightly with
trimming, but was more than compensated for by reductions in variability.
Figure.
Trimmed data ⫽ % Data Excluded
Conclusion: In ORAL Scan, significance of inhibition of structural damage
was demonstrated for both tofacitinib doses after just 1% trimming, indicating that
significance in the primary analysis was not dependent on extreme data. Trimmed
analyses give improved insight into the influence of extreme values and should be
considered as one of the sensitivity analyses of choice for structural data.
References
1. van der Heijde et al. Arthritis Rheum 2011; 63: S1017-18.
2. Rahman et al. Ann Rheum Dis. 2011;70:1631-40.
Disclosure: R. B. M. Landewé, Pfizer Inc., Abbott, Janssen, Merck, 2, Abbott, Amgen,
Astra, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Janssen, Pfizer, UCB, Vertex, 5;
D. van der Heijde, Abbott, Amgen, AstraZeneca, BMS, Centocon, Chugai, Eli-Lilly, GSK,
Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth, 5,
Imaging Rheumatology, 4; C. Connell, Pfizer Inc., 1, Pfizer Inc., 3; J. Bradley, Pfizer Inc.,
1, Pfizer Inc., 3; D. Gruben, Pfizer Inc., 3, Pfizer Inc., 1; M. Brown, Pfizer Inc., 1, Pfizer
Inc., 3.
1015
Analysis of Integrated Radiographic Data for Two Long-Term, Open-Label
Extension Studies of Adalimumab. Désirée van der Heijde1, Robert Landewé2,
Edward C. Keystone3, Ferdinand C. Breedveld1, Shufang Liu4 and Neelufar
Mozaffarian4 1Leiden University Medical Center, Leiden, Netherlands, 2Academic Medical Center, Amsterdam, Netherlands, 3University of Toronto, Toronto, ON, 4Abbott, Abbott Park, IL
Background/Purpose: The assessment of radiographic data from long-term
studies in patients (pts) with rheumatoid arthritis (RA) poses a significant
challenge, given the potential involvement of multiple readers who typically
evaluate films from only a subset of the available time points, often re-scoring
Conclusion: Longitudinal, data integration analyses factoring in
mTSS from all available assessments enabled a robust estimate of total
radiographic progression in 2 long-term studies of ADA⫾MTX. Moreover, the present analysis confirmed the radiographic efficacy of long-term
therapy with ADA⫾MTX.
S439
Monday, November 12
previously read images. This analysis describes an integration approach to
evaluate the complete set of radiographic scores assessed over several years (yrs)
from long-term studies of adalimumab (ADA).
Methods: Data from 2 large, multicenter, phase 3, randomized, placebo
(PBO)-controlled trials of ADA were analyzed: PREMIER (MTX-naı̈ve pts,
early RA1), had a 2-yr double-blind (DB) period followed by an ongoing 8-yr
open-label extension (OLE); DE019 (MTX-inadequate responders, longstanding RA2), had a 1-yr DB period followed by a completed 9-yr OLE. Pts
received OL ADA⫾MTX in both OLEs. This post hoc analysis evaluated
radiographic data based on randomization to the original PBO⫹MTX and
standard dose ADA⫹MTX arms through 8 yrs of treatment in PREMIER and
10 yrs in DE019. Radiographic progression was assessed using the change in
modified total Sharp score (⌬mTSS) from baseline (BL). Radiographs
were assessed at Yrs 2, 3, 5, and 8 (PREMIER) and Yrs 1, 2, 3, 5, 6, 8,
and 10 (DE019). At each assessment yr, radiographs from BL and selected prior yrs were re-read. A mixed effect model was used to evaluate
the repeated measurements at different time points within different
assessment yrs in the integrated analysis. ⌬mTSS at each time point was
estimated by least square mean and summarized alongside the most recent
assessment yr of PREMIER (Yr 8, which included repeat reads for BL, and
Yrs 2 and 6) and DE019 (Yr 10, which included repeat reads for BL, and Yrs
1 and 8).
Results: Radiographic data from 452 pts in PREMIER (215,
PBO⫹MTX; 237, ADA⫹MTX) and 327 pts in DE019 (162, PBO⫹MTX;
165, ADA⫹MTX) with BL and ⱖ1 post-BL radiograph were identified.
Radiographic progression was most pronounced in pts receiving PBO⫹MTX
during the DB periods, but progression slowed dramatically upon switch to
OL ADA⫾MTX therapy in both trials (Figure). Following up to 8 yrs of
treatment, pts in PREMIER experienced ⌬mTSS estimates of 11.1
(PBO⫹MTX) and 3.9 (ADA⫹MTX) units; pts in DE019 experienced
estimates of 6.6 (PBO⫹MTX) and 0.9 (ADA⫹MTX) units through up to 10
yrs of treatment. The estimated curves in each of the studies revealed subtle
changes in progression rates not seen in their respective most recent
assessment yr.
Reference
1 Arthritis Rheum 2006;54:26–37; 2Arthritis Rheum 2004;50:1400-11.
1017
Disclosure: D. van der Heijde, Abbott, Amgen, AstraZeneca, BMS, Centocor,
Chugai, Eli-Lilly, GSK, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis,
Schering-Plough, UCB, Wyeth, 5, Imaging Rheumatology bv, 4; R. Landewé,
Abbott, Amgen, Centocor, Pfizer/Wyeth, UCB, and BMS, 2, Abbott, Amgen,
Centocor, Pfizer/Wyeth, UCB, and BMS, 5, Abbott, Amgen, Centocor, Pfizer/
Wyeth, UCB, and BMS, 8; E. C. Keystone, Abbott, Amgen, AstraZeneca, BMS,
Centocor, Genzyme, Merck, Novartis, Pfizer, Roche, and UCB, 2, Abbott, AstraZeneca, Biotest, BMS, Centocor, Genentech, Merck, Nycomed, Pfizer, Roche, and
UCB, 5, Abbott, Amgen, BMS, Janssen, Merck, Pfizer, Roche, and UCB, 8; F. C.
Breedveld, Centocor, Schering-Plough, Amgen/Wyeth, and Abbott, 5; S. Liu,
Abbott Laboratories, 1, Abbott Laboratories, 3; N. Mozaffarian, Abbott Laboratories, 1, Abbott Laboratories, 3.
Monday, November 12
1016
The Effect of Evaluation Variability At the Unit of Measurement On the
Reliability of Omeract Ramris and Van Der Heijde-Modified Sharp
Score. Ruben Tavares1, Naveen Parasu2, Karen Finlay2, Erik Jurriaans2, Hao
Wu1, Karen A. Beattie1, Maggie Larche1, Lawrence E. Hart3, William G.
Bensen4, Raja S. Bobba1, Alfred A. Cividino1, Colin E. Webber5, Jean-Eric
Tarride6 and Jonathan D. Adachi7. 1McMaster University, Hamilton, ON,
2
Hamilton Health Sciences, Hamilton, 3St. Joseph’s Health Care, Hamilton,
ON, 4St. Joseph’s Hospital and McMaster University, Hamilton, ON, Hamilton, ON, 5Hamilton Health Sciences, Hamilton, ON, 6Programs for Assessment of Technology in Health (PATH) Research Institute, Hamilton, ON,
7
Charlton Medical Centre, Hamilton, ON
Background/Purpose: The Outcome Measures in Rheumatology
(OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Score
(RAMRIS) and van der Heijde-modified Sharp score (vdHSS) are
recognized semi-quantitative measures for the evaluation of rheumatoid
arthritis (RA) disease progression on magnetic resonance imaging (MRI)
and radiography (X-ray), respectively. The smallest detectable difference
(SDD) is used to quantify the reliability between ratings of status scores
in scale units. To date, the SDD has been evaluated at the overall or
component feature score levels of analysis thereby ignoring variability at
the unit of measurement. The objective of this study was to determine the
reliability of RAMRIS and vdHSS at the unit of measurement across four
radiologists and to compare it to the conventional approach.
Methods: A paired, cross-sectional study of RA patients with varying
symptom duration (mean 6.8 years (SD 6.4) for MRI, 7.6 years (SD 7.3)
for X-ray) was conducted. 19 MR image sets of metacarpophalangeal
joints (MCP) 2–5 and 9 X-ray image sets of both hands, wrists, and
forefeet were each independently evaluated by 4 radiologists using
RAMRIS and vdHSS, respectively. Shrout and Fleiss fixed and random
effects intra-class correlation coefficients (fICC and rICC, respectively),
and SDD were calculated for overall and component feature scores, as
well as at the unit of measurement.
Results: At the unit of measurement, the RAMRIS erosion, edema,
and synovitis fICC were 0.71, 0.56, and 0.41, respectively. The corresponding SDD values (rounded to scale unit) for erosion, edema, and
synovitis were 2, 1 and 2. Overall and component feature score reliability
measures were dependent on the anatomy compared. For single MCP 2–5
joint sets (i.e. per hands), the fICC for the overall RAMRIS and
component feature subscore for erosion, edema, and synovitis were 0.66,
0.55, 0.60, and 0.39. The corresponding SDD values were 11, 7, 4, and 5.
For X-ray, erosion and joint space narrowing (JSN) fICC at the unit of
measurement were 0.61 and 0.69, and the associated SDD values were
both 2. For the hands, wrists and feet, the overall and component feature
scores for erosion and JSN were 0.69, 0.60, and 0.85. The corresponding
SDD values were 39, 34, and 11.
Conclusion: The conventional approach to the calculation of reliability for overall or component feature scores fails to account for variability
at the unit of measurement. In order for reliability of composite measure
scores to be valid, the assumption is made that the SDD at the unit of
measurement is less than the scale unit. The study findings suggest that
this prerequisite assumption may be false. The validity of literature
evidence for the reliability of diagnostic imaging and composite measures
in general is therefore questionable.
Disclosure: R. Tavares, None; N. Parasu, None; K. Finlay, None; E. Jurriaans,
None; H. Wu, None; K. A. Beattie, None; M. Larche, None; L. E. Hart, None; W. G.
Bensen, None; R. S. Bobba, None; A. A. Cividino, None; C. E. Webber, None; J. E.
Tarride, None; J. D. Adachi, None.
Bye Bye Biopsy: Diffusion Tensor and Dynamic Contrast Enhance
Magnetic Resonance Imaging Parameters Reflect Molecular Events of
Inflammation in the Synovium. Vikas Agarwal1, Rishi Awasthi2,
Deepak Tripathi3, Vinita Agrawal3, Ram Kishore Singh Rathore4, Kusum
Sharma5, CM Pandey3 and Rakesh K. Gupta3. 1Sanjay Gandhi Post
Graduate Institute of Medical Sciences, Lucknow, Lucknow, India,
2
Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow,
India, Lucknow, India, 3Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow, Lucknow, India, 4Indian Institute of Technology,
Kanpur, India, 5Postgraduate Institute of Medical Education and Research, Chandigarh, India
Background/Purpose: Chronic synovial inflammation is characterized by accumulation of inflammatory cells and increased vascularity.
Synovial histology remains the most definitive way to delineate the
severity of inflammation. Herein we hypothesize that Diffusion tensor
imaging (DTI) derived metrics may delineate the aggregation of the
inflammatory cells. Dynamic contrast enhanced (DCE) imaging may
provide information regarding vascularity in the inflamed synovium.
Combination of these may provide information about the ongoing inflammation.
Methods: Patients with chronic knee arthritis underwent conventional,
DTI and DCE MRI (3T) followed by arthroscopic synovial biopsy. Masks
of synovial regions that enhanced on post contrast T1-weighted imaging
were created using an automated segmentation algorithm. Created masks
were used to segment the inflamed synovium to extract various DCE and
DTI metrics. Synovium was subjected to histopathology, immunohistochemistry (IHC), culture and PCR.
Results: There were 65 patients (45 male) with mean age 39 years
[range 18–76] and mean disease duration 29 months [range 4–192].
Fifteen patients had tuberculosis and rest had; undifferentiated spondyloarthropathy (n⫽14), chronic monoarthritis (n⫽11), chronic undifferentiated monoarthritis (n⫽10), rheumatoid arthritis (n⫽6), osteoarthritis
(n⫽3), ankylosing spondylitis (n⫽2), reactive arthritis (n⫽2) and juvenile
idiopathic arthritis and leprosy one each.
The mean values of various DTI and DCE and IHC parameters are
presented in (Table-1). Amongst the DTI parameters, FA significantly
correlated with all the inflammatory cells infiltrating into the synovium
(Table-2) and various proinflammatory cytokines. FA was the best
predictor of infiltrating T cells, B cells, plasma cells, macrophages,
adhesion molecule and proinflammatory cytokines. DCE parameters
significantly correlated with CD34 and blood volume was the best
predictor of CD34.
Table 1. Mean values of DTI, DCE, IHC markers
DTI indices
Mean ⴞSD
FA
MD (⫻10⫺3 mm2sec⫺1)
CL
CP
CS
DCE indices
BF(ml/100gm/min)
BV(ml/100gm)
k ep(min⫺1)
PCI
Immune cells in synovium
CD3
CD4
CD8
CD20
CD34
CD54
CD68
CD138
TOTAL CELLS
IL-1␤
TNF-␣
0.22 ⫾ 0.031
1.63 ⫾ 0.51
0.06 ⫾ 0.027
0.15 ⫾ 0.054
0.75 ⫾ 0.023
109.9 ⫾ 42.8
9.5 ⫾ 4.2
2.5 ⫾ 1.0
1820.4 ⫾ 211.6
154.94 ⫾ 48.65
63.42 ⫾ 32.85
53.58 ⫾ 17.63
39.34 ⫾ 13.96
52.94 ⫾ 17.28
36.35 ⫾ 13.14
163.2 ⫾ 34.62
36.06 ⫾ 14.49
489.66 ⫾ 106.39
31.09 ⫾ 18.15
24.71 ⫾ 11.52
FA: Fractional Anisotropy, MD: Mean Diffusivity, CL:Linear anisotropy,
CP:Planar anisotropy, CS:Spherical isotropy, BV: Blood Volume, BF: Blood Flow,
ktrans: Volume transfer constant, PCI: post-contrast signal intensity.
S440
Table 2. Correlation between the values of DTI & DCE -MRI indices with
various inflammatory cells, adhesion molecule and proinflammatory cytokines and
angiogenesis marker in the synovium (n⫽65)
DCE- Angiogenesis
MRI
Marker in
Indices the synovium
Infiltrating Immune cells in synovium
DTI-MRI
Indices
CD3
CD 4
CD 8
CD 20 CD 68 CD 138 CD 54 TNF-␣ IL-1␤
FA
0.800# 0.773#
ADC
-0.396# -0.391# -0.468# -0.087 -0.283*
-0.079
-0.203
CL
CP
0.452# 0.325#
0.044 0.054
0.257* 0.172
0.019 0.083
CS
-0.307* -0.376* -0.354# 0.069 -0.351#
0.078
PCI
-0.070
0.177
0.111
0.859# 0.276* 0.681#
0.410# 0.258* 0.141
0.127 0.025 0.106
0.102
0.067 -0.036
0.308* 0.513# 0.418* 0.604#
Total
Inflammatory
cells
CD 34
0.913#
BF
0.814#
-0.019 0.305*
0.431#
BV
0.848#
0.237 0.510#
0.087 0.067
0.464#
0.072
kep
0.308*
-0.159
-0.151 -0.346*
-0.322#
-0.156
0.15
0.069
PCI
0.156
0.107
# p⬍0.01 level
* P⬍0.05
Figure 1. Run 1 Reader Measured Erosion Volume Differences Plotted against
R2’s Measures
Disclosure: V. Agarwal, None; R. Awasthi, None; D. Tripathi, None; V. Agrawal,
None; R. K. S. Rathore, None; K. Sharma, None; C. Pandey, None; R. K. Gupta,
None.
1018
Reliability of the Early Erosions in Rheumatoid Arthritis Software
When Quantifying Bone Loss. Melissa XP. Koh1, Joshua WJ. Barbosa1,
Ruben Tavares1, Stephen Tytus1, Patrick Emond1, Chris Gordon1, George
Ioannidis1, Karen A. Beattie1, William G. Bensen2, Raja S. Bobba1, Alfred A.
Cividino1, Lawrence E. Hart3, Maggie Larche1, Arthur N. Lau1 and Jonathan
D. Adachi4. 1McMaster University, Hamilton, ON, 2St. Joseph’s Hospital
and McMaster University, Hamilton, ON, 3St. Joseph’s Health Care, Hamilton, ON, 4St. Joseph’s Health Care and McMaster University, Hamilton, ON
Background/Purpose: Instruments designed to determine the clinical
relevance of bone erosions captured by magnetic resonance imaging (MRI) in
rheumatoid arthritis (RA) patients have been set-back by inconsistency in
both intra and inter-rater reliability. The developed Early Erosions in
Rheumatoid Arthritis (EERA) software holds promise for increasing reliability across readers by quantifying RA patient erosions in a semi-automated
fashion using an amalgamation of conventional Region Growing and LevelSet Segmentation algorithms. The principle aim of this study was to
determine intra and inter-rater reliability when applying EERA software to
the quantification of erosions in the metacarpal phalanges (MCPs) of RA
patients.
Methods: Two readers, R1 and R2, trained to use EERA software, but
otherwise inexperienced with conventional quantification techniques, evaluated erosions captured by MRI in the second through fifth MCPs of 50
patients diagnosed with RA under the American College of Rheumatology
1987 revised definition. A 1T magnet, 100mm diameter cylindrical transmit
and receive coil, and a 3D spoiled gradient echo sequence were used in
acquiring the images. Images were evaluated by each reader twice with a 72
hour wait period between runs. Intra and inter-rater reliabilities for the total
volume measures between the two readers and two runs were assessed via
intra-class correlations, ICC(2,1), with 95% confidence intervals. For each
run, volume differences between readers were graphed against R2’s volume
measures in Bland-Altman difference plots so as to visually capture the
degree to which scores varied.
Results: Of the 50 participants recruited for the study, 16 were male and
34 were female. Study subjects had a mean age of 57 (SD⫽11.5)yr, a mean
weight of 78 (SD⫽15.6)kg, and a mean height of 169 (SD⫽13.9)cm. Readers
identified 64 ⫾ 1 erosions in the patients: 15 of these occurred in second
MCP, 33 ⫾ 1 in the third MCP, 12 ⫾ 1 in the fourth MCP, and 4 in the fifth
MCP. Mean erosion size, as determined by R1 during the first and second
runs, were 87.1 (SD⫽118.9)mm3 and 88.1 (SD⫽121.2)mm3 respectively.
R2’s measures had a mean erosion volume of 90.7 (SD⫽130.1)mm3 for the
first run and 103.2 (SD⫽151.0)mm3 for the second run. For both runs,
agreement between readers was better for smaller sized erosions decreasing
appreciably beyond 100mm3 (See Figure 1. Run 2 results are not shown but
are available upon request). The intra-rater reliability had an ICC value of
0.956 with the 95% confidence interval ranging from 0.935 to 0.970. Between
R1 and R2, the inter-rater reliability had an ICC value of 0.921 with a 95%
confidence interval from 0.886 to 0.946.
Conclusion: Results obtained suggest that EERA software can be
applied to acquire MCP erosion volume measures in a reliable manner.
Disclosure: M. X. Koh, None; J. W. Barbosa, None; R. Tavares, None; S. Tytus,
None; P. Emond, None; C. Gordon, None; G. Ioannidis, None; K. A. Beattie, None;
W. G. Bensen, None; R. S. Bobba, None; A. A. Cividino, None; L. E. Hart, None;
M. Larche, None; A. N. Lau, None; J. D. Adachi, Abbott, Amgen, Bristol Myers
Squibb, and Roche Pharmaceutcals, 2.
1019
Visualization of Cartilage in High-Resolution Magnetic Resonance
Imaging Is a New Imaging Biomarker for the Quantification of
Joint Damage in Rheumatoid Arthritis. Barbara Herz1, Stephanie
Finzel1, Andreas Albrecht1, Juergen Rech1, Matthias Englbrecht1, Goetz
Welsch2 and Georg Schett3. 1University of Erlangen-Nuremberg, Erlangen, Germany, 2Department of Traumatic Surgery, University Clinic of
Erlangen-Nuremberg, Erlangen, Germany, Erlangen, Germany, 3Institute
for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen,
Germany
Background/Purpose: Recent achievements in Magnetic Resonance
Imaging (MRI) have been the gradient-echo-based T1-delayed
gadolinium-enhanced MRI of cartilage (dGEMRIC) focussing on the
detection of proteoglycan content in cartilage; moreover, the multi-echo
and spin-echo T2-mapping has been developed for the assessment of
cartilage hydration and collagen microstructure. Current MRI-studies
suggest a link between dGEMRIC and T2-mapping and early changes of
cartilage in inflammatory diseases. However, their diagnostic value in
inflammatory diseases has not yet been fully clarified..To investigate the
relation between morphological and biochemical alterations in the cartilage of patients with Rheumatoid Arthritis (RA) by high-resolution
3Tesla-MRI.
Methods: 29 RA-patients received a 3Tesla-MRI scan of the 2nd and
3rd metacarpophalangeal (MCP) joint of the dominant hand. T2-mapping
and dGEMRIC were performed with 2 small-diameter surface coils
designed for high-resolution imaging of cartilage (0.26⫻0.26⫻105mm
voxel size; Verio Siemens Healthcare, Erlangen, Germany). T2 and T1
relaxation times were obtained via a region-of-interest (ROI) evaluation.
MCP heads and bases were scored semiquantitatively for synovitis, bone
marrow edema (BME) and bone erosion (BE) using the RA MRI scoring
(RAMRIS) system; joint space and cartilage thickness were measured
perpendicular to the joint plane in all 3 joint regions (fig. 1a).
Results: Inter- and intraobserver agreement was good (details see fig.
1b). For correlation analysis mean values of real and total joint spaces
(RJS, TJS), RAMRIS-subscores, and ROIs of dGEMRIC- and T2evaluations were used; image 1a shows details of source data acquisition,
image 1c data of correlation analysis. Interestingly, early changes of
cartilage such as BME and synovitis in RAMRIS as compared to
dGEMRIC were correlated negative (p⫽0.029; p⫽0.003); likewise, BME
and synovitis showed positive correlation (p⫽0.013; p⫽0.015) in T2. In
contrast, periarticular changes occurring later in the course of the disease
such as BE did not correlate with dGEMRIC (p⫽0.704) and weakly with
T2 (p⫽0.026). All joint space subanalyses of MCP3 despite RJS correlated with dGEMRIC and T2 mainly in medial region (TJS p⫽0.017; TCT
p⫽0.020; CT p⫽0.018). Additionally, in dGEMRIC MCP2 and RJS
correlated in ulnar side (p⫽0.001).
S441
Monday, November 12
Conclusion: DTI and DCE metrics capture cellular and molecular events
and correlated with the degree of synovial inflammation. They may replace
synovial histology in future.
Monday, November 12
1st Proximal Phalanx
1st Metatarsal
2nd Proximal Phalanx
2nd Metatarsal
3rd Proximal Phalanx
3rd Metatarsal
4th Proximal Phalanx
4th Metatarsal
5th Proximal Phalanx
5th Metatarsal
Total
Conclusion: High-resolution MRI using dGEMRIC and T2-mapping
enables meticulous detection of very early inflammatory changes in
cartilage which are known to precede RA-typical periarticular bone
damage. This is important both for early discovery of those damages,
adequate therapy decisions and therapy monitoring; moreover, it may also
have an impact on the development of anti-inflammatory drugs in the
future. Additional studies on mechanical influences on cartilage are
needed to further evaluate the mechanisms of joint space alterations.
Disclosure: B. Herz, None; S. Finzel, None; A. Albrecht, None; J. Rech, None; M.
Englbrecht, None; G. Welsch, None; G. Schett, None.
Dorsal
Medial
Dorsal
Lateral
Plantar
Medial
Plantar
Lateral
7
6
0
6
1
3
1
6
2
10
42
3
4
1
5
1
4
1
3
4
11
37
5
13
5
9
6
10
6
12
9
14
89
7
19
8
6
6
8
6
6
5
14
75
Conclusion: This is the first study to report the location of erosions at
the MTP joints in patients with RA and forefoot pain. The results confirm
the hypothesis of this exploratory study; erosions were more commonly
reported on the plantar aspect of the distal and proximal parts of the MTP
joints, often in sites not readily imaged using standard ultrasound
protocols. Further work is required to determine the relationship between
forefoot pain, deformity and raised plantar pressures with the location of
erosions at the MTP joints in patients with RA. Furthermore, these study
findings highlight the need to image the dorsal and plantar aspect of the
MTP joint when using ultrasound alone to detect erosions in RA.
Disclosure: H. J. Siddle, None; R. J. Hodgson, None; A. J. Grainger, None; A. C.
Redmond, None; R. J. Wakefield, None; P. S. Helliwell, None.
1021
1020
Location of Erosions At the Metatarsophalangeal Joints in Patients
with Rheumatoid Arthritis. Heidi J. Siddle1, Richard J. Hodgson2,
Andrew J. Grainger3, Anthony C. Redmond4, Richard J. Wakefield4 and
Philip S. Helliwell5. 1University of Leeds, Leeds, United Kingdom,
2
NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, United
Kingdom, 3Leeds Teaching Hospitals NHS Trust and NIHR Leeds
Musculoskeletal Biomedical Research Unit, Leeds, United Kingdom,
4
University of Leeds and NIHR Leeds Musculoskeletal Biomedical
Research Unit, Leeds, United Kingdom, 5NIHR Leeds Biomedical Research Unit, University of Leeds and Leeds Teaching Hospitals NHS
Trust, Leeds, United Kingdom
Background/Purpose: The forefoot is described as the most common
site of symptoms in the foot and ankle of patients with rheumatoid arthritis
(RA). Pressure under the forefoot area is significantly increased in patients
with RA compared to normal subjects and forefoot peak pressures have
been reported to correlate with pain, damage and higher erosion scores at
the MTP joints. Damage to plantar structures such as the capsule and
plantar plate of the MTP joints in patients with RA is associated with bone
erosion, suggesting altered biomechanics or mechanical effects due to
capsule or plantar plate abnormalities may cause bone changes. While a
tendency towards a lateral distribution has been noted in the hands, the
location of erosions at the MTP joints has not been previously reported in
patients with RA. This exploratory study hypothesised that the majority of
erosions at the MTP joints in patients with RA are on the plantar aspect,
contributing to pain, damage and increased pressure.
Methods: In 24 patients with RA the more symptomatic forefoot was
imaged using 3Tesla MRI. T1 weighted sagittal and short axis post
gadolinium sequences were acquired through the MTP joints. Images
were scored for bone erosion in the distal and proximal part of the MTP
joints using the RAMRIS system. The base of the proximal phalanx and
the head of the metatarsal were divided into quadrants to determine the
location of erosions in dorsal-medial, dorsal lateral, plantar medial and
plantar lateral regions.
Results: Seventeen females and seven males with a mean age of 55.5
years, disease duration 10.6 years (range 0.6 – 36) and self reported foot pain
measured by 100mm visual analogue scale (VAS) of 43.4 (SD 27.9) took part
in the study. Eighteen patients were rheumatoid factor positive, the mean (SD)
DAS44 (CRP) and DAS44 (ESR) were 2.5 (0.8) and 2.6 (0.9) respectively.
The location of erosions at the MTP joints in patients with RA is shown in the
table below. The majority of erosions are reported on the plantar aspect of the
MTP joints.
Magnetic Resonance Imaging in Follow-up of Clinical Remission in
Juvenile Idiopathic Arthritis. Mira van Veenendaal1, Robert Hemke2,
Marjolein I. Bos1, Mario Maas2, Marion A. J. Van Rossum1 and Taco W.
Kuijpers1. 1Emma Children’s Hospital/Academic Medical Center (AMC),
Amsterdam, Netherlands, 2Academic Medical Center (AMC), Amsterdam,
Netherlands
Background/Purpose: Despite clinical remission, a substantial proportion of Juvenile Idiopathic Arthritis (JIA) patients will flare after a period of
inactive disease. MRI has proven to depict subclinical inflammation as
reflected by synovial hypertrophy, and may therefore be useful to identify
patients at risk for flaring during follow-up.
The purpose of this study, focussing on the main target joint, was to use
MRI in JIA patients in clinical remission, and to identify inflammatory
changes as compared to clinical status over time.
Methods: In this prospective study, 16 patients with JIA (median age 11.8
years [IQR, 10.5–14.5], median disease duration 3.2 years [IQR, 1.8–5.6]) in
clinical remission (fulfilling the Pediatric Rheumatology International Trials
Organization (PRINTO) preliminary criteria for clinical remission) werestudied with MRI at 2 consecutive time points (median interval 16.1 months [IQR
14.4–17.1]) and assessed for clinical relapse. Initial clinical remission was
achieved in 14 patients on medication (CRM) (median duration inactive
disease 11.0 months [IQR 7.2–13.7]) and in 2 patients off medication (CR)
(median duration inactive disease 28.7 months [IQR 15.7–28.7]). Contrastenhanced MRI of the formerly most involved knee was performed to evaluate
the degree of synovial hypertrophy, using the validated Juvenile Arthritis
MRI Scoring (JAMRIS) (synovial hypertrophy score; ⬍2 mm⫽0, 2–4
mm⫽1 and ⬎4 mm⫽2, at 8 knee regions).
Results: The first MRI showed signs of subclinical synovitis in 8 patients
(50 %) and no synovitis in 8 patients. The second MRI in follow-up
demonstrated an increased score of synovial hypertrophy as compared to the
first MRI in the 6 patients with relapse of arthritis. In contrast, all patients with
sustained clinical remission showed either stable (6 patients) or improved (4
patients) scores of synovial hypertrophy. CRP and erythrocyte sedimentation
rate were not increased at both MRI time points.
Conclusion: A large degree of JIA patients who satisfy the PRINTO
remission criteria with normal findings on clinical and laboratory assessment
had MRI based synovitis in this study, suggestive of ongoing disease activity.
Increase of synovial hypertrophy over time was related to disease flaring,
whereas stable or further reduction of synovial hypertrophy was associated
with sustained clinical remission. Serial MRI allows for adequate follow-up
of underlying disease even when clinically silent.
Disclosure: M. van Veenendaal, None; R. Hemke, None; M. I. Bos, None; M. Maas,
None; M. A. J. Van Rossum, None; T. W. Kuijpers, None.
S442
1022
Imaging of Ankle Joints by MRI in Murine Models of Inflammatory
Arthritis. Shawn M. Rose1, Harris R. Perlman1, Emily Alex Waters2 and
Thomas Meade2. 1Northwestern University, Chicago, IL, 2Northwestern
University, Evanston, IL
Table. MRI scores at baseline, week 6 and week 28/end of study
Relative contribution to
total RASSS progression
(in %)
Cervical segment (12 VCs)
Lumbar segment (12 VCs)
Thoracic segment (4 VCs)
Total (28 VCs)
Expected
Observed
43
43
14
100
55
29
16
100
P-value for the
difference
0.09
0.04
0.70
Conclusion: The determination of a RASSS for status or progression of
radiographic abnormalities in the spine is frequently impossible or strongly
influenced by non-contributory imputation. In comparison to the conventional
mSASSS method, the contribution of thoracic VCs in the RASSS-method is
negligible, and does not justify the additional scoring efforts.
Reference
A&R:61,764-71
Disclosure: S. M. Rose, None; H. R. Perlman, None; E. A. Waters, None; T. Meade,
None.
Disclosure: S. Ramiro, None; A. M. Van Tubergen, None; C. Stolwijk, None; R.
Landewé, None; D. van der Heijde, None.
1023
1024
Scoring Radiographic Progression in Axial Spa: Should We Use the
Modified Stoke in Ankylosing Spondylitis Spine Score or the Radiographic Ankylosing Spondylitis Spinal Score? Sofia Ramiro1, A.M. Van
Tubergen2, Carmen Stolwijk2, Robert Landewé3 and Désirée van der Heijde4.
1
Academic Medical Center, University of Amsterdam, The Netherlands
and Hospital Garcia de Orta, Almada, Portugal, 2Maastricht University
Medical Center, Maastricht, Netherlands, 3Academic Medical Center, University of Amsterdam and Atrium Medical Center, Heerlen, Netherlands,
4
Leiden University Medical Center, Leiden, Netherlands
What Constitutes the Characteristic Fat Lesion On MRI of the Sacroiliac
Joints in Early Spondyloarthritis? Ulrich Weber1, Susanne Juhl Pedersen2, Veronika Zubler1, Kaspar Rufibach3, Stanley Chan4, Robert GW
Lambert4, Mikkel Ostergaard5 and Walter P. Maksymowych4. 1Balgrist
University Hospital, Zurich, Switzerland, 2Copenhagen University Hospital
Glostrup, Copenhagen, Denmark, 3University of Zurich, Zurich, Switzerland,
4
University of Alberta, Edmonton, AB, 5Copenhagen University Hospital at
Glostrup, Glostrup, Denmark
Background/Purpose: Radiographic damage is one of the core outcomes
in axial SpA and it is usually assessed with the modified Stoke Ankylosing
Spondylitis (AS) Spine Score (mSASSS). The recently proposed Radiographic AS Spinal Score (RASSS)[1] includes an assessment of the lower
thoracic vertebrae, under the hypothesis that most progression occurred in
these segments. We aimed to compare the mSASSS and RASSS with regard
to efficiency and added value.
Background/Purpose: It is well known that fat infiltration (FI) of bone
marrow may be observed on T1-weighted MRI in the sacroiliac joints (SIJ) of
healthy individuals and patients with mechanical back pain and with spondyloarthritis (SpA). But it is unclear whether the MRI features of FI allow
characterization of FI as pathological rather than physiological. Moreover, it
is unclear if this might have diagnostic utility in early SpA. We aimed to
assess which MRI features of fat contribute to diagnostic utility of SIJ MRI
in 2 inception cohorts of early SpA.
S443
Monday, November 12
Background/Purpose: One of the fundamental shortcomings in the field
of experimental rheumatology is the inability to non-invasively monitor the
development of inflammatory arthritis longitudinally. Magnetic resonance
imaging (MRI) overcomes this limitation, by allowing for detailed examination of anatomical structures as well as the assessment of joint and soft tissue
inflammation. Here, we have utilized cutting-edge MRI technologies to image
ankle joints in control (C57BL/6) and arthritic (K/BxN serum transferinduced arthritis (STIA) and K/BxAg7) mice over time. Further, the MRI data
was validated against both clinical, histological, and in vivo imaging system
(IVIS) assessments of inflammatory arthritis.
Methods: C57BL/6 mice were injected with PBS (controls) or 100 mL of
K/BxN serum at day 0. Mice were scored clinically and imaged via IVIS and
MRI at days 0, 3, 7, 15, and 21 after arthritis induction. MRI imaging was also
performed on ankle joints from 10- and 21-week-old K/BxAg7 mice. Arthritis
severity was assessed by measurement of ankle width and clinical score.
Decalcified ankle joint specimens were sectioned and stained with hematoxylin and eosin for histological analysis. Luminescence acquisition was performed using an IVIS Spectrum System 10 minutes after intraperitoneal
injection of 100 mL (200 mg/kg) of XenoLight Rediject Inflammation Probe.
Radiance signal intensity from normalized gated analyses of forepaw and
hindpaw joints was quantified utilizing Living Image software. Ankle joint
MRI was performed on a 9.4T Bruker Biospec MRI system. Two highresolution 3D images were acquired; a gradient echo pulse sequence
(FLASH) to evaluate bone and a spin echo sequence (MSME) to evaluate
inflammation (long T2 signal volume). Amira software was used to perform
MRI long T2 signal analyses and bone reconstructions. Graphpad Prism
software was used for ANOVA and linear regression analyses with statistical
significance established at p ⬍ 0.05.
Results: Arthritic STIA animals demonstrated increased clinical, histological, IVIS, and MRI measures of disease severity compared to controls.
Peak arthritis intensity occurred at day 7 and complete resolution of
inflammation was observed by day 21. Following induction of arthritis, the
majority of increased long T2 signal and volume expansion of ankle joints
occurred in a juxtaarticular rather than intrarticular fashion. Ankle joint bone
destruction in K/BxAg7 mice was readily detectible via MRI as early as age
10 weeks. Linear regression analyses demonstrated a strong correlation
between clinical score and paw joint radiance intensity by IVIS (R2 ⫽ 0.54,
p ⬍0.0001). There was also a statistically significant relationship between
ankle joint width and volume of long T2 signal by MRI (R2 ⫽ 0.57, p
⬍0.0001).
Conclusion: MRI is an optimal technology for anatomic localization of
articular and soft tissue changes during the development and resolution of
inflammatory arthritis. Future studies may combine MRI imaging with
various in vivo labeling agents to investigate joint disease in a cell-type
specific fashion.
Methods: Two-yearly spinal radiographs from patients followed in the
Outcome in AS International Study (OASIS) were used. Two readers
independently scored the x-rays, and averaged scores per vertebral corner
(VC) were used. Only radiographs with ⱕ3 missing VCs per segment
(cervical and lumbar, the latter with 4 thoracic VCs included as described
for the RASSS) were included, so that both scores could be calculated.
Status- and 2-year progression scores of both scoring methods were
compared, first in terms of their availability. To assess the potential
additional value of including the thoracic segment in the score, the relative
contribution (in %) to the 2-year total RASSS progression of each spinal
segment (cervical, thoracic and lumbar) was determined, and compared to
the expected contribution, assuming a balanced segmental progression and
proportional to the number of sites (12 cervical VCs, 4 thoracic VCs and
12 lumbar VCs).
Results: The mSASSS could be scored in a total of 809 radiographs. The
RASSS could be calculated in 78% of these radiographs. In 58% of those, the
RASSS was calculated based on 1 or 2 present thoracic VC scores (of the 4
possible thoracic VC scores), and the remaining 2–3 had to be imputed
because they were missing (these imputed VCs were therefore uninformative). There were 520 two-year mSASSS interval progression scores available, and in 63% of them a 2-year RASSS interval progression score could be
determined.
Of all the radiographs in which both scores could be determined
(n⫽629), the mean (SD) status- score was 15.5 (17.9) units for the
mSASSS and 18.0 (20.9) units for the RASSS. The mean (SD) 2-year
interval progression scores (in 330 two-year intervals) were 2.0 (3.6) for
the mSASSS and 2.4 (4.4) for the RASSS. Exclusive progression of the
thoracic segment occurred in only 5% of the cases. There were no
significant differences between the observed and expected contributions of
the thoracic segment to progression (Table), whilst progression was more
frequently than expected observed in the cervical spine, and less frequently in the lumbar spine.
Monday, November 12
Methods: Cohort A comprised 69 consecutive patients ⱕ50 years
referred from rheumatology and primary care practices for assessment of
clinically suspected SpA, cohort B comprised 88 consecutive patients ⱕ50
years with acute anterior uveitis and back pain. They were classified
according to clinical examination and pelvic X-ray as having nonradiographic axial SpA (nr-axSpA) (n⫽20 and 31 for cohorts A and B,
respectively), ankylosing spondylitis (AS) (n⫽10 and 24), or mechanical
back pain (MBP) (n⫽39 and 33). Cohort A also comprised 20 healthy
volunteers (HV). SIJ MRI were assessed independently in random order by 4
blinded readers for the following morphological features of FI: distinct border
around the region of FI, homogeneity of the T1-weighted signal, proximity to
subchondral bone, and association with other SIJ lesions (bone marrow
edema (BME), erosion (ER)).
Results: In cohort A and B, FI in ⱖ2 SIJ quadrants was recorded by any
2 readers in AS in 90% and 100%, in nr-axSpA in 45% and 48%, in MBP in
36% and 24%, respectively, and in HV in 10%. Inter-reader agreement for FI
expressed as intraclass correlation coefficient over all 4 readers was 0.59 and
0.75 for cohort A and B.
ⱖ2). Comparison of BL disease characteristics based on BL spine and SIJ
scores ⬍2 vs. ⱖ2 were generally comparable except for a greater proportion
of males among those with spine and SIJ scores ⱖ2, and younger age and
shorter symptom duration among those with spine and SIJ scores ⬍2. The
cumulative probability plot (figure) shows a similar distribution of SPARCC
spine scores regardless of presence or absence of SIJ inflammation on MRI.
The most frequently involved DVUs with bone marrow edema were in the
lower thoracic and lumbar spine.
Diagnostic utility (mean of 4 readers for cohort A/B) of SIJ FI in nr-axSpA vs MBP
patients
Feature
Sensitivity
Specificity
Positive
LR
Negative
LR
FI per se
FI with distinct border
Homogeneous FI
Subchondral FI
FI with any 2 features
FI⫹BME
FI⫹ER
0.44/0.42
0.21/0.21
0.20/0.26
0.36/0.35
0.24/0.30
0.19/0.18
0.21/0.24
0.73/0.78
0.97/0.90
0.97/0.93
0.85/0.83
0.97/0.92
0.99/0.92
0.99/0.93
1.62/1.91
8.29/2.13
6.24/3.78
2.36/2.04
9.26/3.58
14.63/2.13
33.15/3.55
0.77/0.74
0.81/0.88
0.83/0.80
0.75/0.78
0.78/0.77
0.82/0.90
0.79/0.81
BME: Bone marrow edema. ER: Erosion. FI: Fat infiltration. LR: Likelihood
ratio. FI with any 2 features: ⱖ2 features out of FI with distinct border/
Homogeneous FI/Subchondral FI
Conclusion: SIJ FI characterized by a distinct border or homogeneity on
MRI had substantial diagnostic utility in early SpA. FI in combination with
BME or ER also showed high diagnostic utility.
Disclosure: U. Weber, None; S. J. Pedersen, None; V. Zubler, None; K. Rufibach,
None; S. Chan, None; R. G. Lambert, None; M. Ostergaard, None; W. P.
Maksymowych, None.
Figure.
Conclusion: Assessment by experienced readers shows that spinal inflammation on MRI may be observed in half of nr-axSpA pts without SIJ
inflammation on MRI. MRI of both sites might be of value when evaluating
pts with nr-axSpA. These data in pts with long-standing disease need to be
confirmed in pts with shorter disease duration.
Disclosure: D. van der Heijde, Abbott Laboratories; Amgen; AstraZeneca; BMS;
Centocor: Chugai; Eli-Lilly; GSK; Merck; Novartis; Pfizer; Roche; Sanofi-Aventis;
Schering-Plough; UCB; Wyeth, 5, Abbott Laboratories; Amgen; AstraZeneca; BMS;
Centocor: Chugai; Eli-Lilly; GSK; Merck; Novartis; Pfizer; Roche; Sanofi-Aventis;
Schering-Plough; UCB; Wyeth, 2, Imaging Rheumatology, 4; J. Sieper, Abbott, Merck,
Pfizer, and UCB, 2, Abbott, Merck, Pfizer, and UCB, 5, Abbott, Merck, Pfizer, and
UCB, 8; W. P. Maksymowych, Abbott, Amgen, BMS, Eli-Lilly, Janssen, Merck, and
Pfizer, 2, Abbott, Amgen, BMS, Eli-Lilly, Janssen, Merck, and Pfizer, 5; M. A. Brown,
Abbott Laboratories, 5; S. S. Rathmann, Abbott Laboratories, 3, Abbott Laboratories,
1; A. L. Pangan, Abbott Laboratories, 3, Abbott Laboratories, 1.
1026
1025
Spinal Inflammation in the Absence of SI Joint Inflammation On MRI in
Patients with Active Non-Radiographic Axial Spondyloarthritis. Désirée
van der Heijde1, Joachim Sieper2, Walter P. Maksymowych3, Matthew A.
Brown4, Suchitrita S. Rathmann5 and Aileen L. Pangan5. 1Leiden University
Medical Center, Leiden, Netherlands, 2Charité Universitätesmedizin Berlin,
Berlin, Germany, 3University of Alberta, Edmonton, AB, 4University of
Queensland Diamantina Insititute, Brisbane, Australia, 5Abbott Laboratories,
Abbott Park, IL
Background/Purpose: The imaging arm of the ASAS axial spondyloarthritis (SpA) criteria requires the presence of sacroiliitis on MRI or radiographs. In patients (pts) with non-radiographic axial SpA (nr-axSpA), there
may be inflammation along the spine in the absence of sacroiliac joint (SIJ)
inflammation on MRI. This analysis evaluated the existence of spinal
inflammation on MRI at baseline (BL) in nr-axSpA pts with and without
inflammation in the SIJs on MRI.
Methods: ABILITY-1 is an ongoing multicenter, randomized, controlled
trial of adalimumab vs. placebo in pts with nr-axSpA classified using the
ASAS axial SpA criteria, who had an inadequate response, intolerance to, or
contraindication for NSAIDs. MRI of the SIJ and spine performed at BL were
centrally scored using the SPARCC method (6-DVU method for the spine) by
2 independent readers blinded to the treatment codes. Mean scores of the
readers were used. SPARCC score ⱖ2 for either the SIJ or spine was used as
the operational definition of positive MRI evidence of inflammation. For these
analyses, all pts were combined, independent of randomization.
Results: Mean symptom duration of the study population (N⫽185) was
10 yrs. At BL, 48% of pts were reported by the local investigator to have past
or present MRI evidence of sacroiliitis as required by the ASAS axial SpA
criteria. Of pts with available BL SPARCC scores, 40% had a BL SIJ score
ⱖ2 and 52% had a BL spine score ⱖ2. Of the pts with BL SPARCC SIJ score
⬍2, 49% had evidence of spinal inflammation (BL SPARCC spine score
Psoriatic Arthritis and Spondyloarthritis: Inflammation Assessed
by “Head to Toe” Wholebody Magnetic Resonance Imaging—A
Comparison with Clinical Joint Examination. René Panduro Poggenborg1, Susanne Juhl Pedersen2, Iris Eshed3, Inge Juul Sørensen2,
Ole Rintek Madsen4, J.M. Møller5 and Mikkel Østergaard6. 1Copenhagen University Hospital in Glostrup, Copenhagen, Denmark, 2Glostrup
Hospital, Copenhagen, Denmark, 3Sheba Medical Center, Tel Hashomer,
Israel, 4Copenhagen University Hospital in Gentofte, Copenhagen,
Denmark, 5Copenhagen University Hospital in Herlev, Copenhagen,
Denmark, 6Copenhagen University Hospital Glostrup, Glostrup,
Denmark
Background/Purpose: Psoriatic arthritis (PsA) and spondyloarthritis
(SpA) is associated with a varied pattern of axial and peripheral inflammation. Wholebody magnetic resonance imaging (WBMRI) is a new
imaging modality where patients are scanned from head to toe in one
single examination. The purpose was to explore the potential of WBMRI
for detecting peripheral and axial inflammation.
Methods: Patients with clinically active peripheral PsA (Moll and
Wright, n⫽19) or axial SpA (ESSG, n⫽19) and healthy subjects
(HS, n⫽12) were included. T1-weighted pre/post-contrast and STIR sequences were performed on a 3 tesla MRI unit. Synovitis and bone
marrow oedema (BME) were evaluated at sites included in the 78-tender
joint count (TJC). Axially, BME was evaluated dichotomously in each
discovertebral unit (DVU) of the spine, and in each quadrant of the
sacroiliac joints (SIJ).
Results: Characteristics median (range): PsA/SpA/HS age 49(23–79)/
42(26–61)/32(20–61) yrs. PsA/SpA disease duration: 4 (0–34)/17 (5–48)
yrs; 78-TJC: 11(3–65)/3(0–17), 76-swollen joint count (SJC): 5 (0–20)/
1(0–5), and BASDAI score 45(9–85)/55(2–93) mm.
WBMRI assessment was done in 3800 joints included in the TJC, and
S444
Disclosure: R. P. Poggenborg, None; S. J. Pedersen, None; I. Eshed, None; I. J.
Sørensen, None; O. R. Madsen, None; J. M. Møller, None; M. Østergaard, Abbott
Laboratories, Amgen, Bristol-Meyers Squibb, Centocor, Genmab, Glaxo-Smith-Kline,
Janssen, Merck, Mundipharma, Novartis, Novo, Pfizer, Roche, Schering-Plough, UCB,
Wyeth, 2.
1027
Frequency of MRI-Detected Hip Osteoarthritis Features in Persons with
Chronic Hip Pain and the Diagnostic Performance of Radiography
Using MRI As the Reference. Li Xu1, Daichi Hayashi1, Ali Guermazi1,
David J. Hunter2, Anton Winterstein3, Ling Li4, Klaus Bohndorf3 and Frank
Roemer3. 1Boston University School of Medicine, Boston, MA, 2University
of Sydney, Sydney, Australia, 3Klinikum Augsburg, Augsburg, Germany,
4
New England Baptist Hospital, Boston, MA
Background/Purpose: Conventional radiography has been the standard
imaging tool to diagnose and grade the severity of hip OA. However,
radiography cannot visualize the bone marrow, cartilage and articular soft
tissues that are relevant for clinical manifestation and structural progression of
disease. The Hip Osteoarthritis MRI Scoring System (HOAMS) was recently
developed to enable MRI-based whole-organ semiquantitative assessment of
the hip. Frequency distribution of OA-associated features in the various
anatomical subregions of the hip has not been described before. Further, the
diagnostic performance of radiography to detect these abnormalities is
unknown. Our aim was to describe the frequency of MRI-detected features of
hip OA (cartilage damage, subchondral cysts, osteophytes and attrition) in
various subregions of the hip joint and to evaluate the diagnostic performance
of radiography for detection of these features using MRI as the reference.
Methods: 52 consecutive patients with chronic hip pain (mean age ⫾SD
63.5⫾9.5 years; 54% women) without inflammatory arthritis or recent trauma
were imaged by 1.5T MRI. Of these, 44 subjects (85%) underwent weightbearing antero-posterior pelvic radiography. For MRI assessment, the hip
joint was subdivided into the following subregions (modified HOAMS
system): latero-superior, centro-medial, anterior and posterior. According to
HOAMS, cartilage was graded 0 to 4 based on extent (depth and area) of
surface damage. Subchondral cysts and osteophytes were graded 0–3 and
0–4, respectively based on size. Bone attrition was noted as absent or present
in the latero-superior subregion only. Presence of radiographic joint space
narrowing (JSN) was compared to MRI-assessed cartilage damage. Sensitivity and specificity of radiography for diagnosing each feature (presence or
absence) were calculated using MRI as the reference standard, and the AUC
was calculated from the ROC curve for each feature.
Results: 21 of 44 subjects had radiographic OA. Frequency of diffuse
cartilage damage (for n⫽44) (HOAMS grade 3–4) in the latero-superior,
centro-medial, anterior and posterior subregions was 58%, 58%, 35% and
33%, respectively. Frequency of subchondral cysts (gradeⱖ1) and osteophytes (gradeⱖ1) was 31% and 64% in the latero-superior, 12% and 77% in
the centro-medial, 27% and 15% in the anterior, 8% and 35% in the posterior
subregions, respectively. Frequency of bone attrition in the latero-superior
subregion was 17%. Sensitivity, specificity and AUC of radiography to detect
MRI assessed cartilage damage were 64%, 88% and 0.76 for JSN, 84%, 71%
and 0.78 for osteophytes, 44%, 89% and 0.67 for subchondral cyst, and 78%,
86% and 0.82 for attrition.
Conclusion: In this cohort of subjects with hip pain diffuse cartilage
damage and osteophytes were more frequent in the latero-superior and
centro-medial subregions, while subchondral cysts were more frequent in the
latero-superior and anterior subregions. Radiography offers acceptable diagnostic performance for attrition, diffuse cartilage damage (in the form of joint
space narrowing) and osteophytes, but shows low sensitivity in detecting
acetabular subchondral cysts a finding explained by the projectional drawbacks of radiography.
Disclosure: L. Xu, None; D. Hayashi, None; A. Guermazi, Boston Imaging Core Lab,
1, Stryker, 5, Merck Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5, Novartis
Pharmaceutical Corporation, 5; D. J. Hunter, None; A. Winterstein, None; L. Li,
None; K. Bohndorf, Boston Imaging Core Lab, 1; F. Roemer, Boston Imaging Core
Lab, 1, National Institute of Health, 5, Merck Serono, 5.
1028
Semi-Quantitative Assessment of Bone Marrow Edema and SynovitisEffusion in Osteoarthritis with the Knee Inflammation MRI Scoring
System: A Target Lesion Based Methodology. Walter P. Maksymowych1,
Ulrich Weber2, Marcus Pianta3 and Robert GW Lambert1. 1University of
Alberta, Edmonton, AB, 2Balgrist University Hospital, Zurich, Switzerland,
3
University of Alberta, AB
Background/Purpose: Current MRI scoring methods for assessment of
bone marrow lesions (BML) in the knee of patients with osteoarthritis rely on
a complex subdivision of the knee into 15 subregions and then a further
estimation of the proportion of subregion with BML1. Scoring of synovitiseffusion (S-E) is based on a restricted grading scheme assessing the whole
joint (0⫽ none, 3 ⫽ large) which limits responsiveness. We aimed to develop
and conduct preliminary validation of an MRI method for direct semiquantitative assessment of BML and S-E, that focuses on detection of change
(Knee Inflammation MRI Scoring System (KIMRISS)).
Methods: Assessment of BML is based on assessment of coronal and
sagittal images for medial/lateral knee compartments and axial/sagittal
images for patella-femoral compartment using a fluid-sensitive MRI sequence
(STIR, T2 FatSat). Size of a BML lesion is defined according to the largest
continuous increase in signal assessed in all dimensions and number of slices
in which the increased signal can be detected (small ⫽ ⬍1cm in all
dimensions on 2 slices; moderate ⫽ ⬎1cm but NOT ⬎2 cm in ⱖ2
dimensions; large ⫽ ⬎2cm in ⱖ 2 dimensions). A weighting is applied to
change in BML size (1.5⫻ and 2⫻ for moderate and large lesions,
respectively). Size of S-E is assessed in each of 4 compartments (medial and
lateral patellar recess, suprapatellar, semimembranosus bursa) according to a
0–4 grading scheme and a weighting is applied for change in S-E size (1.5⫻
and 2⫻ for grade 3 and 4 lesions, respectively). MRI scans were performed
on the knee joints of 15 patients enrolled into an open label trial of an
anti-TNF agent in subjects with persistent pain due to knee osteoarthritis and
clinical evidence of effusion who had failed conventional therapy. Scans were
performed at baseline and 12 weeks and independently reviewed by 3 readers
blinded to timepoint. Reliability of change scores was assessed by intraclass
correlation coefficient (ICC) and responsiveness by standardized response
mean (SRM). We assessed correlations with WOMAC pain, patient global,
and target joint clinical effusion score.
Results: Reliability of detection of change in KIMRISS BML (ICC for 3
reader pairs ⫽ 0.71. 0.73. 0.75), KIMRISS S-E (ICC for 3 reader pairs ⫽
0.78, 0.82, 0.86), and Total KIMRISS (ICC for 3 reader pairs ⫽ 0.77, 0.81,
0.89) was very good with substantial responsiveness after 12 weeks of
treatment (Table). Improvement in Total KIMRISS score was observed in 12
patients although change in either the Total KIMRISS or KIMRISS BML did
not significantly correlate with change in WOMAC pain or patient global.
KIMRISS S-E did not correlate with target joint effusion score.
S445
Monday, November 12
synovitis/BME were detected in 593 (16%)/207 (5%) joints, synovitis/
BME was absent in 1929 (51%)/1860 (49%) joints, and 1278 (34%)/1733
(54%) joints were not possible to evaluate. Evaluation was most frequently possible in the hip joints (188 joints (94%)), knees (186 (93%)),
and the spine (in overall 94% of DVUs). In contrast, no temperomandibular joints, and only 17 (8%) of elbows could be evaluated.
In PsA, synovitis was found most frequently in carpometacarpal
(CMC) (19 joints (61%)) and shoulder (18 (53%)) joints. In SpA,
synovitis was found most frequently in 1st metatarsophalangeal joints (21
(67%)), and shoulders (17 (50%)).
In patients, the best agreement between WBMRI synovitis and clinical
swelling was found at the right hand proximal interphalangeal (PIP)
(kappa: 0.65), left hand 3rd distal interphalangeal joint (0.63), and the
right hand 3rd PIP joints (0.62). The best agreement between WBMRI
synovitis and tenderness was found at left foot 2nd and 3rd PIP (0.78;
0.47), and right hand 2nd PIP (0.70) joints.
In PsA, we found a significant correlation between SJC-28 and BME
assessed in 28 and 78 joints (Spearman’s rho: 0.54, P⬍0.05; 0.69,
P⬍0.005). WBMRI synovitis did not correlate significantly with clinical
joint examination. Scores of BME assessed in 78 joints were significantly
higher in PsA/SpA compared to HS (Mann-Whitney, P⬍0.05).
BME in the spine was detected in PsA/SpA in median 2 (0–6)/1
(0–11) DVU, respectively, and BME in the SIJ was detected in 0 (0–2)/0
(0–8) quadrants, respectively. Sum scores of BME detected in spine and
SIJ were for PsA: 2 (0–7) and SpA: 4 (0–11), which were significantly
higher than in HS (1 (0–4)) (P⬍0.05).
Conclusion: Wholebody MRI scores of axial and peripheral bone
marrow oedema are significantly higher in clinically active PsA and
SpA patients than in healthy subjects. In PsA, we found a significant
correlation between number of joints with BME and SJC, whereas TJC
did not correlate. WBMRI is a promising imaging modality, as it
allows simultaneous visualisation of inflammation in peripheral and axial
joints.
KIMRISS BML
KIMRISS Synovitis-Effusion
KIMRISS Total
ICC (3 readers)
SRM
0.73
0.82
0.81
0.82
0.70
0.88
Conclusion: The KIMRISS methodology for MRI-based semiquantitative assessment of acute lesions in knee joints is responsive and is
capable of reliably detecting change. It merits further validation in inflammatory knee joint disorders.
1. Hunter et al. Ostearthritis Cartilage 2011; 19: 990
Disclosure: W. P. Maksymowych, None; U. Weber, None; M. Pianta, None; R. G.
Lambert, None.
Monday, November 12
1029
Frequency of Mediopatellar Plica in Persons with Chronic Knee Pain
and Its Cross-Sectional Association with Patellofemoral Cartilage Damage and Bone Marrow Lesions: Data From the Joints On Glucosamine
Study. Li Xu1, Daichi Hayashi1, Ali Guermazi1, C. Kent Kwoh2, Michael J.
Hannon3, Mohamed Jarraya1, Carolyn E. Moore4, John M. Jakicic5, Stephanie M. Green6 and Frank Roemer7. 1Boston University School of Medicine,
Boston, MA, 2University of Pittsburgh and VA Healthcare System, Pittsburgh, PA, 3University of Pittsburgh School of Medicine, Pittsburgh, PA,
4
Texas Women’s University, Houston, TX, 5University of Pittsburgh, PA,
6
University of Pittsburgh, Pittsburgh, PA, 7Klinikum Augsburg, Augsburg,
Germany
Background/Purpose: Osteoarthritis (OA) commonly occurs in the
patellofemoral joint (PFJ) and knee pain in subjects with knee OA often
emanates from the PFJ rather than the tibiofemoral joint (TFJ). Despite this,
research into risk factors and mechanisms for PFJ OA is limited compared to
that of the TFJ. Mediopatellar plica (MPP) is often observed in conjunction
with patello-femoral structural damage and plica syndrome is a common
cause of knee pain. However, it is unclear if MPP is an independent risk factor
for structural PFJ damage or if MPP is an incidental finding of questionable
relevance. Our aim was to describe the frequency of different types of MPP
in a cohort of subjects with knee pain and to assess the cross-sectional
association of MPP with cartilage damage and bone marrow lesions (BMLs)
in the PFJ.
Methods: 177 subjects aged 35–65 with chronic, frequent knee pain were
included. 3T MRI of both knees was performed and a total of 342 knees were
included. MPP was scored as Types A, B, and C according to a grading
system modified from the Sakakibara arthroscopic classification, which takes
into account the relative size of the plica in relation to the osteochondral
junction of the anterior medial trochlea. Using the Whole Organ Magnetic
Resonance Imaging Score (WORMS) system, cartilage (graded 0 to 6) and
BMLs (graded 0 to 3) were semiquantitatively assessed for the medial patella,
medial trochlea, lateral patella, and lateral trochlea. In addition Hoffasynovitis and effusion-synovitis were scored from 0 to 3. Anatomical
measurements of the PFJ that are potential risk factors for cartilage loss
included the patellar length ratio (PLR), lateral patellar tilt angle (LPTA),
bisect offset (BO), and sulcus angle (SA) on MR images. The frequencies of
each type of MPP were recorded. Further, presence of MPP (any type) and its
cross-sectional association with cartilage damage (defined as WORMS score
ⱖ2) and BMLs (defined as WORMS score ⱖ1) in the PFJ was assessed using
logistic regression. Adjustment was made for age, gender, body mass index
(BMI), PLR, LPTA, BO, SA, and Hoffa- and effusion-synovitis.
Results: The mean age of subjects was 52 (SD⫾6) years, 95 (53.7%)
were men, 160 (90.4%) were white and 144 (81.4%) had a BMI ⱖ25.
Altogether 163 (47.7%) knees exhibited MPP (76 knees (22.2%) were Type
A, 69 knees (20.2%) were Type B, and 18 knees (5.3%) were Type C).
Significant cross-sectional associations between MPP and cartilage damage
were observed for the medial patella (adjusted odds ratio (aOR) 2.12, 95% CI
1.23–3.64), but not for the medial trochlea or the lateral PFJ. No associations
were found for MPP and presence of BMLs in the medial and lateral
patellofemoral compartments.
Conclusion: Type A and B plicae were common while type C plicae were
less common. The presence of MPP is cross-sectionally associated with
medial patellar cartilage damage. No increased risk was observed for presence
of MPP and cartilage damage at the medial trochlea or the lateral compartment. No associations were found between MPP and BMLs in any of the PF
subregions. The latter finding might be explained by different loading
conditions in the PFJ in comparison to the TFJ.
Disclosure: L. Xu, None; D. Hayashi, None; A. Guermazi, Boston Imaging Core Lab,
1, Stryker, 5, Merck Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5, Novartis
Pharmaceutical Corporation, 5; C. K. Kwoh, AstraZeneca, 2, Beverage Institute, 2,
Novartis Pharmaceutical Corporation, 5, Pfizer Inc, 5; M. J. Hannon, None; M.
Jarraya, None; C. E. Moore, None; J. M. Jakicic, None; S. M. Green, None;
F. Roemer, Boston Imaging Core Lab, 1, National Institute of Health, 5, Merck Serono,
5.
1030
Frequency and Fluctuation of Susceptibility Artifacts in the TibioFemoral Joint Space in Painful Knees On 3T MRI and Association with
Meniscal Tears, Radiographic Joint Space Narrowing and Calcifications.
Daichi Hayashi1, Mohamed Jarraya1, Ali Guermazi1, C. Kent Kwoh2,
Michael J. Hannon3, Carolyn E. Moore4, John M. Jakicic5, Stephanie M.
Green6 and Frank Roemer7. 1Boston University School of Medicine, Boston,
MA, 2Univ of Pittsburgh, Pittsburgh, PA, 3University of Pittsburgh School of
Medicine, Pittsburgh, PA, 4Texas Women’s University, Houston, TX, 5University of Pittsburgh, PA, 6University of Pittsburgh, Pittsburgh, PA, 7Klinikum Augsburg, Augsburg, Germany
Background/Purpose: Linear or punctate hypointensities are commonly
seen on gradient echo (GRE) sequences in the tibiofemoral joint (TFJ) space
of osteoarthritic joints. These magnetic susceptibility artifacts (SAs) are
thought to represent vacuum phenomenon, a common radiologic finding in
OA joints and vertebral disks. They appear adjacent to the cartilage or menisci
and cartilage assessment may be impaired due to signal loss or be misinterpreted as a lesion. Aim was to assess the frequency of SAs in the TFJ space
on dual-echo steady state (DESS, a GRE sequence very sensitive to magnetic
susceptibility) and on intermediate-weighted (IW) fat-suppressed (fs) sequence, and assess associations with intraarticular calcifications and joint
space narrowing (JSN) on X-ray (XR), and with MRI-detected meniscal
damage in the TFJ.
Methods: 346 knees of 177 subjects aged 35–65 with knee pain were
included. 3T MRI was performed at baseline and at 6-month follow-up (f/u).
Baseline anteroposterior knee XR were read for JSN according to the OARSI
atlas and linear/punctate calcifications within the TFJ were recorded as
present or absent. The WORMS system was used to assess meniscal damage
on MRI, and the presence of any damage (grade ⱖ1) was recorded at
baseline. Linear/punctate hypointensities representing SAs in the TFJ space
were assessed on coronal DESS and IW fs sequences. Readings were done
blinded and in a random order. XR, DESS and IW images were each read on
separate reading sessions ⬎2 weeks apart. ␬ statistics were applied to assess
concordance between findings on the baseline DESS and IW fs or XR.
Results: Subjects had a mean age of 52 (SD⫾6) years, BMI of 29⫾4, and
95 (54%) were men. Baseline Kellgren-Lawrence (KL) grades (for worst
knee) were: KL 0– 37 (21%) knees; KL 1– 14 (8%) knees; KL 2– 26 (15%)
knees; KL 3– 81 (46%) knees; KL 4– 19 (11%). On XR, 44 (13%) and 9 (3%)
knees had medial and lateral JSN, respectively; and 7 (2%) and 14 (4%) knees
had calcifications in the medial and lateral TFJ space, respectively. On MRI,
126 (36%) knees had medial and 31 (9%) knees had lateral meniscal damage.
In the medial TFJ, 13 and 4 knees showed SAs at baseline on DESS and IW
fs, respectively. On DESS, 6 of 13 knees had persistent SA at f/u and 6 knees
had incident SA at f/u. In the lateral TFJ, 5 and 1 knees showed SAs at
baseline on DESS and IW fs, respectively. On DESS, 2 of 5 knees had
persistent SAs at f/u and 1 new SA was noted at f/u. In the medial TFJ,
compared to knees without SAs on DESS, knees with SAs were more likely
to have medial meniscal damage (9/13, 69% vs. 117/333, 35%, p⫽0.017) and
medial JSN (5/13, 38%, vs. 39/333, 60%, p⫽0.016). Agreement on presence/
absence of SAs between DESS and IW was ␬⫽0.46 (95%CI 0.17–0.75) and
that between SAs on DESS and calcifications on XR was ␬⫽0.18 (-0.06 –
0.42) in the medial TFJ. We could not calculate p-values or ␬ in the lateral
TFJ due to a very small number of SAs.
Conclusion: SAs on GRE sequence in the TFJ were seen in ⬍5% of
knees in this cohort. SAs are more frequently seen in knees with medial
meniscal tears and medial JSN, which suggests an association with more
advanced OA-related joint damage. SAs on MRI rarely correspond to
XR-detected calcifications and commonly show longitudinal changes, which
support the theory that these represent vacuum phenomenon.
Disclosure: D. Hayashi, None; M. Jarraya, None; A. Guermazi, Boston Imaging
Core Lab, 1, Stryker, 5, Merck Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5,
Novartis Pharmaceutical Corporation, 5; C. K. Kwoh, Novartis Pharmaceutical Corporation, 5, Pfizer Inc, 5; M. J. Hannon, None; C. E. Moore, None; J. M. Jakicic,
None; S. M. Green, None; F. Roemer, Boston Imaging Core Lab, 1, National Institute
of Health, 5, Merck Serono, 5.
S446
1031
High Degree of Symmetricity of MRI-Detected Articular Tissue
Damage in Subjects with Knee Pain: A within-Person Analysis From
the JOG Study. Frank Roemer1, C. Kent Kwoh2, Michael J. Hannon3,
Robert M. Boudreau4, Stephanie M. Green4, John M. Jakicic5, Carolyn E.
Moore6 and Ali Guermazi7. 1Klinikum Augsburg, Augsburg, Germany,
2
University of Pittsburgh and VA Healthcare System, Pittsburgh, PA,
3
University of Pittsburgh School of Medicine, Pittsburgh, PA, 4University
of Pittsburgh, Pittsburgh, PA, 5University of Pittsburgh, PA, 6Texas
Women’s University, Houston, TX, 7Boston University School of Medicine, Boston, MA
Table 1. Expected and exact overall % agreement and w kappa for different
articular plates
Plate (Worst
grade in plate)
Exact %
agreement
Expected %
agreement
Weighted
kappa
Standard
Error
Patella
88.99%
73.00%
0.59
0.054
Femoral Trochlea
91.12%
80.73%
0.54
0.058
Medial Femur
86.09%
79.55%
0.32
0.055
Lateral Femur
89.94%
85.28%
0.32
0.069
Cartilage
Medial tibia
86.39%
79.27%
0.34
0.057
Lateral Tibia
90.53%
85.25%
0.36
0.059
Patella
82.64%
70.64%
0.41
0.058
Femoral Trochlea
83.63%
75.11%
0.34
0.059
Medial Femur
86.39%
81.54%
0.27
0.060
Lateral Femur
94.67%
93.08%
0.23
0.060
BMLs
Medial tibia
87.50%
83.55%
0.24
0.061
Lateral Tibia
90.53%
89.80%
0.07
0.061
Subregions ranked by
descending order of
w kappa value
(4 highest shown)
Cartilage
1. Lateral patella
2. Lateral fem. ant.
3. Medial tib. central
4. Medial patella
BMLs
1. Lat. femur post.
2. Lateral patella
3. Medial fem central
4. Lateral fem. ant.
Exact %
agreement
Expected %
agreement
Non-weighted
kappa
Standard
Error
84.52%
84.02%
82.25%
77.38%
51.70%
61.63%
62.05%
52.56%
0.68
0.58
0.53
0.52
0.077
0.076
0.077
0.077
96.45%
74.56%
79.29%
78.11%
92.05%
58.99%
70.21%
68.89%
0.55
0.38
0.30
0.30
0.076
0.077
0.075
0.077
Conclusion: A higher degree of symmetricity of articular tissue damage
than expected by chance was observed in this cohort of subjects with knee
pain. These findings support the hypothesis that OA is a multifactorial disease
triggered by risk factors on an individual joint level but also by person-based
risk factors that predispose joints not only to radiographic OA but also to
articular tissue damage commonly associated with OA.
Disclosure: F. Roemer, Boston Imaging Core Lab, 1, National Institute of Health, 5,
Merck Serono, 5; C. K. Kwoh, None; M. J. Hannon, None; R. M. Boudreau, None;
S. M. Green, None; J. M. Jakicic, None; C. E. Moore, None; A. Guermazi, Boston
Imaging Core Lab, 1, Stryker, 5, Merck Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5, Novartis Pharmaceutical Corporation, 5.
1032
Medial Meniscal Root Tears and the Association with Meniscal Extrusion, Prevalent Cartilage Damage and Longitudinal Cartilage Loss: The
MOST Study. Mohamed Jarraya1, David T. Feslon1, Daichi Hayashi1, Frank
Roemer2, Yuqing Zhang1, Jingbo Niu1, Michel Crema1, Martin Englund3,
John A. Lynch4, Michael C. Nevitt5, James Torner6, C.E. Lewis7 and Ali
Guermazi1. 1Boston University, Boston, MA, 2Klinikum Augsburg, Augsburg, Germany, 3Lund University, Lund, Sweden, 4University of California
at San Francisco, San Francisco, CA, 5University of California-San Francisco, San Francisco, CA, 6University of Iowa, Iowa City, IA, 7University of
Alabama at Birmingham, Birmingham City, AL
Background/Purpose: The meniscal root is a ligamentous structure that
anchors the posterior horn of the meniscus to the tibial plateau. The
association of isolated meniscal root tears with progression of osteoarthritis or
cartilage loss has not been examined. Aim of the study was to assess the
cross-sectional association of medial meniscal root tears with prevalent
medial tibiofemoral cartilage damage and medial meniscal extrusion in
subjects with radiographic osteoarthritis. We further wished to assess if
isolated medial meniscal root tears increase the risk of incident and progressive cartilage damage in the medial tibiofemoral compartment at 30-month
follow up.
Methods: The Multicenter Osteoarthritis (MOST) Study is a longitudinal
observational study of subjects with or at risk for knee osteoarthritis. Knees
were randomly selected from subjects with radiographic OA at baseline and
read for presence of absence of root tear (␬⫽1 for intrareader agreement).
Cartilage damage was graded from 0 to 6 in each of the 5 medial tibiofemoral
subregions according to WORMS scoring system. Prevalent cartilage damage
was defined as any score ⱖ2 in at least one subregion. Longitudinal
progression of cartilage damage was studied for 548 patients who had follow
up MRIs read, and was defined as at least within grade or more increase in at
least one subregion including incident cartilage damage. Meniscal extrusion
was recorded as present or absent. Isolated meniscal root tear was defined as
the presence of a root tear without any additional meniscal damage
(WORMS1–4). Knees were divided into 3 groups: knees with an isolated
medial meniscal root tear (i.e., exposed group), those without root tears but
with other meniscal damage (i.e., referent group A); and knees without root
tear or meniscal damage (i.e., referent group B). In the longitudinal analysis,
we calculated relative risk (RR) of cartilage worsening comparing the
exposed group and the group A with the group B.
Results: Of 594 knees included in the cross-sectional analysis (64.1%
women, mean age 62.8 ⫹/⫺ 7.9, mean BMI 30.9 ⫹/⫺5.2), 37 knees were in
the exposed group, 293 in referent group A and 264 in referent group B.
Exposed knees showed higher prevalence of meniscal extrusion than referent
group B (91.9% vs. 60.7%, p⬍0.0001). Prevalence of cartilage damage was
S447
Monday, November 12
Background/Purpose: Several risk factors for osteoarthritis (OA)
have been described to be associated with an increased risk for incident
radiographic OA, on a local (joint) or systemic (person) level. While
radiography depicts articular changes only late in the disease process,
magnetic resonance imaging (MRI) is capable of visualizing tissue
pathology at a much earlier stage. Most MRI-based studies have used a
one knee per person approach and thus data on bilaterality of OA features
is sparse. Study aim was to describe symmetricity of MRI-detected OA
features in a cohort with knee pain.
Methods: 169 subjects aged 35–65 with chronic, frequent knee pain
were included in the Joint in Glucosamine (JOG) study. 3T MRI of both
knees was performed using the same pulse sequence protocol as in the
Osteoarthritis Initiative (OAI). Knees were semiquantitatively assessed
according to the WORMS system by one expert MSK radiologist.
Cartilage damage and bone marrow lesions (BMLs) were read in five
plates (medial/lateral femur, medial lateral tibia, patella, femoral trochlea)
while meniscal damage was read in three medial and three lateral
subregions. Chi2 tests were used to compare the proportion of people with
unilateral tissue pathology to the proportion what would be expected if the
two knees were independent. For this analysis, all MRI features were
divided into present (scoreⱖ1) and absent (score⫽0). We further used
linear weighted (w) kappa statistics to describe agreement between knees
for cartilage damage and BMLs in the same articular plates using the full
WORMS scores (0–4 for cartilage and 0–3 for BML).
Results: 52.1 % of participants were men, mean age was 51.2 (⫾6.2)
years old, mean BMI was 29.0 (⫾ 4.1). The worst Kellgren/Lawrence
(KL) grades in either knee were: K/L 0: 37 (21.9%) knees, K/L 1: 14
(8.3%) knees, K/L 2: 26 (15.4%) knees, K/L 3: 78 (46.2%) knees K/L 4:
14 (8.3). All plates showed a significant lower degree of unilaterality for
any cartilage damage (ranging between 15.5% and 32.0%) than expected
(ranging between 27.1% and 50.2%). For any BMLs the degree of
unilaterality was lower for the patella, trochlea, medial tibia, and medial
femur; for any meniscal damage the degree of unilaterality was lower for
all medial meniscal subregions but not lateral. All plates showed higher
overall % agreement (range 82.6–94.7%) than expected (range 73.0–
93.1%) for cartilage damage and BMLs. Moderate agreement (defined as
w-kappa 0.4–0.6) was observed for patellar and trochlear cartilage
damage (0.59 and 0.54) and patellar (0.41) BMLs.
Table 2. Expected and exact overall % agreement and kappa for different
articular subregions in descending order by kappa
also higher in the exposed group than in group B (97.3% vs 63.7%,
p⬍0.0001) but not group A (97.3% vs 95.2%, p⫽0.057). Of 548 knees
included in the longitudinal analysis, 33 knees were in the exposed group, 270
in group A, and 245 in group B. The adjusted RRs of cartilage loss in the
exposed group and the group A were 2.04 (95%CI 1.19 – 3.49) and 1.84 (95%
CI 1.32 - 2.58), respectively, when compared with group B.
Conclusion: Knees with isolated medial meniscal root tears exhibit a
higher prevalence of ipsicompartimental extrusion when compared to knees
without meniscal damage. Isolated meniscal root tears increase the risk of
ipsicompartmental cartilage loss longitudinally.
Monday, November 12
Disclosure: M. Jarraya, None; D. T. Feslon, None; D. Hayashi, None; F. Roemer,
Boston Imaging Core Lab, 1, National Institute of Health, 5, Merck Serono, 5; Y.
Zhang, None; J. Niu, None; M. Crema, None; M. Englund, None; J. A. Lynch,
None; M. C. Nevitt, None; J. Torner, None; C. E. Lewis, None; A. Guermazi, Boston
Imaging Core Lab, 1, Stryker, 5, Merck Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5, Novartis Pharmaceutical Corporation, 5.
1033
Reliability and Responsiveness of Two Methods for Assessment of
Magnetic Resonance Imaging Abnormalities in Hip Osteoarthritis in a
Placebo-Controlled Trial of Intra-Articular Steroid Injection. Walter P.
Maksymowych1, Jolanda Cibere2, Ulrich Weber3, Jacob Jaremko1, Damien
Loeuille4, Veronika Zubler3, Frank Roemer5, Eric C. Sayre6 and Robert GW
Lambert1. 1University of Alberta, Edmonton, AB, 2Arthritis Research Ctr of
CA, Vancouver, BC, 3Balgrist University Hospital, Zurich, Switzerland,
4
CHU Brabois, Vandoeuvre les Nancy, France, 5Klinikum Augsburg, Augsburg, Germany, 6Arthritis Research Centre of Canada, Vancouver, BC
Background/Purpose: Inflammation in osteoarthritis (OA) is the basis
for the use of steroid injection therapy which has demonstrated efficacy for
symptoms of hip OA in a randomized placebo-controlled trial1. Both
synovitis and bone marrow lesions (BML) have been associated with pain in
OA and can be detected on MRI. Two scoring methods have been developed
which assess synovitis-effusion but score BML using different approaches:
1) the Hip Inflammation MRI Scoring System (HIMRISS) assesses BML
using consecutive images in the coronal plane and a dichotomous (yes/no)
scoring method; 2) the Hip Osteoarthritis MRI Scoring System (HOAMS) is
a whole joint scoring system which assesses BML according to volume of
region affected on both coronal and sagittal scans. We aimed to determine the
reliability and responsiveness of both methods for detecting change in these
MRI lesions and associations with clinical changes in patients receiving
steroid injection therapy.
Methods: Six readers (3 radiologists, 3 rheumatologists) assessed MRI
scans of hip joints from 18 patients enrolled into a randomized double-blinded
placebo-controlled trial of intra-articular steroid treatment for hip OA. Scans
were performed at baseline and the primary endpoint at 8 weeks. Coronal
STIR sequences of the hip joints were evaluated. For HIMRISS, the sum of
femoral BML scores (0–65), acetabular BML scores (0–35), effusion score
(0–30) and total score was calculated based on femoral and acetabular
subregion readings. In HOAMS, BML (0–3) and synovitis (0–2), were
assessed in femoral and acetabular subregions and summed scores for all
subregions were calculated for BML (0–45) and synovitis (0–8). Reliability
of change scores was assessed using intra-class correlation coefficient (ICC),
responsiveness by standardized response mean (SRM) and Guyatt’s effect
size (ES). We assessed associations with WOMAC pain subscale in the same
patients and a second cohort of 27 patients with early OA by regression
analysis.
Results: Inter-observer reliability of change scores was very good to
excellent for femoral BML, and good to very good for synovitis-effusion and
acetabular BML despite limited training. Reliability was comparable between
radiologists and rheumatologists. Responsiveness and discrimination was
moderate to high for synovitis-effusion. Significant associations were noted
between BML or synovitis scores and pain scores for baseline values (p ⱕ
0.001 in combined N⫽45) but not change values (N⫽18). The association
with pain was particularly evident in patients with early OA (N⫽27) with the
HIMRISS synovitis-effusion (p ⫽ 0.001) and HOAMS synovitis (p ⫽ 0.005)
scores.
Total HIMRISS
Femoral BML
HIMRISS
Acetabular BML
HIMRISS
ICC
(change)
ICC
(Rheumatologist)
ICC
(Radiologist)
SRM
Guyatt’s
ES
0.77
0.81
0.76
0.80
0.82
0.82
0.16
0.03
0.33
0.08
0.49
0.52
0.54
0.14
0.19
Synovitis-effusion
HIMRISS
HOAMS BML
HOAMS Synovitis
0.35
0.48
0.36
0.55
0.69
0.71
0.58
0.73
0.58
0.71
0.69
0.18
0.44
0.29
0.95
Conclusion: Change in BML and synovitis on MRI is reliably detected
using both HOAMS and HIMRISS but only synovitis scores are responsive
to treatment. Association with pain is primarily evident in early OA and with
scores for synovitis-effusion.
1. Lambert et al. Arthritis Rheum 2007; 56: 2278
Disclosure: W. P. Maksymowych, None; J. Cibere, None; U. Weber, None; J.
Jaremko, None; D. Loeuille, None; V. Zubler, None; F. Roemer, None; E. C. Sayre,
None; R. G. Lambert, None.
1034
Changing Osteoarthritis Treatment Assessment Paradigms: Subchondral Bone Is a More Responsive Measure of Progression Than the
Current Radiographic Standard. Michael A. Bowes1, Christopher B.
Wolstenholme1, Devan Hopkinson1, Graham R. Vincent1 and Philip G.
Conaghan2. 1Imorphics Ltd, Manchester, United Kingdom, 2University of
Leeds, Leeds, United Kingdom
Background/Purpose: Radiographic joint space width (JSW) assessment, a surrogate for cartilage assessment, is the standard for structure
modification trials of osteoarthritis (OA). However the subchondral bone is
integral to OA progression and modern image analysis techniques allow
accurate, automated identification of bone in MR images. The objective of
this study was a comparison of the sensitivity of 3D bone area measures in
MR images with minimum medial JSW in radiographs in all subjects in the
Osteoarthritis Initiative dataset with definite medial OA over a 2 year period,
representative of a typical OA clinical trial.
Methods: 828 subjects with medial OA and MR images at baseline, 12
and 24 months, and available radiograph scoring were selected from the
Osteoarthritis Initiative dataset; medial OA was defined as KLⱖ2 and
presence of medial osteophytes. Femur, tibia and patella bones were automatically segmented from MRIs using active appearance models1. Anatomical areas were automatically identified within the model2 and were measured
at each time-point. All regions of the articulating surface of the femur, tibia
and patella were included in the analysis. Minimum medial joint space width
(minMJSW) was provided by the OAI, using a semi-automated software
method3. Sensitivity of both methods to change was assessed using the
standardised response mean (mean/SD of change).
Results: Mean age (SD) of the case group was 62 years (8.8); BMI
29.7(4.8); KL 2.55(0.65); 35% females. MinMJSW showed significant
change at 12 and 24 months with SRM values of ⫺0.16 and ⫺0.33. Change
in bone area was significant in all regions for all time-points, except the lateral
femur at 12 months (see Figure 1). Medial femur compartments provided the
greatest sensitivity to change, with SRM values typically twice those of
minMJSW. Tibial compartments and the notch of the femur also showed
higher SRM figures than minMJSW, while patellar compartments had
comparable SRMs to the radiographic measure. Only the lateral femoral
compartments had lower SRMs than the minMJSW method.
Figure 1. Sensitivity of bone area to change, compared with minMJSW measures
on 828 subjects.
Mean Change
Year 1
Year 2
Minimum median JSW
MF
TrFMed
LF
TrFLat
Notch
MT
LT
MP
LP
⫺0.1 (0.04)
0.52 (0.09)
0.55 (0.1)
0.1 (0.12)*
0.1 (0.09)
0.44 (0.1)
0.45 (0.1)
0.34 (0.1)
0.34 (0.16)
0.33 (0.16)
⫺0.23 (0.05)
1 (0.12)
1.1 (0.12)
0.17 (0.16)
0.35 (0.1)
0.73 (0.11)
0.87 (0.12)
0.69 (0.12)
0.91 (0.2)
0.95 (0.19)
SRM
Year 1
Year 2
⫺0.16
0.39
0.39
0.05
0.07
0.31
0.31
0.23
0.15
0.14
⫺0.33
0.57
0.63
0.07
0.23
0.45
0.48
0.38
0.31
0.34
JSW values are in mm, bone area change in % change in bone area from baseline
(95% confidence limits). All changes were highly significant except* which was
not significant
Conclusion: Change in bone area was more sensitive than the minMJSW
method in a number of knee compartments, particularly in the medial femur
S448
and tibia. Measurement of bone change provided a more responsive tool for
monitoring OA progression in a cohort selected for typical OA trial characteristics.
References
1 Cootes, T. F, G. J. Edwards, and C. J. TaylorIEEE Trans Patt Anal Mach
Intell 23.6 (2001): 681-85.
2 Williams, T. G., et al. Br.J.Radiol. 83.995 (2010): 940-48.
3 Duryea J, Li J, Peterfy CG, Gordon C, Genant HK. Med Phys. 2000 Mar:
27(2): 580-91
Disclosure: M. A. Bowes, Imorphics Ltd, 1, Imorphics Ltd, 3; C. B. Wolstenholme,
Imorphics Ltd, 3, Imorphics Ltd, 1; D. Hopkinson, None; G. R. Vincent, Imorphics
Ltd, 3, Imorphics Ltd, 1; P. G. Conaghan, None.
1035
Background/Purpose: Radiographic descriptions of gout have noted
the tendency to hypertrophic bone changes. The aim of this study was to
characterise the features of new bone formation (NBF) in gout, and to
determine the relationship between NBF and other radiographic features
of disease, particularly erosion and tophus.
Methods: Paired plain radiographs (XR) and computed tomography
(CT) scans of 798 individual hand and wrist joints from 20 patients with
gout were analyzed. Following a structured review of a separate set of
images, films were scored for the presence of the following features of
NBF: spur, osteophyte, periosteal NBF, ankylosis and sclerosis (Figure).
Sites for NBF scoring were those included in the gout-modified Sharp-van
der Heijde method for erosion scoring. The relationship between NBF and
other imaging features of gout (erosion and tophus) was analysed.
The Prevalence of Chondrocalcinosis of the Acromioclavicular Joint On
Chest Radiographs and correlation with Calcium Pyrophosphate Dihydrate Crystal Deposition Disease. Konstantinos M. Parperis, Guillermo F.
Carrera, Keith E. Baynes, Alan P. Mautz, Melissa S. DuBois, Ross M.
Cerniglia and Lawrence M. Ryan. Medical College of Wisconsin, Milwaukee, WI
Background/Purpose: Digital imaging combined with picture archiving and communication system (PACS) access allows detailed image
retrieval and magnification. Calcium pyrophosphate dihydrate (CPPD)
crystals preferentially deposit in fibrocartilages, the cartilage of the
acromioclavicular (AC) joint being one such structure. We sought to
determine if careful examination of the AC joints on magnified PACS
imaging of routine chest films would be useful in identifying chondrocalcinosis (CC).
Methods: Retrospective radiographic readings and chart reviews
involving all 1920 patients aged 50 or more who had routine outpatient
chest radiographs over a 4 month period were performed. CC was
identified as linear or punctate cartilage calcifications. Knee radiographs
were available for comparison in 489 patients. Medical records were
reviewed to abstract demographics, chest film reports, and diagnoses.
Results: AC joint CC was identified in 1.1% (21/1920) of consecutive
chest films. Patients with AC joint CC were 75 (⫾ 11.6 S.D.) years of age
versus 65 (⫾10.5 S.D.) in those without CC (p⬍0.0002, Wilcoxon rank
sum). There was no significant gender difference in the prevalence of AC
CC. 489 patients had knee films. 6 of these patients had AC joint CC and
of these 5 also had knee CC (83%). Of the 483 without AC joint CC 62
(12%) had knee CC (p⫽0.002 Fischer’s exact). Of the patients with AC
joint CC only 14% had a diagnosis of CPPD recorded on the chart and
none had AC joint calcification noted on the official radiology report.
Patients with AC joint CC were more likely to have a recorded history of
CPPD crystal disease than those without AC joint CC (14% versus 1%,
p⫽0.0017 Fischer’s exact).
Conclusion: By using digital imaging and PACS software magnification, AC joint CC is discernible on routine chest films. The prevalence of
AC joint CC increases with age and is usually an indicator of associated
knee CC. AC joint CC is most often overlooked by radiologists reading
routine chest images. Rheumatologists (and radiologists) should consider
scrutiny of available chest films for AC joint CC. A finding of AC joint
CC should heighten suspicion of pseudogout or secondary osteoarthritis in
appropriate clinical settings. And AC joint CC in a young patient should
alert the clinician to the possibility of an associated metabolic condition.
Moreover, such scrutiny is without cost other than less than a minute of
time.
Disclosure: K. M. Parperis, None; G. F. Carrera, None; K. E. Baynes, None; A. P.
Mautz, None; M. S. DuBois, None; R. M. Cerniglia, None; L. M. Ryan, None.
1037
Figure. Examples of the features of new bone formation (NBF) observed by plain
radiography and computed tomography in patients with gout. A. Spur. B. Osteophyte. C. Periosteal NBF. D. Ankylosis. E. Sclerosis. Top panel shows plain
radiographic images and lower panel shows CT images.
Results: The most frequent forms of NBF were bone sclerosis (28.6%
of all assessed joints using CT) and osteophyte (30.5%). Spur and
periosteal NBF were less common (17.8% and 6.0% respectively), and
ankylosis was rare (0.6%). On both XR and CT, joints with bone erosion
were more likely to have NBF; for XR, odds ratios (OR) 64.9 for spur,
64.9 for osteophyte, 119.8 for periosteal NBF, 30.1 for ankylosis and
101.1 for sclerosis (p for all ⬍0.0001); and for CT, OR 45.1 for spur, 3.3
for osteophyte, 16.6 for periosteal NBF, 26.6 for ankylosis and 32.3 for
sclerosis (p for all ⬍0.01). Similarly, on CT, joints with intraosseous
tophus were more likely to have NBF; OR 48.4 for spur, 3.3 for
osteophyte, 14.5 for periosteal NBF, 35.1 for ankylosis and 39.1 for
sclerosis (p for all ⬍0.001).
Conclusion: This detailed quantitative analysis has demonstrated that
NBF occurs more frequently in joints affected by other features of gout.
This work suggests a connection between bone loss, tophus, and formation
of new bone during the process of joint remodelling in gout.
Disclosure: N. Dalbeth, None; A. Milligan, None; B. Clark, None; F. M. McQueen,
None; A. Doyle, None.
Magnetic Resonance Imaging (MRI) Assessment of Inflammatory Myopathy: Quantitative Fat-Corrected Muscle T2 and Conventional T2 Measurement Versus Standard MRI and Clinical Metrics.
Lawrence Yao1, Adrienne L. Yip2, Sepehr Mesdaghinia3, Ashkan Shademan3, Joseph A. Shrader1, Anna V. Jansen2, Frederick W. Miller2 and
Lisa G. Rider2. 1Clinical Center, NIH, Bethesda, MD, 2NIEHS, NIH,
Bethesda, MD, 3NIEHS, NIH, Bethesda
Background/Purpose: Active muscle disease in patients with idiopathic inflammatory myopathies (IIM) is characterized by prolonged
muscle T2 relaxation on MRI. We examined the utility of MR T2 maps,
and a method of correcting these maps for varying fat content, as
quantitative, semi-automated alternatives to conventional MRI in the
evaluation of IIM. MRI measures were also validated against other
myositis metrics.
Methods: Forty-four IIM patients (8 dermatomyositis [DM], 13
polymyositis [PM], 22 juvenile DM, 1 juvenile PM) underwent MRI of
the thighs at 1.5 Tesla and extensive clinical testing, including assessment
of Physician Global Activity (PGA), muscle strength by isometric
dynamometry (QMT), functional assessment by Childhood Myositis
Assessment Scale (CMAS) and Childhood Health Assessment Questionnaire (CHAQ), and the Myositis Damage Index (MDI). Follow-up
imaging was also performed 11 months later in 20 patients after therapy.
MRI included a Carr-Purcell-Meiboom-Gill sequence and a Dixon-based
S449
Monday, November 12
Characterisation of New Bone Formation in Gout: A Quantitative
Site-by-Site Analysis Using Plain Radiography and Computed Tomography. Nicola Dalbeth1, Aaron Milligan2, Barnaby Clark2, Fiona M. McQueen1 and Anthony Doyle1. 1University of Auckland, Auckland, New
Zealand, 2Department of Radiology, Auckland District Health Board, Auckland, New Zealand
1036
Monday, November 12
fat water separation sequence, for generation of T2, fat fraction (FF), and
fat-corrected T2 (fc-T2) maps, and Short Tau Inversion Recovery (STIR)
and T1 spin echo (SE) sequences for standard visual assessment. Muscle
edema and damage were visually scored on STIR and T1 SE images,
respectively, using a semi-quantitative rating system that incorporates
anatomic extent and severity of findings. T2, fc-T2, and fat fraction (FF)
values were tabulated for the thigh muscles of each patient with an
automated segmentation algorithm.
Results: STIR scores correlated significantly with mean T2 and mean fc-T2
values (Spearman rs⫽ 0.65 and 0.61, p⬍ 0.001), while T1 damage scores
correlated with mean FF (rs⫽ 0.67, p⬍ 0.001). Baseline mean T2, mean fc-T2,
and visual STIR scores correlated significantly with the CMAS (rs ⫽ ⫺0.50,
⫺0.36, ⫺0.55, respectively, p⬍0.05) and CHAQ (rs ⫽ 0.46, 0.35, 0.43 respectively, p⬍ 0.05), and with QMT (rs ⫽ ⫺0.49, ⫺0.52, ⫺0.48, respectively,
p⬍0.05). MDI muscle damage scores correlated significantly with visual T1
damage scores (rs ⫽ 0.72, p⬍0.001) and mean FF measurements (rs ⫽ 0.67,
p⬍0.001). For 20 patients evaluated after a change in therapy, standardized
response means for visual STIR, mean fc-T2, and mean T2 scores were ⫺0.52,
⫺0.31, ⫺0.12, respectively. The change in PGA assessment correlated with
changes in STIR (rs ⫽ 0.74, p⬍0.01) and mean fc-T2 scores (rs ⫽ 0.46, p⬍0.05).
However, changes in STIR scores and mean fc-T2 values were discordant with
outcomes, based on 20% improvement in PGA, in 5 and 6 of 20 patients,
respectively.
Conclusion: Semi-automated survey of quantitative thigh muscle T2,
FF, and fc-T2 MRI maps have good content validity with visual scoring
of clinical MRI. These quantitative MRI measures have good construct
validity with other measures of myositis disease activity and damage,
particularly muscle measures. While fc-T2 appears to be more responsive
than conventional T2, fc-T2 and T2 are less responsive than visual STIR
scores. Additionally, both visual and quantitative MR analysis of thigh
muscles exhibited limited agreement with global disease improvement
after therapy, as reflected by the PGA assessment.
Disclosure: L. Yao, None; A. L. Yip, None; S. Mesdaghinia, None; A. Shademan, None; J. A. Shrader, None; A. V. Jansen, None; F. W. Miller, None; L. G.
Rider, None.
1038
Assessment of Aortic Stiffness by Cardiac Magnetic Resonance
Imaging in Systemic Autoimmune Rheumatic Diseases. Galia Karp1,
Arik Wolak2, Nina Baram3, Victor Novack4, Philip Rosen3, Yael Perl5,
Talia Wolak6, Ilan Shelef3 and Mahmoud Abu-Shakra7. 1Department of
Medicine, Soroka Medical Centre and Ben Gurion University, BeerSheva, Israel, 2Dept. of Cardiology, Cardiac MRI unit, Soroka University
Medical Center, and Ben Gurion University, Beer-Sheva, Israel, 3Radiology division, Soroka University Medical Center and Ben Gurion University, 4Department of Medicine, Clinical Research center, Soroka University Medical Center and Ben Gurion University, 5Clinical Research
center, Soroka University Medical Center and Ben Gurion University,
6
Department of Medicine and Hypertension unit, Soroka University
Medical Center and Ben-Gurion University, 7Department of Medicine and
Rheumatology, Soroka Medical Centre and Ben Gurion University,
Beer-Sheva, Israel
Background/Purpose: Systemic Lupus Erythematosus (SLE) and rheumatoid arthritis (RA) are known to cause premature arterial aging and early
atherosclerosis hence leading to increased stiffness of the large arteries.
Recently, Cardiac MRI (CMRI) was introduced as a new technique for
assessment of aortic stiffness by measuring the Pulse Wave Velocity (PWV).
Therefore, we aimed to assess aortic stiffness by CMRI in RA and SLE
patients.
Methods: We prospectively recruited 25 RA female patients, 26 SLE
female patients and adjusted controls that matched each patient for age,
comorbidities (hypertension, diabetes mellitus, dyslipidemia) and smoking
status. Clinical and laboratory data were gathered. CMRI was performed
using a 1.5T scanner and included phase contrast images of the ascending and
descending aorta. Dedicated cardiovascular analysis software was used to
measure the flow at the level of the ascending and the descending aorta. The
distance between these 2 levels was obtained and PWV was calculated
accordingly
Results: The mean age of RA patients and their healthy control group was
51.83⫾15.14 and 51.33⫾14.47 respectively. Systolic Blood pressure was
higher amongst RA patients, 132.61⫾15.16 mmHg versus 121.72⫾20.55
mmHg for controls (p⫽0.02). PWV was higher among the RA group;
9.11⫾3.96 for RA and 7.79⫾2.98 for the control group (p⫽0.13). SLE
patients were younger than RA patients, averaging 41.31⫾13.51. SLE
patients were heavier and had larger waist circumference than their controls.
Their Framingham score was slightly lower than their paired controls. PWV
was higher than their paired controls, 6.67⫾2.39 vs. 6.03⫾2.23 (p⫽0.02),
thus reaching statistical significance. We further found positive correlation
between SLE disease activity and PWV (p⫽0.02). This correlation was not
found among RA patients.
Conclusion: PWV is higher amongst SLE patients, as opposed to healthy
controls (p⫽0.02). In addition PWV is positively correlated with SLE disease
activity (p⫽0.02). Amongst RA patients, PWV was higher as opposed to
paired controls, but this failed to achieve statistical significance. Our data raise
the hypothesis that amongst SLE patients, who are known to have significantly higher levels of atherosclerosis, PWV may serve a marker for
cardiovascular morbidity.
Disclosure: G. Karp, None; A. Wolak, None; N. Baram, None; V. Novack, None; P.
Rosen, None; Y. Perl, None; T. Wolak, None; I. Shelef, None; M. Abu-Shakra,
None.
1039
Cardiac Involvement in Systemic Sclerosis: The Added Value of Magnetic Resonance Imaging. Luna Gargani1, Alessandro Pingitore2, Daniele
De Marchi2, Serena Guiducci3, Giancarlo Todiere2, Silvia Bellando Randone3, Cosimo Bruni3, Marica Doveri4, Laura Bazzichi4, Stefano Bombardieri4, Massimo Lombardi2, Eugenio Picano1 and Marco Matucci Cerinic3
1
Institute of Clinical Physiology, National Research Council, Pisa, Italy,
2
Gabriele Monasterio Foundation, CNR-Regione Toscana, Pisa, Italy, 3Department of Biomedicine, Division of Rheumatology AOUC, Excellence
Centre for Research, Florence, Italy, 4Rheumatology Unit, University of Pisa,
Pisa, Italy
Background/Purpose: Cardiac involvement in systemic sclerosis (SSc)
affects the prognosis of the disease. Myocardial fibrosis is the pathological
hallmark of this complication and has been reported in 50-80% of cases in
necropsy. Echocardiography is the routine imaging tool to easily detect
cardiac involvement, but it is not accurate to detect myocardial fibrosis.
Delayed gadolinium enhancement (DE) cardiovascular magnetic resonance
(CMR) is the gold-standard for myocardial fibrosis assessment. The aim of
the present study was to evaluate the added value of DE-CMR to echocolorDoppler in SSc patients.
Methods: After a thorough clinical characterization, 171 SSc patients
(age⫽52⫾14, 91% females, 22% diffuse form) underwent, on the same day,
a comprehensive echocardiogram, including tissue Doppler imaging (TDI),
and a DE-CMR.
Results: Echocardiography showed normal systolic function (ejection
fraction⬎50%) and wall motion score index (⫽1) in 100% of patients,
whereas DE-CMR showed a pattern of non-ischaemic myocardial fibrosis in
12/53 (23%) patients. In 2/53 patients (4%), T2-weighted CMR showed
myocardial oedema, that resolved after steroid therapy. No clinical parameter
(age, duration of disease, limited or cutaneous form, Scl-70 positivity,
Rodnan skin score, activity score) was an independent predictor of the
presence of myocardial fibrosis.
Conclusion: Subclinical cardiac involvement is relatively frequent in SSc
and is not necessarily related to duration of disease or other clinical
characteristics. CMR can detect different patterns of reversible (by T2weighted) and irreversible (by DE) cardiac involvement (see figure), not
detectable by echocardiography.
Disclosure: L. Gargani, None; A. Pingitore, None; D. De Marchi, None; S.
Guiducci, None; G. Todiere, None; S. Bellando Randone, None; C. Bruni, None; M.
Doveri, None; L. Bazzichi, None; S. Bombardieri, None; M. Lombardi, None; E.
Picano, None; M. Matucci Cerinic, None.
S450
1040
Combined High-Resolution Single Photon Emission Computed Tomography and Magnetic Resonance Imaging for Therapy Monitoring in
Rheumatoid Arthritis. Philipp Sewerin1, Christian Buchbender1, Katalin
Mattes-György1, Falk Miese1, Hans-Jörg Wittsack1, Christof Specker2, Gerald Antoch1, Matthias Schneider3, Axel Scherer1 and Ben Ostendorf1.
1
Heinrich-Heine-University, Düsseldorf, Germany, 2Hospital Essen Sued,
Essem, Germany, 3Heinrich-Heine-University, Duesseldorf, Germany
Disclosure: P. Sewerin, None; C. Buchbender, None; K. Mattes-György, None; F.
Miese, None; H. J. Wittsack, None; C. Specker, None; G. Antoch, None; M.
Schneider, None; A. Scherer, None; B. Ostendorf, None.
1041
Whole-Body Magnetic Resonance Imaging - A New Diagnostic Tool in
the Assessment of Activity in Juvenile Dermatomyositis Patients? Tania
Monteiro de Castro1, Henrique Lederman1, Maria Teresa Terreri1, Wanda I.
Caldana1, Edmar Zanoteli2 and Maria Odete Hilario1. 1Federal University of
São Paulo, São Paulo, Brazil, 2University of São Paulo, São Paulo, Brazil
Background/Purpose: Juvenile dermatomyositis (JDM) is a rare autoimmune disorder, but remains the most commonly chronic inflammatory
myopathy among children. A redefinition of the diagnostic criteria is currently
underway and is likely to lead to non-invasive exams such as magnetic
resonance (MR) imaging, in place of electromyography and muscle biopsy in
the diagnosis of the disease. Our goal was to demonstrate the benefit of
whole-body MR imaging as a diagnostic tool in the detection of muscle
inflammatory activity in JDM and to correlate these findings with clinical
evaluation including muscle strength, laboratorial exams, nailfold capillaroscopy and muscle biopsy.
Methods: Thirty-three patients aged 6–19 years (median age, 12.1 years),
22 girls with a diagnose of JDM according to Bohan & Peter criteria were
evaluated at any point during their illness course using clinical examination,
muscle enzymes determination, muscle strength tests such as Childhood
Myositis Assessment Scale (CMAS) and Manual Muscle Testing (MMT),
nailfold capillaroscopy and short tau inversion recovery (STIR) whole-body
MR imaging. JDM activity was evaluated by Disease Activity Score (DAS).
An open muscle biopsy was performed in deltoids or biceps braquialis if
muscle disease activity was detected on MR exam.
Results: Whole-body scanning gave a complete assessment of all muscles
groups and disease activity was detected in STIR MR imaging in four
(12.1%) patients confirmed by muscle biopsy. All four patients had elevation
of at least one muscle enzyme and the nailfold capillaroscopy showed
scleroderma (SD) pattern in these patients. CMAS, MMT and DAS means
were 25.7, 32.3 and 9 respectively in patients with altered MR, and 48.1, 77
and 2.35 respectively in patients whose MR were normal. Twenty-nine
Disclosure: T. Monteiro de Castro, None; H. Lederman, None; M. T. Terreri, None;
W. I. Caldana, None; E. Zanoteli, None; M. O. Hilario, None.
1042
Psoriatic Arthritis Patients Assessed by Dynamic Contrast-Enhanced
MRI in High Disease Versus Minimal Disease Activity State - a CrossSectional Study Correlating Conventional MRI and Clinical Composite
Measures. René Panduro Poggenborg1, Pernille Bøyesen2, Charlotte Wiell3,
Susanne Juhl Pedersen4, Inge Juul Sørensen5, Ole Rintek Madsen6, Ole Slot1,
Jakob M. Møller7, Mikael Boesen8, Henning Bliddal9, Olga Kubassova10 and
Mikkel Østergaard11. 1Copenhagen University Hospital in Glostrup, Copenhagen, Denmark, 2Diakonhjemmet Hospital, Olso, Norway, 3Copenhagen
University Hospital in Gentofte, Copenhagen, Denmark, 4Copenhagen University Hospital Glostrup, Copenhagen, Denmark, 5Glostrup Hospital, Copenhagen, Denmark, 6DANBIO, On behalf of Depts of Rheumatology,
North, South, Central, Zealand and Capital Region, Copenhagen, Denmark,
7
Copenhagen University Hospital in Herlev, Copenhagen, Denmark, 8Copenhagen University Hospital at Frederiksberg, Copenhagen, Denmark, 9Copenhagen University Hospital at Frederiksberg, Frederiksberg, Denmark, 10Image Analysis Ltd., Leeds, United Kingdom, 11Glostrup Hospital, Glostrup,
Denmark
Background/Purpose: Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) has been validated in rheumatoid arthritis for measuring inflammation, but has rarely been studied in psoriatic arthritis (PsA).
The purpose was to investigate whether DCE-MRI can discriminate PsA
patients with high disease activity from minimal disease activity (MDA)(1),
and to correlate DCE-MRI findings with conventional MRI and clinical
measures.
Methods: PsA patients fulfilling CASPAR criteria were eligible in this
investigator-initiated study of patients with either high disease activity (group 1)
or MDA (group 2). Inclusion criteria were for group 1: swollen joint count
(SJC)ⱖ6, tender joints count (TJC)ⱖ6, hand involvement and clinical indication
for initiation of anti-TNF therapy, and for group 2: hand involvement within 1
year, long-term treatment with adalimumab 40 mg eow, and fulfilling criteria for
MDA (at least 5 out of 7: TJCⱕ1; SJC’1; body surface areaⱕ3%; PtGAⱕ20;
painⱕ15; HAQⱕ0.5; 13-enthesitisⱕ1). DAS28 and the new Disease Activity
index for PSoriatic Arthritis (DAPSA)(2) score (sum of SCJ, TJC, PtGA, pain
and CRP) was calculated. The validated PsAMRIS scoring system (3) was used
for analyzing conventional MRI (0.6 tesla). PsAMRIS total inflammation was
calculated by adding synovitis, flexor tenosynovitis, periarticular inflammation
and bone marrow oedema scores. DCE-MRI were analysed by Dynamika
software (Image Analysis Ltd., Leeds, UK). Regions of interest (ROIs) were
drawn around 2.-5. metacarpophalalangeal joints, excluding large blood vessels.
The ROIs were used for automatic computing of the number of pixels with
plateau and washout pattern (Np⫹w), the initial rate of enhancement (IRE), and
maximum enhancement (ME).
Results: Patient characteristics were: 9 males/8 females, median age 45
(25–63) years, joint/skin disease duration 8 (2–59)/15(2–59) years (no
difference between groups). Clinical and imaging data are shown in the table.
Np⫹w
IRE ⫻ 103
ME
Np⫹w* IRE
Np⫹w* ME
PsAMRIS synovitis
PsAMRIS total inflammation
DAS28 score
DAPSA score
Group 1: High
disease activity
(nⴝ9)
Group 2:
Minimal Disease
Activity (nⴝ8)
P value
712 (13–1587)
8 (5–33)
1.20 (1.17–1.33)
5.4 (0.4–15.9)
946 (16–1903)
3 (0–5)
16 (1–24)
5.5 (3.9–6.4)
64.9 (30.9–103.3)
362 (25–1316)
10 (6–14)
1.21 (1.16–1.33)
2.8 (0.2–13.2)
434 (29–1608)
2 (0–5)
7.5 (3–18)
1.4 (1.1–2.4)
2.4 (0.1–5.6)
0.25
0.29
0.92
0.44
0.29
0.59
0.19
0.01
0.01
Median (range). Groups compared using Krustal-Wallis test.
S451
Monday, November 12
Background/Purpose: To evaluate whether combined multi-pinhole
single photon emission computed tomography (MPH-SPECT) with
technetium-99m-labelled disphosphonates (Tc99m-DPD) and magnetic resonance imaging (MRI) detect changes in inflammation in early rheumatoid
arthritis (ERA) patients under methotrexat (MTX) therapy and to investigate
the relation between Tc99m-DPD uptake and the development of erosion.
Methods: MPH-SPECT and MRI of metacarpophalangeal joints (MCP)
have been prospectively performed in 10 consecutive ERA patients (8 female,
2 male; 49 ⫾ 13 years [mean ⫾ SD]), range: 24–68) prior to and 6 months
after initiation of MTX. The Tc99m-DPD uptake was measured using a
region of analysis. The course of synovitis, bone marrow edema (BME) and
erosions were scored according to the Rheumatoid Arthritis MRI Score
(RAMRIS) criteria.
Results: The frequency of increased Tc99m-DPD uptake, synovitis and
BME decreased under MTX therapy; but the number of bone erosions
increased. Joints with progressive and newly developed erosions on follow-up
had a higher baseline Tc99m-DPD uptake (2.64 ⫾1.23 vs. 1.43 ⫾0.91) (p⬍
0.001). Joints with persistent synovitis did not show higher Tc99m-DPD
uptake values (1.56 ⫾1.27 vs. 1.47 ⫾ 0.75) (p⫽0.74). There was no
correlation between persistence of synovitis and the development of erosions
(Fc⫽ 0.3, p⫽ 0.12).
Conclusion: Persistence of synovitis seems to be independent from
Tc99m-DPD uptake and the development of erosions, while early increased
bone metabolism is found in MCP joints which show erosive progression
under MTX therapy. Hybrid MPH-SPECT and MRI might thus provide
valuable additional information for individual risk-stratified therapeutic decisions.
patients had inactive disease (24 with medication and five without medication). Nailfold capillaroscopy was normal in 16 patients and with SD pattern
in nine patients (not done in four patients). Muscle strength tests (CMAS and
MMT) were normal in 16 out of 29 patients (MMT not done in four patients).
Conclusion: Whole-body MR allows us to evaluate the extent and
symmetry of muscle disease and inflammatory activity in a single exam by
revealing muscles groups not seen with standard protocols. Nailfold capillaroscopy is an important additional exam to assess disease activity. Muscle
strength tests are important to evaluate not only the disease in the acute phase,
but the accumulated effect over the same time.
We found a significant correlation between the DCE-MRI parameters
(Np⫹w*IRE, Np⫹w*ME and Np⫹w) and PsAMRIS total inflammation (Spearman’s rho: 0.53, 0.51 and 0.51; all P⬍0.05). DCE-MRI parameters were not
statistically significant correlated with clinical measures, but Np⫹w*IRE,
Np⫹w*ME and Np⫹w were numerically lower in the MDA group.
Conclusion: DCE-MRI parameters correlated significantly with PsAMRIS total inflammation score, and showed a trend toward higher values in the
high disease activity versus the MDA group. DCE-MRI is a promising
method for assessing joint inflammation in PsA. However, a larger longitudinal study is needed to clarify, if DCE-MRI is superior to conventional MRI
for discriminating between disease activity levels.
Ref
Monday, November 12
1. Coates, ARD 2009;
2. FitzGerald, ARD 2011;
3. Østergaard, JRheum 2009
Disclosure: R. P. Poggenborg, Abbott Laboratories, 5; P. Bøyesen, None; C. Wiell,
None; S. J. Pedersen, None; I. J. Sørensen, None; O. Rintek Madsen, None; O. Slot,
None; J. M. Møller, None; M. Boesen, None; H. Bliddal, None; O. Kubassova, Image
Analysis Ltd., 4; M. Østergaard, None.
1043
Assessment of Rheumatoid Arthritis Disease Activity by Power Doppler
Ultrasonography: Association with Routine Clinical Indices and Its
Usefulness in Detecting Remission. Hiroaki Taguchi, Kazuo Nishi, Takeo
Kudo and Yutaka Okano. Kawasaki Municipal Kawasaki Hospital, Kawasaki, Japan
Background/Purpose: Power Doppler ultrasonography (PDUS) is sensitive for detecting synovitis in patients with rheumatoid arthritis (RA). We
aimed to clarify the association of PDUS findings with routine clinical indices
and its usefulness in detecting disease remission.
Methods: We studied 72 RA patients with mean age 62.5 years, mean
disease duration 5.6 years, and 61% women. We examined 22 joints including
bilateral wrists, metacarpo-phalangeal, and proximal interphalangeal joints
using PDUS to evaluate the presence of inflammation with scoring from 0 to
3 according to the signal intensity of each joint, and the sum score (ranging
from 0 to 66) was defined as “PDUS score”. Clinical disease activity
score/indices including DAS28CRP, SDAI, and CDAI were also recorded.
Clinical remission was defined according to the following criteria:
DAS28CRP ⬍ 2.3, SDAI ⱕ 3.3, CDAI ⱕ 2.8, and Boolean-based definition.
Sonographic remission was defined by absence of PDUS signals.
Results: Mean values ⫾ SD of DAS28CRP, SDAI, and CDAI were
3.3⫾1.5, 18.8 ⫾15.0, and 17.3⫾13.5, respectively. Mean values ⫾ SD of
PDUS score was 6.2 ⫾ 6.3 and significantly correlated with all three clinical
disease activity score/indices; among them the correlation with SDAI was
strongest (r⫽0.77, p⬍0.001). PDUS score was more significantly correlated
with swollen joint counts (r⫽0.73), patient global assessment (GA) (r⫽0.77),
or evaluator GA (r⫽0.85), than with tender joint counts (r⫽0.50) or serum
CRP (r⫽0.61). Remission was observed in 17 (24%) patients by DAS28CRP,
in 11 (15%) by SDAI, in 12 (17%) by CDAI, and in 14 (19%) by
Boolean-based definition, respectively. Sonographic remission was observed
in 9 (13%) patients. In 36-59% of the patients satisfying clinical remission
criteria, the PDUS signals were detected indicating the presence of synovitis
(Table 1). Values of DAS28CRP, SDAI, and CDAI of patients with
sonographic remission were 1.3, 1.7, and 1.9, respectively.
Table 1. Distribution of patients with absence and presence of PDUS signals for
patients with clinical disease remission defined by DAS28CRP, SDAI, CDAI, and
Boolean-based criteria.
DAS28CRP ⬍2.3
SDAI ⱕ3.3
CDAI ⱕ2.8
Boolean-based criteria
n
sonographic signals
absence
presence
17
11
12
14
7 (41%)
7 (64%)
7 (58%)
8 (57%)
10 (59%)
4 (36%)
5 (42%)
6 (43%)
Conclusion: PDUS is useful for evaluating RA disease activity, is
exceedingly sensitive, and is a useful method for detecting “pure” RA disease
remission.
Disclosure: H. Taguchi, None; K. Nishi, None; T. Kudo, None; Y. Okano, None.
1044
Ultrasound Scores of Enthesitis and Dactylitis Do Not Correlate with
Corresponding Clinical Findings in Psoriasis Arthritis. Rusmir Husic1, Josef
Hermann1, Judith Gretler2, Winfried B. Graninger1 and Christian Dejaco1.
1
Medical University Graz, Graz, Austria, 2Auenbruggerplatz 15, Graz, Austria
Background/Purpose: To compare sonography verified inflammation of
entheses, tendons and joints with corresponding clinical findings in psoriasis
arthritis (PsA) patients.
Methods: Prospective study of 70 consecutive PsA patients [mean age 51.1
(⫾SD 11.6) years, 30% female, median disease duration 7.0 (range 0–44.7)
years]. Clinical and ultrasound examination was performed at 68 joints and 14
entheses (lateral epicondyle, triceps insertion, quadrizeps insertion, proximal and
distal insertion of patellar ligament, Achilles tendon, plantar fascia), and clinical
scores including the Disease Activity index for PSoriatic Arthritis (DAPSA),
composite psoriatic disease activity index (CPDAI), dactylitis score, Leeds
enthesitis index (LEI), HAQ and PASI were calculated. Sonography was
performed by two rheumatologists blinded to clinical data using an ESAOTE
Twice ultrasound device. Synovial hypertrophy and/or joint effusion (SH/E) as
well as Power Doppler (PD) were graded at each joint from 0 to 3 in accordance
with prior publications. At hands and feet we also recorded the presence of
perisynovitis and tenosynovitis. For grading of enthesitis by ultrasound the
MASEI and GUESS scores were used. Ultrasound signs of dactylitis were
defined by the presence of synovitis plus tenosynovitis at MCP/MTP, PIP and
DIP joints.
Results: The median DAPSA was 12.1 (0.1–70.2), mean CPDAI 4.8 (⫾2.5),
median clinical Dactylitis score 0 (0–10), median LEI 0 (0–4), mean HAQ 0.73
(⫾0.81) and median PASI 1.0 (0–23.2). Using sonography, we found SH/E
and/or PD at 12 (range 3–35) [median SH/E score 16.0 (range 3.0–56.0)] and/or
2 (0–19) [PD-score 3.0 (0–31.0)] joints, respectively. Eighteen patients (25.7%)
had evidence of perisynovitis in at least one MCP joint and 20 (28.6%) patients
demonstrated flexor tenosynovitis affecting at least one whole finger or toe.
Median MASEI and GUESS scores were 32.5 (7.0–73.0) and 13.0 (4.0–27.0),
respectively. Ultrasound signs of dactylitis were found in 5 (7.1%) patients.
DAPSA showed a moderate correlation with total SH/E (corrcoeff 0.35,
p⫽0.003) and PD-scores (corrcoeff 0.36, p⫽0.002), as well as with the number
of joints affected by SH/E (corrcoeff 0.24, p⫽0.045) and/or PD (corrcoeff 0.32,
p⫽0.006). Total CPDAI did not correlate with SH/E, PD, enthesitis or dactilytis
scores; however, within the CPDAI-joint domain we found differences concerning SH/E- and PD-scores between patients with no [n⫽17, median SH/E 12.0
(3.0–32.0); PD-score 1.0 (0–11.0)] and moderate [n⫽17, SH/E 25.0 (6.0–43.0),
p⫽0.009; PD 5.0 (0–31.0), p⫽0.005] or high clinical activity [n⫽26, SH/E 18.5
(6.0–56.0), p⫽0.025; PD 5.5 (0–30.0), p⫽0.005). In the CPDAI enthesitis and
dactilyitis domains no differences were found, comparing the MASES/GUESS
and ultrasound defined dactylitis, respectively between the groups. No correlation
was found between clinical and sonographic dactylitis scores; or LEI (clinical)
and MASEI/GUESS (sonography).
Conclusion: No association was found between sonographic and clinical
assessment of enthesitis and dactylitis in PsA patients. Ultrasound verified joint
inflammation moderately correlated with DAPSA and CPAI joint components.
Disclosure: R. Husic, None; J. Hermann, None; J. Gretler, None; W. B. Graninger,
None; C. Dejaco, None.
1045
Dynamic Contrast-Enhanced Magnetic Resonance Imaging of the Wrist
in Rheumatoid Arthritis Patients Treated with Methotrexate, IntraArticular Glucocorticoid and Adalimumab/Placebo. Mette Bjørndal
Axelsen1, Merete L. Hetland2, Kim Hørslev-Petersen3, Kristian StengaardPedersen4, Peter Junker5, Jan Pødenphant6, Jakob M. Møller7, Henning
Bliddal8, Olga Kubassova9, Mikael Boesen10 and Mikkel Østergaard1.
1
Copenhagen University Hospital at Glostrup, Copenhagen, Denmark, 2Copenhagen University and Glostrup Hospital, Copenhagen, Denmark, 3University of Southern Denmark, Graasten, Denmark, 4Arhus University Hospital, Aarhus, Denmark, 5Odense University Hospital, Odense C, Denmark,
6
Copenhagen University at Gentofte, Hellerup, Denmark, 7Copenhagen
University Hospital in Herlev, Copenhagen, Denmark, 8The Parker Institute,
Copenhagen University Hospital at Frederiksberg, Copenhagen, Denmark,
9
Image Analysis Ltd., Leeds, United Kingdom, 10Copenhagen University
Hospital at Frederiksberg, Copenhagen, Denmark
Background/Purpose: To validate parameters of dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI) in an early rheumatoid arthritis (RA)
S452
Table 1. Clinical and MRI data at baseline and at follow-up visits.
Baseline
DAS28(CRP)
CRP (mg/mL)
Patient⬘s VAS
pain
Patient⬘s VAS
global
Patient⬘s VAS
fatique
Health Assessment
Questionnaire
VAS doctor
Swollen Joint
Count 28
Tender Joint
Count 28
Number of
Enhancing
voxels (Nvoxel)
Maximum
Enhancement
(ME)
Initial Rate of
Enhancement
(IRE) (%/s)
ME⫻Nvoxel
IRE⫻Nvoxel
(%/s)
4.75 (3.5–6.1)
14 (7–116)
48 (12–82)
6 months
12 months
2.2 (1.8–2.8)***
7 (7–11)**
11 (2–37)***
2.0 (1.7–3.9)***
7 (7–47)*
22 (1–72)*
54 (19–98)
22 (3–45)***
24 (0–75)*
46 (9–90)
18 (2–83)NS
30 (0–85)NS
1.0 (0.0–1.875)
51 (15–76)
3 (1–7)
5 (2–17)
0.130 (0–1)***
5 (0–16)***
0 (0–1)***
0 (0–2)***
24 months
2.1 (1.7–3.3)***
7 (7–31)*
15 (0–72)***
21 (0–67)***
24.5 (0–68)*
0 (0–2)
3 (0–33)***
0 (0–0)
0 (0–3)
548 (0–3786)
73 (0–1763) NS
181 (0–1694)NS
74 (0–617)NS
1.21 (0–1.39)
1.17 (0.00–1.32)NS
1.19 (0–1.39)NS
1.23 (0–1.51)NS
0.45 (0.0–1.20)
0.35 (0–0.9)NS
0.40 (0.0–1.0)NS
0.6 (0.0–1.7)NS
215 (0–2350)NS
63 (0–1694)NS
90 (0–929)NS
44 (0–1049)NS
666 (0–5251)
246 (0–4543)
85 (0–2329)NS
26 (0–1587)NS
Disclosure: S. Y. Kawashiri, None; T. Suzuki, None; Y. Nakashima, None; A.
Okada, None; N. Iwamoto, None; K. Ichinose, None; M. Tamai, None; K. Arima,
None; H. Nakamura, None; T. Origuchi, None; M. Uetani, None; K. Aoyagi, None;
A. Kawakami, None.
0.125 (0.0–1.00)** 0.13 (0.0–1.0)**
2 (0–26)***
0 (0–1)
Background/Purpose: Automated Breast Volume Scanner (ABVS) is an
ultrasonic device to be developed for the automated scanning for mammary
glands. We have tried to explore the clinical application of ABVS toward the
synovial lesion in patients with rheumatoid arthritis (RA).
Methods: Ten active RA patients of mean 54 y.o., whose mean disease
duration 15 months and DAS28-ESR 5.69, were recruited. Patients gave their
informed consent to be subjected to the protocol that was approved by the
Institutional Review Board of Nagasaki University. We have examined in
total 100 metacarpophalangeal (MCP) joints as well as 20 wrist joints at
dorsal sites by both ABVS (ACUSON S2000) and conventional ultrasonography (US) at the same day consecutively. ABVS was scanned in a water
tank. Presence of synovial hypertrophy and bone erosion by gray-scale were
examined by both methods, and the association of both methods was
calculated by kappa coefficient.
Results: The scanning time of ABVS was 2 min per patient and that of
conventional US was 15 min per patient, respectively. ABVS detected
synovial hypertrophy in 10 MCP joints and 13 wrist joints whereas conventional US detected synovial hypertrophy in 11 MCP joints and 13 wrist joints.
Kappa coefficient of synovial hypertrophy was 0.84 in MCP joints and 0.78
in wrist joints, respectively. ABVS detected bone erosion in 2 MCP joints and
5 wrist joints whereas conventional US detected bone erosion in 5 MCP joints
and 6 wrist joints. Kappa coefficient of bone erosion was 0.56 in MCP joints
and 0.90 in wrist joints, respectively.
Conclusion: Present data have shown a substantial agreement of
ABVS with conventional US to find the synovial hypertrophy and bone
erosion of wrist and finger joints in patients with RA. Since ABVS is able
to scan the wrist and finger joints automatically in a short time, ABVS is
a helpful new ultrasonic method to examine joint injury in patients with
RA.
1047
Evaluation of Ankle Swelling Due to Löfgrenⴕs Syndrome: A Pilot Study
Using B -mode and Power Doppler Ultrasonography. Emmanuelle LeBras1, Sandra Balser1, Valentin S. Schäfer1, Boris P. Ehrenstein1, Patrick
Hoffstetter1, Martina Müller2, Martin Fleck1 and Wolfgang Hartung1.
1
Asklepios Klinikum Bad Abbach, Bad Abbach, Germany, 2University
Clinic Regensburg, Regensburg
Values are presented as medians (minimum–maximum). VAS: visual analog scale. Change from
baseline: Wilcoxon Signed Ranks Test, *: p⬍0.05, **: p⬍0.01, ***: p⬍0.005, NS: not significant.
All clinical parameters decreased during follow-up, while there were no
statistically significant changes for the DCE-MRI parameters, which may
reflect lack of power. Furthermore, it should be emphasized that only 3 of the
examined wrist joints were clinically affected at baseline.
Conclusion: DCE-MRI is a promising outcome measure in clinical trials,
but MRI at baseline must include clinically involved joints.
Disclosure: M. B. Axelsen, Abbott Laboratories, 2; M. L. Hetland, Roche, 5, Pfizer
Inc, 5, MSD, 5, Bristol-Myers Squibb, 5, UCB Nordic, 5, Abbott Laboratories, 5; K.
Hørslev-Petersen, Abbott Immunology Pharmaceuticals, 2; K. Stengaard-Pedersen,
Pfizer Inc, 5, Roche Pharmaceuticals, 5, Abbott Immunology Pharmaceuticals, 5,
Grünenthal, 5, Danish Association against Rheumatism, 5; P. Junker, None; J.
Pødenphant, None; J. M. Møller, None; H. Bliddal, None; O. Kubassova, Image
Analysis Ltd., 4; M. Boesen, Image Analysis, 5; M. Østergaard, Abbott Laboratories,
2, Centocor, Inc., 5, Merck Pharmaceuticals, 5, Mundipharma, 8, Novo, 8, Pfizer Inc, 5,
Roche Pharmaceuticals, 5, UCB Nordic, 5.
1046
Automated Breast Volume Scanner (ABVS), a New Automated Ultrasonic Device, Is Useful to Examine Joint Injury in Patients with
Rheumatoid Arthritis. Shin-ya Kawashiri1, Takahisa Suzuki1, Yoshikazu
Nakashima1, Akitomo Okada1, Naoki Iwamoto1, Kunihiro Ichinose1, Mami
Tamai1, Kazuhiko Arima2, Hideki Nakamura2, Tomoki Origuchi1, Masataka
Uetani1, Kiyoshi Aoyagi1 and Atsushi Kawakami1. 1Nagasaki University
Graduate School of Biomedical Sciences, Nagasaki, Japan, 2Nagasaki University, Nagasaki, Japan
Background/Purpose: Patients suffering from acute sarcoidosis frequently present with bilateral painfull swelling of the ankles, establishing
ankle arthritis as a hallmark of Löfgren’s syndrome. Standardized high
resolution musculoskeletal ultrasound (MUS) including power Doppler
has been utilized to further characterize the nature of the ankle swelling in
patients presenting with Löfgren’s syndrome.
Methods: Ankle joints of 36 consecutive patients suffering from
Löfgren’s syndrom were investigated by high resolution MUS using Band power Doppler mode. Presence of effusion/synovitis and tenosynovitis has been determined, and hyperperfusion was scored in a semiquantitative fashion (grade 0–3).
Results: The majority of patients (26/36; 72,2%) did not present
characteristic arthrosonographic findings of an acute arthritis (distension
of the capsule and hyperperfusion). Ankle joint effusion was only
observed in 9 of the 36 patients (25%). Remarkably, 88,8% of these
patients had an ankle effusion grade I and only 11,1% presented an
effusion grade II. Instead, an extensive subcutaneous edema indicating
periarthritis was detected in 23 of 26 patients (88,4%). In addition,
tenosynovitis could be visualized in 14 patients (38,8%).
Conclusion: Utilizing MUS including power Doppler, the present results
clearly demonstrate that ankle swelling in patients suffering from Löfgren⬘s
syndrome is predominantely due to periaticular soft tissue swelling and
tenosynovitis. In contrast, distinct articular synovitis is rare and if present only
of mild degree without relevant power Doppler activity.
Disclosure: E. LeBras, None; S. Balser, None; V. S. Schäfer, None; B. P. Ehrenstein,
Abbott Immunology Pharmaceuticals, 5, Pfizer Inc, 5, Roche Pharmaceuticals, 5; P.
Hoffstetter, None; M. Müller, None; M. Fleck, Abbott Immunology Pharmaceuticals,
5, Roche Pharmaceuticals, 5, Pfizer Inc, 5; W. Hartung, Abbott Immunology
Pharmaceuticals, 5, Pfizer Inc, 5.
S453
Monday, November 12
clinical trial by comparison with clinical parameters of disease activity, and by
investigating the sensitivity to change during a 2-year-follow-up.
Methods: 14 early RA patients diagnosed according to the ACR1987
criteria within 6 months of inclusion and with a DAS28 ⱖ3.2 (9/5 women/
men, median aged 37 [range 27-69] years, disease duration 82 [42-129] days)
were randomized 1:1 to treatment with methotrexate (MTX) and adalimumab
or MTX and placebo. Any swollen joints were injected with triamcinolone
(max 4 joints/4 ml per visit) in a 2-year-follow-up. If continuous disease
activity was present, treatment was intensified. Conventional MRI and
DCE-MRI of the right wrist were performed at baseline, and after 6, 12 and
24 months using a 0.6 Tesla MRI-unit. A 3-slice dynamic sequence was
obtained at the time of injection of the contrast agent (Gadoteric acid 0.2
mL/kg). DCE-MRI parameters: TR 33ms, TE 4.2ms, flip angle 25°, FOV 200
mm2, matrix 108⫻192, slice thickness 3 mm.
On DCE-MR images, the wrist were manually delineated using the image
software Dynamika version 4.6.0 (Image analysis Ltd., Leeds, UK, www.image
analysis.org) and for these regions of interest (ROI) the number of enhancing
voxels (Nvoxel), the initial rate of enhancement (IRE), the maximum enhancement (ME), the IRE⫻Nvoxel and ME⫻Nvoxel were extracted by the software
and compared to clinical parameters of disease activity.
Results:
Monday, November 12
1048
1049
Tenosynovitis in Carpal Tunnel Syndrome - Prevalence and Comparison
Between Ultrasonography, Surgery and Histology. David F. Ten Cate1, Nick
Glaser1, Jolanda J. Luime2, K.H. Lam3, Johannes W.G. Jacobs4, Ruud W. Selles2,
Johanna Hazes5 and M. Bertleff6. 1Erasmus Medical Center, Rotterdam, Netherlands, 2Erasmus MC - University Medical Center, Rotterdam, Netherlands,
3
Erasmus University Medical Center, Netherlands, 4University Medical Center
Utrecht, Utrecht, Netherlands, 5Erasmus Medical Centre Rotterdam, Rotterdam,
Netherlands, 6Xpert Clinic, Rotterdam, Netherlands
The Prevalence of the Ultrasonographic Positive Power Doppler Synovitis Is High and Predicts the Risk of Relapse and Structural Progression
in Rheumatoid Arthritis in Clinical Remission: A Systematic Literature
Review and Meta Analysis. Huong Nguyen1, Adeline Ruyssen-Witrand1,
Arnaud L. Constantin1, Violaine Foltz2, Frédérique Gandjbakhch2 and Alain
G. Cantagrel1. 1Purpan University Hospital, Toulouse, France, 2Pitié Salpétrière Hospital, Paris, France
Background/Purpose: Carpal tunnel syndrome (CTS) is a common
neuropathy affecting the median nerve. CTS occurs more frequently in
inflammatory arthropathies, such as rheumatoid arthritis (RA). This may
relate to the presence of tenosynovitis in the wrist. Patients with tenosynovitis
might be better treated conservatively with a diagnostic rheumatological
consultation and other non-surgical methods, such as a glucocorticoid
injection. However, flexor tenosynovitis at carpal tunnel level is not always
easy to detect at clinical examination, but may be detected reliably by
ultrasonography (US). Our aim was to determine the presence of tensynovitis
detected at US in idiopathic CTS patients referred for surgery and to compare
this with the peroperative evaluation and histological findings.
Methods: The wrists of 34 consecutive idiopathic CTS patients, with an
indication for carpal tunnel release, were assessed before surgery with
greyscale US (GSUS) and power Doppler US (PDUS) at the volar aspect of
the wrist. Flexor tenosynovitis was scored according OMERACT US definitions. During surgery, tenosynovitis was evaluated by the surgeon according
to a three-grade tenosynovitis classification system. Biopsy specimens were
obtained in 28 patients; tenosynovitis was scored histologically by a pathologist according to a three-grade scoring system.
Results: US Tenosynovitis was detected in 59% of the patients. Peroperative, surgical tenosynovitis was detected in 88% of the patients. The
pathologist found minor tenosynovitis in 17% of the patients, while 79%
showed reactive changes (Table 1). The agreement between the respective
modalities is presented in tables 2 and 3.
Table 1. Prevalence of tenosynovitis
TS ⫹
TS ⫹/⫺
TS⫺
US
Surgery
Histology
59%
N.A.
41%
46%
42%
12%
17%
79%
4%
- TS: Tenosynovitis
- For surgery and histology TS ⫹/⫺ is grade 1
Table 2. Comparison US-Surgery
Background/Purpose: Ultrasonography (US) can detect synovitis in
patients with rheumatoid arthritis (RA) more sensitively than clinical examination either in active disease or in remission.1,2 There are many definitions
of clinical remission, no consensus on US assessment of RA activity and the
clinical implication of residual US synovitis is hotly debated.3,4 This study is
to assess the prevalence of residual US synovial hypertrophy (USGS⫹) and
US power Doppler (PD) activity in patients in clinical remission and evaluate
the predictive value of this residual synovitis in terms of relapse and structural
progression.
Methods: A systematic literature search was performed in the Medline,
Embase and Rheumatology meeting databases up to 28 May 2012. The
prevalence of USGS⫹, cold synovitis (USGS⫹/PD-), active synovitis
(USGS⫹/PD⫹) and complete remission (USGS-/PD-) were collected taking
into account the definition of clinical remission, the stage of RA (early or
established disease) and the US examination method. A meta-analysis
assessing the risk of relapse or structural progression in patients with
USGS⫹/PD⫹ compared to other patients was performed calculating the odds
ratio (ORMH) and 95% confidence interval [95%CI] with the MantelHaenszel method.
Results: 18 studies including 1528 patients were included in this systematic literature review. All of the studies used the OMERACT method for US
scoring. The prevalence of US GS⫹, USGS⫹/PD-, USGS⫹/PD⫹ and
USGS-/PD- were 81.8 %, 40%, 43% and 15.7%, respectively. USGS⫹ or
USGS⫹/PD⫹ prevalence was comparable between the different definitions
of clinical remission (DAS44, DAS28, SDAI, ACR 1981 or ACR/EULAR
2011) and between the different US examination methods (from 5 to 44 joints
assessed). The prevalence of USGS⫹ and USGS⫹/PD⫹ was higher in the
patients with established RA in comparison to patients with early RA
(respectively 87% of USGS⫹ compared to 64%, p⬍0.001 and 45% of
USGS⫹/PD⫹ compared to 34%, p⬍0.001). According to the results of the
meta-analysis performed on 4 studies5–8 (including 178 patients) and 3
studies5, 9, 10 (including 173 patients), the presence of USGS⫹/PD⫹ was
associated with an increased risk of relapse (ORMH[95%CI]⫽2.9, [1.5,5.9],
p⫽0.002) and an increased risk of structural progression (OR[95%CI]⫽ 12.8,
[1.3, 126.8], p⫽0.03), respectively, over 1 to 2 years.
Conclusion: The prevalence of residual US synovitis is high in patients in
clinical remission. Residual USGS⫹/PD⫹ increase the risk of relapse and
structural progression in these patients.
Surgery
TS⫹
TS⫺
US
TSⴙ
17
13
30
3
1
4
TSⴚ
20
14
34
Surgical TS: Grade 1 ⫹ grade 2. Histological TS: Grade 2 (expert opinion)
Table 3. Comparison US-Histology
Histology
TS⫹
TS⫺
US
TSⴙ
TSⴚ
4
1
5
12
11
23
16
15
28
Surgical TS: Grade 1 ⫹ grade 2. Histological TS: Grade 2 (expert opinion)
Conclusion: In idiopathic CTS patients undergoing surgery, frequently tenosynovial changes are found at US and surgical evaluation, but
histology did not confirm this entirely. Tenosynovitis was seen, histologically, in only a minority of all cases. However, reactive changes can be
observed in a large number of cases and this could also be the basis of the
surgical and ultrasonographic findings. The exact definition of tenosynovitis in these three modalities needs further investigation.
Disclosure: D. F. Ten Cate, None; N. Glaser, None; J. J. Luime, None; K. H. Lam,
None; J. W. G. Jacobs, None; R. W. Selles, None; J. Hazes, None; M. Bertleff, None.
Disclosure: H. Nguyen, None; A. Ruyssen-Witrand, None; A. L. Constantin, None;
V. Foltz, None; F. Gandjbakhch, None; A. G. Cantagrel, None.
1050
Assessment of Validity of Magnetic Resonance Imaging Measures of
Joint Inflammation and Damage in Rheumatoid Arthritis Wrist/Hand a Systematic Literature Review. TG Woodworth1, O. Morgacheva2, OM
Troum3, OL Pimienta3, P. Maranian2, V.K. Ranganath2 and D.E. Furst2.
1
Visiting Clinical Researcher, David Geffen School of Medicine, UCLA, Los
Angeles, CA, 2David Geffen School of Medicine, UCLA, Los Angeles, CA,
3
USC Keck School of Medicine, Santa Monica, CA
Background/Purpose: Limitation of x-ray joint damage is a key indicator of therapeutic efficacy in rheumatoid arthritis (RA). Although magnetic
resonance imaging (MRI) is increasingly used due to its greater sensitivity vs
radiographs, summary evidence validating MRI features of RA joint inflammation and damage is lacking. By systematic literature review (SLR), we
examined the validity of MRI for assessment of RA wrist/hand features
according to Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria.
Methods: An SLR in PubMed with Cochrane hedge was conducted using
search terms: RA, AND MRI, AND specific terms i.e., synovitis, joint space
narrowing (JSN), erosions or bone marrow edema (BME) AND humans AND
randomized controlled trials [RCTs], clinical studies; 1970 to Aug 2011;
English. Pairs of authors evaluated titles/abstracts, selecting articles for
extraction according to these criteria: adults with RA, MRI of hands and/or
S454
Table. Validation status for measurement with 1.5T MRI images of synovitis,
tenosynovitis, osteitis, erosions, joint space narrowing (JSN)—number of articles
providing data
Type of
validity
Criterion
Content
Construct
(Discriminant)
Describes
Extent to joint features
which regardless of
measure age, gender, Correlation
RA
with clinical
agrees with
duration, assessment of
“gold
standard” treatment joint status
Definition
Synovitis
(RAMRIS)
1
2
12
0
1
3
Tenosynovitis
1
5
4
Construct
(Convergent)
Compares correlation
coefficients between
scores on the same
health component, as
measured by two
different instruments
1
IntraInterResponsiveness rater
rater
to change reliability reliability Summary
Sensitivity
to change
7
Two or
more # validated
Same
of 7
reader readers
score
required
scores
similarly similarly validity
(ICCs) (ICCs) criteria
1
0
1
1
1
13
0
1
5
1
BME/Osteitis
(RAMRIS)
1
3
9
2
0
4
JSN
1
1
*(a)
3
References
1. Palm Ø, Bernklev T, Moum B, Gran JT. Non-inflammatory joint pain in
patients with inflammatory bowel disease is prevalent and has a significant impact on
health related quality of life. J. Rheumatol. 2005 Sep;32(9):1755-9.
2. Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in
inflammatory bowel disease: their articular distribution and natural history. Gut 1998
Mar;42(3):387-91.
3. de Vlam K, Mielants H, Cuvelier C, de Keyser F, Veys EM, de Vos M.
Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence
and HLA association. J Rheumatol 2000 Dec;27(12):2860-5.
Disclosure: W. Stomp, None; L. K. P. M. Brakenhoff, None; F. A. van Gaalen,
None; D. van der Heijde, None; H. H. Fidder, None; D. W. Hommes, None; M.
Reijnierse, None; J. L. Bloem, None.
6
5
7
2
1
5
7
7
6
1052
6
5
6
Systematic Review of the Association Between Magnetic Resonance
Imaging and Radiographic Detection of Erosions in Rheumatoid Arthritis. Ruben Tavares1, Stephen R. Tytus2, Karen A. Beattie1, Maggie Larche1,
Naveen Parasu3, Colin E. Webber4, Lawrence E. Hart5 and Jonathan D.
Adachi6. 1McMaster University, Hamilton, ON, 2Northern Ontario School of
Medicine, Sudbury, Qatar, 3Hamilton Health Sciences, Hamilton, 4Hamilton
Health Sciences, Hamilton, ON, 5St. Joseph’s Health Care, Hamilton, ON,
6
Charlton Medical Centre, Hamilton, ON
1
Erosions
(RAMRIS)
gadolinium sequences. MRI images were evaluated by two musculoskeletal
radiologists in consensus for the presence of synovitis, tenosynovitis, bone
marrow edema and erosions. The readers were blinded for all patient
information.
Results: MR imaging of the MCP, PIP and/or DIP 2–5 joints of the hand
was performed in 10 patients and 10 matched controls, MRI of the knee in 4
patients and 4 matched controls. A total amount of 62 painful joints were
evaluated and 62 corresponding joints in the control group. Minimal synovitis
was seen in one of the MCP joints in two of the arthralgia patients (3.2% of
all painful joints) and in none of the control group (p⫽0.50). Bone marrow
edema was not appreciated in the arthralgia patients, but a small amount of
bone-marrow edema was seen in a MCP joint of a control (1.6% of total
joints, p⫽1.00). Tenosynovitis and erosions were absent in both groups.
Conclusion: Subclinical inflammation on MRI was not seen more often
in painful joints in arthralgia patients than in joints of controls. No anatomical
substrate was found for arthralgia in IBD patients.
1
2
3
7
*(b)
5
2
1
1⫽statistically significant validation; 0⫽non-significant data; ICC ⫽ intra/inter-class correlation coefficient
Conclusion: Using a rigorous PRISMA-compliant method for quality
assurance and uniform article extraction in a SLR, we found that synovitis,
osteitis/BME, and erosions are the best-validated features of joint inflammation and damage for RA wrist and hand. Assessment of other measurement
methods, field strengths and joints requires further work.
* Requires histology: a) Jain A, et al. Arthritis Rheum 2001;44:1754⌸60; b)
Jimenez-Boj E, et al. Arthritis Rheum 2007;56:1118⌸24.
Disclosure: T. Woodworth, None; O. Morgacheva, None; O. Troum, Genentech, 2,
Genentech, 5; O. Pimienta, None; P. Maranian, None; V. K. Ranganath, UCB, BMS,
Celgene, 2, UCB, 5; D. E. Furst, BMS, Centocor, UCB, Genentech, Amgen, 2, BMS,
Centocor, UCB, Amgen, Abbott, 5.
1051
Magnetic Resonance Imaging in Inflammatory Bowel Disease Patients
with Arthralgia. W. Stomp1, L.K.P.M. Brakenhoff1, F.A. van Gaalen1, D.
van der Heijde1, H.H. Fidder2, D.W. Hommes3, M. Reijnierse1 and J.L
Bloem1. 1Leiden University Medical Center, Leiden, Netherlands, 2University Medical Center Utrecht, Utrecht, Netherlands, 3University of California
Los Angeles, Los Angeles, CA
Background/Purpose: Joint manifestations frequently occur in chronic
inflammatory bowel diseases (IBD). Arthralgia, non-inflammatory joint pain
without objective evidence of swelling or effusion, is present in 8–30% of all
patients.(1–3) An underlying cause of arthralgia in IBD patients is not known
and might be autoimmune related, which might express on MR as bone
marrow edema. The purpose of this study is to assess whether inflammatory
changes, including bone marrow edema can be detected on MRI in IBD
patients with joint pain without clinical synovitis.
Methods: The most painful peripheral joint, without clinical signs of
inflammation based on examination by a rheumatologist, at most 2 weeks
prior to MR, was scanned in 14 IBD patients (11 Crohn’s disease/3 ulcerative
colitis) on a 1.5T extremity MRI. In addition the same joints were scanned in
a control group of 14 IBD patients who were matched for form of IBD,
disease duration, sex and age without joint complaints. MR imaging was
performed according to a standard arthritis protocol including T1 and
fat-suppressed T2 weighted images and T1 weigthed fat-suppressed post
Background/Purpose: In rheumatoid arthritis (RA), disparities between
erosive bone lesion detection on magnetic resonance imaging (MRI) and
X-ray require reconciliation. It is hypothesized that early erosions detectable
on MRI increase in size with disease progression to become detectable on
radiography (X-ray). The study’s objectives were 1) to compare the relative
diagnostic test accuracy of X-ray for MRI-detected erosions; and 2) to
determine if MRI erosions develop into X-ray erosions over time.
Methods: A systematic review was conducted. Medline (Jan 1996-Apr
2011) and EMBASE (Jan 1998-Apr 2011) citation indexes were searched
using the PICO strategy. RA studies with paired comparisons of erosion
detection on X-ray and MRI at the joint or more precise level of analysis were
included. Two reviewers independently screened the titles, abstracts and full
articles to determine eligibility. Disagreements on eligibility between reviewers were mutually resolved by discussion or arbitrated by a third, independent
reviewer if mutual resolution was not achieved. Cross-sectional comparisons
were examined overall and then sorted by study sample symptom duration.
Temporal explorations sorted data by time between initial MRI and subsequent X-ray. Study quality was evaluated using the Quality Assessment of
Diagnostic Accuracy Studies (QUADAS) and reported. Cochrane Collaboration Review Manager software was used to manage and analyze the data
collected.
Results: Sixteen eligible studies reporting 34 unique datasets comprising
10,953 paired observations were included. The relative diagnostic test
accuracy results were heterogeneous across studies. Sensitivity results ranged
from 0.00 (95% CI: 0.00–0.04) to 0.87 (95% CI: 0.60–0.98). Average
sensitivity weighted by study sample size was 0.28 (95% CI: 0.28–0.29).
Specificity ranged from 0.38 (95% CI: 0.14–0.68) to 1.00 (95% CI:
0.99–1.00). The weighted mean specificity was 0.97 (95%CI: 0.97-0.97). The
sensitivity of X-ray for MRI erosions appeared to increase with increasing
symptom duration. Sensitivity ranged from 0.07 (95% CI: 0.01–0.24) for
patients with a mean symptom duration of 0.25 years, to 0.34 (95% CI:
0.20–0.51) for patients with 14 years symptom duration. Specificity decreased slightly with increasing symptom duration. Specificity ranged from
approximately 0.99 (95% CI: 0.97–1.00) to 0.92 (95% CI: 0.88–0.95) for
S455
Monday, November 12
wrists assessing at least one of the following: synovitis, BME/osteitis,
tenosynovitis, erosions, JSN; RCT, observational study, or case series ⱖ10
patients. To achieve ⱖ 95% consistent data extraction, authors evaluated the
same 5 articles, ensuring consensus on data extraction methods. Each author
then extracted a proportion of the articles. Data extracted included MRI, field
strength, measurement methods, and validity criteria: criterion, content,
construct, reliability, responsiveness, and discrimination. Level of evidence
was assessed using Cochrane Handbook criteria, adapted for imaging research.
Results: Of 575 MRI titles/abstracts, 180 met criteria with 81 having at
least 1 type of validation. Although MRI measurement methods were
developed using several approaches, OMERACT RA MRI scoring (RAMRIS) was determined to be the dominant method. As 43 articles utilized 1.5T,
and 7 used other field strengths; only 1.5T articles were analyzed. (Table) 19
articles including 6 RCTs using 1.5T and RAMRIS were extracted seeking
validation of MRI measures. The table summarizes the number of articles
with data for validation. Histologic or radiographic evidence for criterion
validity was extracted from 5 other articles.
symptom durations ranging from 0.25 to 9.5 years, respectively. Studies
varied by sample symptom duration, anatomy investigated, MRI magnetic
strength, definition of erosion, number of X-ray projections, use of prescribed
scoring systems, number of raters, unit of analysis, and QUADAS parameters.
Conclusion: X-ray has low sensitivity and high specificity for MRI
erosions. The relationship between X-ray and MRI erosion detection is
dependent on symptom duration and the time interval between imaging
interventions. As the time between initial MRI and follow-up X-ray increases,
there is decreasing specificity of X-ray for MRI erosions. This suggests that
erosive progression is not limited to joints initially detected on MRI. Sources
of study heterogeneity and potential bias warrant attention in future comparative investigations.
Disclosure: R. Tavares, None; S. R. Tytus, None; K. A. Beattie, None; M. Larche,
None; N. Parasu, None; C. E. Webber, None; L. E. Hart, None; J. D. Adachi, None.
Monday, November 12
1053
Severe Joint Injury Assessed by Musculoskeletal Ultrasonography
(MSKUS) Predicts the Presence of MRI-Proven Osteitis in Patients with
Rheumatoid Arthritis. Shin-ya Kawashiri1, Takahisa Suzuki1, Yoshikazu
Nakashima1, Yoshiro Horai1, Naoki Iwamoto2, Kunihiro Ichinose1, Kazuhiko
Arima2, Mami Tamai2, Hideki Nakamura2, Tomoki Origuchi1, Kiyoshi
Aoyagi1 and Atsushi Kawakami1. 1Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki, Japan, 2Nagasaki University, Nagasaki,
Japan
Background/Purpose: MRI-proven osteitis is known as the prognostic
factor toward radiographic progression in patients with rheumatoid arthritis
(RA). Musculoskeletal ultrasonography (MSKUS) is another high sensitive
imaging modality to find joint injury of RA patients. We have tried to explore
whether MSKUS assessment of synovial joint injury predict the presence of
MRI-proven osteitis in patients with RA.
Methods: Thirty RA patients, who fulfilled 2010 RA classification
criteria and are naı̈ve to disease-modifying antirheumatic drugs (DMARDs)
including biologics or glucocorticoids, are consecutively enrolled in this study
from May 2010 through December 2011. Twenty-two joints from each
patient including bilateral wrists and finger joints of the 1st - 5th metacarpophalangeal (MCP) joints, the 1st interpharangeal (IP) joint and the 2nd–5th
proximal interpharangeal (PIP) joints were examined by both MSKUS and
plain MRI. Therefore, a total of 660 joints were investigated by both methods
in the present study. Power Doppler (PD) and gray scale (GS) assessment of
articular synovitis by a semi-quantitative manner as well as the presence of
bone erosion were examined by MSKUS. Plain MRI-proven osteitis was
evaluated by RAMRI scoring (RAMRIS) technique. The Cochran-Armitage
test was used to investigate a correlation of each MSKUS finding with
MRI-proven osteitis.
Results: The mean disease duration, age, DAS28-ESR, prevalence of RF
and anti-cyclic citrullinated peptide antibodies (ACPA) at examination were
4 months, 62 years-old, 5.06, 83.3% and 73.3%, respectively. MSKUSproven bone erosion was found in 40 sites and MRI-proven osteitis 64 sites,
respectively. A remarkable correlation of the PD grade (p ⬍ 0.0001), GS
grade (p ⬍ 0.0001) and the presence of MSKUS-proven bone erosion (p ⬍
0.0001) with the presence of osteitis was demonstrated by the CochranArmitage test.
Conclusion: Our present data suggest that severe joint injury assessed by
MSKUS predicts the presence of MRI-proven osteitis in patients with
rheumatoid arthritis.
Disclosure: S. Y. Kawashiri, None; T. Suzuki, None; Y. Nakashima, None; Y.
Horai, None; N. Iwamoto, None; K. Ichinose, None; K. Arima, None; M. Tamai,
None; H. Nakamura, None; T. Origuchi, None; K. Aoyagi, None; A. Kawakami,
None.
1054
Diffusion Tensor and Dynamic Contrast Enhanced Perfusion Imaging
Metrics Discriminate Chronic Tubercular Synovitis From Chronic Inflammatory Synovitis of the Knee. Vikas Agarwal1, Rakesh K. Gupta2,
Rishi Awasthi2, Deepak Tripathi2, Prativa Sahoo3, Vinita Agrawal2, Kusum
Sharma4, Rungmei Marak5, Ram Kishore Singh Rathore3 and CM Pandey2.
1
Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow,
Lucknow, India, 2Sanjay Gandhi Postgraduate Institute of Medical Sciences,
Lucknow, Lucknow, India, 3Indian Institute of Technology, Kanpur, India,
4
Postgraduate Institute of Medical Education and Research, Chandigarh,
India, 5Microbiology, Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow, Lucknow, India
Background/Purpose: The study was performed to quantify dynamic
contrast enhanced (DCE) and diffusion tensor imaging (DTI) metrics in
synovium of patients with tubercular synovitis (TS) and chronic inflammatory
synovitis (CIS) with an aim to discriminate between TS and CIS.
Methods: Seventy-three patients with knee synovitis (18–75 years, 51
Male) underwent conventional, DTI and DCE-MRI. DTI and DCE data were
quantified from the segmented contrast enhanced synovium. Descriptive
statistics, Box-plot with Tukey’s hinges were produced for all DTI (fractional
anisotropy, FA and mean diffusivity, MD) and perfusion metrics (blood
volume, BV; blood flow, BF and volume transfer constant, ktrans). The mean
difference between the two groups was compared using Student’s t-test for
independent samples. To classify subjects into TS and CIS, two-group
discriminant function analysis with stepwise inclusion of variables was
performed.
Results: Out of 73 patients, 15 were detected to have TS, while rests
were found to have CIS. DCE (BV, BF) and DTI metrics (FA, MD)
were significantly (p⬍0.001) different between the two groups (TS:
BV⫽14.35⫾4.21 ml/100gm, CIS:BV⫽4.57⫾2.77 ml/100gm, TS
BF⫽155.7⫾29.5 ml/100gm/min, CIS BF⫽94.9⫾34.5 ml/100gm/min, TS
FA⫽0.26⫾0.02, MD⫽1.23⫾0.39⫻10⫺3 mm2sec⫺1; CIS FA⫽0.20⫾0.02,
MD⫽1.7⫾0.5⫻10⫺3 mm2sec⫺1). Discriminant analysis revealed BV and
FA as discriminators of TS and CIS. It classified 93.3% of TS and 100% of
CIS correctly. The overall model classified 98.6% cases correctly.
Conclusion: DTI and DCE-MRI metrics are able to discriminate TS from
CIS. FA and BV may be used as non-invasive image biomarkers for its
differentiation.
Disclosure: V. Agarwal, None; R. K. Gupta, None; R. Awasthi, None; D. Tripathi,
None; P. Sahoo, None; V. Agrawal, None; K. Sharma, None; R. Marak, None;
R. K. S. Rathore, None; C. Pandey, None.
ACR/ARHP Poster Session B
Innate Immunity and Rheumatic Disease
Monday, November 12, 2012, 9:00 AM–6:00 PM
1055
Sec61 Is Indispensable for Antigen Cross-Presentation and the Development of Lupus Nephritis: A Novel ‘Self-Organized Criticality Theory’
Explaining the Cause of Systemic Lupus Erythematosus (SLE). Ken
Tsumiyama and Shunichi Shiozawa. Kyushu University Beppu Hospital,
Beppu, Japan
Background/Purpose: We found that systemic lupus erythematosus
(SLE) was induced experimentally by repeatedly immunizing the mice
normally not prone to autoimmune diseases by any exogenous antigen so far
examined (Tsumiyama K et al. PLoS One 4(12):e8382, 2009). We have then
proposed a novel ‘self-organized criticality theory’ that explains the cause of
SLE. Systemic autoimmunity, or SLE, necessarily takes place when host’s
immune system is overstimulated by repeated exposure to antigen to levels
that surpass the immune system’s stability limit, i.e., self-organized criticality.
The autoreactive lymphocyte clones, which we name autoantibody-inducing
CD4⫹ T cells (aiCD4⫹ T cells) are newly generated via de novo T cell
receptor (TCR) revision from thymus-passed non-autoreactive clones at
peripheral lymphoid organs. They not only stimulated B cells to generate
varieties of autoantibodies but also helped final differentiation of CD8⫹ T cell
into cytotoxic T lymphocyte (CTL) via antigen cross-presentation to induce
tissue injuries identical to SLE. Here we show the essential role of a
translocon Sec61 for antigen cross-presentstion and lupus tissue injuries with
regard to self-organized criticality theory.
Methods: Bone marrow-derived dendritic cell (BMDC) of BALB/c mice
was cultured with fluorescent-labeled ovalbumin (OVA). Early endosome
antigen 1 (EEA1) and calnexin were detected by using immunofluorescent
staining to identify endosome and endoplasmic reticulum (ER), respectively.
A translocon Sec61 was also detected to examine whether or not engulfed
antigen is exported from endosome to cytoplasm through Sec61. For in vivo
study, BALB/c mice were repeatedly immunized with OVA to induce SLE.
The CD11c⫹ DC isolated form spleen (spDC) of the mice immunized 12⫻
with OVA was cultured with fluorescent-labeled OVA to examine localization of engulfed antigen. Localization of OVA, EEA1, calnexin and Sec61 in
BMDC and spDC was examined under confocal laser microscopy. Further,
exotoxin A was co-immunized with OVA to inhibit Sec61 in vivo in BALB/c
mice. Renal lesion and the generation of CTL were assessed by proteinuria
and the number of IFN␥-producing CD8⫹ T cell.
S456
Results: In BMDC, OVA was co-localized with an endosomal marker
EEA1 until 15 min of culture, and subsequently separated from EEA1. OVA
did not co-localize with an ER marker calnexin. Instead, OVA was colocalized with a translocon Sec61. The same result was obtained using spDC,
suggesting that OVA could be exported from endosome directly to cytoplasm
via Sec61. After repeated immunization with OVA, we found that the amount
of Sec61 localized in endosome was gradually and significantly increased
compared with control. While we showed previously that antigen crosspresentation is a pre-requisite for lupus tissue injury inducing nephritis, we
did found that treatment of BALB/c mice with a Sec61 inhibitor exotoxin A
inhibited both the generation of CTL and lupus nephritis.
Conclusion: Direct export of antigen from endosome to cytoplasm via
Sec61 is essential not only for antigen cross-presentation but also development of lupus nephritis.
Disclosure: K. Tsumiyama, None; S. Shiozawa, None.
Fc Receptor Gamma-Dependent Autoimmune Endocarditis in K/BxN
Mice. Patricia M. Hobday1, Jennifer L. Auger1, J. Sjef Verbeek2, Jeffrey V.
Ravetch3 and Bryce A. Binstadt1. 1University of Minnesota, Minneapolis,
MN, 2Leiden University Medical Center, Leiden, Netherlands, 3The Rockefeller University, New York, NY
Background/Purpose: Arthritis and endocarditis co-exist in several
human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. K/BxN TCR transgenic mice, well
known for their inflammatory arthritis, also develop spontaneous endocarditis. FcR␥, the cytoplasmic signaling molecule shared by the three activating
Fc␥ receptors in the mouse (Fc␥RI, III, and IV), is required for endocarditis
in K/BxN mice. Here we addressed two main questions: first, which of the
three activating Fc␥ receptors is required for endocarditis in this model and
second, what FcR␥-expressing cell type drives endocarditis.
Methods: Knockout alleles of each of the activating Fc␥ receptors
(Fc␥RI⫺/⫺, Fc␥RIII⫺/⫺, and Fc␥RIV⫺/⫺) were bred into the K/BxN
system. In addition, we utilized a reciprocal bone marrow transplantation
approach to determine if endocarditis depended on FcR␥ expression by bone
marrow-derived cells or by radio-resistant host cells. We assessed hearts for
the presence of endocarditis via standard hematoxylin and eosin staining.
Additionally, we used immunohistochemistry to examine the expression of
the three activating Fc␥ receptors in the cardiac valves as well as the isotypes
of antibodies bound to the inflamed cardiac valves.
Results: Although IgG1 is the predominant autoantibody isotype in
K/BxN mice, we found that IgG1, IgG2b, and IgG2c were all bound to their
inflamed cardiac valves. We also detected expression of each of the activating
Fc␥ receptors in the cardiac valves. K/BxN mice lacking expression of Fc␥RI,
Fc␥RIII, or Fc␥RIV developed endocarditis with equivalent severity to
control mice. The bone marrow transplant experiments revealed that recipient
mice lacking FcR␥ were protected from endocarditis. Surprisingly, the
presence or absence of FcR␥ on bone marrow-derived donor cells did not
influence the severity of endocarditis.
Conclusion: Our results indicate that no single activating Fc␥ receptor is
solely required for the development of endocarditis in K/BxN mice. The
simplest explanation for these findings is that there is redundancy among the
activating Fc␥ receptors in driving endocarditis. This interpretation is consistent with our data showing that multiple immunoglobulin isotypes are bound
to the inflamed valves and that that each of the activating Fc␥ receptors can
be detected in the valves. A less likely explanation is that an FcR␥-utilizing
receptor type other than the activating Fc␥ receptors is at play. We also
conclude that FcR␥ chain expression by radio-resistant host cells rather than
by radiosensitive, bone-marrow derived cells is required for the development
of endocarditis. Candidate cell types include cardiac stromal cells and/or
radio-resistant dendritic cells. Our findings provide new insight into the
pathogenesis of cardiovascular inflammation in the setting of autoantibodyassociated diseases.
Disclosure: P. M. Hobday, None; J. L. Auger, None; J. S. Verbeek, None; J. V.
Ravetch, None; B. A. Binstadt, None.
1057
A Specific Inhibitor of Spleen Tyrosine Kinase, PRT062607, Is a Potent
Modulator of Innate Immune Cell Function. Lynn A. Kamen, Gillian
Stephens, Anjali Pandey and Uma Sinha. Portola Pharmaceuticals, South San
Francisco, CA
Disclosure: L. A. Kamen, Portola Pharmaceuticals Inc, 1; G. Stephens, Portola
Pharmaceuticals, 3; A. Pandey, Portola Pharmaceuticals, 1; U. Sinha, Portola Pharmaceuticals, 1.
1058
Fulminant Toll-Like Receptor 9-Induced Macrophage Activation Syndrome and Hemophagocytosis Occur Independently of Interferon
Gamma. Scott W. Canna1, Julia Wrobel2, Portia A. Kreiger3, Michele E.
Paessler1 and Edward M. Behrens1. 1Childrens Hospital of Philadelphia,
Philadelphia, PA, 2The Children’s Hospital of Philadelphia, Philadelphia, PA,
3
Nemours/A.I. DuPont Hospital for Children, Wilmington, DE
Background/Purpose: Macrophage Activation Syndrome (MAS) is a
potentially lethal cytokine storm syndrome that complicates various rheumatic diseases. We have previously shown that Toll-like Receptor (TLR9)
mediated MAS is Interferon gamma (IFNg) dependent, and others have
demonstrated IFNg-dependence in models of Hemophagocytic Lymphohistiocytosis. We have also shown the critical role of IL-10 in regulating
TLR9-induced MAS, and mice co-treated with TLR9-agonism and IL-10
receptor blockade (IL10RB) develop “fulminant MAS.” This study seeks to
determine the role of IFNg in the fulminant MAS model.
Methods: We gave CpG1826 repeatedly to WT and transgenic mice as
described. Antibodies inhibiting the action of the IL-10 receptor (IL10RB,
1B1.3A) and IL-12p40 (C17.8) were given as described. All injections were
intraperitoneal. We then evaluated for signs of MAS.
Results: Fulminant MAS resulted in greatly enhanced serum IL-10,
IL-12, and IFNg. While dendritic cell populations were dominant producers
of IFNg in IL-10 sufficiency, in fulminant MAS IFNg was also produced by
hepatic NK and CD8 T cells. When IL-12 was blocked in fulminant MAS
mice, disease progression was unaltered, despite much lower serum IFNg.
Strikingly, we also observed the continued presence of hemophagocytes
(HPCs) despite IL-12 blockade. This observation caused us to question
whether fulminant MAS was due to enhanced IFNg activity or whether,
distinct from the IL-10 sufficient scenario, other proinflammatory forces were
at work. Administration of CpG and IL10RB to IFNg⫺/⫺ mice resulted in
fulminant MAS nearly comparable to that seen in WT mice. Notably,
S457
Monday, November 12
1056
Background/Purpose: Tumor Necrosis Factor-␣ (TNF-␣) is an essential
component of the inflammatory stimuli leading to rheumatoid arthritis (RA).
Therapeutics targeting TNF-␣ are the standard of care but are not always
capable of inhibiting disease progression. Thus, there is an unmet need for
novel targets for treatment of RA. Spleen tyrosine kinase (Syk) is a
non-receptor tyrosine kinase that plays an important role in phagocyte
(macrophage and neutrophil) activation. Phagocytes are known to be important in the pathology of RA; the purpose of this study was to evaluate the
impact of Syk inhibition in modulating phagocyte activation.
Methods: Macrophages were generated by culturing peripheral blood
monocytes from healthy human volunteers with M-CSF (5ng/mL) for five
days. Neutrophils were isolated from human peripheral blood on a Ficoll
gradient and separated from erythrocytes via dextran sedimentation. As a
surrogate for pathogenic autoantibodies in the arthritic synovial joint, immune complex was used for activation of macrophages and neutrophils.
Immune complex was prepared by preincubating chicken egg ovalbumin
with goat anti-chicken egg ovalbumin IgG at 37°C. To mimic integrinmediated activation, plate-bound poly-RGD (20 ␮g/mL) was used as a
stimulus. TNF-␣ release from macrophages was measured via ELISA (R and
D Systems). The SOD-inhibitable oxidative burst response in neutrophils was
measured through cytochrome c reduction in a plate-based absorbance assay.
Specific Syk inhibitor, PRT062607 (P505-15) was added in vitro to the
experimental system containing human macrophages or neutrophils.
Results: Syk inhibition by PRT062607 suppressed inflammatory cytokine release. Cytokine levels, as measured by TNF-␣ release from macrophages stimulated with immune complex, was potently inhibited by
PRT062607 (IC50⫽0.070␮M). Furthermore, PRT062607 treatment was a
potent inhibitor of neutrophil-mediated superoxide production in response to
various physiologically relevant stimuli (integrin ligation IC50⫽0.037␮M and
immune complex stimulation IC50⫽0.195␮M). Interestingly TNF-␣ alone
was able to facilitate neutrophil-mediated superoxide production, and this
activity was potently suppressed by PRT062607 (IC50⫽0.065␮M).
Conclusion: Together these data indicate a novel role for Syk inhibition
in controlling TNF-␣-mediated inflammation. These results suggest that in
addition to decreasing immune cell activation and inflammation in the joint,
Syk inhibition could also partly mimic the effects of an anti- TNF-␣ therapy.
Thus, Syk inhibition by a small molecule kinase inhibitor has the potential to
be a novel mode of therapy in RA.
Monday, November 12
IFNg⫺/⫺ mice were spared from severe anemia and severe hepatitis but
developed all other aspects of fulminant MAS including HPCs. Thus, while
certain aspects of disease (anemia and hepatitis) are IFNg-dependent, fulminant MAS, including hemophagocytosis, occurs independent of IFNg. Interestingly, blockade of type I interferon signaling (using IFNAR⫺/⫺ mice) did
not prevent disease in the IL-10 sufficient situation, but partially abrogated
fulminant MAS. HPCs also persisted despite Type I IFN receptor blockade.
Conclusion: In the TLR9-mediated model, IL-12 functions to induce
IFNg. However, fulminant MAS is largely IFNg-independent. This suggests
that therapeutic targeting of IFNg may not be sufficient in all cases of
hemophagocytic syndrome. Furthermore, our results dissociate the development of IFNg-induced “consumptive” anemia and hepatitis, and the presence
of HPCs. Thus, the goal of chemotherapeutic elimination of HPCs may not be
of benefit for many aspects of the disease, since their presence does not
correlate with either anemia or hepatitis.
Disclosure: S. W. Canna, None; J. Wrobel, None; P. A. Kreiger, None; M. E.
Paessler, None; E. M. Behrens, None.
1059
Endogenous Complement Factor H Plays an Important Role in Controlling Immune Complex-Induced Inflammatory Arthritis. Nirmal K.
Banda1, Gaurav Mehta1, Viviana P. Ferreira2, Claudio Cortes2, Michael K.
Pangburn3, William P. Arend1 and V. Michael Holers1. 1University of
Colorado School of Medicine, Aurora, CO, 2University of Toledo Health
Science Campus, Toledo, OH, 3University of Texas Health Sciences Center,
Tyler, TX
Background/Purpose: The complement system, a major component of
innate immunity, likely plays an important role in the pathogenesis of
rheumatoid arthritis (RA). Factor H (fH) is an endogenous regulator of the
alternative pathway (AP) that binds surface polyanions in combination with
the C3-derived fragments C3b and C3d initially through its carboxy-terminal
domain containing short consensus repeats (SCR) 19–20, thereby inhibiting
both AP activation and engagement of the AP amplification loop. We have
shown that the AP is uniquely both necessary and sufficient for the
development of collagen antibody-induced arthritis (CAIA) in mice. However, the mechanisms whereby normal control of the AP is overcome and
injury develops are unknown. The hypothesis pursued in the current studies
is that fH plays a critical role in regulating the AP in immune complexinitiated injury in CAIA. We have examined the role of fH in CAIA by
inhibiting its binding to tissues through administration of a recombinant
dominant negative inhibitor containing murine SCR19–20 (rfH19–20), which
impairs fH surface AP regulation, and the use of gene-targeted fH deficient
mice.
Methods: CAIA was induced in C57BL/6 WT, fH⫺/⫺ and fH⫹/⫺ mice by
injecting four anti-type II collagen (CII) mAbs i.p. on day 0 and lipopolysaccharide (LPS) i.p. on day 3. Intraperitoneal injections of 100 and 300
␮g/mouse of rfH19–20 were carried out 15 min after the injection of mAb to
CII on day 0 and again 15 min after LPS on day 3. Blood was drawn
intraorbitally from all mice at day 0 prior to injection of mAb to CII, at day
3 prior to LPS injection, and at day 10 prior to sacrifice. All mice were
sacrificed on day 10 for histopathologic scoring of injury and immunohistochemical analysis of C3 deposition. Control experiments were performed
using rfH3–5 which does not inhibit fH binding to tissues. The absolute levels
of C3, fH and C5a in serum of mice were measured by ELISA.
Results: Both doses of rfH19–20 significantly increased the clinical
disease activity score (DAS) using a sub-maximal dose (0.5 mg/mouse) of
anti-CII mAbs. Scores for histopathologic injury and C3 deposition on the
surface of the cartilage and in the synovium increased with treatment in an
identical fashion. No significant differences in the DAS were observed when
WT mice were treated with 300 ␮g/mouse of control rfH3–5. fH⫺/⫺ mice,
compared with WT mice, were resistant to CAIA due to the significantly
reduced serum levels of C3. WT and fH⫹/⫺ mice have identical serum levels
of C3, but fH⫹/⫺ mice have 30% reduced levels of fH. WT and fH⫹/⫺ mice
developed indistinguishable DAS using a sub-maximal dose as well as a
maximum dose (8 mg) of anti-CII mAb. In addition, though, the DAS at day
10 in fH⫹/⫺ mice treated with 300 ␮g/mouse of rfH19–20 increased to 5.5 ⫾
0.65 compared with untreated fH⫹/⫺ mice which was 1.75 ⫾ 0.25 (p ⬍ 0.05).
Conclusion: We show for the first time that endogenous fH makes a
significant contribution to regulating immune complex-induced injury in
CAIA through binding to target surfaces via SCR19–20 and blocking AP
activation and amplification.
Disclosure: N. K. Banda, None; G. Mehta, None; V. P. Ferreira, None; C. Cortes,
None; M. K. Pangburn, Complement Technology Inc, 4; W. P. Arend, None; V. M.
Holers, None.
1060
Protein Kinase C Inhibitor Generates Human Tolerogenic Dendritic
Cells That Induce Tr1 and Foxp3ⴙ Regulatory T Cells. Takuya Matsumoto, Hitoshi Hasegawa, Jun Ishizaki, Koichiro Suemori, Sachiko Onishi and
Masaki Yasukawa. Ehime University Graduate School of Medicine, Toon,
Japan
Background/Purpose: Tolerogenic dendritic cells (tDCs) play a critical
role in immune tolerance and are involved in the pathogenesis of autoimmune
diseases such as rheumatoid arthritis. Suppression by tDCs is primarily
mediated via the induction of regulatory T cells (Treg). tDCs are induced in
the presence of specific biological agents. Therefore, we screened the
molecules that enhanced induction of tDCs from the libraries of lipids, nuclear
receptor ligands, and kinase inhibitors. Of these, protein kinase C inhibitors
(PKCIs) such as bisindolylmaleimide I, Go6983, and Ro32–0243, suppressed
the expression of CD80, CD83, and CD86 on DCs and suppressed allogenic
T cell responses. In this study, we showed the characterization of PKCItreated human tDCs and application to the therapy for autoimmune diseases.
Methods: Mature DCs (mDCs) were prepared from human monocytes by
treating with GM-CSF and IL-4 for 5 days, and then induced maturation wtih
TNF-alpha for 48h. PKCI-treated tDCs were generated by adding bisindolylmaleimide I, Go6983, or Ro32–0243 during this process. We analyzed the
cell surface expression on DCs, cytokine production, and phagocytic ability.
Furthermore, we examined the effects of these molecules on stability and
plasticity of DCs, antigen presenting, allogenic T cell responses, and induction of Tr1 and Treg cells.
Results: DCs treated with PKC inhibitors such as bisindolylmaleimide I,
Go6983, and Ro32–0243 decreased the expression levels of CD40, CD80,
CD83, CD86, and HLA class I significantly but not those of CD1a, CD11c,
and HLA classII compared with mDCs. Moreover, PKCI-treated tDCs
produced 15–20-fold and 2–4-fold higher concentration of IL-10 and TGFbeta than mDCs, respectively, resulting in a strong reduction of allogenic T
cell responses. From the co-culture of DCs and naı̈ve T cells, PKCI-treated
tDCs induced IL-10-producing Tr1 cells and Foxp3⫹ regulatory T cells.
PKCI-treated tDCs retained phagocytic ability as well as immature DCs
(iDCs). PKC I-treated tDCs kept the low expression levels of CD80, CD83,
and CD86 and suppressive properties at least one week after stimulated with
a cocktail of proinflammatory cytokines or LPS, whereas iDCs recovered the
similar expression levels to mDCs and did not have suppressive properties.
Conclusion: We showed that PKCI-treated human DCs acted as a strong
and stable tDCs. PKCI-treated tDCs may be useful method to the therapy for
autoimmune diseases.
Disclosure: T. Matsumoto, None; H. Hasegawa, None; J. Ishizaki, None; K.
Suemori, None; S. Onishi, None; M. Yasukawa, None.
1061
Generation of Myeloid-Derived Suppressor Cells in Vitro From Murine
Bone Marrow Precursors. Julia Kurko, Beata Tryniszewska, Tibor A.
Rauch, Colt Egelston, Tibor T. Glant and Katalin Mikecz. Rush University
Medical Center, Chicago, IL
Background/Purpose: Myeloid-derived suppressor cells (MDSCs) are
innate immune cells that expand under pathological conditions (such as
cancer and autoimmune diseases) in response to local growth factors or
cytokines. MDSCs are a heterogeneous population of immature myeloid
lineage (monocyte-like and granulocyte-like) cells with immunosuppressive
ability. These cells have the potential to down-regulate autoreactive T cell
responses in autoimmune diseases such as rheumatoid arthritis (RA). Using
proteoglycan (PG)-induced arthritis (PGIA), a mouse model of RA, we
previously reported that MDSCs are present in synovial fluid (SF) of the
arthritic joints of mice and suppress antigen-specific T cell proliferation. As
the number of cells that can be collected from murine SF is limited and SF
MDSCs do not expand in culture, we sought an alternative source for
generating greater quantities of MDSCs for potential therapeutic intervention
(via cell transfer) in PGIA.
Methods: Bone marrow (BM) cells were isolated from naı̈ve BALB/c
mice and cultured in the presence of recombinant murine granulocyte
macrophage colony-stimulating factor (GM-CSF), granulocyte colonystimulating factor (G-CSF) and interleukin-6 (IL-6) for up to 7 days. After
S458
Disclosure: J. Kurko, None; B. Tryniszewska, None; T. A. Rauch, None; C.
Egelston, None; T. T. Glant, None; K. Mikecz, None.
1062
Identification of Highly Potent and Selective Interleukin-1 ReceptorAssociated Kinase 4 Inhibitors for the Treatment of Rheumatic Diseases.
Divya Chaudhary1, Shaughnessy Robinson2, Craig E. Masse1, Matthew D.
Wessel2, Shawn Watts2, Jeremy Greenwood2, Mee Shelley2, Mark Brewer2,
Geraldine Harriman1, Leah L. Frye2, Ronald T. Wester1, Rosana Kapeller1
and Donna Romero1. 1Nimbus Discovery, Inc., Cambridge, MA,
2
Schrödinger, Inc., New York, NY
Background/Purpose: Interleukin-1 receptor-associated kinase 4
(IRAK4) is a key mediator of the innate immune response orchestrated by
interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). IRAK4 activation is mediated
by MYD88, a common signaling adaptor protein downstream of these
receptors. Mutations leading to inactivation or activation of MYD88 have
been reported in patients with immune deficiencies and cancer, respectively.
In addition, IRAK4-deficient humans are protected from chronic inflammatory diseases. Thus, IRAK4 is an attractive therapeutic target for the treatment
of autoimmune diseases such as lupus. Historically, identification of potent
and selective IRAK4 inhibitors has been challenging due to structural features in the catalytic binding site that block access to the hydrophobic back
pocket. We have developed new structure-activity relationship (SAR) insights, including the identification of unstable (high-energy) hydration sites,
which guide the design of potent and selective small molecule ligands.
Methods: Using this innovative structure-based approach, we designed,
synthesized and tested small molecule inhibitors based on hits originated from
a virtual screen. These novel compounds were profiled for IRAK4 kinase
inhibition, selectivity, and drug-like properties. Furthermore, selected compounds were tested in THP1 cells, human peripheral blood mononuclear
cells (hPBMCs) and whole blood for impact on LPS-, IL-1-, R848-, and/or
CpG-mediated signaling. The inhibitors were also tested in vivo in acute LPS
challenge and chronic collagen induced arthritis (CIA) models.
Results: Here, we feature three highly potent, selective IRAK4 inhibitors,
ND-346, ND-2110 and ND-2158. The Kis of ND-346, ND-2110, and
ND-2158 for IRAK4 are 50, 7.5 and 1 nM, respectively. These compounds
are highly selective against 334 kinases, and are potent inhibitors of
IL-1-induced IRAK1 degradation in MRC5 cells, LPS-, IL-1-, R848 (TLR-7
agonist)- and CpG (TLR-9 agonist)-induced cytokine production in hPBMCs
and whole blood. Furthermore, these compounds are efficacious in the acute
LPS challenge model in vivo, and ND-346 shows efficacy in rat CIA at 10
mg/kg (PO, QD).
Conclusion: Utilizing unique and innovative structure-based drug design,
we have rapidly discovered potent and selective IRAK4 inhibitors as potential
drug candidates for the treatment of chronic rheumatic diseases.
Disclosure: D. Chaudhary, None; S. Robinson, None; C. E. Masse, None; M. D.
Wessel, None; S. Watts, None; J. Greenwood, None; M. Shelley, None; M. Brewer,
None; G. Harriman, None; L. L. Frye, None; R. T. Wester, None; R. Kapeller,
None; D. Romero, None.
1063
Dysfunction of Natural Killer and Natural Killer T Cells in Patients with
Adult Onset Still’s Disease. Young-Nan Cho1, Sung-Ji Lee1, Tae-Jong
Kim2, Hye-Mi Jin1, Dong-Jin Park2, Seung-Jung Kee1 and Yong-Wook
Park1. 1Chonnam National University Medical School and Hospital,
Gwangju, South Korea, 2Chonnam National University Medical School,
Gwangju, South Korea
Background/Purpose: Adult onset Still’s disease (AOSD) is an uncommon systemic inflammatory disorder of unknown etiology. Natural killer
(NK) cell dysfunction is frequently observed in some human autoimmune
disease, such as systemic lupus erythematosus and rheumatoid arthritis.
However, NK cell function has not previously been investigated in AOSD.
Furthermore, the relation between NK and NKT cells has not been determined. Purpose of this study is to examine the levels and functions of NK and
NKT cells, to investigate relationships between NK and NKT cells, and to
determine the clinical relevance of NKT cell levels in patients with AOSD.
Methods: Patients with active untreated AOSD (n ⫽ 25) and age- and
sex-matched healthy controls (n ⫽ 25) were enrolled in the study. NK and
NKT cell levels were measured by flow cytometry. Peripheral blood mononuclear cells were cultured in vitro with ␣-galactosylceramide (␣-GalCer).
NK cytotoxicities against K562 cells and proliferation indices of NKT cells
were estimated by flow cytometry.
Results: Percentages and absolute numbers of NKT cells were significantly lower in the peripheral blood of patients than in healthy controls.
Proliferative responses of NKT cells to ␣-GalCer were also lower in patients,
and this was found to be due to proinflammatory cytokines and NKT cell
apoptosis. In addition, NK cytotoxicities were found to be significantly lower
in patients than in healthy controls, but NK cell levels were comparable in the
two groups. Notably, this NKT cell deficiency was found to be correlated with
NK cell dysfunction and to reflect an active disease status. Furthermore,
␣-GalCer-mediated NK cytotoxicity, showing the interaction between NK
and NKT cells, was significantly lower in patients than in healthy controls.
Conclusion: Our findings show that NKT cells are numerically and
functionally deficient in AOSD. In addition, we report a novel observation
that NK cell dysfunction is related to NKT cell deficiency. These findings
provide important information concerning the pathogenesis of AOSD.
Disclosure: Y. N. Cho, None; S. J. Lee, None; T. J. Kim, None; H. M. Jin, None;
D. J. Park, None; S. J. Kee, None; Y. W. Park, None.
1064
CD1c-Expressing Myeloid Dendritic Cells From Joints of Rheumatoid
Arthritis Patients Produce Increased Levels of T Cell-Attracting Chemokines and Strongly Activate Autologous T Cells. F.M. Moret, C.E. Hack,
F.P.J.G. Lafeber, T.R.D.J. Radstake and J.A.G. van Roon. University Medical Center Utrecht, Utrecht, Netherlands
Background/Purpose: Myeloid dendritic cells (mDCs) are potent T
cell-activating antigen-presenting cells that have been implicated to play a
crucial role in the regulation of tolerance and pro-inflammatory immune
responses in many disease states, including rheumatoid arthritis (RA). Despite
this, studies that have reported on the role of naturally occurring circulating
mDCs in RA are scarce. Recently, CD1c mDCs from RA patients were
suggested to migrate from the circulation to the joint where they exhibit a
semi-mature phenotype. However, data on the capacity of these CD1c mDCs
to regulate T cell activation in RA are lacking. The present study investigated
the expression profiles of co-stimulatory molecules and pro-inflammatory
mediators secreted by CD1c mDCs from synovial fluid (SF) versus peripheral
blood (PB) of RA patients and studied their capacity to stimulate autologous
CD4 T cell proliferation and cytokine production.
Methods: CD1c mDC numbers and their expression of surface molecules
involved in T cell activation were assessed by FACS analysis in SF and PB
from RA patients (n⫽9). Production of inflammatory mediators by CD1c
mDCs from SF and PB of RA patients (n⫽6) was determined after 20h of
S459
Monday, November 12
harvest, the phenotype of cells was evaluated by flow cytometry. Their
suppressive function towards PG-specific T cells was tested by co-culture
with PG-loaded BM-derived dendritic cells (DCs) and T cells from naı̈ve
PG-specific T cell receptor transgenic (PG-TCR-Tg) mice. The mechanisms
of MDSC-mediated suppression were investigated using inhibitors of MDSCproduced effector molecules including arginase-1, inducible nitric oxide (NO)
synthase (iNOS), and reactive oxygen species. Expression of MDSC effector
molecules was analyzed by RT-PCR and Western blot.
Results: Similar to SF MDSCs, BM-derived MDSCs expressed the
common myeloid marker CD11b. However, unlike SF MDSCs, BM MDSCs
contained a smaller population of Ly6G positive (granulocyte-like) cells, and
the majority of them expressed both Ly6G and the monocytoid cell surface
marker Ly6C. Upon co-culture with PG-TCR-Tg T cells in the presence of
PG-loaded DCs, BM MDSCs profoundly inhibited the proliferation of T
cells, thereby confirming their suppressor activity. BM cells grown with
GM-CSF, G-CSF, and IL-6 for only 3 days already showed potent suppressive effect on T cell proliferation. Despite expression of Ly6C by most BM
MDSCs, these cells retained their suppressor activity after depletion of the
Ly6C positive population. Experiments with inhibitors of MDSC effector
molecules revealed that the primary mechanism of suppression of T cell
proliferation was via NO release. Indeed, iNOS expression in BM MDSCs
was found elevated at both mRNA and protein levels.
Conclusion: We developed an in vitro culture method of generating large
quantities of immunosupressive murine MDSCs. Characterization of the
phenotype, gene expression, suppressor activity of BM-derived MDSCs
revealed that these cells are similar to SF MDSCs, but are dominated by a less
mature (double Ly6C/Ly6G positive) population. BM-derived MDSCs appear to be suitable for in vivo cell transfer experiments.
Monday, November 12
culture by multiplex immunoassay (measuring 51 cytokines). The capacity
of CD1c mDCs from SF (n⫽5) and PB (n⫽11) to activate autologous CD4
T cell proliferation in the absence of additional stimuli was measured after 6
days of culture by 3H-thymidine incorporation assay. Additionally, T-cell
cytokine production was measured upon ionomycin/PMA restimulation.
Results: The number of CD1c mDCs was significantly increased in SF
versus PB of RA patients (mean 5.0% vs. 0.6%, resp., p⬍0.01). mDCs from
SF showed increased expression of CD80 and CD86 (CD80: MFI 131 vs. 68,
p⬍0.04; CD86: 157 vs. 89, p⬍0.02, resp.). Furthermore, the number of
positive mDCs for HLA-II, CD80 and CD40 was significantly increased in
SF versus PB (all p⬍0.05). Numerous cytokines were abundantly and equally
produced by mDCs both from PB and SF (incl. IL-12, IL-23, IL-13, IL-21).
mDCs from SF produced higher IP10, MIG, TARC, and OPG concentrations as compared to mDCs from PB (IP10: 247 vs. 54, p⬍0.05; MIG: 90 vs.
24, p⬍0.01; TARC: 26 vs. 1, p⬍0.01; OPG: 354 vs. 156, p⬍0.05, resp., all
pg/ml). By contrast, MDC secretion by mDCs from SF was significantly
lower than mDCs from PB (2456 vs. 4397 pg/ml, p⬍0.05, resp.). mDCs from
SF had a strongly increased capacity to induce proliferation of CD4 T cells
as compared to mDCs from PB (ratio DC:T cell 1:5, 26935 vs. 1503 CPM,
p⬍0.01, resp.). The augmented T cell proliferation was associated with a
strongly increased IFN␥, IL-17, and IL-4 cytokine production (ratio DC:T cell
1:5, SF vs. PB, IFN␥: 3428 vs. 179 pg/ml; IL-17: 363 vs. 39 pg/ml; IL-4: 193
vs. 17 pg/ml, resp.).
Conclusion: The present study indicates that increased numbers of CD1c
mDCs in SF play an essential role in the inflammation cascade by the
secretion of specific T cell-attracting chemokines and the activation of
self-reactive T cells to induce Th1, Th17, and Th2 activity. Targeting of CD1c
mDCs or the specific triggers of these cells could represent a novel therapeutic
approach to prevent immunopathology of RA.
Disclosure: F. M. Moret, None; C. E. Hack, None; F. P. J. G. Lafeber, None;
T. R. D. J. Radstake, None; J. A. G. van Roon, None.
1065
Hypoxia-Inducible Factor-1␣: Trigger of Toll-Like Receptor SignallingEngaged Inflammation in Rheumatoid Arthritis. Fanlei Hu1, Rong Mu1,
Jiaxin Zhu1, Wenwei Shao2, Lianjie Shi1, Philip L. Cohen3, Xiaoyan Qiu2
and Zhanguo Li1. 1Peking University People’s Hospital, Beijing, China,
2
School of Basic Medical Science, Peking University, Beijing, China,
3
Temple University, Philadelphia, PA
Background/Purpose: Hyperplasia of synovial fibroblasts, infiltration
with lymphocytes, and tissue hypoxia are the major characteristics of
rheumatoid arthritis (RA). Data has confirmed the central role of toll-like
receptors (TLRs) in RA. However, much remains unknown regarding the
impact of hypoxia on TLR signalling-induced inflammatory response in RA.
The aim of this study was to reveal the effect of hypoxia and its regulator
hypoxia-inducible factor-1␣ (HIF-1␣) on the inflammatory response in
rheumatoid arthritis synovial fibroblast (RASF) upon the recognition of
pathogen molecules.
Methods: Hypoxia was induced in RASF by incubation with Na2S2O4.
TLR3 ligand polyIC, TLR2 ligand PGN, TLR4 ligand LPS, and TLR9 ligand
CpG were used to stimulate the cells. Effects of hypoxia on these ligandsinduced inflammatory cytokines and matrix metalloproteinases (MMPs) were
determined by RT-PCR, realtime PCR, and ELISA. Overexpressing HIF-1␣
as well as knocking-down its expression by siRNA were used to reveal its
fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry, realtime PCR, and ELISA analyses after RASF/T
cell coculture.
Results: Hypoxia potentiated the expression of inflammatory cytokines,
MMPs, and VEGF in RASF stimulated by different TLR ligands, especially
polyIC, a synthetic mimic of dsRNA from virus or apoptotic cells. HIF-1␣
played a fundamental role in this synergy. Moreover, overexpression of
HIF-1␣ enhanced RASF-mediated inflammatory T cell expansion, inducing
more proinflammatory IFN-␥ and IL-17 production.
Conclusion: Our findings suggest that hypoxia and HIF-1␣ may function
collaboratively with TLR-engaged inflammatory response to excerbrate the
pathogenesis of RA, and HIF-1␣ might serve as a therapeutic target for this
disease.
Disclosure: F. Hu, None; R. Mu, None; J. Zhu, None; W. Shao, None; L. Shi, None;
P. L. Cohen, None; X. Qiu, None; Z. Li, None.
1066
Extrathymic Autoimmune Regulator (AIRE) Expression in Rheumatoid
Arthritis. A.R. Noort1, K.P.M. van Zoest1, M.C. Lebre1, P. P. Tak2 and S.W.
Tas1. 1Academic Medical Center/University of Amsterdam, Amsterdam,
Netherlands, 2Academic Medical Center/University of Amsterdam and
GlaxoSmithKline, Amsterdam, Netherlands
Background/Purpose: The Autoimmune Regulator (AIRE) is a transcription factor that is involved in the negative selection of self-reactive
thymocytes in the thymus and therefore is pivotal in the establishment of
central tolerance. It has been suggested that non-canonical NF-kappaB
signaling is required for thymic AIRE expression. Recently, AIRE protein has
also been detected in peripheral lymphoid organs, predominantly in dendritic
cells (DC). In these peripheral sites, AIRE was found to regulate the
expression of a group of tissue-specific antigens that is distinct from those
expressed in the thymus, suggesting that peripheral AIRE may play a
complementary role in tolerance induction. It is currently unknown whether
AIRE may play a role in inflamed tissues associated with ectopic lymphoid
neogenesis, such as rheumatoid arthritis (RA) synovial tissue (ST).
Objective: To document and further characterize extrathymic AIRE
expressing cells in ST and paired peripheral blood (PB) mononuclear cells
(MCs) as well synovial fluid (SF) MCs of RA patients.
Methods: ST was obtained via mini-arthroscopy from inflamed joints of
RA or undifferentiated arthritis (UA) patients. Expression of AIRE was
evaluated using immunohistochemistry and immunofluorescence (IF) microscopy. AIRE expression was also investigated in PB and SF DC using flow
cytometry.
Results: AIRE expressing cells were detected in 80% of analyzed RA ST
and in contrast only in 25% of UA ST. Further characterization using
double-immunofluorescence microscopy revealed that these cells were predominantly CD1c (BDCA1)⫹ myeloid (m)DC. Interestingly, a significantly
higher percentage of CD1c⫹ mDC in RA SF expressed AIRE (55 ⫹ 5 %;
n⫽12) compared to RA PB (20 ⫹ 3 %; n⫽12; p⬍0.05) and healthy PB
(19.7 ⫹ 2 %; n⫽5; p⬍0.05).
Conclusion: Extrathymic AIRE expressing cells are present in RA ST
and RA SF, suggesting a role in synovial inflammation. These AIRE
expressing cells appear to be mainly CD1c⫹ mDCs. Extrathymic AIRE
expression in RA synovial inflammation may be an attempt to control
inflammation through the induction of peripheral tolerance to antigens
involved in the perpetuation of the chronic inflammatory response. This
mechanism may be exploited to develop new treatments for RA patients.
Disclosure: A. R. Noort, None; K. P. M. van Zoest, None; M. C. Lebre, None; P. P.
Tak, None; S. W. Tas, None.
1067
Spontaneous Aggregation of the Anti-Viral Mavs Protein in Certain
Systemic Lupus Erythematosus Patients May Explain Excessive Type I
Interferon Production. Philip L. Cohen1 and Wen-Hai Shao2. 1Temple
University, Philadelphia, PA, 2Temple University School of Medicine,
Philadelphia, PA
Background/Purpose: Patients with systemic lupus (SLE) often have
increased type I interferon levels (IFN-I) and activation of IFN-inducible
genes (IFN signature). The mitochondrial adaptor protein MAVS (also known
as IPS1, VISA or CARDIF) is a key intermediary in the RIG-I pathway,
where viral RNA triggers a conformational change in RIG-I, leading to
MAVS activation and then downstream activation of IKK and TBK1, with
subsequent IFN production driven by IRF-3/7 (IRF3 for IFN-beta; IRF7 for
IFN-alpha) and NFkB activation and translocation. Using in vitro methods, it
has been observed that MAVS may form large prion-like aggregates that
might stimulate IFN-I activation in a potent and prolonged fashion (Hou et.
al., Cell 146:448, 2011). We wondered if such aggregates might be detectable
ex vivo in SLE patients, and whether they might play a role in the sustained
increased production of IFN-I.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated
from 17 patients fulfilling ACR criteria for SLE, and from 9 controls. Thirty
million PBMCs were lysed and supernatants loaded onto semi-denaturing
1.5% vertical agarose gels. After electrophoresis, the proteins were transferred
to membranes for immunoblotting with anti-MAVS antibody or anti-betaactin.
Results: Four of 17 SLE patients showed clear MAVS aggregation,
with essentially all of their MAVS protein in a high molecular weight
aggregated form. None of 9 controls had abnormal MAVS. Three of the four
S460
aggregation-positive SLE patients had nephritis and the fourth had lung
involvement. SLEDAI scores of MAVS-aggregate positive SLE patients did
not differ from patients with normal molecular weight MAVS. Patient 4 (P-4)
shows the aggregated MAVS phenotype in the western blot below (Panel B,
P-4). Denatured MAVS immunoblotting is shown in panel A and actin
immunoblotting in panel C. N-1 and N-2 are normal controls. P-1 has less
protein loaded and no MAVS band is discernible.
Disclosure: P. L. Cohen, None; W. H. Shao, None.
The Effects of TNF Stimulation On Control of Apoptosis in Neutrophils.
Direkrit Chiewchengchol, Connie Lam, Kate Roberts, Helen Wright, Huw
Thomas, Robert Moots and Steven Edwards. University of Liverpool, Liverpool, United Kingdom
Background/Purpose: TNF is a key regulator of immune function and
plays a pivotal role in inflammatory conditions such as rheumatoid arthritis.
Human neutrophils express and release TNF, and are activated by it.
Neutrophil responses to TNF are bimodal: low concentrations of TNF (10
ng/mL) delay apoptosis but higher concentrations (⬎20 ng/mL) accelerate
apoptosis. When neutrophils are activated to express TNF, complex regulatory mechanisms must control their response to both autocrine and paracrine
signalling. This study investigated the mechanisms by which neutrophils
respond to anti-apoptotic concentrations of TNF and control apoptosis delay.
Methods: Human neutrophils were exposed to 10 ng/mL of TNF:
apoptosis was determined by flow cytometry (annexin V/PI binding); gene
expression was determined by analysis of mRNA levels, flow cytometery and
western blotting.
Results: Transcriptome analysis revealed that TNF signalling significantly increased mRNA levels for TNF, ICAM1, TNFAIP3, CD40, BFL1
plus several genes associated with NF-kB signalling. In contrast, mRNA
levels of TNF receptor 1, TNF receptor 2, FADD, Bax and Caspase 8 were
all significantly down-regulated. Many of these changes in mRNA levels
were paralleled by changes in protein levels. These data indicate that
neutrophils contribute to TNF-mediated signalling pathways via activated
secretion of this cytokine. In parallel, they up-regulate genes that delay
apoptosis (e.g. BFL1) but down-regulate expression of pro-apoptotic genes
such as Bax and FADD.
Conclusion: These data shed important new insights into understanding
the function of neutrophils in inflammation and inflammatory diseases;
neutrophils contribute to TNF-mediated inflammation and in doing so
become more resistant to apoptosis.
Disclosure: D. Chiewchengchol, None; C. Lam, None; K. Roberts, None; H. Wright,
None; H. Thomas, None; R. Moots, None; S. Edwards, None.
1068
1070
A Selective Inhibitor of Endosomal Toll-Like Receptors, IMO-8400,
Suppresses Activation of Multiple Cytokines, Th17 Response and Inflammasome Activation. Weiven Jiang, Fugang Zhu, Dong Yu, Ekambar R.
Kandimalla. Nicola La Monica and Sudhir Agrawal, Idera Pharmaceuticals,
Cambridge, MA
CD11cⴙ Dendritic Cells Play an Important Proinflammatory Role in
Inflammatory Arthritis. Antonia Puchner1, Stephan Blüml2, Harald Leiss2,
Victoria Saferding2 and Kurt Redlich2. 1Medical University Vienna, Vienna,
Austria, 2Medical University of Vienna, Vienna, Austria
Background/Purpose: In autoimmune diseases, activation of Th1 and
Th17 pathways has been associated with disease maintenance and progression. Engagement of endosomal Toll-like receptors (TLRs) 7, 8 and 9 through
interaction with immune complexes containing nucleic acids induces production of proinflammatory cytokines leading to the activation of Th1 and Th17
responses. Blocking the engagement of these receptors through an antagonist
may inhibit this pathway, thus providing a novel approach to the treatment of
autoimmune diseases.
Methods: In C57BL/6 mice, psoriasis-like skin lesions were induced by
intradermal injection of IL-23. Skin lesions were examined histopathologically and gene expression was monitored. IL-23 injection stimulated upregulation in the skin of genes of multiple cytokines (including IL-12, IL-21,
IL-23 and IL-17) keratinocyte peptides (including LL-37) and inflammasome
protein NLRP3. Treatment of mice with IMO-8400 was carried out by
subcutaneous administration.
Results: IMO-8400 was well tolerated at the dose level used in this study.
IMO-8400 treatment showed reduction in epidermal hyperplasia and infiltration of leukocytes. In addition, mice treated with IMO-8400 showed suppression of multiple cytokines including IL-12, IL-21, IL-23 and IL-17 compared
to untreated mice. Expression of inflammasome protein NLRP3 and of
keratinocyte genes Defensin B4, S100a4 and LL-37 was also suppressed in
IMO-8400 treated mice compared to untreated mice.
Conclusion: Treatment with IMO-8400 exerts a therapeutic effect on the
IL-23 mediated induction of psoriatic lesions by blocking Th1 and Th17
pathways and NLRP3. IMO-8400 is in development for the treatment of lupus
and other autoimmune diseases.
Background/Purpose: Dendritic cells (DCs) play an important role in
bridging innate and adaptive immune responses by serving as antigen
presenting cells. Therefore DCs are implicated in the initiation of chronic
autoimmune diseases, including rheumatoid arthritis. Using the K/BxN serum
transfer arthritis, a model of human rheumatoid arthritis, which depends only
on the innate immune system, allowed us to investigate the innate role of
dendritic cells in inflammatory arthritis.
Methods: KBxN serum transfer arthritis was induced in CD11c-diphteria
toxin receptor (DTR) transgenic mice, which express the human diphtheriatoxin receptor under the CD11c promoter. This allows for specific depletion
of CD11c⫹ cells by administration of diphtheria toxin (DT). DT or PBS was
given on day ⫺1, 3, 6 and 9 and the severity of arthritis was determined
clinically and histologically. In addition, serum transfer arthritis was induced
in wild type animals who also received DT.
Results: Efficient depletion of DCs after injection of DT was confirmed
by flow cytometry and histological analysis of spleens of CD11c-DTR
transgenic mice. Clinical scores of arthritis showed that CD11c-DTR transgenic mice had significantly reduced paw swelling and loss of grip strength
after administration of DT when compared to PBS treated animals. Moreover,
histological analysis showed decreased synovial inflammation and a trend
towards reduced local bone destruction in these animals. In contrast, in wild
type mice receiving DT we detected identical clinical signs of arthritis as in
PBS treated animals, indicating that DT has no unspecific effects on the
development of arthritis.
Conclusion: These data show that DCs are involved in innate reactions
leading to inflammatory arthritis and therefore could be an important target
for treating rheumatoid arthritis.
Disclosure: W. Jiang, Idera Pharmaceuticals, 3; F. Zhu, Idera Pharmaceuticals, 3; D.
Yu, Idera Pharmaceuticals, 3; E. R. Kandimalla, Idera Pharmaceuticals, 3; N. La
Monica, Idera Pharmaceuticals, 3; S. Agrawal, Idera Pharmaceuticals, 3.
Disclosure: A. Puchner, None; S. Blüml, None; H. Leiss, None; V. Saferding, None;
K. Redlich, None.
S461
Monday, November 12
Conclusion: This is the first report of aggregated MAVS in human cells.
The significance of this abnormality needs further investigation, it is possible
that prolonged and increased IFN-I production could result from such MAVS
aggregation, and that the poorly degradable prion-like protein could signal
IFN-I production for prolonged periods.
1069
1071
Monday, November 12
TLR3 As a Therapeutic Target for OA? Ashwini Maratha and Sinead M.
Miggin. Immune Signalling Laboratory, Maynooth, Ireland
Background/Purpose: Osteoarthritis (OA) is a multifactorial and most
disabling disease that affects millions of people globally, with a largely
unknown aetiology. OA is now considered a whole-joint inflammatory
disease, associated with synovitis of the fibroblast-like synoviocytes (FLS).
FLS are sentinel cells that contribute to OA pathogenesis, possibly through
activation of the innate immune Toll-Like Receptors (TLRs) aiding in
induction of inflammatory mediators and cellular infiltration, however, the
exact role of TLRs in OA is poorly understood. The aim of the research work
was to characterise the role and functionality of TLRs in OA and to identify
the key TLR/s that modulate OA pathology.
Methods: TLR3 neutralisation assays, ELISA, Proteomics, Confocal
analysis, Immunoblot analysis, Luciferase reporter gene assays.
Results: Interestingly, we found that TLR3, activated by Poly(I:C)/
dsRNA, RNA from necrotic cells or OA synovial fluid, plays a key role in OA
and this was confirmed by neutralisation of TLR3 expression which shifted
the balance from pro-inflammatory to an anti-inflammatory cytokine milieu.
Next, using a proteomic approach, we found that prohibitin 1 (PHB1), an
anti-proliferative and anti-inflammatory molecule, was drastically downregulated in FLS upon poly(I:C) stimulation and in whole synovial tissue
biopsies from early and late stage OA. Interestingly, neutralisation of surface
bound TLR3 in FLS restored the PHB1 levels and showed an immunomodulatory/signal transduction modulatory role by employing anti-TLR3
antibody. These findings were supported by confocal and immunoblot
analysis in FLS and through luciferase reporter gene assays in HEK293TLR3, MAVS-wild type and deficient MEFs.
Conclusion: Thus, our data suggests that TLR3 hyper-activation plays a
key role in perpetuating synovial inflammation in OA and suggests that
therapeutic intervention of OA may be achieved through TLR3 blockade.
Kindly supported by the Health Research Board of Ireland.
Disclosure: A. Maratha, None; S. M. Miggin, None.
1072
Enzymatic Lipid Oxidation Contributes to the Maintenance of SelfTolerance by Regulating Antigen Clearance and Dendritic Cell Function.
Stefan Uderhardt1, Tobias Rothe1, Elisabeth Zinser1, Olga Oskolkova2,
Martin Herrmann3, Alexander Steinkasserer4, Valery Bochkov2, Georg
Schett5 and Gerhard Kronke1. 1University of Erlangen, Erlangen, Germany,
2
Department of Vascular Biology and Thrombosis Research, Center for
Physiology and Pharmacology, Medical University of Vienna, Vienna,
Austria, Vienna, Austria, 3PhD, Erlangen, Germany, 4Department of Immune
Modulation at the Department of Dermatology, University Hospital Erlangen,
Erlangen, Germany, 5Institute for Clinical Immunology, University of
Erlangen-Nuremberg, Erlangen, Germany
Background/Purpose: During inflammation and tissue damage, pathogens as well as dying cells are ingested by different phagocytes such as
macrophages and dendritic cells. The uptake of particles and subsequent
presentation of derived antigens by antigen presenting cells (APC) are key
events in the initiation of an adaptive immune response. Thus, both the nature
and the activation state of the respective phagocyte determine the resulting
immune response ranging from specific immunity to tolerance. However,
defects and alterations of these processes are associated with chronic
inflammation and autoimmunity. Specific lipid oxidation products, generated
by the enzyme 12/15-lipoxygenase (12/15-LO) were implicated in the active
resolution of inflammation and limitation of inflammation-associated tissue
damage. In this study, we investigated the potential role of enzymatic lipid
oxidation by 12/15-LO during initiation of an adaptive immune response and
the maintenance of self-tolerance.
Methods: We studied both the clearance of AC and pathogens, as well as
the maturation and function of monocyte-derived, antigen-presenting phagocytes in wildtype and 12/15-LO ⫺/⫺ animals in vitro and in vivo, respectively.
Results: We observed a pivotal role of 12/15-LO in the maintenance of
self-tolerance as aged 12/15-LO-deficient mice spontaneously developed
autoimmune features indicating a break of self-tolerance. Moreover, a loss of
12/15-LO resulted in an exacerbation of a murine disease model of experimental autoimmune encephalomyelitis (EAE), which resembles clinical and
pathological hallmarks of human multiple sclerosis.
Consistently, 12/15-LO ⫺/⫺ mice showed a disturbed clearance of AC
under inflammatory conditions, with a clear shift of phagocytosis towards
pro-inflammatory antigen-presenting cells. In addition, we could detect a
marked expression of 12/15-LO in in vitro-generated bone marrow-derived
dendritic cells (BMDC). Interestingly, BMDC isolated from 12/15-LO ⫺/⫺
mice presented an increased expression of co-stimulatory molecules on their
surface, accompanied by an altered pro-inflammatory cytokine profile. Under
inflammatory conditions, the uptake of AC-derived model-antigens by APC
from 12/15-LO ⫺/⫺ mice resulted in an increased antigen presentation and
subsequent T cell activation, both in vitro and in vivo. By adding 12/15-LOgenerated phospholipid oxidation products, we were, in turn, able to restore an
anti-inflammatory clearance of AC in vitro and in vivo, down-regulate
co-stimulatory markers expressed by APC and, thereby, limit T cell activation
in vitro.
Conclusion: Together, these data indicate a potential regulatory role of
enzymatic lipid oxidation by 12/15-LO during the initiation of an adaptive
immune response by both orchestrating a cell- and context-specific clearance
of antigens by different phagocyte subsets and regulating the maturation and
activation status of the respective APC.
Disclosure: S. Uderhardt, None; T. Rothe, None; E. Zinser, None; O. Oskolkova,
None; M. Herrmann, None; A. Steinkasserer, None; V. Bochkov, None; G. Schett,
None; G. Kronke, None.
1073
Increased Oxidative Burst in Neutrophils but Not Monocytes in Systemic
Lupus Erythematosus. Sandro F. Perazzio1, Reinaldo Salomao1, Neusa P.
Silva2 and Luis Eduardo C. Andrade3. 1Federal University of Sao Paulo, Sao
Paulo, Brazil, 2Escola Paulista de Medicina - Universidade Federal de São
Paulo, Sao Paulo, Brazil, 3Universidade Federal de São Paulo, Sao Paulo,
Brazil
Background/Purpose: The role of innate immunity in the pathogenesis of Systemic Lupus Erythematosus (SLE) has acquired increasing
importance lately. Chronic Granulomatosus Disease (CGD), a hereditary
inability of phagocytes in producing Reactive Oxygen Species (ROS), has
been associated with increased frequency of discoid lupus erythematosus
(2.7%) and with SLE (0.5%). This study aimed to evaluate the oxidative
response in monocytes and neutrophils from SLE patients and healthy
controls (HC) at basal state and after bacterial stimulus.
Methods: 300 SLE patients and 301 age- and gender-paired HC
(blood donors) were clinically examined and evaluated for quantification
of the oxidative burst in phagocytes by flow cytometry based on the
oxidation of 2,7-dichlorofluorescein-diacetate before and after stimuli
with Staphilococcus aureus and Pseudomonas aeruginosa. There was a
7-day wash-out period for immunosuppressant drugs before sample
collection.
Results: No patient or HC presented oxidative burst profile compatible
with CGD, however one patient was classified as carrier of defective gene
(0.33%). SLE neutrophils had higher basal oxidative activity than HC
[mean fluorescence intensity (MFI)⫽53.77⫾11.38 versus 15.08⫾2.63,
respectively; p⬍0.001]. ROS production was also significantly higher in
SLE as compared with HC after stimulation with S. aureus
(MFI⫽355.46⫾58.55 versus 151.92⫾28.25, respectively; p⬍0.001) or P.
aeruginosa (MFI⫽82.53⫾10.1 versus 48.99⫾6.74, respectively,
p⬍0.001). Furthermore, the neutrophilic response after bacterial stimuli
(DMFI ⫽ post-stimulus MFI minus basal MFI) was more intense in SLE
than in HC (S aureus: 301.69⫾54.42 versus 118.38⫾26.03, respectively;
p⬍0.001; P aeruginosa: 28.76⫾12.3 versus 15.45⫾5.15, respectively;
p⬍0.001). Oxidative burst profile was not associated with disease activity
(SLEDAIⱖ6) or severity (SLICC-DIⱖ2). Neutrophil basal ROS production was higher in patients with lupus nephritis (median MFI⫽39.43;
ranging from 1.0 to 167.4) than in patients without nephritis (median
MFI⫽27.29; ranging from 1.2 to 143.9; p⫽0.014). In addition neutrophils
from patients with lupus nephritis (n⫽166) presented higher increment in
ROS production after stimulus with S. aureus (median DMFI⫽320.1;
ranging from 194.9 to 826.1) than neutrophils from patients without
nephritis (n⫽133; median ⌬MFI⫽278.5; ranging from 149.9 to 649.9;
p⫽0.03). These differences in ROS production were not observed in
monocytes from patients with lupus nephritis. There was no association of
PMN oxidative burst profile and the therapeutic regimen.
Conclusion: Neutrophils from SLE patients presented increased basal
ROS production and increased oxidative response to bacterial stimuli.
These findings were particularly evident in patients with kidney involvement. The present findings corroborate the important role of innate
S462
immunity in SLE and implicate neutrophils in the pathophysiology of the
disease.
Disclosure: S. F. Perazzio, None; R. Salomao, None; N. P. Silva, FAPESP, 2; L. E. C.
Andrade, Fleury Medicine and Health Laboratories, 5.
1074
TLR2 Deletion Promotes Arthritis and Joint Destruction Through
Reduction of IL-10. Qi Quan Huang1, Renee E. Koessler1, Robert Birkett2,
Harris R. Perlman1, Lianping Xing3 and Richard M. Pope4. 1Northwestern
University, Chicago, IL, 2Northwestern University Feinberg School of
Medicine, Chicago, IL, 3University of Rochester, Rochester, NY, 4Northwestern Univ Med School, Chicago, IL
Disclosure: Q. Q. Huang, None; R. E. Koessler, None; R. Birkett, None; H. R.
Perlman, None; L. Xing, None; R. M. Pope, None.
1075
Effects of siRNA Depletion of Interferon Regulatory Factor 5 On
Pro-Inflammatory Cytokine Production and IgG Secretion by Primary
Human Immune Cells in Response to TLR7/8 Stimulation. Dinesh
Srinivasan1, Sandip Panicker2, Gang Lu1, Yajuan Gu1, Rothschild Soto2,
Seng-Lai Tan1 and Julie Demartino1 1Hoffmann-La Roche, Nutley, NJ,
2
Hoffmann La Roche, Nutley, NJ
Background/Purpose: Interferon regulatory factor 5 (IRF5) has been identified as a genetic risk factor for multiple human autoimmune disorders, including
systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis and
systemic sclerosis. Knockout animal studies suggest IRF5 plays an important role
Disclosure: D. Srinivasan, Employment, 3; S. Panicker, Employment, 3; G. Lu,
Employment, 3; Y. Gu, Hoffmann-La Roche, Inc., 3; R. Soto, Hoffmann-La Roche,
Inc., 3; S. L. Tan, Hoffmann-La Roche, Inc., 3; J. Demartino, None.
1076
FLIP in Dendritic Cells May Regulate Hematopoietic Homeostasis and
Modulating Inflammation and Immunity. Qi Quan Huang1, Robert Birkett2, Harris R. Perlman1 and Richard M. Pope3. 1Northwestern University,
Chicago, IL, 2Northwestern University Feinberg School of Medicine, Chicago, IL, 3Northwestern Univ Med School, Chicago, IL
Background/Purpose: We previously demonstrated that FLIP in myeloid
linage cells is necessary for neutrophil homeostasis and macrophage differentiation. Therefore studies were performed to determine the in vivo role of FLIP in
CD11c positive dendritic cells.
Methods: Mice with Flip deficient in dendritic cells (Flipf/f, CD11c cre/⫹)
were generated by crossing Flipf/f mice with a CD11ccre transgenic line. Cell
types and differential in peripheral blood were determined by complete blood
count. Cell types from different organs were determined by immunophenotyping
employing multi-color fluorochrome-conjugated cell marker antibodies, analyzed
by Flow cytometry. Age and gender matched mice were used as controls.
Results: Many phenotypic disorders developed in Flipf/f, CD11ccre/⫹ mice,
including growth retardation (significantly reduced body size and weight) with
increased severity in females, and approximately 15% died prematurely. Almost
40% of the mice that reached 4 months of age or older spontaneously experienced
an arthropathy characterized by joint swelling and/or deformity. Proteinuria was
not observed. All Flipf/f, CD11ccre/⫹ mice developed lymphadenopathy, but the
spleens were normal both in size and in cell numbers. Immunophenotype analysis
demonstrated a significant reduction CD11c,CD8 dendritic cells in the spleens of
the Flipf/f, CD11ccre/⫹ mice. In Flipf/f, CD11ccre/⫹ mice granulocytes were
significantly increased in peripheral blood, spleens, lymph nodes and peritoneal
cavities and they infiltrated in all organs examined. Although circulating monocytes were significantly increased in Flipf/f, CD11ccre/⫹ mice, there is no
difference in macrophage numbers in the organs examined. Although B cell
numbers were increased in the lymph nodes of Flipf/f, CD11ccre/⫹ mice, which
may contribute to lymphadenopathy, neither B cells nor T cells were increased in
the peripheral blood or other organs.
S463
Monday, November 12
Background/Purpose: TLR2 signaling pathway has been suggested as a
potential therapeutic target in RA. However, studies with mice deficient in TLR2
(TLR2⫺/⫺) and IL-1Ra suggest that TLR2 may suppress arthritis mediated
through increased interferon-␥, and reduced TGF␤ and T regulatory cell function.
In order to determine the role of TLR2 deletion on the effector phase of arthritis,
studies were performed with the K/BxN serum transfer model of RA, mediated
by antibodies to glucose-6-phosphate isomerase (GPI) which results in an
immune complex-mediated arthritis.
Methods: Wild type and homozygous Tlr2tm1Kir mutation (Tlr2⫺/⫺) mice
on the C57Bl/6 background were injected intraperitoneally with 100 ml anti-GPI
serum and evaluated between days 0 to 9 post-induction by ankle swelling and
clinical score. Ankles were harvested and sections analyzed by hematoxylin and
eosin, and TRAP activity staining for osteoclasts. IL-1b, IL-10, RANKL and
osteoprotegerin (OPG) in ankle homogenates were quantified by ELISA. Bone
marrow-derived macrophages (BMM) were generated from wild type and
Tlr2⫺/⫺ mice by in vitro differentiation in GM-CSF for 7 days. BMM activation
was induced by incubation with model immune complexes employing mouse
IgG coated on plastic plates for 4 hours. Supernatants were assessed for TNF␣
and IL-10 expression by ELISA. The macrophage Fc receptor mediated macrophage signaling was assessed by immunoblot analysis employing phosphoantibodies to Akt, p38, and ERK. Fc receptor expression on cell membranes was
determined employing antibodies to CD16/CD32, analyzed by flow cytometry.
Macrophage Fc receptor isoform expression at mRNA level was determined by
quantitative real-time RT-PCR.
Results: The transfer of anti-GPI serum resulted in significantly worse
arthritis in TLR2⫺/⫺ mice compared to wild type controls. Histological exam
demonstrated more inflammation and joint destruction. Examination of the joints
homogenates collected at the peak of inflammation (day7 post-induction) revealed increased IL-1b and decreased IL-10 in TLR2⫺/⫺ mice. TLR2 deficiency
also resulted in increased osteoclasts, identified by TRAP staining. There was a
trend toward reduction of OPG (p ⫽ 0.056) in the ankles of TLR2⫺/⫺ mice, and
a strong negative correlation (p ⬍ 0.001) between OPG and joint swelling. There
was no difference in the expression of inhibitory or activating Fc receptors in
TLR2⫺/⫺ mice. However, activation of TLR2⫺/⫺ macrophages with immune
complexes resulted in significantly reduced IL-10, while there was no difference
in TNFa, compared to the controls. Macrophages from the TLR2⫺/⫺ demonstrated decreased activation of Akt, but not ERK or p38, following activation with
immune complexes.
Conclusion: These observations demonstrate that deletion of TLR2 exacerbates serum transfer-induced arthritis. In the absence of TLR2, there was a
reduction of IL-10 in the joints, and this may be due to the reduced activation of
Akt by immune complexes. These observations demonstrate cross-talk between
TLR2 and Fc receptor signaling modulates the effector phase of inflammatory
arthritis.
in the regulation of pro-inflammatory cytokine production, type I interferon
production as well as IgG secretion. The aim of this study was to examine the
contribution of IRF5 to pro-inflammatory cytokine production and IgG secretion
by primary human immune cells in response to TLR7/8 agonist, R848,. For
comparison purpose, the role of NFkB and interferon regulatory factor 7 was also
evaluated.
Methods: Monocytes and total B cells were isolated from healthy volunteers.
Monocytes were further differentiated into monocyte derived dendritic cells
(MDDC) using IL-4 and GM-CSF or into monocyte derived macrophages
(MDMC) using GM-CSF. Expression of IRF5 was confirmed by Western Blot
analysis and mRNA expression analysis. siRNA to IRF5 were introduced using
Amaxa Nucleofector. Knockdown of IRF5 in the MDDC, MDMC and B cells
was confirmed by Western Blot. Cells were then stimulated with R848 o/n and
cytokine levels in the supernatant were measured. Cytokines measured included
IL-6, TNF-a, IL-12 and IL-23 and were detected using Alphalisa or ELISA based
methods. IgG levels in supernatant from B cells were measured after 7 days. Data
were normalized to cell number as determined by CellTiter-Glo® viability assay
(Promega).
Results: Western blot data and mRNA expression analysis confirmed the
expression of IRF5 in the cell types tested. As expected, expression of IRF5 in
MDDC and MDMC increased during differentiation. Using nucleofection, we
typically obtained about 40–60% depletion of IRF5 proteinby the siRNA, which
persisted up to 48h. We found that the knockdown of IRF5 in MDDC, MDMC
and B cells significantly attenuated IL-6 and TNF-a produced by R848 stimulated
cells. The level of attenuation was similar to that obtained using siRelA. No
additional attenuation was observed when the siRNA to both IRF5 and RelA
were combined. siIRF7 did not significantly attenuate IL-6 or TNF-a levels in
MDDC. IL-12 and IL-23 production from MDDC stimulated with R848 were
both attenuated by siIRF5. Interestingly, siRelA blocked IL-12 but did not affect
IL-23 production from MDDC. In B cells, the siIRF5, but not siRelA, completely
blocked R848 and CpGB-mediated IgG secretion.
Conclusion: In this report, we extend the known literature surrounding the
role of IRF5 as a critical regulator of both pro-inflammatory cytokine production
and IgG secretion downstream of TLR7/8. Furthermore, IRF5, but not NFkB,
regulates R848-mediated IL-23production from MDDC and plays a critical role
in IgG secretion by B cells.
Conclusion: The survival of CD11c⫹ dendritic cells in the spleen requires
FLIP. The deletion of FLIP in CD11c dendritic cells also results in increased
circulating neutrophils and a multiorgan neutrophil infiltration. A substantial
proportion of these mice develop an arthropathy but proteinuria was not observed.
FLIP expression in CD11c⫹ dendritic cells is necessary for survival in the spleen
and for neutrophil homeostasis.
Disclosure: Q. Q. Huang, None; R. Birkett, None; H. R. Perlman, None; R. M. Pope,
None.
1077
Monday, November 12
p21 Promotes Inflammatory Arthritis Resolution by Facilitating Alternative
Activation of Macrophages. Angelica K. Gierut1, Carla M. Cuda2, Alexander
V. Misharin3, Rana Saber3 and Harris R. Perlman3 1Northwestern Med Faculty
Found, Chicago, IL, 2Northwestern University Feinberg School of Medicine,
Chicago, IL, 3Northwestern University, Chicago, IL
Background/Purpose: Current understanding of pathogenesis suggests
that RA is mainly a Th1 mediated process that promotes robust inflammatory cytokine production by “classically” activated macrophages. This is in
contrast to Th2 diseases such as parasitic infection or allergy that balance potential catastrophic tissue destruction from large worm invasion, or chronic
inflammatory response to ubiquitous proteins, by skewing macrophages to an
alternatively activated state. Alternatively activated cells appear to be generated
from local macrophage proliferation in pure Th2 environments. However, in
conditions with concomitant Th1 stimuli, recruited monocytes can be skewed
toward alternative activation as well. It is unknown what role alternative
macrophages may play in RA. It seems reasonable to assume that their presence
would be favorable given their “anti-inflammatory” properties. However, they
theoretically have the potential to hinder response to, and clearance of, a yet
unknown foreign antigen. Given that alternative macrophages display distinct
proliferating capabilities, it seems reasonable to suspect that proteins controlling
the cell cycle may be involved in their regulation. One such protein, a cyclin
dependent kinase inhibitor, p21, is decreased in RA patient synovium, and is
associated with worse serum transfer-induced arthritis (STIA) compared to wild
type (WT) controls.
Methods: In vitro studies were done with bone marrow derived macrophages
(BMDMs) and thioglycollate induced peritoneal macrophages (PMs). Cells were
treated with stimuli for classical, alternative, and regulatory macrophage differentiation. Supernatants were analyzed for production of cytokines by ELISA, and
for nitric oxide (NO) by colorimetry. Quantigene assays were performed for
various genetic markers of macrophage phenotype. Mice were also injected IP
with thioglycollate and IL-4, with or without BRDU added 3 hours prior to
harvest. Peritoneal cells were assessed by flow cytometry. Finally, mice were
treated with IV IL-4 ⫹ KBxN serum and observed for arthritis.
Results: In vitro analysis of skewed BMDMs and PMs revealed increased
production of nitric oxide in p21⫺/⫺ cells stimulated with interferon gamma ⫹
lipopolysaccharide compared to B6 control cells. Conversely, p21⫺/⫺ BMDMs
and PMs stimulated by IL-4 had less relm alpha mRNA, a marker of alternative
activation. In vivo studies were concordant in that p21⫺/⫺ mice treated with
thioglycollate ⫹ IL-4 had less relm alpha protein expression by flow cytometry.
Intriguingly, there was increased local proliferation of p21⫺/⫺ PMs as measured
by 3 hr BRDU incorporation. However, recently recruited p21⫺/⫺ monocytes
showed significantly less proliferation compared to B6. Finally, IV IL-4 significantly dampened STIA in B6 mice whereas arthritis in p21⫺/⫺ mice was not
attenuated.
Conclusion: p21 may promote homeostasis during inflammatory conditions
by potentiating recruited monocytes and possibly local macrophage differentiation into alternatively activated states. This appears to be independent of its role
as a cell-cycle inhibitor because monocytes recruited to inflammatory sites have
less proliferation in the absence of p21.
of Amsterdam/University of Pavia, IRCCS Policlinico San Matteo Foundation,
Amsterdam/Pavia, Netherlands, 4Instituto de Medicina Molecular, Faculdade de
Medicina da Universidade de Lisboa, Lisbon, Portugal, 5Academic Medical
Center/University of Amsterdam, Amsterddam, Netherlands, 6Academic Medical Center/University of Amsterdam & Atrium Medical Center, Amsterdam,
Netherlands, 7Academic Medical Center/University of Amsterdam, Amsterdam,
Netherlands
Background/Purpose: Rheumatoid arthritis (RA) is the most common
rheumatic disease which mainly affects women. In the last decade, it is known
that prolactin (PRL) is a sex hormone with immunomodulatory properties. It has
been shown that high prolactin levels are associated with an increase of the
disease activity postpartum and that the PRL inhibitor, bromocriptine, improves
disease activity of patients with RA. Furthermore, the serum PRL levels
correlated positively with the Larsen score.
Recently, the prolactin receptor (PRLR), belonging to the family of cytokine
receptors, has been described in atherosclerotic plaques, mainly on macrophages.
The objective of the study is to determine 1) the level of PRL in RA patients
related to rheumatoid factor (RF), anti-cylic citrullinated peptide antibodies
(ACPA), erosive disease and response to anti-TNF treatment 2) PRLR expression
in synovial tissue of RA, psoriatic arthritis (PsA) and osteoarthritis (OA) patients
3) the phenotype of the PRLR expressing cell.
Methods: Serum prolactin levels were measured using immunofluorescent
metric assay in patients with RA before TNF-␣ blockade (n⫽101). The
expression of PRLR was determined in synovial tissue (ST) of RA (n⫽91), PsA
(n⫽15) and OA (n⫽9) patients using digital image analysis. Immunofluorescence
(IF) was used to detect the PRLR expressing cell type.
Results: A trend towards higher PRL levels were found in patients who are
rheumatoid factor positive compared to rheumatoid factor negative RA patients
(5.0 (2–24) and 7.3 (2.5–36) ␮g/L; P⫽0.06). When the PRL levels were divided
into 3 categories, the percentage of the RF positive patients had significantly
higher PRL levels (P⫽0.021). A trend towards higher PRL levels were also seen
in patients who are ACPA positive (P⫽0.063) and similar results with erosive
disease (P⫽0.057). Baseline PRL levels were significantly lower in nonresponders (median (range): 5.3 (2.0–22) ug/L) than in moderate (7.0 (2.5–36))
and responders (8.5 (4.0–19)) on anti-TNF treatment (P⫽0.025). Overall, the
prolactin levels were similar between females and males.
PRLR expression was higher in RA (median (range): 0.055 (0.000–5.673)
IOD/nuclei/mm2) and PsA (0.182 (0.000–5.336)) compared to OA (0.000
(0.000–0.908); P⫽0.024; Fig 1). Using IF, co-localisation was observed with
macrophages and endothelial cells. The expression of the PRLR was also
confirmed by RT-PCR in macrophages.
Disclosure: A. K. Gierut, None; C. M. Cuda, None; A. V. Misharin, None; R. Saber,
None; H. R. Perlman, None.
1078
Prolactin Is Increased in Responders to Anti-TNF␣ Treatment and the Role
of the Prolactin Receptor in Rheumatoid Arthritis. Man Wai Tang1, Danielle
Marie Gerlag2, Veronica Codullo3, Elsa Vieira-Sousa4, Anne Q. Reuwer5,
Marcel T. Twickler5, Robert B. M. Landewé6 and Paul Peter Tak7. 1Academic
Medical Center/University of Amsterdam, Amsterdam, Netherlands, 2Academic
Medical Center, Amsterdam, Netherlands, 3Academic Medical Center/University
Conclusion: Higher levels of PRL are found in patients who respond to
anti-TNF treatment. The expression of the PRLR in synovial tissue, mainly by
macrophages, is higher in the inflammatory diseases (RA and PsA) than in
OA. Our combined data suggest an important role of prolactin and its receptor
in RA.
Disclosure: M. W. Tang, None; D. M. Gerlag, None; V. Codullo, None; E.
Vieira-Sousa, None; A. Q. Reuwer, None; M. T. Twickler, None; R. B. M. Landewé,
None; P. P. Tak, GlaxoSmithKline, 3.
S464
Disclosure: J. Wahle, Novo Nordisk, 3; J. Bui, Novo Nordisk, 3; K. Bontadelli, Novo
Nordisk, 3.
1079
ⴙ
ⴙ
Polyclonal CD4 Foxp3 treg Cells Induce TGFb-Dependent Tolerogenic Dendritic Cells That Suppress Murine Lupus-Like Syndrome. Qin
Lan1 and Song G. Zheng2. 1University of Southern California, Los Angeles,
CA, 2Keck School of Medicine of USC, Los Angeles, CA
⫹
Disclosure: Q. Lan, None; S. G. Zheng, None.
1080
Effect of Anti-NKG2A Antibody Treatment On NK Cell Receptor
Expression in Rheumatoid Arthritis Patients. Joseph Wahle, John Bui and
Kristen Bontadelli. Novo Nordisk, Seattle, WA
Background/Purpose: This study explored the effect of in vitro blockade of
the NKG2A HLA-E interaction on peripheral NK cells from rheumatoid arthritis
patients. To block this interaction we have utilized an anti-NKG2A monoclonal
antibody, NNC141-0100, a novel therapeutic mAb designed for the treatment of
rheumatoid arthritis.
Natural killer cells are potent members of the innate immune system with
both cytotoxic and cytokine producing ability. NK cells express a myriad of germ
line encoded receptors on their surface that provide multiple pathways via which
NK cells activity can be regulated. These receptors include both activating
receptors, that recognize stress inducible ligands, and inhibitory receptors that
provide protection to self via the recognition of HLA molecules. One such
inhibitory receptor is NKG2A, which functions as a heterodimeric receptor with
CD94, in order to recognize HLA-E and thereby block NK cell activation.
Additionally, NK cells express a number of chemokine receptors and other
homing related molecules. The expression of these molecules is crucial for the
NK cell to maintain proper lymphoid and non-lymphoid tissue distribution as well
as for NK cells to home to and remain at the site of inflammation.
Methods: A whole blood culture system that allows for up to 48 hours of
whole blood culturing was utilized for all experiments. This technique allowed for
exploring the effect of NKG2A blockade in the context of the complex
interactions that exist in the periphery with minimal manipulation.
Results: The addition of the anti-NKG2A mAb to the whole blood cultures
led to alteration of the surface phenotype of NK cells from rheumatoid arthritis
patients. These alterations included the up-regulation of chemokine receptors as
well as the modulation of CD27. This appeared to be a specific pattern of
up-regulation as a wide panel of NK related receptors were explored and were not
found to be altered. This up-regulation was also found to be rapid occurring within
24 hours of culture. Finally the effect was specific to RA patients as similar
changes were not seen in normal donors.
Conclusion: These results indicate that treatment with an anti-NKG2A mAb
may alter the homing potential of an NK cell to the site of inflammation. Once at
the site of inflammation the presence of the anti-NKG2A mAb may skew the
inhibitory balance and thus enable the elimination of stressed and/or inflamed
cells. These two activities provide a novel mechanism of action, via the
anti-NKG2A mAb, for the treatment of RA.
Toll-Like Receptor 7, 8 and 9 Activation of Primary Human Cells by
Lupus Immune Complexes Is Dependent On Interleukin 1 Receptor
Associated Kinase 4 Activity. Aaron Winkler, Weiyong Sun, Ken Dower,
Elizabeth A. Murphy, Julia Shin, Michael Luong, Michael J. Primiano,
Varenka A. Rodriguez, Tatyana Souza, Lih-Ling Lin, J. Perry Hall, Katherine
Lee, Vikram R. Rao and Margaret Fleming. Pfizer, Cambridge, MA
Background/Purpose: Genetic, in vitro and in vivo evidence strongly
implicate the activation of nucleic acid sensing toll like receptors (TLR) 7, 8,
and 9 in the pathophysiology of systemic lupus erythematosus (SLE). IRAK4
is a serine/threonine kinase activated by TLRs that utilizes the MyD88
adaptor protein for signaling. The relative importance of IRAK4 scaffolding
and kinase functions in signaling is not clear. Indeed, at least one recent report
indicates profound differences between species, stimuli, and cell types with
regard to the requirement of IRAK4 kinase activity for cell activation[1].
Utilizing a potent, selective and cell-permeable small molecule inhibitor of
IRAK4, we queried the importance of IRAK4 kinase activity in primary
human cell based assays utilizing SLE disease relevant stimuli.
Methods: Sera from SLE patients was screened for the ability to induce
interferon-alpha (IFN-␣) protein release from primary human plasmacytoid
dendritic cells (pDC). Immunoglobulin-G (IgG) was purified from SLE sera
that could induce IFN from pDCs, and then combined with debris from
apoptotic U937 cells as a source of TLR 7, 8 and 9 ligands, to form SLE
immune complexes (SLE-IC). Human peripheral blood mononuclear cells
(PBMC) were stimulated with SLE-IC, and type I interferon (i.e., IFN-␣)
release in cell culture supernatant was assayed by ELISA. Type I IFN
exposure can be monitored in whole blood from SLE patients using an
IFN-responsive gene signature, so the expression of IFN-induced genes was
assayed in RNA from SLE-IC stimulated PBMC using quantitative real-time
polymerase chain reaction (qRT-PCR). As auto-antibody production by B
cells is also a key component of pathophysiology in SLE, B cell activation
and differentiation induced by TLR ligands was measured by flow cytometry,
and cytokine release by B cells was measured by ELISA.
Results: The IRAK4 inhibitor potently blocked SLE-IC induced type I
IFN release and IFN gene signature in PBMC. This compound also blocked
B cell activation- B cell surface activation marker expression in response to
R848 in whole blood, 7 day plasma cell differentiation in PBMC, and
cytokine expression by purified B cells exposed to IFN-␣ and R848.
Conclusion: Using a potent and selective inhibitor of IRAK4 kinase
activity in primary human cells, we can demonstrate that IRAK4 kinase
activity is essential to inflammatory cytokine release, type I IFN production,
and B cell activation, all of which are components of SLE pathophysiology
in vivo.
References
1. Chiang, E.Y., X. Yu, and J.L. Grogan, Immune Complex-Mediated Cell
Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients
Elaborate Different Requirements for IRAK1/4 Kinase Activity across Human Cell
Types. The Journal of Immunology. 186(2): p. 1279–1288.
Disclosure: A. Winkler, Pfizer Inc, 3; W. Sun, Pfizer Inc, 3; K. Dower, Pfizer Inc, 3;
E. A. Murphy, Pfizer Inc, 3; J. Shin, Pfizer Inc, 3; M. Luong, Pfizer Inc, 3; M. J.
Primiano, Pfizer Inc, 3; V. A. Rodriguez, Pfizer Inc, 3; T. Souza, Pfizer Inc, 3; L. L.
Lin, Pfizer Inc, 3; J. P. Hall, Pfizer Inc, 3; K. Lee, None; V. R. Rao, Pfizer Inc, 3; M.
Fleming, Pfizer Inc, 3.
ACR/ARHP Poster Session B
Orthopedics, Low Back Pain, and Rehabilitation Poster
Monday, November 12, 2012, 9:00 AM–6:00 PM
1082
Predictors of Persistence in People with Subacute Low Back Pain.
Souraya Torbey, Ali Mansour, Kristina Herrmann, Marwan Baliki, Thomas J.
Schnitzer and A. Vania Apkarian. Northwestern University, Chicago, IL
Background/Purpose: Acute pain is a vital adaptive and protective
mechanism. Conversely, chronic pain is a persistent, maladaptive response
that outlasts the normal healing period of an injury or insult, and may result
in drastic deterioration of quality of life, sometimes for the rest of life. In a
S465
Monday, November 12
Background/Purpose: Interplay between Foxp3 regulatory T cells (Treg)
and dendritic cells (DCs) maintains immunologic tolerance, but the effects of each
cell on the other are not well understood.
Methods: Naive CD4⫹Foxp3- cells isolated from DBA/2 mice were
stimulated with anti-CD3/CD28 antibodies with IL-2 and TGF-␤ to develop
polyclonal CD4⫹ iTregs. These cells were adoptively transferred to D2B6F1
mice that also received D2 spleen cells. Anti-IL-10R, Anti-TGF␤ or ALK5
(TGF␤RI) inhibitor was administrated in some groups of mice. To determine
molecular mechanism, TGF␤RII DC conditional KO mice were developed and
colitis model was used. DC numbers and phenotypes were determined in chronic
lupus mice before and after iTreg or Tcon cell treatment. DC were sorted in iTreg
or Tcon treated groups and were adoptively transferred to another lupus mice to
determine the therpeutic role of DC subsets.
Results: We report that polyclonal CD4⫹Foxp3⫹ Treg cells induced ex-vivo
with TGF␤ (iTreg) suppress a lupus-like chronic graft-versus-host disease by
preventing the expansion of immunogenic DCs and inducing protective DCs that
generate additional recipient CD4⫹Foxp3⫹ cells. The protective effects of the
transferred iTreg cells required both IL-10 and TGF␤, but the tolerogenic effects
of the iTreg on DCs, and the immunosuppressive effects of these DCs, was
exclusively TGF␤-dependent. The iTreg were unable to tolerize Tgfbr2-deficient
DCs.
Conclusion: These results support the essential role of DCs in “infectious
tolerance” and emphasize the central role of TGF␤ in protective iTreg/DCs
interactions in vivo.
1081
Monday, November 12
longitudinal brain imaging study of people with subacute back pain, we
recently identified brain markers by fMRI that predict transition to chronic
pain. Here we investigate, in the same study, behavioral biomarkers that may
be predictive of pain chronification.
Methods: 62 patients with new onset subacute back pain (less than 3 mo
duration, no back pain for at least a year prior to symptom onset) were seen
6 times over one year. At each visit, pain intensity was determined using a
100mm visual analog scale, behavioral questionnaires completed and fMRI
brain scans obtained. For this analysis, the subacute group was divided into
persisting (SBPp) and recovering (SBPr) groups using a greater than 20 %
change criterion, from the baseline visit to the one year visit. Multivariate
logistic regression was utilized to evaluate individual behavioral parameters
and their association with pain persistence.
Results: There were 32 males and 30 females, with mean age at study
onset of 43⫾11 yrs, mean pain duration 10 weeks, and mean initial VAS pain
intensity was 64⫾16. By the end of one year, there were 36 SBPr and 26
SBPp. No significant group differences in VAS pain intensity were evident at
baseline. However, when evaluated over time, SBPp and SBPr segregated as
early as their second visit (within 2 weeks) and the divergence persisted until
the final visit at one year. The Neuropathic Pain Scale (NPS), the McGill Pain
Questionnaire affective (MPQa), Pain detect (pDetect) and smoking status
were significantly different between SBPr and SBPp groups at baseline
(t-test). Smoking status at time of entry into the study was the strongest
predictor of SBPr and SBPp groups at one year from symptom onset, odds
ratio ⫽ 5, CI 1.6–16, p⬍0.007, accuracy ⫽ 0.67. NPS, MPQa and pDetect
were correlated with each other, and their logistic multiple regression was not
significant. Thus, all three parameters reflect interrelated properties of back
pain. In a multiple regression logistic model when we include all four
parameters, only smoking status remains significant with a stronger odds
ratio ⫽ 13.5, CI ⫽ 2.5–75, p⫽0.003, accuracy ⫽0.84; thus after correcting
for pain characteristics the effects of smoking on pain chronification are even
stronger.
Conclusion: There is a strong association between smoking at the time of
the onset of back pain symptoms and longer term pain chronification. As this
observation was not a prespecified hypothesis of the study, we label the
observed result as an association that needs to be validated in a systematic
study.
Disclosure: S. Torbey, None; A. Mansour, None; K. Herrmann, None; M. Baliki,
None; T. J. Schnitzer, None; A. V. Apkarian, None.
1083
Physicians’ Recommendations for Total Knee Arthroplasty in Younger
Persons with Moderate Osteoarthritis. Liana Fraenkel1, Lawrence Weis2
and Lisa G. Suter2. 1Yale University School of Medicine, Veterans Affairs
Connecticut Healthcare System, New Haven, CT, 2Yale University, New
Haven, CT
Background/Purpose: Rates of total knee arthroplasty (TKA) are increasing among all age groups. The most rapidly growing population of
patients undergoing TKA are those under the age of 65. This reason for this
increasing prevalence is unclear. While physicians’ recommendations regarding use of TKA are likely to be fairly uniform for patients with severe OA,
little is known regarding physicians’ decision-making for younger patients
with less severe arthritis. The objective of this study was to gain insight into
the factors influencing physicians’ recommendations for younger persons
with OA using an experimental 2⫻2⫻2 design.
Methods: A convenience sample of rheumatologists and orthopedic
surgeons, recruited at their respective national meetings, completed a survey
including a standardized scenario of a 62 year old person with knee OA who
has moderate knee pain limiting strenuous activity despite medical management. The scenarios varied on patient gender, employment status (business
manager vs retired), and x-ray (mild vs moderate OA). Each subject rated
their recommendation for a single scenario (distributed randomly) on a
7-point scale. Recommendation was treated as a dichotomous variable: For vs
Against TKA.
Results: 406 surgeons [mean age (SD) ⫽ 49 (10), 18% female] and 494
rheumatologists; [mean age (SD) ⫽ 48 (10), 44% female] participated.
Overall, 51% of both surgeons and rheumatologists recommended TKA. As
expected, both groups recommended TKA more frequently for scenarios
including more severe radiographic OA (Table 1). However, this feature had
a greater influence among rheumatologists than orthopedic surgeons. Orthopedic surgeons were more likely to recommend TKA for male vs female
patients. Whereas, rheumatologists were less likely to recommend referral for
TKA for business managers compared to housewives or retired men. The
influence of physicians’ demographic characteristics on TKA recommendation is presented in Table 2. Younger physicians, regardless of specialty, were
more likely to recommend TKA (p ⬍0.05). Rheumatologist’ recommendations for TKA did not vary by geographic location; however, American and
Asian surgeons were more likely to recommend TKA compared to their
European counterparts.
Table 1. Influence of Patient Characteristics on Physicians’ Recommendations
for TKA
Patient Characteristics
Moderate vs Mild radiographic changes
Male vs Female
Working outside of the home vs
Retired/Housewife
Percent of
Rheumatologists
Recommending
TKA
Percent of
Orthopedic Surgeons
Recommending
TKA
60 vs 41, p⬍0.0001
49 vs 52, p⫽0.5
42 vs 56, p⫽0.002
56 vs 47, p⫽0.05
59 vs 44, p⫽0.002
49 vs 53, p⫽0.4
Table 2. Influence of Physician Characteristics on their Recommendations for
TKA
Physician Characteristics
Percent of
Rheumatologists
Recommending TKA
Percent of
Orthopedic Surgeons
Recommending TKA
Age (⬍50 vs ⱖ 50)
Male vs Female
Location (Asia vs Europe vs US)
55 vs 46, p⫽0.03
50 vs 53, p⫽0.5
54 vs 49 vs 52, p⫽0.8
57 vs 47, p⫽0.04
51 vs 56, p⫽0.7
67 vs 34 vs 52,
p⫽0.006
Conclusion: Physicians recommendations for TKA vary significantly for
younger patients with moderate OA. Recommendations are influenced by
both physician and patient characteristics.
Disclosure: L. Fraenkel, None; L. Weis, None; L. G. Suter, None.
1084
In Vivo Kinematics of Three-Component Mobile-Bearing Total Ankle
Replacement for Rheumatoid Arthritis. Keiji Iwamoto1, Tetsuya Tomita1,
Takaharu Yamazaki2, Kenrin Shi1, Norimasa Shimizu1, Masahiro Kurita1,
Kazuma Futai1, Yasuo Kunugiza1, Hideki Yoshikawa1 and Kazuomi Sugamoto1. 1Osaka University Graduate School of Medicine, Osaka, Japan,
2
Osaka University, Osaka, Japan
Background/Purpose: The standard treatment for end-stage arthritis of
the ankle joint due to rheumatoid arthritis (RA) has been an ankle arthrodesis.
Patients with RA who require surgery usually already have degeneration of
the subtalar and midtarsal joints. Fusion of the ankle and hindfoot will result
in functional problems with gait. Thus, total ankle replacement (TAR) that
can relieve pain while retaining ankle movement is important for patients with
RA. However, high complication rates and low survivorship are still problematic in TAR, as compared to total knee and hip replacements. This could
primarily be due to implant loosening and subsidence induced by excessive
articular contact stress during ankle motion. A better understanding of ankle
kinematics after TAR may be important to explain the failures in TAR,
especially those attributed to loosening and subsidence. The purpose of this
paper was to study in vivo kinematics of a three-component mobile-bearing
TAR by 3D-evaluation of fluoroscopic imaging of ankle motion.
Methods: We investigated ten ankles in 7 patients with RA implanted
with a three-component mobile-bearing TAR (FINE Total Ankle System,
Nakashima Medical, Okayama, Japan), which allows not only internal/
external rotation but also anteroposterior translation. Fluoroscopic images
were obtained while each patient was asked to perform normal gait with full
weight-bearing on the implanted ankle. Thereafter tibio-talar motion was
analyzed by 2D/3D registration technique; a reproduction method of the
spatial position of each component in TAR, from single-view fluoroscopic
images by use of computer-assisted design models. We evaluated the
dorsi-/plantarflexion angle, internal/external rotation angle and anteroposterior translation between the components.
Results: The average range of tibio-talar motion during the stance phase
of gait with full weight-bearing on the implanted ankle was 11.2⫾2.7°. The
average range of internal/external rotation was 3.9⫾1.4°. However, large
intersubject variability resulted in the lack of a uniform pattern of rotational
movement. The average absolute amount of anteroposterior translation was
1.6⫾0.7mm.
Conclusion: The range of motion, with regard to plantar/dorsi flextion,
was not so wide as expected, and was almost the same with other non-mobile
S466
TAR. As intended by mobile bearing design, however, the tibial and talar
components rotated internally/externally with respect to each other. Anteroposterior translation was also observed but was within small amount. These
results suggest that mobile bearing TAR should be advantageous in durability
with expectation that it could compensate rotational malposition of the
components as well as malalignment of the subtalar joint.
Disclosure: K. Iwamoto, None; T. Tomita, None; T. Yamazaki, None; K. Shi, None;
N. Shimizu, None; M. Kurita, None; K. Futai, None; Y. Kunugiza, None; H.
Yoshikawa, None; K. Sugamoto, None.
1085
Background/Purpose: Both total knee replacement (TKR) and total hip
replacement (THR) reliably relieve pain, restore function, and ensure mobility
in patients with advanced joint arthritis; however these results are not uniform
across all patient populations. Previous studies have shown baseline differences between patients undergoing TKR and THR. We compared baseline
demographic and symptom profiles in a national research consortium of
advanced OA patients undergoing primary TKR and THR to evaluate these
differences.
Methods: Patients undergoing primary TKR and THR between 7/1/2011
and 3/30/2012 were identified from the national research consortium which
collects comprehensive data on enrolled patients from 89 surgeons across 27
states. Gathered data includes patient demographics, comorbidity (Charlson
Comorbidity Index), operative joint pain severity, physical function (SF-36;
Physical Component Score (PCS)), emotional health (SF-36 Mental Component Score (MCS)), and musculoskeletal burden of illness (Hip and Knee
Disability and Osteoarthritis Outcome Scores;Oswestry Disability Index.
Descriptive statistics compared baseline demographic and symptom profiles.
Results: Our analysis compared 1362 primary TKR patients and 1013
primary THR patients. TKR patients were significantly older (66.5 vs. 64.3
years), more obese (BMI 31.7 vs. 29.3), and less educated (p⬍0.005). TKR
patients had higher rates of comorbidities, specifically diabetes, gastrointestinal ulcers, and cerebrovascular disease (pⱕ0.006). THR patients had
significantly worse physical function (PCS 31.6 vs. 33.3), lower back pain
(35.6% vs. 30.5% moderate-severe), and operative joint pain, stiffness, and
function (p⬍0.005).
Conclusion: Patients undergoing primary TKR are older with more
comorbidities, however THR patient baseline functional and musculoskeletal
disability are significantly greater than primary TKR patients, which may help
explain the variability in results shown after primary TKR as compared to
primary THR.
Disclosure: P. D. Franklin, Zimmer, Inc., 2; B. Snyder, None; J. Allison, None; W.
Li, None; M. Rosal, None; L. R. Harrold, None; B. Barton, None; D. Ayers, None.
1086
Has the Level of Disability At Time of TKR Changed Over the Past 10
Years?: Results From Two National Cohorts. Patricia D. Franklin1,
Wenjun Li1, Benjamin Snyder1, Courtland Lewis2, Philip Noble3 and David
Ayers1. 1University of Massachusetts Medical School, Worcester, MA, 2CT
Joint Replacement Institute, St. Francis Hospital, Hartford, CT, 3Baylor
College of Medicine, Houston, TX
Background/Purpose: A growing numbers of younger adults report knee
pain consistent with OA, although parallel analyses of knee x-rays show no
increase in classic radiographic signs of OA. To evaluate whether surgeons
are performing TKR at an earlier stage in the condition, we compared
pre-operative demographic and symptom profiles from 2 national cohorts of
TKR patients, one from 2011–2012 and another from 2000–2004.
Methods: Following informed consent, we collected comprehensive
demographic, comorbidity, and patient-reported pain and physical function from a national sample of 2011-12 TKR patients, across 27 states with
89 surgeons. Comparable data collected by one implant manufacturer between 2000–2004 from 136 surgeons in 31 states were analyzed. Descriptive statistics compared the demographic and symptom profiles of the two
cohorts.
Disclosure: P. D. Franklin, Zimmer, Inc., 2; W. Li, None; B. Snyder, None; C. Lewis,
None; P. Noble, Zimmer;,Stryker,Omni,SN, 7; D. Ayers, None.
1087
Do Younger TKR Patients Have Similar Disability At Time of Surgery
As Older Adults? Patricia D. Franklin1, Wenjun Li1, Leslie R. Harrold2,
Benjamin Snyder1, Courtland Lewis3, Philip Noble4 and David Ayers1.
1
University of Massachusetts Medical School, Worcester, MA, 2UMass
Medical School, Worcester, MA, 3CT Joint Replacement Institute, St. Francis
Hospital, Hartford, CT, 4Baylor College of Medicine, Houston, TX
Background/Purpose: The trend toward greater numbers of workingaged patients choosing TKR has raised concerns that younger patients may
receive surgery prematurely. We compared the severity of operative knee
pain and functional status in younger versus older TKR patients.
Methods: Patients undergoing primary TKR from 7/1/11 through 3/30/12
were identified from a national research consortium which enrolls patients
from 89 surgeons in 27 US states. Patients, surgeons and hospitals submit data
including the SF 36 Physical Component Score (PCS), the Knee injury and
Osteoarthritis Outcome Score (KOOS) and the Oswestry Low Back Pain
Disability Questionnaire. The KOOS data were used to estimate the Western
Ontario and McMaster Universities Arthritis Index (WOMAC). We compared those ⬍65 to those who were ⱖ65 years of age using descriptive
statistics.
Results: Primary TKR was performed in 570 younger (⬍65) and 769
older (ⱖ65) patients. Younger patients were less likely to be white (89% vs.
92%, p⫽0.02), and had a greater body mass index (mean BMI 33.0 vs. 30.7,
p⬍0.0001). Younger patients reported greater pain (48.9 vs. 53.8, p⬍0.001)
and stiffness (38.5 vs. 46.7, p⬍0.001) in the operative knee joint. Overall
function as measured by the WOMAC and SF36 PCS were similar in the two
age groups (WOMAC 51.9 vs. 53.8; PCS 32.8 vs. 33.8). Function levels in
both groups reflect significant impairment at time of surgery.
Conclusion: At the time of TKR, younger and older patients have similar
levels of functional impairment suggesting surgeons use comparable standards for selecting TKR in younger and older adults.
Disclosure: P. D. Franklin, Zimmer, Inc., 2; W. Li, None; L. R. Harrold, None; B.
Snyder, None; C. Lewis, None; P. Noble, Zimmer;,Stryker,Omni,SN, 7; D. Ayers,
None.
1088
Factors Influencing Long-Term Recovery of Total Knee Arthroplasty.
C. Allyson Jones1, Gian S. Jhangri2 and Maria E. Suarez-Almazor3. 1Departments of Physical Therapy and School of Public Health, University of
Alberta, Edmonton, AB, 2School of Public Health, University of Alberta,
Edmonton, AB, 3University of Texas MD Anderson Cancer Center, Houston,
TX
Background/Purpose: Although a number of studies have examined
short term outcomes after total knee arthroplasty (TKA), few have prospectively examined the long term trajectory of recovery of health-related quality
of life. The aim of this study was to identify patient-related outcomes that
explained the pattern of pain and functional recovery over 10 years for TKA.
Methods: This is a prospective observational study that followed a
community-based cohort of patients receiving elective primary TKA within a
month before surgery, 6 months, 3 years and 10 years after surgery. Data were
collected from patient interviews, chart reviews and regional administrative
databases. Joint pain and function were measured using the Western Ontario
and McMaster Universities Osteoarthritis Index (WOMAC). Health status
S467
Monday, November 12
Differences in Baseline Characteristics Between TKR and THR Patients:
Results From a National Research Consortium. Patricia D. Franklin1,
Benjamin Snyder1, Jeroan Allison2, Wenjun Li1, Milagros Rosal1, Leslie R.
Harrold3, Bruce Barton2 and David Ayers1. 1University of Massachusetts
Medical School, Worcester, MA, 2University of Massachusetts Medical
School, 3UMass Medical School, Worcester, MA
Results: There were minimal differences between the two cohorts in
terms of age (2011-12: 66.5 years, vs. 2000/4: 67.6 years; p0.05). The more
recent patient cohort consisted of fewer females (57%) compared to the earlier
group (66%). Pre-operative physical function scores (SF36/PCS) were 3
points higher in 2011-12 than 2000-04 (33.6⫾0.3 vs. 30.3⫾0.1; p⬍0.0000).
The 2000–2004 cohort (n⫽7686) had a mean BMI of 32 vs 31.7 for the
2011-12 cohort (n⫽1362). When compared to the national PCS norm of 50
(SD⫽10), TKR patients from both time periods reported pre-operative
function levels almost 2 standard deviations below the national norm.
Conclusion: The profile of primary TKR patients changed between
2000-04, and 2011-12. Today, patients are younger and have a higher
pre-operative physical function scores. They continue to report significant
levels of disability with mean pre-TKR PCS significantly lower than average
OA patients.
Monday, November 12
was evaluated over time using the SF-36. Effect sizes were calculated to
measure change over time. Pre-operative and operative factors were inspected
as possible variables that predicted the pattern of recovery. Linear mixed
models for pain and functional recovery were used to evaluate changes over
time while adjusting for covariates.
Results: Of the 289 patients followed, the mean age was 69.4 (SD 9.2)
yrs;170 (59%) were female. At 10 years 145 patients responded. The mean
number of comorbid conditions was 3.5 (SD 2.0) at baseline and 4.7 (SD 2.3)
at 10 years. WOMAC pain score mean difference from baseline to 6 months
was 33.0 (95% 30.5, 35.5) with the largest effect size (ES) of 1.89. Long-term
change was much smaller from 6 months to 3 years (ES 0.18) and from 3 to10
years (ES 0.03). Smaller changes were seen with function; baseline to 6
months (ES 1.65), 6 months to 3 years (ES 0.07) and 3 to 10 years (ES
⫺0.13). The ES of the SF-36 physical summary score at 6 months was 1.17
and over the 10 years was 1.87. After adjusting for age and gender, the 10
year trajectory for pain was explained by baseline health status (SF-36
summary scores), and baseline WOMAC pain (p⬍ 0.05). The 10 year
trajectory for function had similar covariates which explained the trajectory,
in that baseline WOMAC function and health status were significant factors.
In-hospital complications, prosthesis-type, and obesity did not impact longterm recovery pattern.
Conclusion: Pain and functional recovery after TKA occurs primarily
within 6 months after surgery with negligible change from 3 to 10 years.
Greater pain, dysfunction and lower overall health at baseline explained
slower long-term recovery patterns for TKA.
Disclosure: C. A. Jones, None; G. S. Jhangri, None; M. E. Suarez-Almazor, None.
1089
The Number of Ruptured Tendons As a Prognostic Factor for Reconstructing Extensor Tendon Rupture in Patients with Rheumatoid Arthritis. Yu Sakuma, Kensuke Ochi, Takuji Iwamoto, Shinji Yoshida, Asami
Saitou, Katsunori Ikari and Shigeki Momohara. Institute of Rheumatology,
Tokyo Women’s Medical University, Tokyo, Japan
Background/Purpose: Extensor tendon rupture seen in patients with
rheumatoid arthritis (RA) is usually surgically treated in combination with
extensor tendon reconstruction and wrist arthroplasty. However, limited data
exist in literature concerning factors significantly correlating with poor
prognosis of the extensor tendon reconstruction. The purpose of this study is
to investigate factors significantly correlating with poor prognosis of the
extensor tendon reconstruction.
Methods: Total of 68 RA patients (mean age of 52 years old; 57 females)
who underwent combined surgical procedures of tendon reconstruction and
wrist arthroplasty because of spontaneous extensor tendon ruptures were
investigated. The result of extensor tendon reconstruction was evaluated as
“good”, “fair” and “poor”. This evaluation was defined based on active
flexion and extension lag of metacarophalangeal (MP) joint of the affected
fingers at 3 months after the surgery. The cases in which active flexion arc
was greater than 45 degrees and extension lag was less than 15 degrees were
defined as “good”. The cases, in which active flexion arc was greater than 45
degrees and extension lag ranged from 15 to 45 degrees, or active flexion arc
was less than 45 degrees and extension lag was less than 15 degrees, were
defined as “fair”. All other cases were defined as “poor”. We investigated the
relation among clinical factors such as age at surgery, the number of ruptured
extensor tendons, duration between onset of rupture and surgery, methods for
reconstructing ruptured tendons, surgical procedures for wrist arthroplasty,
the time interval between surgery and beginning of postoperative rehabilitation, and the frequency of ambulatory visit for rehabilitation, and the
postoperative results by using multiple regression analysis. The correlation
between factors relating to the postoperative result and duration between
onset of rupture and surgery were additionally analyzed using single regression analysis.
Results: Forty-two (61.8%) patients were evaluated as “good”, while
19(28.0%) and 7(10.3%) patients were evaluated as “fair” and “poor”,
respectively. Number of ruptured tendons was the only independent variable
which significantly related to poor postoperative results (p⫽0.0002). The
longer duration between onset of rupture and surgery had significant correlation between increased number of ruptured tendons (p⫽0.03).
Conclusion: Increased number of ruptured extensor tendons significantly
correlated with poor postoperative result of extensor tendon reconstruction in
patients with RA. The number of increased ruptured extensor tendons also
significantly correlated with duration between onset of rupture and surgery.
We therefore recommend surgical intervention at early stage of extensor
tendon rupture, in which only few tendons are suspected to be involved, to
result in better prognosis.
Disclosure: Y. Sakuma, None; K. Ochi, None; T. Iwamoto, None; S. Yoshida, None;
A. Saitou, None; K. Ikari, None; S. Momohara, None.
1090
A Comparison of Patient-Reported and Measured Range of Motion in a
Cohort of Total Knee Replacement Patients. Jamie E. Collins, Benjamin
N. Rome, Vladislav Lerner, Jeffrey N. Katz and Elena Losina. Brigham and
Women’s Hospital, Boston, MA
Background/Purpose: Range of motion (ROM) is an important component of the assessment of total knee replacement (TKR) outcome. Traditionally, ROM is measured by a clinician or trained researcher, making ROM less
practical than self-report measures that can be obtained by phone or mail.
Recently, Gioe et al. developed a method that presents patients a set of lateral
knee photographs depicting varying levels of flexion and extension and asks
the patients to select the photographs that most closely resemble their motion.
We aimed to compare this self-reported method of assessing flexion and
extension with clinical measurement before and after TKR.
Methods: As part of a prospective cohort study of consecutive patients
undergoing TKR, patients were asked to self report flexion and extension on
their operated knee using the method of Gioe et al. In addition, flexion and
extension were measured using a goniometer by a trained research assistant.
These measures were obtained preoperatively and at three and six months
postoperatively. We compared self-reported ROM category with measured
ROM for both flexion and extension using ANOVA. We dichotomized
flexion at 90 degrees and determined the sensitivity and specificity of the
self-report flexion categories for identifying patients with poor ROM.
Results: One hundred and one patients provided both self-report and
RA-measured ROM at baseline. There was a significant association between
self-report ROM category and ROM measurement for both flexion and
extension (P⬍0.001). The Spearman correlation coefficient was 0.51 for
extension and 0.45 for flexion, indicating moderate correlation. We combined
all 3 visits to assess sensitivity and specificity of self-report flexion categories.
Overall 15 of 25 patients with poor measured flexion (ⱕ90°) also selfreported poor flexion (to 90° or lower) for a sensitivity of 60% and 177 of 190
patients without poor flexion (⬎90°) did not self-report poor flexion (to 100°
or higher) for a specificity of 93%. The negative predictive value for
self-report was 95%, indicating that the vast majority of patients self-reporting
adequate flexion do not have poor flexion.
Table 1. Performance of self-report flexion categories for identifying patients
with poor ROM
Measured Flexion
Self Report – How well can
you bend your knee?
To 90° or lower
To 100° or higher
Total
Sensitivity
Specificity
Predictive Value⫹
Predictive Value-
ⱕ90°
15
⬎90°
13
10
25
177
190
60.0%
93.2%
53.6%
94.7%
Conclusion: Patient self-reported ROM may be a useful outcome measurement for TKR when clinical ROM measurement is not possible. These
findings are based on a small sample in one center and should be confirmed.
Self-report is particularly effective (⬎90% specificity) in confirming adequate
ROM.
Disclosure: J. E. Collins, None; B. N. Rome, None; V. Lerner, None; J. N. Katz,
None; E. Losina, None.
1091
Trends in Patient Physical Activity Before and After Primary Total Hip
Arthroplasty. Anne Lübbeke, Dorith Zimmermann, Constantinos Roussos,
Alexis Bonvin, Robin Peter and Pierre Hoffmeyer. Geneva University
Hospitals, Geneva, Switzerland
Background/Purpose: Total hip arthroplasties (THA) are performed to
reduce pain and enhance patients’ function and physical activity (PA) level.
PA is also recognized as the most important patient-related factor determining
S468
Disclosure: A. Lübbeke, None; D. Zimmermann, None; C. Roussos, None; A.
Bonvin, None; R. Peter, None; P. Hoffmeyer, None.
1092
Effect of FULL Contact FOOT Orthosis On Plantar Fasciitis. Hilda A.
Oliveira1, Anamaria Jones1, Emilia Moreira1, Fabio Jennings1 and Jamil
Natour2. 1Universidade Federal de Sao Paulo, Sao Paulo, Brazil, 2Universidade Federal de São Paulo, São Paulo, Brazil
Background/Purpose: Plantar fasciitis (PF) is an inflammation of the
foot plantar fascia, characterized by stiffness in the medial arch and ankle,
especially during first steps, and can have a significant effect on activities of
daily living. Insoles are one of the most often employed methods for the
treatment of PF. The full contact foot orthosis is the most recommended, as
it redistributes the load uniformly throughout the sole of the foot. However,
few studies have demonstrated the effectiveness of this device and there is no
consensus on which type of insole is the most adequate. The aim of the
present study was to assess the effectiveness of a full contact foot orthosis
regarding pain, foot function and quality of life in patients with PF.
Methods: Seventy-four patients were randomly allocated to an experimental group (n⫽37) using a full contact foot orthosis or a control group
(n⫽37) using a sham insole. Evaluations were performed of pain (VAS),
quality of life (SF-36), foot function (FFI and FSHQ), six-minute walk test
and static/dynamic baropodometry (AM Cube FootWalk Pro program). The
groups were evaluated at baseline and after 45, 90 and 180 days after
randomization by a blinded evaluator.
Results: The groups were homogeneous at baseline regarding clinical and
demographic characteristics. In the comparisons over time, we found better
results for the experimental group for pain during walking on the right feet
(p⫽0.008 - Figure 1). In the intragroup analysis we found in both groups
improvement regarding pain during walking on the left feet, the six-minute
walk test, foot function and some quality of life parameters, with no
statistically significant differences between groups. No changes in foot
pressure were found with the use of the insole.
Conclusion: The benefit of the use of full contact foot orthosis for the
treatment of PF was restricted to the improvement in pain during walking in
right feet.
Disclosure: H. A. Oliveira, None; A. Jones, None; E. Moreira, None; F. Jennings,
None; J. Natour, None.
1093
Obesity Is Not a Risk Factor for Poor Pain and Function Two Years
After Total Knee Replacement. Lisa A. Mandl. Mark P. Figgie, Alejandro
Gonzalez Della Valle, Michael Alexiades and Susan M. Goodman, Hospital
for Special Surgery, New York, NY
Background/Purpose: Almost 90% of referring physicians think obesity
increases the likelihood of poor outcomes after total knee replacement (TKR).
However, current data are conflicting. The purpose of this study is to assess
of the association of body mass index (BMI) with pain, function and
satisfaction 2 years after primary TKR.
Methods: Institutional TKR Registry patients who had a primary TKR
between July 2007 and June 2009 and BMI⬎18.5 were enrolled. Poor pain
and function were defined as WOMAC score ⬍⫽ 60. Data were collected
prior to surgery and 2 years post-op. Multivariate regressions were performed
to evaluate the association between BMI at baseline and poor pain and
function at 2 years, controlling for gender, age, race, Deyo Comorbidity score
and educational attainment. Expectations were measured with a validated
TKR Expectations Survey.
Results: 2524 patients were included in the analysis. BMI ⬎ 40 were
more likely to be non-Caucasian, female, have less education and more
co-morbidities. Pre-operatively, both pain and function were least severe in
⬍25 BMI category, increasing as BMI increased. At 2 years, change in
WOMAC pain and function showed a step wise, dose dependant improvement across BMI categories, with BMI ⬎ 40 showing the most improvement.
At 2 years, there was a statistically significant trend towards lower BMI
categories having the least pain (p-value⫽0.0003) and best function, (pvalue⬍0.0001), but the differences between groups were not clinically
significant. In the multivariate regressions, there were no statistically significant associations between any BMI category or number of co-morbidities
and poor pain or function at 2 years. Being female significantly increased the
risk of having poor pain (OR 1.6; 95% CI 1.2–2.2) or poor function (OR 1.5;
95% CI 1.1–2.1) at 2 years. Being Caucasian decreased the risk of poor pain
(OR 0.6; 95% CI 0.4–0.9) or poor function (OR 0.5; 95% CI 0.3–0.7).
Having only high school education also increased the risk of poor pain (OR
1.5; 95% CI 1.1– 2.1) and poor function (OR 1.9; 95% CI 1.4–2.6) at 2 years.
Age group 61–70 showed a decreased risk of poor pain compared to age
⬍⫽60, (OR 0.5; 95% CI 0.4– 0.8). At 2 years, 20.4% of patients lost weight,
(mean weight loss 0.6 lbs ⫹/⫺ 2.7), with the greatest loss in BMI ⬎40 (2.7
lbs, ⫹/⫺ 5). There were no significant differences in expectations or
satisfaction between BMI categories.
Conclusion: Although obese patients have worse pain and function at
the time they elect TKR, their outcomes at 2 years are not clinically
significantly different than other patients. However, race and educational
S469
Monday, November 12
implant survival. Furthermore, unrealistic patient expectations regarding PA
after surgery have been identified as one of the reasons for increased
dissatisfaction. Detailed assessement of PA before and after THA is lacking.
Our objective was to evaluate (1) how patient’s PA level evolves: prior to
disease onset, prior to THA, and at 5 and 10 years postoperative, and (2)
whether PA level before and after THA has changed over the last decade
across birth cohorts of identical age.
Methods: Patients included are part of a prospective hospital-based
cohort of all THAs of a University hospital and followed longitudinally since
1996. We included all primary THAs between 1/2000 and 4/2012. PA was
assessed by the physician and self-reported, preoperatively and at 5 and 10
years postoperative. Moreover, PA was evaluated with the UCLA activity
scale. To determine PA evolution over the course of OA and THA,
cross-sectional analyses were performed to assess mean UCLA scores over
four periods: prior to disease, prior to surgery, 5- and 10-years postoperative
independently of the year of surgery. Separate analyses were performed for
men and women and by age categories (⬍55, 55–64, 65–74, ⱖ75 yrs. at
operation). To analyze secular trends in PA, cross-sectional analyses were
performed at three time periods within identical ages categories (2000–2003,
2004–2007, 2008–2011).
Results: Overall, lifestyle was assessed preoperatively for 2916 THAs
and postoperatively for 1565 THAs. The UCLA score was assessed at
follow-up for 1345 THAs. Mean age at operation was 68.4 years, 56% were
women.
Prior to surgery 61% of patients reported a sedentary lifestyle compared
to 45% at 5 years postoperative (RD 16%, 95% CI 12; 20). The proportion of
patients with sedentary lifestyle prior to surgery decreased from 68% in
2000–2003 to 54% in 2007–2011 (RD 14%, 95% CI 9; 18) despite a similar
mean age (p⫽0.1). Sedentary lifestyle 5 years after surgery was reported by
53% of those operated 2000–2003 compared to 39% of those operated
2004–2007 (RD 14%, 95% CI 9; 20).
Mean UCLA scores prior to OA onset, prior to THA and 5 and 10 years
postoperative were respectively in men 8.4, 3.7, 6.2 and 6.2 and in women
6.1, 3.4, 5.1 and 4.8.
Prior to surgery UCLA scores were similar across age categories ranging
form 3.7 in the youngest to 3.2 in the eldest group (p⫽0.8). Five years
postoperative UCLA scores declined as age increased. Across the four age
categories the mean UCLA scores were respectively 6.7, 6.4, 5.6 and 4.2
(p⬍0.0001). Ten years postoperative mean UCLA scores were 6.4, 6.4, 5.2
and 3.8, respectively (p⬍0.0001).
Conclusion: Primary THA substantially and durably improved PA levels
in men and women and in all age categories. Activity levels were lower in
women than in men at all times. In the last decade the proportion of patients
with an active lifestyle before and after THA increased by 14%.
attainment were significantly associated with poor outcomes. Obese
patients have similar expectations and are as satisfied as patients with
lower BMI. More research should be done on the effect of race and
education on TKR outcomes. Obesity should not be regarded as a risk
factor for poor outcomes after primary TKR.
Patient Characteristics
Overweight
Obese class
I
Obese class
II
Obese class
III
(18.5 <
BMI <25)
Nⴝ523
(25 < BMI
<30)
Nⴝ902
(30 < BMI
<35)
Nⴝ633
(35 < BMI
<40)
Nⴝ289
(40 < BMI)
Nⴝ177
P-value
Age
71.0 ⫾ 10.0
69.1 ⫾ 9.7
66.7 ⫾ 9.2
64.8 ⫾ 8.9
64.3 ⫾ 7.9
Female
Caucasian
365 (70.3%)
491 (93.9%)
476 (53.0%)
824 (91.4%)
359 (57.2%)
560 (88.5%)
200 (69.4%)
251 (86.9%)
132 (75.4%)
156 (88.1%)
⬍0.0001
0.0027
56 (17.9%)
153 (24.1%)
140 (29.4%)
72 (29.4%)
51 (30.3%)
⬍0.0001*
Some college or college
graduate
254 (81.2%)
416 (65.5%)
286 (60.0%)
130 (53.2%)
82 (48.8%)
Masters professional
or doctorate degrees
0 Deyo comorbidities
207 (66.1%)
323 (50.9%)
203 (42.6%)
86 (35.2%)
42 (25.0%)
409 (79.4%)
664 (75.5%)
435 (70.7%)
195 (68.8%)
100 (59.0%)
1-2 Deyo comorbidities
103 (20.0%)
214 (24.3%)
178 (28.9%)
86 (30.3%)
67 (39.5%)
High school or less
Monday, November 12
Average
Weight
>ⴝ 3 Deyo
comorbidities
⬍0.0001
⬍0.0001*
7 (1.4%)
20 (2.3%)
15 (2.4%)
7 (2.5%)
8 (4.7%)
Pre-Operative
WOMAC Pain
59.4 ⫾ 17.1
57.0 ⫾ 17.5
53.6 ⫾ 17.1
51.0 ⫾ 18.3
46.5 ⫾ 16.3
2-Year Post-Operative
WOMAC Pain
Change in WOMAC
Pain
Pre-Operative
WOMAC Function
89.2 ⫾ 15.1
88.9 ⫾ 14.5
86.9 ⫾ 16.2
84.8 ⫾ 17.2
86.0 ⫾ 16.5
0.0001
29.9 ⫾ 20.0
31.9 ⫾ 19.6
33.3 ⫾ 20.2
34.0 ⫾ 21.6
39.3 ⫾ 21.9
⬍0.0001
58.7 ⫾ 17.5
57.6 ⫾ 17.2
52.6 ⫾ 17.0
49.7 ⫾ 17.7
43.5 ⫾ 15.9
⬍0.0001
2-Year Post-Operative
WOMAC Function
87.9 ⫾ 15.5
87.3 ⫾ 15.0
84.7 ⫾ 17.0
82.8 ⫾ 18.2
82.2 ⫾ 16.6
⬍0.0001
Change in WOMAC
Function
Change in Weight (lbs)
29.0 ⫾ 20.1
30.5 ⫾ 18.8
32.4 ⫾ 19.1
34.1 ⫾ 18.6
38.0 ⫾ 20.5
⬍0.0001
0.2 ⫾ 1.7
⫺0.3 ⫾ 1.9
⫺0.8 ⫾ 2.7
⫺1.3 ⫾ 3.2
⫺2.7 ⫾ 5.5
⬍0.0001
Somewhat/Very
Satisfied with
Relieving Pain
453 (90.2%)
797 (93.1%)
547 (91.0%)
253 (90.7%)
152 (92.7%)
0.333
Somewhat/Very
Satisfied with
Improving
413 (83.4%)
695 (82.1%)
495 (83.2%)
230 (82.4%)
123 (76.9%)
0.401
445 (88.3%)
786 (91.5%)
537 (89.2%)
252 (89.7%)
148 (91.4%)
0.333
Disclosure: A. P. Goode, None; J. K. Freburger, None; T. S. Carey, None; C. E.
Cook, None; J. Renner, None; S. D. Rundell, None; J. M. Jordan, Algynomics, Inc.,
1, Johnson and Johnson, 5, Johnson & Johnson, 2, Interleukin Genetics, Inc., 5, Eli Lilly
and Company, 5, Mutual Pharmaceutical Company, 5.
⬍0.0001
1095
Metal Concentrations in Patients with Failed Metal-On-Metal Hip
Prostheses Determine the Inflammatory Phenotype in Peri-Implant
Tissue. Erja-Leena Paukkeri1, Riku Korhonen1, Antti Eskelinen2, Marko
Pesu3, Kaija Vasama4, Teemu Moilanen2 and Eeva Moilanen1. 1The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland, 2Coxa Hospital for
Joint Replacement, Tampere, Finland, 3Immunoregulation, Institute of Biomedical Technology, University of Tampere, Tampere, Finland, 4Fimlab
Laboratories, Tampere, Finland
ability to do
recreational
activities
Overall Somewhat/
Very Satisfied with
TKR
were present in 51.8% and 24.9% of participants, respectfully. Disc space
narrowing was present in 57.6%, OST present in 88.1% and FOA present in
57.9% of participants. Those with LBS were 32% as likely than those without
LBS to have DSN (adjusted odds ratio [aOR] 1.32 ((95% CI 1.09, 1.52)). No
association was found with FOA and either LBS or LBS with associated leg
symptoms. No significant association was found between OST and LBS with
associated leg symptoms.
A significant interaction (p⬍0.001) was observed between race and OST
with LBS. African Americans (AAs) with OST were more likely (aOR 1.78
((95% CI 1.25, 2.55)) to report LBS than AAs without OST. There was no
effect among Caucasians.
Conclusion: Modest associations were found between DSN and LBS but
no significant associations were found with LBS and associated leg symptoms. LBS with associated leg symptoms may have an etiology other than
disc degeneration; suggesting that plain film radiographs may have limited
clinical utility for this subgroup.
*ⴝ test for trend
Disclosure: L. A. Mandl, None; M. P. Figgie, None; A. Gonzalez Della Valle, None;
M. Alexiades, None; S. M. Goodman, None.
1094
The Relationship Between Lumbar Spine Individual Radiographic Features and Low Back Symptoms with and without Associated Leg
Symptoms: The Johnston County Osteoarthritis Project. Adam P.
Goode1, Janet K. Freburger2, Timothy S. Carey3, Chad E. Cook4, Jordan
Renner5, Sean D. Rundell6 and Joanne M. Jordan7. 1Duke University,
Durham, NC, 2University of NC CB 7590, Chapel Hill, NC, 3Cecil G. Sheps
Center for Health Services Research University of North Carolina, Chapel
Hill, NC, 4Walsh University, OH, 5University of North Carolina, Chapel Hill,
NC, 6University of Washington, Seatle, WA, 7University of North Carolina
Thurston Arthritis Research Center, Chapel Hill, NC
Background/Purpose: Little is known of the relationships between low back
symptoms (LBS) and associated leg symptoms and lumbar spine individual
radiographic features (IRF). We examined the associations between LBS, with
and without associated leg symptoms, and lumbar spine IRF of disc space
narrowing (DSN), vertebral osteophytes (OST) and facet joint osteoarthritis
(FOA) and determined if these associations differed by race or gender.
Methods: 840 newly enrolled participants in the Johnston County
Osteoarthritis Project from 2003-04 having data on lumbar spine IRF (DSN,
OST and FOA) were the subjects (mean age 60.1 (SD 10.3), 62.3% female,
37.6% African American, mean body mass index (BMI) 31.3 (SD 7.4)).
Lateral lumbar spine films were graded for each lumbar level in a semiquantitative fashion (0–3) for DSN and OST according to the Burnett Atlas,
while FOA was graded present or absent. Low back symptoms with and
without associated leg symptoms were determined with the following
questions “On most days have you had symptoms of pain, aching or stiffness
in your low back? “and” On most days do you have pain (sciatica) radiating
down your right or left leg?” Two outcome groups were created: LBS and
LBS with associated leg symptoms. Each group was compared separately to
those with no symptoms. Logistic regression models were used for all
analyses while adjusting for BMI, race, gender and age. Interactions between
lumbar spine IRF and race or gender were tested with likelihood ratios tests
(p⬍0.10 for significance).
Results: Low back symptoms and LBS with associated leg symptoms
Background/Purpose: Hip arthroplasty is the standard treatment of a
painful hip destruction in rheumatoid arthritis and osteoarthritis. The use of
metal-on-metal (MoM) bearing surfaces in total hip arthroplasty gained
popularity especially in young and active patients during the last decade.
Recently, worrisome failures due to inflammatory soft tissue reactions related
to wear particles have been widely reported. The pathogenesis of this reaction
is unknown. The aim of the present study was to clarify the inflammatory
responses in peri-implant tissue in patients with a failure of MoM articulation.
Methods: Sixteen patients with a failed Articular Surface Replacement
(ASR) implant were included in the study. Blood metal ion levels were
analysed with coupled plasma mass spectrometry before revision surgery.
Samples of peri-implant tissues collected during revision surgery were
degraded by enzyme digestion and the distributions of cell populations were
analysed by flow cytometry.
Results: In macroscopic observation, peri-implant reactions had variable
amounts of necrotic and granulomatous tissue and cystic pseudotumour
formation. All patients expressed elevated levels of blood chromium and
cobalt, but the patient-to-patient variation was significant. In histological
examination, intensive inflammatory cell infiltration was a characteristic
feature, but only few metal containing cells were observed. An analysis by
flow cytometry showed that the distributions of the inflammatory cells were
mainly polarized either to macrophage-rich (CD45⫹ /CD14⫹ ) or
T-lymphocyte-rich (CD45⫹/CD3⫹) phenotypes with the average portions
being 54 % (macrophages) and 20 % (T-lymphocytes) in macrophagedominated inflammation and 25 % (macrophages) and 54 % (T-lymphocytes)
in T-lymphocyte-dominated conditions. The portions of B-lymphocytes
(CD45⫹/CD19⫹) and granulocytes (CD45⫹/CD15⫹) were small. Interestingly, the levels of blood chromium and cobalt were significantly higher in
patients with macrophage-dominated inflammation than in patients with
T-lymphocyte-dominated inflammation.
Conclusion: The results suggest that the adverse reactions induced by
MoM wear particles contain heterogeneous pathogeneses and the metal levels
seem to be an important factor in the determination of inflammatory
phenotype. The present results support the hypothesis that higher levels of
metal particles cause tissue necrosis and macrophages are recruited to clear
the necrotic debris. The lymphocyte-dominated inflammation may, on the
other hand, reflect a delayed hypersensitivity reaction induced by lower metal
concentrations.
Disclosure: E. L. Paukkeri, None; R. Korhonen, None; A. Eskelinen, None; M.
Pesu, None; K. Vasama, None; T. Moilanen, None; E. Moilanen, None.
S470
1096
Lower Income Paradoxically Associated with Better Patient-Reported
Outcomes After Knee Arthroplasty in the U.S. Jasvinder A. Singh1 and
David Lewallen2. 1University of Alabama at Birmingham, Birmingham, AL,
2
Mayo Clinic college of medicine, Rochester
Disclosure: J. A. Singh, Research and travel grants from Takeda, Savient, Wyeth and
Amgen, 2, Honoraria from Abbott,, Consultant fees from URL Pharma, Savient,
Takeda, ArdeaBioscience, Allergan and Novartis., 5; D. Lewallen, Zimmer, 5, Zimmer,
7, DePuy, Stryker and Zimmer, 2.
ACR/ARHP Poster Session B
Osteoarthritis - Clinical Aspects
Monday, November 12, 2012, 9:00 AM–6:00
PM
1097
The Association of Fat Distribution and Clinically Defined Hand Osteoarthritis: The Netherlands Epidemiology of Obesity Study. A. Willemien
Visser, Marieke Loef, Andreea Ioan-Fascinay, Martin den Heijer, Frits R.
Rosendaal and Margreet Kloppenburg. Leiden University Medical Center,
Leiden, Netherlands
Background/Purpose: Obesity, assessed as body mass index (BMI) ⱖ 30
kg/m2, is an important risk factor for osteoarthritis (OA). BMI depends only upon
height and weight and therefore gives no insight in underlying causal pathways.
The aim of this study was to investigate whether the association of BMI and OA
in the hands, being non-weight bearing joints, can be explained by the amount of
fat mass (FM) and the abdominal fat distribution.
Methods: Data from participants of the NEO (Netherlands Epidemiology
of Obesity) study, a population-based cohort of men and women aged 45–65
years with a BMI ⱖ 27 kg/m2 and a control group with a BMI ⬍ 27 kg/m2,
were used. BMI was assessed by measured weight in kg and length in cm.
Waist-to-hip ratio (WHR) was calculated from waist and hip circumference
measured in cm. FM was assessed in kg using bioelectrical impedance
analysis. In 30% of participants MR imaging of the abdomen, at the level of
the 5th lumbar vertebra, was used to assess the relative amounts of visceral
adipose tissue and subcutaneous adipose tissue in cm3. Hand OA was defined
using the criteria of the American College of Rheumatology; pain was
measured using a standardized questionnaire and physical examination of the
hands was performed by trained research nurses. Pearson correlations were
calculated between BMI and WHR and FM, visceral fat and subcutaneous fat.
Odds ratios (OR) with 95% confidence intervals (CI) were calculated to
associate BMI, WHR, FM, visceral fat and subcutaneous fat with hand OA
using logistic regression analyses, stratified for sex and adjusted for age.
Disclosure: A. W. Visser, None; M. Loef, None; A. Ioan-Fascinay, None; M. den
Heijer, None; F. R. Rosendaal, None; M. Kloppenburg, None.
1098
Knee Osteoarthritis and Frailty in Older Adults: Findings From the
Multicenter Osteoarthritis Study and Osteoarthritis Initiative. Devyani
Misra1, Michael C. Nevitt2, Cora E. Lewis3, James Torner4, David T. Felson1
and Tuhina Neogi1. 1Boston University School of Medicine, Boston, MA,
2
University of California-San Francisco, San Francisco, CA, 3University of
Alabama, Birmingham City, Birmingham, AL, 4University of Iowa, Iowa
City, Iowa City, IA
Background/Purpose: Both knee osteoarthritis (OA) and the frailty
syndrome affect older adults and both are associated with functional
limitation and disability. Frailty in elders is a state of increased vulnerability to adverse outcomes, such as falls, fractures, hospitalization and
even death. While frailty is perceived to occur in thin older adults, it has
been shown to be present in those who are obese, a common feature of
those with knee OA. If knee OA and frailty are associated, then by
extension those with knee OA might be at risk for not only the known OA
outcomes of pain, functional limitation, and disability, but also the
adverse outcomes related to frailty. We therefore examined the crosssectional association of knee OA and frailty in community-dwelling older
adults using data from two large cohorts.
Methods: The Multicenter Osteoarthritis (MOST) Study and the
Osteoarthritis Initiative (OAI) are two NIH-funded longitudinal observational studies of individuals with or at high risk for knee OA. We included
subjects from these two studies who had knee x-rays read and information
on frailty parameters available at baseline and at the 30-mo (MOST) or
24-mo (OAI) follow-up visits. Prevalent knee OA was defined at the
follow-up visit described above as: 1) Radiographic knee OA (ROA):
Kellgren and Lawrence (KL) grade ⱖ2; 2) Symptomatic knee ROA:
presence of ROA plus frequent knee pain; 3) Severity of ROA: highest
KL grade of either knee, with replaced knees considered to be KL grade
4; 4) Number of knees with ROA: subjects categorized as having no
knee ROA, unilateral knee ROA, or bilateral knee ROA. Frailty was
defined using the Study of Osteoporotic Fractures (Ensrud) index as
presence of 2 of 3 of the following criteria: 1) Weight loss ⬎5% between
baseline and the follow-up visit; 2) Inability to rise from chair 4 times
without using support at the follow-up visit; 3) Poor energy from the SF12
questionnaire at the follow-up visit. We evaluated the cross-sectional
association of knee OA (4 definitions) with prevalent frailty at the
follow-up visit using Poisson regression to calculate prevalence ratios
(PR), adjusting for age, sex, BMI, physical activity, education, smoking,
co-morbidities (modified Charlson score), race and study site.
Results: Among 7822 participants (3026 MOST, 4796 OAI; mean age
62⫾8.81, 59% women, mean BMI 29⫾5.44), there were 213 (186 poor
energy, 116 inability to rise from chair and 145 weight loss) prevalent frail
subjects. Prevalence of frailty was higher in those with radiographic knee
OA and symptomatic knee OA, and increased in prevalence with
S471
Monday, November 12
Background/Purpose: To assess whether income is associated with patientreported outcomes (PROs) after primary total knee arthroplasty (TKA).
Methods: We used the prospectively collected data from the Mayo Clinic
Total Joint Registry to assess the association of income with index knee
functional improvement, and moderate-severe pain at 2- and 5-year follow-up
after primary TKA using multivariable-adjusted logistic regression analyses.
Analyses were adjusted for various characteristics previously shown to be
associated with PROs after TKA, namely demographics (age, gender, body
mass index (BMI), comorbidity as measured by Deyo-Charlson index,
American Society of Anesthesiologist (ASA) score as a measure of perioperative mortality, implant fixation (cemented/hybrid versus not cemented),
underlying diagnosis (osteoarthritis, rheumatoid/inflammatory arthritis or
other) and distance from medical center (categorized ⬍100, 100–500 and
⬎500 miles/overseas). ASA score was not collinear with Deyo-Charlson
index (correlation coefficient ⬍0.40).
Results: There were 7,139 primary TKAs at 2-years and 4,234 at 5-years.
In multivariable-adjusted analyses, at 2-year follow-up, both lower income
groups (⬍⫽$35K and ⬎$35–45K) were significantly associated with lower
odds ratio (OR) [95% confidence interval (CI) of moderate-severe pain, OR
0.6 [95% CI, 0.4, 0.9] (p⫽0.02) and 0.7 [95% CI, 0.5, 0.9] (p⫽0.02). The
overall improvement in knee function was rated as ’better’ more often at
2-years by patients with income in the ⬍⫽$35K compared to patients with
income ⬎$45K, with OR of 1.9 [95% CI, 1.0, 3.6] (p⫽0.06), respectively. At
5-years, numerically similar but non-significant odds were noted.
Conclusion: We found that lower income was associated with better pain
outcome and more improvement in knee function postoperatively. Insights
into mediators of these relationships need to be investigated to understand
how income influences outcomes after TKA.
Results: Data from 4562 participants (mean age 56 years, 48% male) were
analyzed, including 425 controls with a BMI ⬍ 27 kg/m2. Median BMI of the
total study population was 30.3 kg/m2 (IQR 28.4–33.1), median FM was 33.5 kg
(IQR 27.5–40.8) and median WHR was 0.94 (IQR 0.88–0.99). Abdominal fat
was measured in a subset of 1524 participants: median visceral fat was 122.8 cm3
(IQR 86.4–167.0) and median subcutaneous fat 306.7 cm3 (IQR 239.7–388.8).
Hand OA was present in 8% of men and 21% of women. BMI was strongly
correlated to FM (men r⫽0.89, women r⫽0.90) and subcutaneous fat (men
r⫽0.72, women r⫽0.82), and moderately to visceral fat (men r⫽0.54, women
r⫽0.57). WHR was moderately correlated to visceral fat (men r⫽0.59, women
r⫽0.46), and only weakly to very weakly correlated to subcutaneous fat (men
r⫽0.36, women, r⫽0.17). BMI was associated with hand OA in women (OR
1.02; 95% CI 1.00–1.04), but not in men. WHR was strongly associated with
hand OA in men (OR 132.2; 95% CI 9.2–1901.9) and in women (OR 10.1; 95%
CI 2.0–50.0). In both sexes, FM and subcutaneous fat were not significantly
associated with hand OA. Visceral fat was associated with hand OA only in men
(OR 1.005; 95% CI 1.001–1.009).
Conclusion: BMI was associated with clinical hand OA only in women.
FM and subcutaneous fat, which were strongly correlated with BMI, were not
associated with hand OA in both men and women. In men, the WHR and
visceral fat were associated with hand OA, suggesting involvement of visceral
fat in the development of hand OA. In women, other underlying processes
might play a role.
increasing x-ray severity and with number of knees involved with OA
(Table).
Composite Factor
Score
Joints Included
Score calculation*
Adjusted† OR (95% CI) for
highest quartile of Pb‡
20 (DIP-8, PIP-8, thumb
IP-2 & CMC-2)
8 (all MCPs except
thumb)
Mean of summed KLG
0.89(0.64–1.23)
Mean of summed KLG
1.10(0.80–1.54)
Knee
4 (bilateral TFJ and PFJ)
Mean of summed KLG
and OST scores
0.77(0.55–1.08)
Spine
5 (L1/2 to L5/S1) OST
& DN at each level
7 (hands-2, knees-2,
hips-2, low back-1)
Mean of summed OST
& DN scores
Mean of summed 0–3
score
1.16(0.84–1.61)
IP/CMC
Table 1. Cross-sectional Association of Knee OA with Prevalent Frailty
Monday, November 12
Knee OA Status
Radiographic Knee OA (yes vs. no)
Symptomatic Knee OA (yes vs. no)
Severity of Radiographic Knee OA:
KL⫽0 (reference)
KL⫽1
KL⫽2
KL⫽3
KL⫽4
Number of Knees with OA:
None (reference)
Unilateral
Bilateral
MCP
Presence of Frailty
Adjusted* PR
Crude PR
(95% CI)
1.67
2.36
1.0
1.41
1.64
1.71
2.52
1.41 (1.02, 1.94)
1.86 (1.38, 2.50)
1.0 (Ref)
1.27 (0.75, 2.15)
1.49 (0.96, 2.31)
1.42 (0.90, 2.26)
1.78 ((1.12, 2.83)
1.0
1.04
2.10
1.0 (Ref)
1.02 (0.67, 1.55)
1.68 (1.19, 2.38)
Symptoms
1.71(1.24–2.36)
*Scores were calculated as the mean score, then standardized by dividing by the standard deviation
†Adjusted for age, sex, race, BMI, and all other factor scores
‡Mean Pb level (SD) in ␮g/dL: Q1 (referent); 0.9 (0.2); Q2: 1.5 (0.2); Q3: 2.1 (0.2); Q4: 4.9 (3.9)
IP: interpholongeol; CMC; c●; D●P: Distol IP; PIP: Pr● IP; MCP: metocarpopholongeol; KLG: Kellgren Lawrence
Grade; OR: odds ratio; CI: confidence interval; TFJ: ●femoral; PFJ: pa●; OST: Osteophyte grade; DN: Disc
narrowing grade; ●b: Whole blood lead level
Conclusion: There was a statistically significant positive association
between blood Pb levels and the composite symptoms score, reflecting
symptoms at multiple joint sites. No associations were seen for multiple
joint rOA in this cross-sectional study.
*Adjusted for age, sex, BMI, physical activity, smoking, education, knee injury,
co-morbidities, study site
1. Nelson AE et al, Arthritis Res Ther 2011;13:R76.
Conclusion: Frailty is present more frequently in persons with knee
OA than those without. Further research is needed to explore whether
knee OA predisposes to frailty, and whether early management of knee
OA might prevent frailty and its related adverse outcomes.
Disclosure: A. E. Nelson, None; X. A. Shi, None; T. A. Schwartz, None; J. B.
Renner, None; K. L. Caldwell, None; C. G. Helmick, None; J. M. Jordan,
Algynomics, Inc., 1, Johnson and Johnson, 5, Johnson & Johnson, 2, Interleukin
Genetics, Inc., 5, Eli Lilly and Company, 5, Mutual Pharmaceutical Company, 5.
Disclosure: D. Misra, None; M. C. Nevitt, None; C. E. Lewis, None; J. Torner, None;
D. T. Felson, None; T. Neogi, None.
1100
1099
Whole Blood Lead Is Associated with Symptoms, but Not Radiographic Osteoarthritis, in Multiple Joint Sites: The Johnston County
Osteoarthritis Project. Amanda E. Nelson1, Xiaoyan A. Shi2, Todd A.
Schwartz3, Jordan B. Renner4, Kathleen L. Caldwell5, Charles G.
Helmick5 and Joanne M. Jordan1. 1University of North Carolina Thurston
Arthritis Research Center, Chapel Hill, NC, 2SAS Institute, Inc, Cary, NC,
3
University of North Carolina Gillings School of Global Public Health,
Dept of Biostatistics, Chapel Hill, NC, 4University of North Carolina
School of Medicine, Dept of Radiology, Chapel Hill, NC, 5Centers for
Disease Control and Prevention, Atlanta, GA
Background/Purpose: We have previously identified associations
between whole blood lead (Pb) and knee osteoarthritis (OA) and with
biomarkers of joint metabolism. We hypothesized that Pb may be
associated with burden of OA as assessed by multiple joint radiographs
and symptoms.
Methods: Whole blood Pb concentrations, representing recent exposure and Pb mobilized from bone, were determined at the Centers for
Disease Control and Prevention using inductively coupled plasmadynamic reaction cell-mass spectrometer analysis; levels were categorized
into quartiles for analysis. We used composite scores obtained from
previously described factor analysis (1) of radiographic OA (rOA) scores
from the hands, knees, and spine, and symptoms scores of the low back,
hands, knees, and hips, to reflect body burden of OA as outcome measures
(categorized due to non-normal distributions). Generalized logit and
proportional odds models were used for these multi-level outcomes, and
were adjusted first for age, body mass index (BMI), race, and sex, and then
additionally for the other joint site scores.
Results: This cross-sectional analysis includes data (collected at a
single visit during 2003-8) for 1659 individuals, 33% male and 35%
African American with a mean age of 65 years and BMI 30 kg/m2. At
individual sites, rOA with symptoms was present in 13% for hand, 12%
for hip, 24% for knee, and 28% for spine. Whole blood Pb was associated
with spine rOA scores (30% increased odds of having higher spine rOA
scores in the highest Pb quartile compared to the lowest, adjusted OR 1.34
[95% CI 1.01–1.77]), although this was no longer significant after
adjustment for the composite scores of other joint sites (Table). The
composite score of symptoms, however, was associated with Pb in models
adjusted for covariates (OR 1.84 [95% CI 1.41, 2.40]) and after adjustment for rOA scores (Table), such that those in the highest quartile of Pb
had 70–85% higher odds of reporting more symptoms compared to those
in the lowest Pb quartile.
A Functional Growth Hormone Receptor Polymorphism, Exon 3
Deleted Ghr, Is Associated with Radiographic Knee Osteoarthritis in
Females with Familial Osteoarthritis At Multiple Sites: The Garp
Study. Kim M.J.A. Claessen1, Margreet Kloppenburg2, H.M. Kroon1,
Jessica Bijsterbosch1, Alberto M. Pereira1, Hans A. Romijn1, Tahar
Straaten van der1, Marian Beekman1, P.E. Slagboom1, Nienke R. Biermasz1 and Ingrid Meulenbelt3. 1Leiden University Medical Center,
Leiden, Netherlands, 2Department Rheumatology and Department of
Clinical Epidemiology, Leiden University Medical Centre, Leiden, The
Netherlands, Leiden, Netherlands, 3The Netherlands Genomics InitiativeSponsored Netherlands Consortium for Healthy Aging, Rotterdam, Netherlands
Background/Purpose: Genetic influences contribute considerably to the
development of osteoarthritis (OA), and are most likely of a polygenic nature.
Until now, genetic studies have identified several genetic variants associated
with primary OA, providing strong clue for the involvement of endochondral
ossification in OA onset. Endochondral ossification is the main process in
longitudinal skeletal growth, and is tightly regulated by a complex network of
hormones, growth factors and extracellular matrix components. One of the
main players in this process is growth hormone (GH), exerting its effects
predominantly through stimulation of insulin-like growth factor-1 (IGF-1)
secretion. This qualifies genetic variations within genes involved in the
GH/IGF-1 axis as obvious candidates for association studies in primary OA.
Recently, presence of a common growth hormone receptor (GHR)
polymorphism, exon 3 deletion (d3-GHR), associated with increased GH
sensitivity of the GHR, was demonstrated to have functional consequences in
various clinical conditions. The aim of the present study was to investigate the
effects of the d3-GHR polymorphism on the extent and characteristics of
radiographic in patients with primary OA at multiple joint sites.
Methods: In a case-control study, we compared frequency of GHRfl-d3
genotype between patients with familial primary OA from the GARP
(Genetics, ARthrosis and Progression) Study, and controls. KellgrenLawrence scores were used to assess ROA in the knee, hip and hand; the
Osteoarthritis Research Society atlas for the assessment of individual ROA
features. Patients and controls were genotyped for 7 single nucleotide
polymorphisms (SNPs) encompassing the d3-GHR gene to allow high
throughput genotyping. One tagSNP was used as proxy for d3-GHR (full LD,
pairwise r2⫽1). Binary logistic regression analyses with robust standard
errors were performed, to assess the relationship between d3-GHR and ROA.
Results: We studied 373 patients (mean age 60.1, 82% female) and 752
controls. GHRfl-d3 genotype was significantly associated with ROA, especially in females (adjusted odds ratio (OR) (95%CI) 1.5(1.1–2.1), p⫽0.017).
Strongest association was found with knee OA (adjusted OR 2.0(1.3–3.0),
p⫽0.002), followed by hand OA (adjusted OR 1.5(1.1–2.1), p⫽0.024). No
S472
such a relationship was found in males. GHRfl-d3 genotype was related to both
osteophytes and joint space narrowing.
Conclusion: GHRd3-fl genotype was associated with knee and hand ROA
in females with a severe primary OA phenotype, indicating a role for the
GH/IGF1 axis in the pathophysiology of primary OA.
Disclosure: K. M. J. A. Claessen, None; M. Kloppenburg, None; H. M. Kroon,
None; J. Bijsterbosch, None; A. M. Pereira, None; H. A. Romijn, None; T. Straaten
van der, None; M. Beekman, None; P. E. Slagboom, None; N. R. Biermasz, None;
I. Meulenbelt, None.
1101
Background/Purpose: Synovitis is one of the major signs of structure
damage in osteoarthritis (OA) progression. Chondroitin sulfate (CS) is an
effective drug in the treatment of OA since it can reduce joint swelling and
effusion in OA patients as described in the NIH-funded GAIT study. Therefore,
the aim of this study was to compare the effect of CS vs. acetaminophen on
synovitis in OA patients and to evaluate their impact on chemokine concentrations.
Methods: Synovitis (synovial hypertrophy⫹effusionⱖ4mm) assessed by
sonography and synovial effusion quantified by artrhocentesis were evaluated in
45 patients treated with CS (800mg/day) or acetaminophen (4g/day) for 6 months.
Patients were followed-up until month 9 to evaluate the carry-over effect.
Symptomatic effect of both treatments was also evaluated by Lequesne Algofunctional Index (baseline,1.5, 3, 6 and 9 months). The levels of CXCL16,
fractalkine/CX3CL1, MCP-1/CCL-2, RANTES/CCL5 and GRO-␣/CXCL1
were determined by ELISA in the plasma and synovial samples collected in each
visit. Analysis of continuous variables was based on analyses of covariance
(ANCOVA) model. Study of the chemokine variations between each time and the
baselines was performed by a Wilcoxon two-related samples test Comparison
between the two groups was obtained using an independent sample t-test for
quantitative variables or a chi-squared test for qualitative variables. P values
ⱕ0.05 were considered statistically significant for each variable.
Results: Eligible patients had clinical and radiographic evidence of OA (K&L
grade 2 and 3) with synovitis. Mean age of patients was 70.4 years being women
72.1% of them. Mean BMI was 28.97. At the end of the study, CS significantly
reduced synovitis compared to acetaminophen (p⬍0.01).This significant reduction was also detected in MCP-1 and fracktalkine synovial levels. Compared to
baseline, CS treated patients showed significant reductions in synovitis (25.5%)
and significant impairment of synovial hypertrophy (61.9% reduction). These
effects were accompanied by significant decreases in synovial and serum MCP-1
content. In contrast, in the acetaminophen-treated group no effect on synovitis was
observed and increased synovial RANTES levels were even detected. Additionally, CS but not acetaminophen effectively reduced functional incapacity after 6
months of treatment (CS-treated group: 11.5⫾2.5 vs. 7.9⫾3.0; p⬍0.01;
acetaminophen-treated group: 9.9⫾4.1 vs. 8.3⫾4.9; n.s.). CS functional improvement remained after 3 months treatment cessation (month 9) thus confirming CS
carry-over effect.
Conclusion: These results indicates that CS but not acetaminophen
effectively reduces synovitis and clinical symptoms in OA patients. Evidence
of an anti-inflammatory effect for CS has been also provided since it can
decrease synovial and plasma levels of relevant chemokines. This study also
adds further support and extends the finings described in the NIH-funded
GAIT study and suggests that CS seems to be a more effective therapeutic
tool for OA and synovial inflammation than analgesics.
This work was supported by grants SAF2011–23777, PI/08/1875, RIER
RD08/0075/0016, RIER RD08/0075/0021 and other grants from Generalitat
Valenciana.
Disclosure: J. Monfort, None; P. Escudero, None; C. Orellana, None; L. Piqueras,
None; L. Tio, None; F. Montañés, None; N. Garcı́a, None; C. Company, None; P.
Benito, None; M. J. Sanz, None.
Immunoreactive Collagen Type II Cleavage Products and Their Nitrated
Forms in Rheumatoid Arthritis and Osteoarthritis: An Outpatient
Cross-Sectional Study. Ruediger Mueller1, Axel Finckh2, Guy Heynen3 and
Johannes von Kempis4. 1Cantonal Hospital, St. Gallen, Switzerland, 2Geneva
University Hospitals, Geneva 14, Switzerland, 3Consulting, CH-6300 Zug,
Switzerland, 4MD, St. Gallen, Switzerland
Background/Purpose: Catabolism of type II collagen (COLII) involves
multiple metalloproteinases, aggrecanases and cathepsin, releasing heterogeneous triple helix cleavage products. The complex regulation of these
enzymes and of inducible NOS (iNOS)includes inflammatory cytokines.
Col2-1 peptide (Col), located towards the N-telopeptide region of COLII
contains a tyrosine residue susceptible to endogenous nitration by reactive
nitrogen species, forming Col-2-1-NO2 (NCol). Specific immunoassays
allow for estimation of nitration index (NI). Using these assays in OA and RA
should show differences since RA, unlike OA, is treated with DMARDs
known to inhibit structural damage progression.
Methods: Serum (S) and Urine (U) Col and NCol were measured by ELISA
in a cross-sectional study (49 RA and 118 outpatients with active hand OA). The
ratio of NCol (nmol)/Col (nmol) provided NI. Clinical variables were age, sex,
DAS and VAS. Urinary fractional excretions (UFE) of biomarkers was calculated
in RA patients.Statistical analysis used STATA® Version 12.1
Results: OA patients were older (64 years vs 58 in RA). Mean DAS28
was 2.64 with 60% receiving corticoids or synthetic and biological DMARD
treatment in RA. VAS pain was higher in OA than RA patients (46 vs.
34;p⬍0.0001). Mean SCol concentrations (nmol/l) and SNCol (pmol/l) were
higher in RA (308⫾17 and 687 ⫾90) than OA (241 ⫾ 13 and 465⫾39;
p⬍0.0001). Mean UCol (nmol/mmol creatinine) was higher in RA than in
OA (16.3 vs. 8.1; p⬍0.0001) whereas UNCol (pmol/mmol creatinine) values
were similar between the 2 groups (22.4 ⫾4.3 in RA and 26.2 ⫾2.1 in OA;
p⬎0.1). Col and NCol UFE were 2.87% (2.25–3.48; 95%CI) in RA and 2.63
% (1.81–3.46; 95%CI) and highly correlated (r-square⫽0.53; p⬍0.0001).The
SCol2-1NI was similar in RA (0.238 %, 95% CI: 0.214–0.262) and in OA
(0.217, 95% CI: 0.19–0.24; p⬎0.05) but the UCol2-1NI was markedly lower
in RA (0.164, 95%CI: 0.141–0.187) than OA (0.37, 95%CI: 0.33–0.42;
p⬍0.0001). In both RA and OA, pairwise comparisons of serum and urine NI
indicated highly significant differences (p⬍0.0001). None of the disease
activity indices were associated with any of the two biomarkers or their ratios
in serum or urine.
Conclusion: Data indicate excess nitrated forms of Col2-1 in the urine of
patients suffering from active OA in comparison to DMARD treated RA
patients, indicating that a greater proportion of OA SNCol immunoreactive
forms pass through the renal glomerular membrane than in RA. In RA,
fractional excretion of both Col and NCol was low and similar for Col and
NCol, excluding a differential renal handling of the detected epitopes. The
excess of urinary nitrated forms in OA vs RA may result from the OA disease
process itself or from DMARD interference with the iNOS activity in RA.
Within patients’ differences between serum and urine NI values indicate
biological heterogeneity of immunoreactive species containing the Col2-1
epitope. The clinical relevance of this heterogeneity is unknown since the
half-life of measured components have not been studied. Additional investigations with specific enzyme inhibitors in OA and biological DMARDs in
early RA are warranted to quantify the dynamics of serum and urine
components of Col2-1 and its nitrated forms.
Disclosure: R. Mueller, None; A. Finckh, Roche, Pfizer, BMS, 2, Roche, Pfizer, BMS,
5; G. Heynen, Artialis SA, 5; J. von Kempis, None.
1103
Cumulative Occupational Physical Load As Risk Factor for Knee
Osteoarthritis. Allison M. Ezzat1, Jolanda Cibere2, Mieke Koehoorn1, Eric
C. Sayre2 and Linda C. Li1. 1University of British Columbia, Vancouver, BC,
2
Arthritis Research Centre of Canada, Vancouver, BC
Background/Purpose: Knee osteoarthritis (OA) results from the interaction of multiple risk factors, one of which may be physically demanding
occupations. The purpose of this study was to determine the association
between cumulative occupational physical load (COPL) and the presence of
knee OA, defined as Symptomatic Radiographic Osteoarthritis (SOA) or
Magnetic Resonance Imaging Osteoarthritis (MRI-OA).
Methods: This was a cross-sectional analysis of symptomatic (n⫽255)
and asymptomatic (n⫽72) knee cohorts recruited as a random sample from
the same population. Participants were 40 to 79 years old. Inclusion criteria
S473
Monday, November 12
Condroitin Sulfate Decreases Chemokine Levels and Synovitis in knee
osteoarthritis Patients. Jordi Monfort1, Paula Escudero2, Cristobal Orellana3, Laura Piqueras4, Laura Tio5, Francisco Montañés1, Natalia Garcı́a5,
Chantal Company2, Pere Benito1 and Maria Jesús Sanz2. 1Hospital del Mar,
Barcelona, Spain, 2Universitary Clinic Hospital Research FoundationINCLIVA, University of Valencia, Valencia, Spain, 3Corporació Sanitaria
Parc Taulı́, Sabadell, Spain, 4University Clinic Hospital Research
Foundation-INCLIVA, University of Valencia, Valencia, Spain, 5GRICIC.
FIMIM, Barcelona, Spain
1102
Monday, November 12
for the symptomatic cohort, Model for the Development of Early Knee Osteoarthritis (MoDEKO), were: 1) pain, aching, or discomfort in/around the knee on
most days of the month at any time in the past; 2) pain, aching or discomfort
in/around the knee in the past 12 months. In the asymptomatic cohort, participants
responded no to both knee pain questions. All participants received a standardized
knee exam, fixed flexion knee radiographs and MRI, and completed a comprehensive questionnaire, which included a detailed lifetime occupational history of
activity level (5 levels) and knee bending/kneeling activities (3 levels) for each
occupation held. Self-reported COPL was calculated by multiplying the number
of years in each occupation by the activity level and by the knee bending within
that occupation, then summing all occupations. COPL was then grouped into
quartiles (QCOPL). SOA was defined by the Kellgren Lawrence x-ray grade ⬎ 2,
plus the presence of knee pain. MRI-OA was defined using a novel definition by
Hunter et al1which required either both group A features: osteophyte formation
and full thickness cartilage loss; or one group A and two group B features: bone
marrow lesion or cyst, meniscal subluxation or tear, partial cartilage loss, or bone
attrition. Weighted analysis was done using logistic regression to examine the
association between QCOPL and the presence of SOA and MRI-OA, respectively, after adjusting for age, sex, body mass index, and two-way interactions.
Results: Participants (women⫽167, men⫽160) were on average 58.5
(SD⫽11.0) years old with a BMI of 26.3 (SD⫽4.7). Of those, 102 (31.2%)
participants had SOA. A monotonic statistically significant relationship was found
between QCOPL and SOA with adjusted odds ratio (OR) of 8.16 (95% CI ⫽
1.89, 35.27) for QCOPL 4 (highest) vs. QCOPL 1 (lowest), and 5.73 (95% CI⫽
1.36, 24.12) for QCOPL 3 vs. 1. A total of 131(40.1%) participants had MRI-OA.
Adjusted OR were also monotonic and statistically significant: QCOPL 4 vs. 1
(OR⫽ 9.54; 95% CI ⫽ 2.65, 34.27); QCOPL 3 vs. 1 (OR⫽ 9.04; 95% CI ⫽ 2.65,
30.88); QCOPL 2 vs. 1 (OR ⫽ 7.18; 95% CI ⫽ 2.17, 23.70).
Conclusion: COPL is a significant risk factor for knee OA. A dose response
relationship between COPL and both SOA and MRI-OA was found. MRI-OA is
a new definition, which has potential to capture early structural disease in a way
not previously quantified. Due to the nature of the cross-sectional study design,
these results should be interpreted cautiously but provide evidence for further
prospective, longitudinal studies.
association between risk factors and PFJ structural damage using logistic
regression with GEE to account for the correlation between regions from the
same knee. We performed analyses in the PFJ overall (damage in any of the
four regions) and for the medial and lateral PFJ separately.
Results: 1268 regions from 317 knees were studied (mean age 63.5 years,
mean BMI 30.5 kg/m2, 67% female). Full-thickness cartilage damage was
present in any PFJ region, medial, and lateral in 20%, 16%, and 25% of
regions, respectively. The hamstring-quadriceps ratio, Insall-Salvati ratio, and
lateral trochlear inclination demonstrated the strongest associations with
overall and lateral PFJ damage (see table). Females and older subjects were
more likely to have medial but not lateral PFJ damage. Femur length was
strongly associated with lateral PFJ damage. Similar results were seen for the
PFJ damage definition including a BML.
(1) Hunter et al. Osteoarthritis and Cartilage 2011; 19(8):963–969.
Tertile 1 (Reference; Low)
Tertile 2
Disclosure: A. M. Ezzat, None; J. Cibere, None; M. Koehoorn, None; E. C. Sayre,
None; L. C. Li, None.
Tertile 3 (High)
Association between demographic, modifiable, structural, and biomechanical risk
factors and full-thickness cartilage damage (WORMS 2.5; ⱖ5) in the PFJ
Any PFJ
Medial PFJ
Lateral PFJ
OR (95% CI)
OR (95% CI)
OR (95% CI)
Demographic risk factors
Age (per 10 years)
1.3 (1.1, 1.7)
1.7 (1.2, 2.4)
1.2 (0.8, 1.8)
Sex (Reference⫽Male)
1.4 (0.9, 2.1)
2.9 (1.5, 5.6)
0.9 (0.5, 1.7)
Race
Other (Reference)
1.0
1.0
1.0
African American
0.9 (0.4, 1.7)
0.6 (0.2, 1.4)
1.1 (0.4,2.9)
Modifiable risk factors
BMI (per 5 units)
Occupational history
No labor (Reference)
1.1 (0.9, 1.3)
1.2 (0.9, 1.5)
1.0 (0.7, 1.3)
1.0
1.0
1.0
Labor
Other
1.0 (0.6, 1.5)
1.0 (0.6, 1.5)
1.2 (0.7, 2.2)
0.7 (0.4, 1.4)
0.8 (0.4, 1.7)
1.3 (0.7, 2.4)
History of knee injury
(Reference⫽none)
0.4 (0.3, 0.7)
0.4 (0.2, 0.7)
0.4 (0.2, 0.9)
History of knee surgery
(Reference⫽none)
0.8 (0.5, 1.5)
1.0 (0.5, 2.2)
0.6 (0.3, 1.5)
Tertile 1 (Weak)
Tertile 2
1.5 (1.0, 2.4)
1.6 (1.0, 2.4)
1.4 (0.7, 2.9)
1.8 (1.0, 3.4)
1.9 (0.9, 3.7)
1.6 (0.8, 3.2)
Tertile 3 (Reference)
1.0
1.0
1.0
1.0
0.8 (0.5, 1.3)
1.0
0.8 (0.5, 1.5)
1.0
0.8 (0.4, 1.6)
1.8 (1.2, 2.6)
1.1 (0.6, 1.9)
2.9 (1.5, 5.6)
Quadriceps strength
Hamstring-quadriceps
strength ratio
Structural risk factors
Insall-Salvati Ratio
Tertile 1 (Reference)
1104
The Association of Demographic, Modifiable, Structural and Biomechanical
Risk Factors with Medial and Lateral Patellofemoral Joint Structural
Damage On MRI: The Multicenter Osteoarthritis Study. Joshua J. Stefanik1,
Ke Wang1, K. Douglas Gross2, Frank Roemer3, John A. Lynch4, Neil Segal5,
Cora E. Lewis6, Michael C. Nevitt4, Ali Guermazi1 and David T. Felson1.
1
Boston University, Boston, MA, 2MGH Institute of Health Professions, Boston,
MA, 3Klinikum Augsburg, Augsburg, Germany, 4University of California-San
Francisco, San Francisco, CA, 5University of Iowa, Iowa City, 6University of
Alabama, Birmingham City, Birmingham, AL
Background/Purpose: Past investigations into risk factors for patellofemoral joint (PFJ) osteoarthritis (OA) have been limited by the use of
radiography, which is insensitive to identify PFJ OA and have focused on
only a few risk factors. MRI offers a unique opportunity to directly visualize
tissue damage in the PFJ, and risk factors related to medial PFJ damage,
which was recently reported as common (Gross, ARD, 2012), can be
distinguished from those related to lateral damage. The purpose of this study
is to evaluate the association between PFJ structural damage on MRI with a
wide spectrum of risk factors including: demographic, modifiable, structural,
and biomechanical factors.
Methods: We analyzed data from the baseline exam of MOST, a
NIH-funded cohort study of persons aged 50–79 years with or at risk for knee
OA. Knees for this study came from persons with x-ray OA in tibiofemoral
joint and/or PFJ. Demographic risk factors included age, sex, and race.
Modifiable risk factors included BMI, occupational history, quadriceps
strength, and hamstring-quadriceps strength ratio. Structural risk factors
included Insall-Salvati ratio (measure of patella alta), lateral trochlear inclination (measure of trochlear morphology), and femur length. Biomechanical
risk factors included varus and valgus alignment (from long limb x-rays).
Cartilage damage and bone marrow lesions (BMLs) were assessed on MRI
using the WORMS scale in 4 regions (medial and lateral patella and trochlea).
PFJ structural damage was defined in two ways: 1) full-thickness cartilage
loss (WORMS 2.5; ⱖ5 on a 0–6 scale) and 2) full-thickness cartilage loss in
addition to a BML (ⱖ1 on a 0–3 scale). We examined the cross-sectional
1.0
1.0
Tertile 2
1.2 (0.8, 1.8)
1.2 (0.7, 2.1)
1.3 (0.7, 2.6)
Tertile 3 (Patella alta)
Lateral trochlear inclination
1.5 (1.0, 2.4)
1.0
1.1 (0.6, 2.0)
2.2 (1.1, 4.1)
Tertile 1 (Flat trochlea)
1.0 (0.6, 1.5)
0.7 (0.4, 1.4)
4.4 (2.1, 9.4)
Tertile 2
Tertile 3 (Reference)
1.8 (1.1, 2.7)
1.0
0.9 (0.5, 1.7)
1.0
1.1 (0.5, 2.2)
1.0
Femur length
Tertile 1 (Reference; Short)
1.0
1.0
1.0
Tertile 2
Tertile 3 (Long)
1.3 (0.9, 2.1)
1.3 (0.8, 2.0)
0.8 (0.5, 1.4)
0.6 (0.3, 1.2)
2.5 (1.2, 5.3)
2.8 (1.3, 6.0)
Biomechanical risk factors
Frontal plane knee alignment
Neutral (Reference)
1.0
1.0
1.0
Valgus
1.5 (0.97, 2.4)
1.1 (0.5, 2.4)
2.2 (1.1, 4.3)
Varus
0.9 (0.6, 1.3)
1.3 (0.7, 2.4)
0.6 (0.3, 1.1)
Conclusion: PFJ structural damage is more strongly related to structural
and demographic factors than to modifiable ones. Risk factors may be
different for medial and lateral PFJ structural damage. Future studies should
evaluate risk factors separately for medial and lateral PFJ damage.
Disclosure: J. J. Stefanik, None; K. Wang, None; K. D. Gross, None; F. Roemer, Boston
Imaging Core Lab, 1, National Institute of Health, 5, Merck Serono, 5; J. A. Lynch, None;
N. Segal, None; C. E. Lewis, None; M. C. Nevitt, None; A. Guermazi, BICL, LLC, 4,
AstraZeneca, Genzyme, Novartis, and MerckSerono, 5; D. T. Felson, None.
1105
Lateral Tibio-Femoral Shift Related to Medial Knee Osteoarthritis. Roy
H. Lidtke1, Berna Goker2, Abdurrahman Tufan2, Laura E. Thorp1 and Joel A.
Block1. 1Rush University Medical Center, Chicago, IL, 2Gazi University
Medical School, Ankara, Turkey
Background/Purpose: Medial knee osteoarthritis (MKOA) has been
shown to be related to malalignment of the knee joint with several radiographs
used to quantify the abnormality. Radiographic observations of a lateral tibial
shift in subjects with MKOA has led the authors to hypothesize that this
finding is more prevalent in MKOA than normal controls and is associated
with MKOA measurable gait parameters.
S474
Disclosure: R. H. Lidtke, None; B. Goker, None; A. Tufan, None; L. E. Thorp,
None; J. A. Block, None.
1106
Evaluation of Foot Posture and Plantar Pressure Changes in Knee
Osteoarthritis: Preliminary Report. Necati Balci and Lale Cerrahoglu.
Celal Bayar University Medical School, Manisa, Turkey
Background/Purpose: Disturbances of weight bearing and walking
pattern occur in patients with knee osteoarthritis (OA) due to impairments in
knee joint. These impairments may lead to changes in the mechanical
alignment of lower limb and dynamic function of the foot. Therefore, it has
been given special attention to foot orthoses and footwear modifications as a
non-operative treatment of knee OA. However, in order to fully understand
the effect of these interventions on the knee and other lower limb joints,
greater knowledge of foot structure is required. We aimed to study the plantar
pressure and foot posture characteristics of knee OA and their relationship
with disease characteristics.
Methods: A total of 78 feet of 39 patients with bilateral knee OA (ACR
criteria) were evaluated regarding clinical and biometrics data. Demographic
and disease characteristics were obtained. The radiographical evaluation was
done based on anterior-posterior tibio-femoral radiographs using the
Kellgren-Lawrence (KL) grading scale (0-4). Barefoot dynamic plantar
pressure and the Arch index (AI) were measured by the 3D footscan system.
The Foot posture index (FPI-6) was obtained. Correlation (Pearson’s correlation coefficient) and regression analyses were performed between various
plantar pressure analysis, clinical parameters and disease-related parameters.
Results: Thirty nine patients (11 male) with mean age 51,53 (standard
deviation (SD):11,89) and mean BMI 30,5 (SD:4,9) were recruited. For dynamic
plantar pressures; grade in right knee according to KL radiologic criteria correlates
with left foot medial heel, left midfoot and left middle forefoot pressures (r⫽0,40,
p⫽0,010; r⫽0,33, p⫽0,040; r⫽ 0,36, p⫽0,022 respectively). Grade in left knee
according to KL radiologic criteria correlates with left heel, left midfoot and
inversely correlates with right foot toe pressure (r⫽0,33, p⫽0,036; r⫽0,41,
p⫽0,010; r⫽-0,41, p⫽0,009 respectively). For foot posture; grade in right knee
according to KL radiologic criteria correlates with right FPI-6, grade in left knee
according to KL radiologic criteria correlates with left FPI-6, right FPI-6 and left
AI (r⫽0,38, p⫽0,015; r⫽0,41, p⫽0,008; r⫽0,41, p⫽0,009; r⫽0,33, p⫽0,036
respectively). In multivariate regression analysis it is found that left KL grade was
most affected from left AI (p⫽0,045).
Conclusion: The dynamic variables of plantar pressure and foot posture are
sensitive to the OA grading. These results suggest that people with the higher OA
grade exhibit a more pronated foot type and shifted pressure distribution. We can
maintain a superior biomechanical correction by advanced evaluation of foot
structure in non-operative treatment of knee OA such as orthoses and footwear
modifications. As a result, the assessment of patients with knee OA in clinical
practice should include simple foot measures and evaluation.
Disclosure: N. Balci, None; L. Cerrahoglu, None.
1107
Baseline Knee Flexion Pain, Age and Joint Line Tenderness Predict the
Progression of Asymptomatic, Radiographic Knee Osteoarthritis to
Symptomatic Knee Osteoarthritis Over 5 Years. Abhiram Gande1 and
James J. Irrgang2. 1University of Pittsburgh School of Medicine, Pittsburgh,
PA, 2University of Pittsburgh, Pittsburgh, PA
Background/Purpose: Knee Osteoarthritis (OA) is the most prevalent form
of OA. Historically, not all people who have tell-tale signs of radiographic knee
osteoarthritis progress to symptomatic knee osteoarthritis, and vice versa. According to a meta-analysis by Bedson et. al, the prevalence of radiographic knee OA
(Rad OA) in symptomatic patients can range between 15–76%. However,
Duncan et. al observed a strong correlation between increased symptoms and
radiographic OA findings. Such inconsistencies may be resolved with a better
understanding of the risk factors for symptomatic knee OA. To date, there has
been no survey of risk factors involved in the progression of baseline asymptomatic Rad OA to symptomatic Rad OA (Symp OA). Therefore, we evaluated the
abilities of various physical exam measures and demographical variables in
predicting such progression over five years.
Methods: Data from the Knee Osteoarthritis Initiative (OAI), a prospective
longitudinal study of biomarkers involved in the onset and progression of OA in
nearly 5000 subjects, were used for this study. Inclusion criteria were individuals
who had Rad OA—score ⱖ 2 on the Kellgren/Lawrence (K-L)—at baseline. The
cases progressed to develop Symp OA—knee pain on most days of the month
over the last 12 months—at 3 years, and remained symptomatic at 4 and 5 years,
while the controls remained asymptomatic at all three time points from baseline.
Cases and controls were matched for baseline knee K-L score, presence of
unilateral or bilateral index knees and consistency of symptoms at all three time
points (3, 4, and 5 years). The predictor variables were age, gender, BMI,
abdominal circumference, walking ability (20m and 400m walk times), chair
stands time, presence of Hand OA, varus/valgus malalignment, medial and lateral
joint line tenderness, knee flexion pain, flexion contracture or hyperextension sign,
bulge sign, patellar tap sign and isometric quadriceps strength corrected for body
weight. Univariate conditional logistic regression was performed and p-values,
odds ratios and 95 %confidence intervals were calculated.
Results: The baseline sample included 2093 individuals with Rad OA
(K-L ⱖ 2). The matching process yielded 94 cases and controls, with similar
demographic data (Table 1). Logistic regression analysis revealed that age
(p⫽0.04), medial joint line tenderness (p⫽0.008), lateral joint line tenderness
(p⫽0.01) and knee flexion pain (p⫽0.047) were significant predictor variables.
95% confidence intervals were ⬎1 and odds ratios were ⬎1 for the four
significant variables.
Conclusion: Age, knee flexion pain, medial and lateral joint line tenderness are measures with significant (p⬍0.05) predictive ability of progression
from baseline Rad OA to Symp OA. As such, these commonly used
demographic and physical exam measures can help physicians identify
individuals with asymptomatic radiographic OA who may be at risk for
developing chronic knee pain. Ultimately, older age and positive signs on
these physical exam measures can serve as markers to initiate aggressive
management to help prevent the onset of symptomatic knee OA.
Disclosure: A. Gande, None; J. J. Irrgang, None.
1108
A Randomized Controlled Trial of Hylan G-F 20 for the Treatment of
Carpometacarpal Osteoarthritis. Lisa A. Mandl1, Scott Wolfe2, Aaron
Daluiski2, Robert N. Hotchkiss1, Stephen L. Lyman3 and Jeffrey N. Katz4.
1
Hospital for Special Surgery, New York, NY, 2Hospital For Special Surgery,
New York, NY, 3Hospital Special Surgery, New York, NY, 4Brigham and
Women’s Hospital, Boston, MA
Background/Purpose: Painful carpometacarpal osteoarthritis (CMC OA) is
associated with substantial impairment, and is often unresponsive to medical
treatment. Hylan G-F 20 has been shown to improve pain and function in patients
with knee OA; however, its effectiveness in CMC OA is unknown.
Methods: 200 patients with radiologic evidence of CMC OA and no
inflammatory arthritis were randomized to receive one of the following three
S475
Monday, November 12
Methods: 90 subjects (69F 21M, Age 60⫾8, BMI 28.3⫾4.0) with
radiographic and symptomatic medial knee OA (K-L grade 2–3, ambulatory
pain ⬎30 mm on a 100 mm VAS) were compared to 24 (18F 6M) age
(59⫾10) and BMI (28.8⫾8.3) matched controls with no knee pain (K-L grade
0–1). Full limb mechanical axis and AP X-rays of the ankles were obtained.
The tibial lateral shift (figure 1), defined as the distance between the center
of the intercondylar notch of the femur and midpoint of the tibial plateau,
was measured using Image J software (US NIH, Bethesda, MD, http://
rsbweb.nih.gov/ij/). Subjects underwent gait analyses using an optoelectronic
camera system and multi-component force plate. Comparisons were performed after matching for speed. The peak external knee Adduction Moment
(%body weight * height, %BW*Ht) and knee adduction angular impulse was
calculated and used as the primary endpoint. Paired t-tests were used to
compare group differences. Pearson’s correlations were calculated to analyze
the relationship between knee moments and the other radiographic parameters
with significance set at p⬍0.05.
Results: The mean ⫾ S.D. lateral tibio-femoral shift was 5.18⫾2.45 mm
in the MKOA group compared to 1.5⫾1.22 mm in the control group
(p⬍0.01). Interestingly there was no relationship between the lateral shift and
mechanical axis (r⫽0.11, p⫽0.23). There was an apparent relationship
between the external knee adduction moment and lateral tibial shift in the
MKOA group with greater lateral tibial shift related to greater knee moments
(r⫽0.46, p⬍0.01). There was no relationship between knee adduction
moments and lateral tibial shift in the control group (r⫽0.13, p⫽0.09). There
was a relationship between knee angular impulse to the lateral shift in the
MKOA group (r⫽0.48, p⬍0.01).
Conclusion: Lateral tibio-femoral shift is greater in MKOA than in
normal controls and is related to increased medial knee loads. These findings
suggest that the lateral tibio-femoral shift may be a new radiographic marker
for MKOA. Further studies are needed to determine the clinical validity of
assessing the tibio-femoral shift.
Monday, November 12
regimens: 1cc of Hylan G-F 20 weekly for 2 weeks; 1cc triamcinolone acetonide
(40mg) followed 1 week later by 1cc 0.5% bupivacaine; or 0.5% 1cc bupivacaine
weekly for 2 weeks. Randomization was double blind and stratified on previous
intra-articular steroid treatment. An experienced hand surgeon performed all
injections without radiologic guidance. Patients were assessed 26 weeks after the
first injection. An intention to treat, last-value carried forward analysis was
performed on all patients who had at least one post-injection visit.
Results: 188 patients were eligible for this analysis. Average age was 66.5
years (range 45–89), 67.7% female and 90.4% Caucasian. 33%, 31% and 38 %
had previously received a corticosteroid injection in the Hylan G-F 20, triamcinolone and bupivacaine groups respectively. 100 (53%) had Kellegren and
Lawrence (K⫹L) Grade ⬍⫽3 in the CMC joint and 88 (47%) had K⫹L Grade
4. At 26 weeks, pain as measured by the Visual Analogue Scale (VAS) showed
statistically and clinically significant improvement in all treatment groups.
However, there was no statistically or clinically significant difference in VAS
between treatment arms at 26 weeks. No treatment arm resulted in clinically
meaningful improvements in function, as measured by the Disabilities of the Arm,
Shoulder and Hand Questionnaire (DASH). In a multivariate regression analysis,
controlling for age, sex, K⫹L grade, baseline pain and treatment assignment,
neither K⫹L Grade nor treatment assignment was associated with a difference in
pain at 26 weeks. Among those with severe K⫹L Grade 4 CMC OA, all three
treatments led to clinically and statistically significant improvements in pain at 26
weeks, with no differences between groups.
Table 1.
All Patients (188)
VAS Baseline (100⫽severe)
VAS 26 weeks
Delta VAS
p-value within group change
DASH Baseline
DASH 26 Weeks
Delta DASH (Nⴝ175*)
p-value within group change
KⴙL <3 (Nⴝ100)
VAS for Pain
VAS at 26 weeks
Delta VAS
p-value within group change
KⴙL 4 (Nⴝ88)
VAS for Pain
VAS at 26 weeks
Delta VAS
P-value within group change
Hylan G-F 20
Mean ⴞ s.d.
Triamcinolone
Mean ⴞ s.d.
Bupivacaine
Mean ⴞ s.d
60.7 ⫾ 19.3
49.8 ⫾ 26.3
-10.9 ⫾ 26.7
0.002
28.8 ⫾ 17.3
26.1 ⫾ 19.0
-3.53 ⫾ 11.4
0.02
63.2 ⫾ 20.2
50.1 ⫾ 29.4
-13.1 ⫾ 29.9
0.003
28.9 ⫾ 17.9
27.0 ⫾ 18.0
-2.88 ⫾ 14.9
0.14
57.1 ⫾ 20.1
42.9 ⫾ 26.5
-14.2 ⫾ 20.8
<0.0001
25.7 ⫾ 17.1
24.2 ⫾ 17.4
-1.39 ⫾ 12.3
0.07
61.7 ⫾ 19.5
51.6 ⫾ 28.8
-10.1 ⫾ 23.7
0.02
64.8 ⫾ 18.8
56.8 ⫾ 31.6
-7.96 ⫾ 29.1
0.22
51.1 ⫾ 23.4
40.6 ⫾ 28.9
-10.5 ⫾ 21.3
0.02
59.3 ⫾ 19.3
47.3 ⫾ 22.6
-12.0 ⫾ 30.9
0.009
61.1 ⫾ 22.1
41.3 ⫾ 23.9
-19.8 ⫾ 30.0
0.003
61.9 ⫾ 16.0
44.8 ⫾ 24.8
-17.1 ⫾ 20.2
<0.0001
* N⫽175 due to missing data
Conclusion: In patients with CMC OA, intra-articular Hylan G-F 20 was
not superior to corticosteroids or bupivacaine in reducing pain and improving
function at 26 weeks. All three treatments resulted in significant improvements in pain, even among patients with severe CMC OA. A variety of
injectable therapies appear to be effective treatments for this condition, even
in those with severe arthritis.
Disclosure: L. A. Mandl, None; S. Wolfe, None; A. Daluiski, None; R. N. Hotchkiss,
None; S. L. Lyman, None; J. N. Katz, None.
1109
Effects of Strontium Ranelate On Hand Osteoarthritis - Analysis of Data
From the Sekoia Trial. E. Maheu1, C. Cadet2 and F. Berenbaum1. 1AP-HP
St Antoine Hospital, Paris, France, 2Paris, France
Background/Purpose: Strontium ranelate (SrRan) has shown the ability
to reduce radiological progression of knee osteoarthritis (OA) over 3 years.
Patients with knee OA are also frequently affected by hand OA. In this
secondary analysis, we assessed the effects of SrRan on radiological and
symptom progression of hand OA.
Methods: This international 3-year, randomized, placebo-controlled
phase III trial was designed to assess the effect of SrRan 1g and 2g/day
compared to placebo on the radiographic progression of knee OA. Main
inclusion criteria were symptomatic primary knee osteoarthritis (ACR criteria), a Kellgren-Lawrence (KL) grade II or III, and a joint space width (JSW)
between 2.5-5 mm. There were no specific inclusion criteria regarding hand
OA. Hand OA radiographic and clinical assessments were secondary outcomes. During the study, baseline and final postero-anterior radiographs of
each hand were performed and scored by 2 independent readers, blinded to
treatment and time sequence, using KL (range 0–128), Kallman (0–204) and
Verbruggen (0–218) scoring methods. Clinical symptoms were assessed at
each visit by the Auscan (0–300) and Functional Index for Hand OA
(FIHOA) (0–30). Between-group analyses were performed using a general
linear model with baseline, center and gender as covariates.
Results: Of the 1669 patients included in the SEKOIA trial, 999 had
radiologic hand OA at baseline (73%). 71% were female. Mean age was
64⫾7 years, body mass index 29.6⫾4.7 kg/m2, and initial knee JSW 3.4⫾0.8
mm. Hand OA was mild in radiologic severity: KL score 21⫾13, Kallman
score 25⫾22 and Verbruggen score 14⫾15. Mean Auscan global score was
96⫹80 mm and mean FIHOA score was: 4⫾5.
The radiographic progression of hand OA observed over 3 years was
modest in the placebo group with a mean change of 2.4⫾3.3 for KL score,
3.7⫾5.3 for Kallman score and 2.0⫾3.9 for Verbruggen score. There was no
difference between the treatment groups for any radiological score. A
significantly higher rate of patients reported an improvement of 20% or more
in the Auscan pain subscale in the SrRan 2 g group (95% CI [0.1; 16.3];
p⫽0.047) compared to placebo.
In erosive patients (ⱖ2 erosive joints, N⫽71), a significant improvement
of KL score (p⫽0.031) in the SrRan 2 g compared to placebo was observed.
In symptomatic patients (FIHOA ⬎5 and pain within the 48 hours prior to the
visit, N⫽126), a trend toward a higher improvement of KL score was noted
in the SrRan 2 g group compared to placebo (p⫽0.079)
Conclusion: Overall, mild hand OA patients showed a very slow
radiological progression, with no between-group difference over 3 years.
However, in subgroup analyses, a slight beneficial effect of strontium ranelate
2g could be observed on pain and a positive effect on the change in KL score
was suggested in the more severe hand OA patients. These results encourage
conducting a specific trial in hand OA in the next future.
Disclosure: E. Maheu, Expanscience, Genévrier, Genzyme, Pierre Fabre, Rottapharm,
Servier, 9, Expanscience, Ibsa-Genévrier, Rottapharm, TRB-Chemedica, 9; C. Cadet,
Expanscience, Servier, 9, Expanscience, Rottapharm, 9; F. Berenbaum, Expanscience,
Pierre Fabre, Servier, TRB-Chemedica, Rottapharm, Génévrier, 9.
1110
Radiologic Progression in Hand Osteoarthritis (OA) Over 2.6 Years Data From the Sekoia Trial. Emmanuel Maheu1, Christian Cadet2 and
Francis Berenbaum1. 1AP-HP, St Antoine Hospital, Paris, France, 2Rheumatology, Paris, France
Background/Purpose: Hand OA is a frequent polyarticular disease. Few
is known with respect to its radiological progression over time, which in
addition is difficult to assess, considering that no radiographic scoring method
has, today, proved being superior to another. The goal of this study was to
assess hand OA radiological progression over 3 years using three validated
scoring methods.
Methods: Data came from an international 3-year, randomized, placebocontrolled phase III trial designed to assess the effect of strontium ranelate
compared to placebo on the radiographic progression of knee OA which included
symptomatic primary knee OA patients (ACR criteria) at a Kellgren-Lawrence
(KL) grade II or III, with a minimal joint space width (JSW) between 2.5–5 mm.
During this trial, baseline and final postero-anterior radiographs of each hand were
performed. Symptoms were assessed using the functional index for Hand OA
(FIHOA; range 0–30) and the AUSCAN (0–300). Two independent readers
scored half of the pairs of radiographs obtained each, blinded to treatment and
time sequence, using the KL (range 0–128), Kallman (0–204) and Verbruggen
anatomical phase (0–218) scoring methods with a good inter-rater reproducibility.
Hand OA radiographic progression was studied in the placebo group by looking
at 1/baseline-end changes in global scores, 2/the numbers of progressors (progression was defined for each global score by a change over each reader’s
smallest detectable difference (SDD)), and 3/the number of patients in whom at
least 1 joint showed a deterioration (from KL0–1 to KLⱖ2; progression of ⱖ1
phase for Verbruggen score).
Results: Of 1669 patients included in the SEKOIA trial, 999 had
radiologic hand OA: 73%. 297 patients in the placebo group had baseline and
post-baseline radiographs. 72% were female, mean age 64⫾7 years, body
mass index 29.5⫾5 kg/m2, and initial knee JSW 3.5⫾0.8 mm. Baseline hand
OA radiologic severity was mild: KL score 21⫾13, Kallman score 24⫾21
and Verbruggen score 13⫾14. FIHOA score was 4⫾5, Auscan global score
was 96⫹80. Mean time interval between baseline and final radiographs was
31.5 months.
S476
Hand OA radiographic progression over 2.6 years was modest with a
mean change of 2.4⫾3.3 for KL score, 3.7⫾5.3 for Kallman score and
2.0⫾4.0 for Verbruggen score.
The numbers (%) of progressors (changeⱖSDD) were 7 (2%), 17 (6%),
and 21 (7%) respectively.
The numbers (%) of patients with at least 1 worsened joint were 169
(57%) for KL and 139 (47%) for Verbruggen score, with respective means of
2.0⫾1.3 and 1.7⫾1.1 worsening joint.
Conclusion: Whatever the radiological scoring method used, and the kind
of analysis performed, mild radiographic hand OA patients showed a very
weak global radiological progression over 2.6 years. In future structuremodification trials in hand OA, analysing the number of patients with at least
one joint worsening could be the most sensitive method.
Model 2: Individual radiographic features (one multivariate model):
Osteophyte
Grade0
1.0 (ref.)
Grade1
2.4 (1.9-3.0)
Grade2
2.7 (1.9-4.0)
Grade3
2.8 (1.7-4.5)
Joint space narrowing
Grade0
1.0 (ref.)
Grade1
0.9 (0.7-1.1)
Grade2
1.4 (1.0-1.8)
Grade3
1.1 (0.7-1.6)
Erosions
Grade0
1.0 (ref.)
Grade1
1.6 (1.0-2.4)
Malalignment
Grade0
1.0 (ref.)
Grade1
1.6 (1.1-2.2)
Disclosure: E. Maheu, Expanscience, Genévrier,Genzyme, Pierre Fabre, Rottapharm,
Servier., 5, Expanscience, Ibsa-Genévrier, Rottapharm, TRB-Chemedica., 9; C. Cadet,
Expanscience, Servier, 5, Expanscience, Rottapharm, 9; F. Berenbaum, Expanscience,
Pierre Fabre, Servier, TRB-Chemedica, Rottapharm, Genévrier, 9.
Conclusion: Erosive development can strongly predict future joint tenderness, and
the association to tenderness seemed to be independent of MRI-defined BMLs and
synovitis. However, future longitudinal MRI studies are warranted.
1.0 (ref.)
2.1 (1.2-3.7)
1.0 (ref.)
1.0 (ref.)
-
Erosive Evolution in Hand Osteoarthritis Is Associated with Incident
Joint Tenderness Independent of MRI-Defined Bone Marrow Lesions
and Synovitis. Ida K. Haugen1, Barbara Slatkowsky-Christensen1, Pernille
Boyesen1, Sølve Sesseng1, Désirée van der Heijde2 and Tore K. Kvien1.
1
Diakonhjemmet Hospital, Oslo, Norway, 2Leiden University Medical Center, Leiden, Netherlands
Background/Purpose: Previous studies have shown no association
between increased amount of radiographic hand osteoarthritis (OA) resulting
in more hand pain/disabilities. In this longitudinal study, our aim was to study
whether radiographic hand OA was related to joint tenderness in crosssectional and longitudinal settings focusing on joint-specific analyses, and
whether presence of MRI-defined synovitis and bone marrow lesions (BMLs)
at follow-up had an effect on the observed longitudinal associations.
Methods: We included 190 patients (173 women, mean (SD) age 61.5
(5.7) years) from the Oslo hand OA cohort with hand radiographs at baseline,
of which 112 (102 women) had 7-years follow-up data. Of those, 89 had
pre-/post-Gd T1w fs MRIs of the distal (DIP) and proximal interphalangeal
(PIP) joints in the right hand, whereas 101 had STIR images. The bilateral
DIP, PIP and carpometacarpal joints were scored for radiographic OA
according to Kellgren-Lawrence scale and OARSI atlas, whereas the right
hand’s DIP and PIP joints were scored for synovitis and BMLs according to
Oslo hand OA MRI score. Joint tenderness on palpation (absent/present) was
assessed by a rheumatologist. To explore the associations between radiographic hand OA and tenderness in the same joint, we performed uni-/
multivariate logistic regression analyses with Generalized Estimating Equations. In the longitudinal analyses only joints with potential for radiographic
progression and without tenderness at baseline were included. Features that
were associated with tenderness in univariate analyses (p⬍0.20) were
included in a multivariate model and excluded by backward selection. All
analyses were adjusted for age and sex. Using the final multivariate model
from the longitudinal analyses, we did additional adjustment for presence of
MRI-defined synovitis (grade 2–3) and BMLs (grade 1–3) at follow-up (only
DIP and PIP joints in right hand included in these analyses).
Results: Incident erosions seemed to be the most important predictor for
incident tenderness, but also progression of osteophytes and JSN remained in
the final model. Sclerosis and cysts were not associated with tenderness in the
multivariate models, and malalignment remained in the final multivariate
model for cross-sectional data only (table). Associations between radiographic progression of osteophytes, JSN and erosions and incident joint
tenderness were similar after adjustment for BMLs and synovitis at follow-up
(data not shown).
Table. Associations between OA severity and joint tenderness in cross-sectional
analyses and between radiographic progression and incident tenderness in longitudinal analyses (no progression as reference).
Grade0
Grade1
Grade2
Grade3
Grade4
Cross-sectional
analyses
(OR, 95% CI)*
Longitudinal
analyses
(OR, 95% CI)*
1.0 (ref.)
1.4 (1.2-1.7)
3.0 (2.4-3.7)
6.8 (4.5-10)
5.3 (3.3-8.6)
1.0 (ref.)
1.2 (0.7-2.0)
1.5 (0.9-2.5)
5.7 (3.0-11)
11 (4.0-33)
1112
Patients with Erosive Osteoarthritis Have Less Extensive Synovitis Than
Patients with Rheumatoid Arthritis On Histopathology. Allen P. Anandarajah1, Stephen Kates2, Kate Burns3 and Ellen Giampoli4. 1Univ of
Rochester Medical Ctr, Rochester, NY, 2University of Rochester Medical
Center, Rochester, 3University of Rochester, Rochester, NY, 4University of
Rochester Medical Ctr, Rochester, NY
Background/Purpose: Patients with erosive osteoarthritis (EOA) often
develop disfiguring deformities and associated decline in hand function. We
have previously demonstrated that synovitis was a common finding on MRI
and histology in patients with EOA and along with BME were associated with
the presence of erosions, on MRI. Treatment of EOA with anti-rheuamtic
disease modifying drugs and anti-tumor necrosis factor therapies however has
not been successful. We therefore sought to identify the difference on
histopathology between EOA and rheumatoid arthritis (RA).
Objective: To compare the extent of synovial inflammation, inflammatory
cell infiltration, vascularity and lymphoid follicles on histopathology specimens from EOA and RA patients
Methods: This was a single center, retrospective, observational study.
The records of all EOA patients from a cohort of 112 patients were reviewed
for pathology or biopsy of any joint. Patients with a diagnosis of EOA had to
meet the following criteria: (1) OA of hands based on the ACR criteria
(2) erosions in at least 2 interphalangeal joints (IP) of which one must be a
distal IP joint (3) be negative for rheumatoid factor and anti-CCP antibody
(4) negative personal and family history of psoriasis and psoriatic arthritis and
(5) absence of history of gout or pseudogout in hands. These were compared
with synovial specimens from 15 RA patients who had elective orthopedic
surgeries. The synovial tissue was graded on a scale of 0–4 (none, minimal,
mild, moderate and marked) for the presence and degree of synovial lining
hyperplasia, the cellularity of the synovial stroma, extent of inflammatory
infiltrate, degree of vasculairy and the number of lymphoid follicles on
routine hematoxylin and eosin stained slides.
Results: A total of 8 synovial specimens (6 proximal interphalangeal
joints and 2 knees) were obtained from 5 patients for the EOA group and 15
specimens (5 knees, 5 wrists, 2 hips, 1 elbow, 1 shoulder and I proximal
interphalangeal joint) from 14 patients was obtained for the RA group. The
EOA group comprised 4 females and 1 male with a mean age of 60.4 while
the RA group was comprised of 12 females and 2 males with an average age
of 59.5. All RA patients were on therapy: 3 on biologic therapies, 1 on
biologic and methotrexate, 7 on methotrexate monotherapy and 3 on methotrexate and hydroxychloroquine. One of the EOA patients was on hydroxychloroquine and one on methotrexate. Synovial hyperplasia and inflammatory
infiltrate were noted in all RA specimens and in most EOA specimens (7 and
6) but the grading of extent revealed mean scores for hyperplasia and
inflammatory infiltrate of 2.6 and 3.1 respectively for RA and 1.4 and 1.1
respectively for EOA. Synovial stroma cellularity and vascularity were also
common in both conditions (14 of 15 RA and 7 of 8 EOA) but again differed
on the grading from 2.5 and 2.4 for RA and 1.4 and 1 for EOA. The presence
of lymphoid follicles was seen in only 1 EOA patients but noted in 7 RA
subjects.
Conclusion: Synovial hypertrophy, synovial stroma cellularity, vasculiary and inflammatory cell infiltrate are commonly seen in both EOA and RA
but the extent of involvement is less in EOA than in RA. The difference in
S477
Monday, November 12
Disclosure: I. K. Haugen, None; B. Slatkowsky-Christensen, None; P. Boyesen,
None; S. Sesseng, None; D. van der Heijde, None; T. K. Kvien, None.
1111
Model 1: Global score:
Kellgren/Lawrence
1.0 (ref.)
1.6 (1.0-2.4)
pathology may the lack of response in EOA to traditional DMARDs and
anti-TNF therapies.
Disclosure: A. P. Anandarajah, None; S. Kates, None; K. Burns, None; E.
Giampoli, None.
1113
Monday, November 12
Characterization of Lumbar Spine Individual Radiographic Features in
African American and White Women and Men: The Johnston County
Osteoarthritis Project. Adam P. Goode1, Amanda E. Nelson2, Kelli D.
Allen3, Jordan Renner4, Timothy S. Carey5 and Joanne M. Jordan2. 1Duke
University, Durham, NC, 2University of North Carolina Thurston Arthritis
Research Center, Chapel Hill, NC, 3Duke and Durham VA Medical Center,
Durham, NC, 4University of North Carolina, Chapel Hill, NC, 5Cecil G.
Sheps Center for Health Services Research University of North Carolina,
Chapel Hill, NC
Background/Purpose: Race and gender differences have been found
to exist in hip and knee osteoarthritis (OA). Whether such differences
occur with lumbar spine individual radiographic features (IRF) of disc
space narrowing (DSN) and vertebral osteophytes (OST) are unknown.
The purposes of these analyses are to describe differences in the severity
of DSN and OST among African American and Caucasian men and
women.
Methods: Lumbar spine radiographs (DSN and OST) were available
for 1,633 participants returning for second follow-up in the Johnston
County Osteoarthritis Project from 2008-11. Participants had a mean age
68.1 (SD 9.2), and were 68.0% female and 31.7% African American
(AA), with mean body mass index (BMI) 31.4 (SD 7.2). Seventy-eight
percent had ⬎⫽12 years education. Lateral lumbar spine films were
graded for each level in a semi-quantitative fashion (0–3) for DSN and
(0–3) for both anterior superior and inferior OST according to the Burnett
Atlas. Lumbar spine IRF were coded (individually for DSN and superior
and inferior OST) based upon a participant’s most severely affected
lumbar level. For all analyses, AAs were the referent group and results
were stratified by gender. Multivariable associations were determined
with proportional odds models while adjusting for age, BMI, and
education.
Results: After adjustment, White women had a significantly greater
odds of DSN (adjusted Odds Ratio [aOR]⫽ 1.56 ((95% CI 1.23, 1.98))
whereas no significant association was found across race for men (aOR⫽
1.24 ((95% CI 0.86, 1.79)). No association was found across race for
either women (aOR⫽1.00 ((95% CI 0.78, 1.28)) or men (aOR⫽ 1.13
((95% CI 0.78, 1.65)) for superior anterior OST. White women (aOR⫽
1.50 ((95% CI 1.16, 1.95)) and White men (aOR⫽ 1.88 ((95% CI 1.27,
2.77)) both had a greater odds of inferior anterior vertebral OST.
Conclusion: Severity of some lumbar spine IRFs differs by race,
suggesting the possibility of anatomic or developmental variation in the
spine. The greater severity of DSN in White women compared to AA
women is important because this IRF has been consistently associated
with low back symptoms. The fact that both White women and White men
had greater severity of inferior vertebral OST, compared with their AA
counterparts, suggests anatomic racial differences in this region.
Disclosure: A. P. Goode, None; A. E. Nelson, None; K. D. Allen, None; J. Renner,
None; T. S. Carey, None; J. M. Jordan, Algynomics, Inc., 1, Johnson and Johnson, 5,
Johnson & Johnson, 2, Interleukin Genetics, Inc., 5, Eli Lilly and Company, 5, Mutual
Pharmaceutical Company, 5.
1114
Prevalence of Radiographic and Symptomatic Hip Osteoarthritis in an
Urban US Population: The Framingham Osteoarthritis Study. Katherine
D. Linsenmeyer1, Ali Guermazi2, Kyu-Chan Kim1, David T. Felson2, Mary
M. Clancy2 and Steven C. Vlad2. 1Boston Medical Center, Boston, MA,
2
Boston University, Boston, MA
Background/Purpose: There are few studies of hip osteoarthritis (OA) in
the United States and none in the last 35 years that have addressed the
prevalence of hip OA in an urban population. Recent estimates from Europe
suggest that 2–5% of the population age 50 and over has symptomatic hip
OA. Our goal was to assess the prevalence of radiographic and symptomatic
hip OA within the Framingham Osteoarthritis cohort.
Methods: We studied the Community sample of the Framingham
Osteoarthritis study which was recruited among those 50–79 years using
random digit dialing from the town of Framingham in 2002–2005. As part of
this examination standing long-limb radiographs of the lower extremities
including the pelvis were obtained using a near horizontal beam. In addition,
subjects answered questions regarding the presence and frequency of joint
symptoms and indicated on a homunculus whether they had hip joint pain on
most days of the previous month. Two reviewers who received training from
an expert musculoskeletal radiologist read all films and verified abnormal
ones with the radiologist. Films where both hips were unreadable were
excluded. Films were also assessed for Kellgren-Lawrence grade: radiographic OA (ROA) was defined as K/L ⱖ 2 (probable joint space narrowing
plus an osteophyte ’ 2). Interobserver kappas were 0.72 between the readers.
Persons with a hip replacement were defined as having hip OA in that joint
(n⫽22 subjects). Symptomatic hip OA (SxOA) was defined as radiographic
OA with ipsilateral hip pain.
Results: Of 1025 subjects with radiographs, 949 films could be evaluated
in both hips. Mean age was 63.5 years (sd 9.0), 56% were women, mean BMI
was 27.9 (sd 4.6), 98.1% were white. 16.9% had radiographic hip OA (20.8%
of men, 13.8% of women). Of those with ROA, 73.1% were unilateral and
26.9% bilateral. 11.7% of subjects under 65 had ROA (67/571) as compared
to 24.7% of subjects 65 and over (93/376). In subjects with BMI ⬍ 25, 19.3%
(53/276) had ROA; for BMI 25–29.9, 16.3% (66/404) had ROA; for BMI ⱖ
30, 15.2% (41/269) had ROA. Both whites and non-whites had similar rates
of ROA (16.9%). Of those with ROA, 21.9% had hip joint pain, yielding a
SxOA prevalence of 3.7% of the total population (4.3% of men, 3.2% of
women).
Conclusion: Around 1/6 of the subjects in this population-based cohort
had radiographic evidence of hip OA; 3.7% of men and women had
symptomatic OA, an estimate similar to studies from Europe.
Disclosure: K. D. Linsenmeyer, None; A. Guermazi, None; K. C. Kim, None; D. T.
Felson, None; M. M. Clancy, None; S. C. Vlad, None.
1115
Relation Between Hip Dysplasia, Pain, and Osteoarthritis in a Cohort of
Patients with Hip Symptoms. Johanne Morvan1, Ronan Bouttier2, Bernard
Mazieres3, Evelyne Verrouil3, Jacques Pouchot4, Anne-Christine Rat5, Joel
Coste6 and Alain Saraux7. 1CH Quimper, Quimper, France, 2CHU Brest,
Brest, 3Hopital de Rangueil, Toulouse, FRANCE, France, 4Hopital Louis
Mourier, Colombes, FRANCE, France, 5Nancy Teaching Hospital, Nancy,
France, 6Université de Lorraine, Paris Descartes University, APEMAC, EA
4360, F- 54 000, France, Nancy, France, 7Université Brest Occidentale, Brest,
France
Background/Purpose: The relationship between acetabular dysplasia
(HD) and hip osteoarthritis remains unclear, especially for mild forms of
dysplasia. Our objectives were to estimate the prevalence of HD in a
population-based sample with hip symptoms and to evaluate potential
associations linking HD, hip osteoarthritis, and hip pain.
Methods: Individuals 40 to 75 years of age with symptoms in one or
both hips were recruited during a multiregional prevalence survey. All
study participants underwent a physical examination and radiographs.
Radiographs were evaluated using Kellgren and Lawrence (KL) staging
(with stages ⱖ2 indicating hip osteoarthritis) and HD parameters (centeredge [CE] angle, acetabular inclination angle [HTE], acetabular depth
[AD], and vertical-center-anterior margin [VCA] angle).
Results: We studied both hips of 842 individuals (1684 hips) among
whom 203 had hip osteoarthritis. Compared to left hips, right hips had
significantly smaller CE angles and significantly greater AD and HTE
values (Pⱕ0.001). Overall, the prevalence of HD ranged from 7.6% to
22.2% of the hips depending on the parameter used. The prevalence of HD
was higher in individuals with hip osteoarthritis, with significant differences for abnormal HTE (19.1% vs. 11.4%; P⬍0.0001) and abnormal CE
(11.3% vs. 7.5%; P⫽0.04). By logistic regression, only abnormal HTE
remained associated with OA (P⫽0.05). Hip pain was more common in
individuals with HD (P⬍0.0001) but the association was not statistically
significant after stratification on osteoarthritis status (P⫽0.25).
Conclusion: Our study confirms the relationship between osteoarthritis and HD, particularly defined based on the HTE angle. HD was not
associated with hip pain.
Disclosure: J. Morvan, None; R. Bouttier, None; B. Mazieres, None; E. Verrouil,
None; J. Pouchot, None; A. C. Rat, None; J. Coste, None; A. Saraux, None.
S478
1116
Diagnostic Value of Internal Rotation Measurement in Patients with
Cam- and Pincer-Type Deformities of the Hip. Stephan Reichenbach1,
Michael Leunig2, Stefan Werlen3, Andreas Limacher1, Christian W.
Pfirrmann4, Reinhold Ganz1 and Peter Jüni1. 1University of Bern, Bern,
Switzerland, 2Schulthess Clinic, Zurich, Switzerland, 3Hospital Sonnenhof, Bern, Switzerland, 4Balgrist University Hospital, Zurich, Switzerland
Disclosure: S. Reichenbach, None; M. Leunig, None; S. Werlen, None; A. Limacher, None; C. W. Pfirrmann, None; R. Ganz, None; P. Jüni, None.
1117
Association Between Hip Bone Marrow Lesions (BMLs) and Bone
Mineral Density: A Cross-Sectional and Longitudinal PopulationBased Study. Harbeer Ahedi1, Dawn Dore1, Leigh Blizzard1, Flavia
Cicuttini2 and Graeme Jones1. 1Menzies Research institute Tasmania,
University of Tasmania, Hobart, 7000, Australia, 2Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, 3004,
Australia
Background/Purpose: Bone marrow lesions (BMLs) have been
identified one of the key pathologic features in knee osteoarthritis (OA)1.
However, there is limited data on hip BMLs and their relation to bone
mass. The aim of this study was to examine the cross-sectional and
longitudinal association between hip BMLs and BMD at three different
sites.
References
1) Dawn Dore et al. Arthritis Research and Therapy 12(6): R222, 2010
Disclosure: H. Ahedi, None; D. Dore, None; L. Blizzard, None; F. Cicuttini, None;
G. Jones, None.
1118
Association Between Hip and Knee Cartilage Measured Using
Radiographs and Magnetic Resonance Imaging: The Tasmanian
Older Adult Cohort Study. Hussain Ijaz Khan1, Dawn Dore1, Guangju
Zhai2, Changhai Ding3, Jean Pierre Pelletier4, Johanne Martel-Pelletier4,
Flavia Cicuttini5 and Graeme Jones1. 1Menzies Research institute Tasmania, University of Tasmania, Hobart, 7000, Australia, 2Discipline of
Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John’s, NL, 3Menzies research institute & Monash University,
Hobart, Australia, 4Osteoarthritis Research Unit, University of Montreal
Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal,
QC, 5Department of Epidemiology and Preventive Medicine, Monash
University, Melbourne, 3004, Australia
Background/Purpose: Cartilage loss is the key pathological
feature of osteoarthritis (OA) and can be assessed indirectly using
radiography or directly through magnetic resonance imaging (MRI). A
number of cross-sectional studies have examined the association of
hand OA with hip or knee OA, suggesting that primary generalised
OA (PGOA) may be a distinct disease in which systemic predisposition
is more important than local (mechanical) factors. However, despite
the high frequency of involvement of the hip and the knee joints in OA,
only a few studies have looked at the radiographic association of joint
space narrowing (JSN) in these two joints with inconsistent results. None
has done so using MRI. The aim of this study was to examine the
association of hip and knee cartilage measured by both radiography and
MRI.
Methods: We studied 151 participants from a cohort study of older
adults. MRI was used to assess hip and knee cartilage volume and
radiography was used to asses JSN at both sites. Correlation analyses were
used to compare cartilage volume measurements and JSN.
Results: In adjusted analysis, there was a consistent, positive association between knee cartilage volume and hip cartilage volume which was
best for total knee cartilage volume (R⫽ 0.23–0.50, all P⫽ ⬍0.05). In
contrast, there was no or at best a weak correlation between hip and knee
JSN (R⫽ ⫺0.01–0.24).
S479
Monday, November 12
Background/Purpose: It has been proposed that femoroacetabular
impingement (FAI) causes early osteoarthritis (OA) in non-dysplastic
hips. FAI occurs predominantly in two different types, ”cam” or ”pincer”.
Cam impingement is due to a cam-type deformity with a non-spherical
femoral head and/or a decreased anterior head-neck offset. Pincer impingement results from increased acetabular depth with over-coverage of
the femoral head, while the head-neck configuration may be normal. FAI
is often seen in young male athletes referred to rheumatologists or
orthopaedic surgeons because of groin pain, and internal rotation in
flexion is usually diminished. The aim of this study was to determine
whether diminished internal rotation can be used to detect FAI in young
asymptomatic males.
Methods: Study subjects were young males aged 18 to 21 undergoing
compulsory conscription for the Swiss army. Participants completed
questionnaires pertaining to pain, stiffness, and physical function, and
internal rotation was measured on a validated examination chair. A
random sample of the examined participants was invited for magnetic
resonance imaging (MRI) of the hip. Cam-type deformities were graded
from 0 to 3: 0⫽normal, 1⫽mild, 2⫽moderate, 3⫽severe. Pincer impingement was defined by increased acetabular depth, which was specified as
the distance (in mm) between the center of the femoral neck and the line
connecting the anterior and posterior acetabular rims. Values were
positive if the center of the femoral neck was lateral to the acetabular rim,
with ⱕ3 mm representing increased acetabular depth. Based on a fitted
receiver operating characteristics (ROC) curve, we estimated sensitivity,
specificity, positive and negative likelihood ratios (LR) for different
internal rotation cutoffs for cam impingement, pincer impingement, and
the combination of both, as compared with the reference group without
deformity on MRI.
Results: 244 asymptomatic males underwent imaging, with a mean
age of 19.9 years. Fifty-nine subjects showed definite cam-type deformity,
eight increased acetabular depth, and eight a combination of both. Area
under ROC-curves were 0.725 for detection of the first group, 0.549 for
detection of the second, and 0.895 for detection of the third group as
compared with the reference group. A cut-off value of 30° of internal
rotation yielded a sensitivity of 0.63 and a specificity of 0.69 for the first
group, 0.13 and 0.69 for the second, and 1.00 and 0.69 for the third. An
internal rotation of ⱖ30° had sufficient power to rule out the combination
of both types of impingement: the crude negative likelihood ratio (LR)
was below 0.10. Conversely, an internal rotation of ⱕ20° had the required
power to rule in the combination of both types of impingement, with a
positive LR of 12.7.
Conclusion: Different cut-offs for internal rotation may be used to
accurately rule in or rule out the combination of cam- and pincer-type
impingement. Internal rotation is not useful for detecting pincer-type
impingement.
Methods: 198 subjects in the Tasmanian Older Adult Cohort (TASOAC) study (average age 64 yrs) with a right hip MRI and dual-energy
x-ray absorptiometry (DXA) scans conducted at two time points, approx.
2.6 years apart, were included in this study. MR images were used to
assess femoral and acetabular hip BML presence and size (cm2) by
manually drawing contours around the outer edges of the BML using
Osiris X (Geneva) software. DEXA scans were used to determine total
hip, femoral neck and spine BMD.
Results: Fifty-five subjects (28 %) had either femoral and/or
acetabular BMLs. In cross-sectional analysis, femoral BMLs were not
associated with either hip or femoral neck BMD whereas acetabular
BMLs were associated with lower hip BMD and femoral neck BMD
(mean diff: ⫺0.05 g/cm2, p⫽0.009 & mean diff: ⫺0.06 g/cm2, p⬍0.001
resp.). Neither was associated with spine BMD. Longitudinally, resolving
acetabular BMLs were associated with an increase in BMD at both hip
(mean diff: ⫹0.02 g/cm2, p⫽0.05) and femoral neck (mean diff: ⫹0.01
g/cm2, p⫽0.02) sites while incident femoral BMLs were associated with
an increase (mean diff: ⫹0.03 g/cm2, p⬍0.001) and resolving femoral
BMLs with a decrease in femoral neck BMD (mean diff: ⫺0.04 g/cm2,
p⫽0.04). Finally, change in femoral BML size was associated with
change in femoral neck BMD (␤eta: ⫹0.03, p⬍0.001) and change in
acetabular BML size was associated with change in femoral neck BMD
(␤eta: ⫺0.01, p⫽0.004).
Conclusion: Hip BMLs are associated with site-specific changes but
not distant changes in bone mass. These results, especially in the
longitudinal data, suggest this is a combination of changes related directly
to the underlying BML pathology as well as changes adjacent to the
disease process perhaps due to pain, disuse or paracrine effects.
Monday, November 12
ing age, sex, K-L grade, effusion, and knee pain provided the highest
prediction accuracy (C-statistic 0.533) for any cartilage loss occurring in at
least one subregion. The best models for prediction of at least within-grade
cartilage loss of ⱖ2 or ⱖ3 included the same variables, i.e., age, sex, K-L
grade and knee pain (C-statistics⫽0.561 for ⱖ2, and 0.571 for ⱖ3 subregions). Risk of full-grade cartilage loss in ⱖ1, ⱖ2, or ⱖ3 subregions was
38.8%, 18.8% and 9.7%, respectively. The same variables were included for
predicting cartilage loss of a full grade in ⱖ1, or ⱖ2, or ⱖ3 subregions as
those for at least within-grade loss. The corresponding C-statistics were 0.559,
0.599, and 0.615 (Figure 1), respectively.
Figure 1. Correlation between hip cartilage volume and total knee cartilage
volume. Line of best fit, R-value and p-value were adjusted for age and sex.
Conclusion: Hip and knee cartilage volume are more strongly associated
than hip and knee radiographic JSN suggesting commonality of cartilage
volume at different anatomic sites. The weaker radiographic association may
reflect less measurement error with MRI or the contribution of multiple
structures to JSN in the knee.
Disclosure: H. I. Khan, None; D. Dore, None; G. Zhai, None; C. Ding, None; J. P.
Pelletier, ArthroLab Inc., 4, Bioibérica S.A., 5; J. Martel-Pelletier, ArthoLab Inc, 2,
Servier, France, 5; F. Cicuttini, None; G. Jones, None.
1119
Prediction of MRI-Detected Cartilage Loss Over 30 Months Using
Simplified Radiographic and Clinical Stratification: The MOST
Study. Frank Roemer1, David T. Felson2, Jingbo Niu2, Yuqing Zhang3,
Michael C. Nevitt4, Michel Crema3, Cora E. Lewis5, James Torner6 and
Ali Guermazi7. 1Klinikum Augsburg, Augsburg, Germany, 2Boston Univ
School of Medicine, Boston, MA, 3Boston University, Boston, MA,
4
University of California-San Francisco, San Francisco, CA, 5University
of Alabama, Birmingham City, Birmingham, AL, 6University of Iowa,
Iowa City, Iowa City, IA, 7Boston University School of Medicine,
Boston, MA
Background/Purpose: MRI-detected cartilage loss is the main structural outcome measure in large studies of knee OA. Definition of subjects
at high risk for cartilage loss is important as this subgroup is likely to
benefit most from interventional efforts and will potentially reduce subject
numbers and duration of clinical trials. A simple stratification strategy is
needed for pre-selecting subjects at high risk. We assessed a set of
potential factors in regard to their predictive capability of cartilage loss
over 30 months.
Methods: The Multicenter Osteoarthritis (MOST) Study is a longitudinal study of subjects with knee OA or at risk of OA. 1.0 T MRI was
performed at baseline and 30 months follow-up in subjects with radiographic knee OA at baseline. MRIs were assessed according to the
WORMS scoring system including within-grade assessment. Altogether
10 tibiofemoral subregions were scored. Cartilage loss was defined as at
least within-grade increase in cartilage score in ⱖ1, ⱖ2, or ⱖ3 subregions. Analyses were repeated with cartilage loss defined as full grade
increase. Six predictors that are commonly acquired in screening efforts,
i.e., gender, age, BMI, Kellgren Lawrence (K-L) grade (0–1, 2, 3–4),
joint effusion (0–1, 2–3) and knee pain (pain on most days during the past
30 days or maximal WOMAC pain score as 0, 1–2, 3–4) were assessed
using a 10-fold cross-validation method. The cross-validation was repeated 10 times, and averaged receiver operating characteristics (ROC)
curve, i.e., C-statistic, was calculated as a measure of the overall
performance. Age and sex were forced in all models. We plotted the ROC
curves for each variable selected in the final model according to crossvalidation method.
Results: Of 544 knees randomly selected from the progression cohort,
risk of at least within-grade cartilage loss occurring in ⱖ1, or ⱖ2, or ⱖ3
subregions was 53.6%, 31.6%, and 18.1%, respectively. The model contain-
Conclusion: Among knees with radiographic OA, age, sex, K-L grade
and knee pain only had the moderate capability of predicting cartilage loss. Of
them the strongest predictors were baseline K-L grade, followed by knee pain.
The prediction accuracy of this model needs to be further validated using
large databases from other populations.
Disclosure: F. Roemer, Boston Imaging Core Lab, 1, National Institute of Health, 5,
Merck Serono, 5; D. T. Felson, None; J. Niu, None; Y. Zhang, None; M. C. Nevitt,
None; M. Crema, Shareholder Boston Imaging Core Lab, LLC, 1; C. E. Lewis, None;
J. Torner, None; A. Guermazi, Boston Imaging Core Lab, 1, Stryker, 5, Merck
Serono, 5, Genzyme Corporation, 5, AstraZeneca, 5, Novartis Pharmaceutical Corporation, 5.
1120
Cartilage Volume Loss Occurs in Most Older Adults and the Rate of
Loss Increases with Age. Andreea M. Harsanyi1, Dawn Dore1, Changhai
Ding1, Jean-Pierre Pelletier2, Johanne Martel-Pelletier2, Flavia Cicutinni3 and
Graeme Jones1. 1Menzies Research institute Tasmania, University of Tasmania, Hobart, 7000, Australia, 2Osteoarthritis Research Unit, University of
Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital,
Montreal, QC, 3Monash University, Melbourne, Australia, Melbourne, Australia
Background/Purpose: Radiographic data suggests knee osteoarthritis is
a relatively static disease even over the long term. It is uncertain how much
this is influenced by measurement error and whether it accurately reflects
what is happening to the cartilage. Initial cross-sectional studies suggest little
S480
Disclosure: A. M. Harsanyi, None; D. Dore, None; C. Ding, None; J. P. Pelletier,
ArthroLab Inc., 4; J. Martel-Pelletier, ArthroLab Inc., 4; F. Cicutinni, None; G.
Jones, None.
1121
Degenerative Medial Meniscal Pathology May Initiate in the Posterior
Horn: Data From the Osteoarthritis Initiative. Robert J. Ward1, Jeffrey B.
Driban1, Eric E. Wong1, Jonathan W. Pack1, Kunal K. Kothari2, Grace H. Lo3
and Timothy E. McAlindon1. 1Tufts Medical Center, Boston, MA, 2Tufts
University School of Medicine, Boston, MA, 3Michael E. DeBakey Veterans
Affairs Medical Center, Houston, TX
Background/Purpose: Meniscal pathology is highly prevalent in knee
Osteoarthritis (OA). However, details regarding the distribution of pathology within the meniscus has yet to be described in patients with and
without radiographic signs of OA. Cross-sectional distribution of medial
meniscal pathology as it relates to the anterior horn, body, and posterior
horn may be informative of the role of the meniscus in the natural history
of OA.
Methods: We studied participants in the Osteoarthritis Initiative
(OAI) progression subcohort who had the OAI core set of magnetic
resonance (MR) images at the 24-month OAI visit and consented to
participate in the Bone ancillary project. By definition, members of the
progression subcohort had at least one symptomatic knee with radiographic evidence of OA.. The right knee was selected as the index knee for
investigation among these participants unless there was a contraindication
for MR imaging; therefore, the index knee did not have OA as a
pre-requisite. A single experienced fellowship trained musculoskeletal
radiologist reviewed the MR images for meniscal pathology by location
(e.g. anterior, body, and posterior horn) within the medial menisci using
a modified International Society of Arthroscopy, Knee Surgery, and
Orthopaedic Sports Medicine (ISAKOS) meniscal tear classification
system. We presented the prevalence of meniscal pathology within the
medial meniscus among this sample both with and without knee OA. PA
standing radiographs were obtained of the same knees and read for
Kellgren-Lawrence grade.
Results: 464 knees were included in the analysis; 454 were right
knees; 244 (53%) men, with a mean age of 63 years (SD). 135 (29.4%)
knees had no radiographic evidence of knee OA (Kellgren-Lawrence
Grade ⫽ 0 or 1). 114 (24.6%) had normal medial menisci, leaving 350
(75.4%) with some pathology in at least one region of the medial menisus.
117 (25.2%) knees had pathologic anterior medial menisci and among
those 98.3% had concurrent findings in the body or posterior horn. 272
(58.6%) medial menisci have pathologic findings in the meniscal body and
among those 97.4% had concurrent findings in the anterior or posterior
meniscal horn. 336 (72.4%) medial menisci had pathologic findings in the
posterior meniscus and among those 263 (78.3%) had concurrent findings
in the body or anterior regions. Finally, 107 (23.1%) had pathologic
findings in all three regions (regardless of type of finding).
Conclusion: Medial meniscal pathology is highly prevalent. In our
sample, of those with medial menisci pathology some damage was also
almost universally found in the posterior horn. Those with posterior horn
damage also very commonly had concurrent pathology in the body and
anterior horn. Isolated involvement of the anterior horn and body of the
medial meniscus are rare. Though this is a cross-sectional study, these
findings suggest that medial meniscal pathology may initiate in the posterior
horn. Longitudinal studies are needed to confirm this possibility.
Disclosure: R. J. Ward, None; J. B. Driban, None; E. E. Wong, None; J. W. Pack,
None; K. K. Kothari, None; G. H. Lo, None; T. E. McAlindon, None.
1122
Identifying Radiographic Phenotypes of Early Knee Osteoarthritis Using
Separate Quantitative Features Might Improve Patient Selection for
More Targeted Treatment. Margot B. Kinds1, Anne C. A. Marijnissen1,
Max A. Viergever1, P.J. Emans2, J.W.J. Bijlsma1, F.P.J.G. Lafeber1 and
P.M.J. Welsing1. 1University Medical Center Utrecht, Utrecht, Netherlands,
2
Maastricht University Medical Center, Maastricht, Netherlands
Background/Purpose: Osteoarthritis (OA) is a degenerative joint disease
characterized by pain and functional disability. The expression of OA varies
significantly between individuals and over time, implying the existence of
different phenotypes. This study aims at identifying phenotypes of progression of radiographic knee OA and to describe their radiographic and clinical
characteristics.
Methods: In individuals with early knee OA from the Cohort Hip &
Cohort Knee (CHECK), baseline, two-year, and five-year follow-up radiographs were evaluated. Separate radiographic OA parameters were quantitatively measured by Knee Images Digital Analysis (KIDA). To identify
phenotypes of radiographic knee OA progression, hierarchical clustering was
performed using the KIDA measurements of participants with complete data
at T0, T2y, and T5y (n⫽417 of 1002). The phenotypes were compared for
development of joint space width (JSW), varus angle, osteophyte area,
eminence height, bone density, and for clinical characteristics at T0. Additionally, logistic regression analysis evaluated whether baseline radiographic
features predicted to which phenotype an individual belonged.
Results: Overall, the radiographic features showed OA progression
during follow-up. Based on the development, five clusters were identified that
were interpreted as ‘severe’ (n⫽17; most progression of all radiographic
features) or ‘no’ (n⫽108) progression, ‘early’ (n⫽110; progression of all
features specifically between T0 and T2y) or ‘late’ (n⫽69; progression of all
features specifically between T2y and T5y) progression, or specific involvement of ‘bone density’ (n⫽113). Clinical characteristics at T0 were not
evidently different between the clusters, and WOMAC scores were only
slightly lower in the ‘no’ cluster than in the other clusters. In the evaluation
of predictors for the different clusters, the area under the curve (AUC)
improved when radiographic features were added to basic demographic and
clinical variables. Kellgren & Lawrence grading was not a significant
predictor for any of the phenotypes. The predictors for ‘early’, ‘late’, and ‘no’
progression phenotypes generally had an opposite effect than the predictors
for the ‘severe’ and ‘bone density’ phenotypes. Larger medial JSW, varus
angle, osteophyte area, eminence height, and bone density at T0 were
associated with ‘severe’ and ‘bone density’ progression. The ‘bone density’
model had AUC⫽0.91. Smaller eminence height and bone density were
associated with ‘early’ and ‘late’ progression (AUC⫽ 0.79, and 0.76
respectively). Larger varus angle and smaller osteophyte area were associated
with ‘no’ progression (AUC⫽0.72).
Conclusion: This is the first study to identify specific phenotypes of
radiographic knee OA progression in individuals with early OA complaints.
Phenotypes represented the level (severe vs. no) and phase of progression
(early vs. late), and the involvement of a specific feature (bone density).
Baseline radiographic features could predict the phenotypes. The phenotypes
might represent relevant subgroups for the evaluation of treatment strategies
in clinical trials, and with that drive the discovery of more targeted treatment.
Disclosure: M. B. Kinds, None; A. C. A. Marijnissen, None; M. A. Viergever, None;
P. J. Emans, None; J. W. J. Bijlsma, None; F. P. J. G. Lafeber, None; P. M. J.
Welsing, None.
S481
Monday, November 12
change in cartilage volume with age but a decrease in thickness. However,
longitudinal studies in younger age groups suggest the rate of cartilage
volume loss increases with age. There are no longitudinal studies in older age
groups.
The aim of this study was to describe cartilage loss over time and the
association between age and knee cartilage volume loss in older adults.
Methods: A total of 407 randomly selected community-dwelling older
adults (mean age 63.2 years, range 51–79 years; 50% female) were measured
at baseline and approximately 2.7 years later. T1-weighted fat-suppressed
magnetic resonance imaging (MRI) was used to measure knee cartilage
volume at the tibial and femoral sites. Body mass index (BMI) and
radiographic osteoarthritis (ROA) were measured by standard protocol. A real
change in volume loss was assessed using the least significant criterion which
takes into account measurement error and the correlation between measurements at baseline and follow up.
Results: On average, participants had 1.5% per annum tibiofemoral
cartilage volume loss. Of the 407, 74% had a decrease larger than measurement error while, 14% which had a genuine increase in volume and only 12%
were unchanged. After adjustment for sex, BMI and ROA, age was significantly associated with annual decrease in medial and total tibial (␤ ⫺0.08 to
⫺0.13%/yr, all P⬍ 0.008) but not lateral tibial cartilage volume (␤ ⫺0.03%/
yr, P⬎0.05). In addition, age was associated with a decrease in medial and
lateral femoral cartilage volume in males (␤ ⫺0.05 to ⫺0.06%/yr, all P
⬍0.01) but not females (␤ ⫺0.001 to 0.005%/yr, P ⬎0.05).
Conclusion: Knee cartilage volume is rarely static even over a three year
time frame. The majority of subjects lose cartilage and this rate of loss
increases with age. These findings suggest radiographs are not sensitive
measures of changes in cartilage volume and challenge the view that
osteoarthritis is largely static over time.
1123
Monday, November 12
Comparison of Anatomic Knee Alignment On Physical Examination and
Radiographs. Iman Hemmati1, Eric C. Sayre2, Ali Guermazi3, Savvakis
Nicolaou1, Anona Thorne4, Joel Singer1 and Jolanda Cibere2. 1University of
British Columbia, Vancouver, BC, 2Arthritis Research Centre of Canada,
Vancouver, BC, 3Boston University, Boston, MA, 4Canadian Institutes of
Health Research HIV Trials Network, Vancouver, BC
Background/Purpose: Severity of knee malalignment is a risk factor
for osteoarthritis (OA) progression. Currently the hip-knee-angle (mechanical axis), assessed on a full-limb radiograph, is the gold standard.
Direct measurement of the anatomic axis using standard knee radiographs
has been validated as an alternative method. In clinical practice, examining knee alignment with a goniometer may be more practical. The aim of
the current study was to 1) evaluate the correlation of knee alignment
angle measured by goniometer on physical examination with the anatomic
angle measured on knee radiographs and 2) to evaluate whether the
relationship is confounded by clinical variables that may affect goniometric measurements.
Methods: A simple random sample (n⫽120) was selected from the
MoDEKO (Model for the Diagnosis of Early Knee Osteoarthritis) cohort,
a population-based cohort of people with knee pain, age 40–79. Knee
alignment was measured to the nearest degree by two methods: 1)
anatomic-axis on fixed-flexion PA knee radiographs and 2) standardized
goniometer assessment on physical examination, previously shown to be
reliable. In this study varus was defined as angle ⬍ 0, valgus ⬎ 0 and 0°
as neutral. On PA radiographs anatomic axis was defined by the
intersection of two lines originating from points bisecting the femur and
tibia and converging at the centre of tibial spine tips. Inter- and intra-rater
reliability of anatomic angle measurements from radiographs were determined by intraclass correlation coefficient (ICC) of two independent
assessors. The correlation of radiographic anatomic angle with goniometer
measurements was analyzed by linear regression. Western Ontario and
McMaster Universities (WOMAC) pain score, body mass index (BMI)
and flexion contracture were assessed as potential confounders. Analysis
was weighted by stratum sampling weights.
Results: Of 120 subjects, 52% were male, with mean (SD) age of 58 (11)
years and BMI of 27 (5). The mean (SD) angle measured on PA radiographs
and goniometer were 2 (3.6) and 3 (2.3) degrees respectively. Intra-rater ICC
for radiographic measurements was 0.93, while inter-rater ICC was 0.83. A
significant correlation was found between radiographic and goniometer
measurements (r ⫽ 0.48; P ⬍ 0.0001). A model was developed to predict
anatomic angle based on goniometer angle: anatomic angle on PA radiographs ⫽ 0.410 ⫹ 0.749*goniometer angle. WOMAC pain score, BMI and
flexion contracture were not significantly associated with PA radiographic
angle and did not significantly change the correlation of radiographic and
goniometric measurements, and so these variables were dropped from the
model.
Conclusion: In this study, knee alignment assessed by goniometer was
significantly correlated with the anatomic axis angle on fixed-flexion PA knee
radiographs. Moreover, factors such as pain, BMI and flexion contracture did
not confound the relationship of goniometric with radiographic angle measurements. Given the ease of application, goniometric measurements may be
preferable to x-ray, although the predictive utility of goniometric alignment
measurement will require further assessment in longitudinal studies of knee
OA.
Disclosure: I. Hemmati, None; E. C. Sayre, None; A. Guermazi, None; S. Nicolaou,
None; A. Thorne, None; J. Singer, None; J. Cibere, None.
1124
Total Knee Replacement As an Osteoarthritis Study Outcome: Predictors Derived From Long-Term Observation Following a Randomized
Clinical Trial. Jean-Pierre Raynauld1, Johanne Martel-Pelletier1, Marc Dorais2, Boulos Haraoui1, Denis Choquette1, François Abram3, André Beaulieu4, Louis Bessette5, Frédéric Morin6, Lukas M. Wildi1 and Jean Pierre
Pelletier7. 1Osteoarthritis Research Unit, University of Montreal Hospital
Research Centre (CRCHUM), Montreal, QC, 2StatSciences Inc., Notre-Dame
de l’Île Perrot, QC, 3Imaging Research & Development, ArthroLab Inc.,
Montreal, QC, 4Faculty of Medicine, Laval University, Quebec, QC, 5Centre
Hospitalier Universitaire de Québec, pavillon CHUL, Sainte-Foy, QC, 6Centre de Recherche Musculo-squelettique, Trois-Rivières, QC, 7Osteoarthritis
Research Unit, University of Montreal Hospital Research Centre
(CRCHUM), Notre-Dame Hospital, Montreal, QC
Background/Purpose: Using data from a 4-year follow-up of knee
OA patients who formerly received treatment with chondroitin sulfate
(CS) within a 6-month clinical trial, we wanted to find predictors of the
incidence of total knee replacement (TKR).
Methods: Knee OA patients participating in a randomized, doubleblind controlled trial evaluating the impact of CS (Bioibérica S.A.,
Barcelona, Spain) (400 mg BID) vs. placebo who had serial MRI
acquisitions (qMRI) and clinical evaluations of the symptomatic knee[1]
were contacted to evaluate retrospectively the incidence of TKR of the
study knee. A sub-group of patients (n⫽57) who received the study
medication and had all the MRI evaluations (intent to treat (ITT)) were
selected for this post hoc retrospective analysis. The TKR incidence was
assessed blindly to the treatment allocation with a standardized phone
interview.
Results: The patients’ mean age was 63.2 years, 63% were female and
the average body mass index (BMI) was 30.7 kg¨ Mm2. A total of 13
TKRs (22.8%) were performed on this sub-population in the time frame of
4 years after completion of the original study. Interestingly, there were
more TKRs performed within the placebo group (n⫽9) than the CS group
(n⫽4) (69% vs. 31%, p⫽0.15, logistic regression). We further investigated the predictors of long-term TKRs for the target knee by comparing,
within the ITT cohort, the patients who had TKR (n⫽13) for the target
knee to those who did not (n⫽44), using data at baseline or the change at
1 year. Baseline values of WOMAC pain (p⫽0.01, logistic regression)
and function (p⫽0.04), bone marrow lesions (BMLs) in the medial tibial
plateau (p⫽0.0008) and global knee (0.02), and C-reactive protein (CRP)
level (p⫽0.05) were strong predictors of TKR. Changes at 1 year in the
medial cartilage volume higher than 7% (p⫽0.03) and the change in
WOMAC pain (p⫽0.02) and function (p⫽0.02) also predicted the
occurrence of TKR. Multivariate analyses controlling for age, sex, and
BMI revealed that baseline presence of BML (p⫽0.003) and WOMAC
pain (p⫽0.006) were independent strong predictors of TKR. Time to
occurrence of the TKR from the study inception also favored the CS group
vs. placebo (Log-Rank, p⫽0.14). Cox regressions that included age, sex,
and BMI in the model indicated that baseline values of WOMAC pain
(p⫽0.0006), presence of BML in the medial compartment (p⫽0.0007)
and CRP (p⫽0.02) were the strongest independent predictors of TKR over
time.
Conclusion: Treatment with CS appeared to reduce the need for TKR.
There are very few OA RCTs that use qMRI to probe knee structural
outcomes. According to this study, predictors of long-term occurrence of
a TKR were greater levels of knee pain, lower level of function and
presence of BML at baseline, and greater loss of cartilage over time. This
study links MRI findings to long-term clinical outcomes.
Reference
[1] Wildi LM, et al. Ann Rheum Dis 2011;70(6):982-9
Disclosure: J. P. Raynauld, ArthroLab Inc., 4; J. Martel-Pelletier, ArthroLab Inc., 4, Bioibérica S.A., 5; M. Dorais, ArthroLab Inc., 5; B. Haraoui,
ArthroLab Inc., 9; D. Choquette, ArthroLab Inc., 9; F. Abram, ArthroLab Inc., 3;
A. Beaulieu, ArthroLab Inc., 9; L. Bessette, ArthroLab Inc., 9; F. Morin,
ArthroLab Inc., 9; L. M. Wildi, None; J. P. Pelletier, ArthroLab Inc., 4, Bioibérica
S.A., 5.
1125
Three Trajectories of Activity Limitations in Early Symptomatic
Knee Osteoarthritis: A 5-Year Follow-up Study. Jasmijn F. M. Holla1,
Marike van der Leeden1, Leo D. Roorda1, Martijn W. Heymans2, Sita
M.A. Bierma-Zeinstra3, Maarten Boers2, Willem F. Lems2, Martijn P.M.
Steultjens4 and Joost Dekker2. 1Reade, Amsterdam, Netherlands, 2VU
University Medical Center, Amsterdam, Netherlands, 3Erasmus MC University Medical Center, Rotterdam, Netherlands, 4Glasgow Caledonian University, Glasgow, Scotland
Background/Purpose: Knee osteoarthritis (OA) is one of the leading
causes of activity limitations among older adults. The course of activity
limitations is highly variable; some patients seem to be stable or even
improve, whereas others deteriorate. The aim of the present study was to
identify subgroups of knee OA patients with different trajectories of
activity limitations, and to describe patient characteristics for each
subgroup.
S482
the effect of time and the effect of progression in course of pain and
function.
Results: Data of 688 CHECK participants with knee pain at baseline were
analyzed, mean age 56 years, BMI 25 kg/m2 and 79% female. The subgroup
of OAI Incidence cohort with infrequent or frequent knee pain consisted of
1417 participants, with a mean age of 56, BMI of 28 kg/m2and 64% female.
At baseline CHECK had less radiographic OA (K&L ⱖ 2) compared to OAI
Incidence subgroup, but at follow-up CHECK had more radiographic progression (42% vs 15% of at least 1 K&L point increase; p⬍ 0.001). A final
longitudinal regression model with pain as outcome showed slight decrease of
course of pain in both cohorts, but a consistent lower level of course of pain
in OAI Incidence subgroup of 2 points (better health). In a final model with
function as outcome, in both cohorts there is a slight decrease of physical
function, but a consistent higher level of function of 10.2 points (worse health)
in CHECK. There is no different effect of time in course of pain (p⫽ 0.7) and
function (p⫽0.06) for CHECK or OAI. There is also no different effect of
progression of joint damage on course of pain and function (both p⫽0.07) for
CHECK or OAI.
Conclusion: In the total group, participants of the OAI Incidence
subgroup and the CHECK participants with knee pain, there is a slight
decrease over time in pain and physical functioning. In CHECK participants
more progression of joint damage over time was observed and these
participants recorded a higher level of pain and function problems. Difference
between the 2 cohorts in course of pain and function could not be explained
by the effect of time or of progression of joint damage on pain and function.
Disclosure: J. F. M. Holla, None; M. van der Leeden, None; L. D. Roorda, None;
M. W. Heymans, None; S. M. A. Bierma-Zeinstra, None; M. Boers, None; W. F.
Lems, None; M. P. M. Steultjens, None; J. Dekker, None.
Background/Purpose: Altered tibiofemoral (TF) joint kinematics and
joint surface interactions have been linked with development and progression of knee osteoarthritis (OA). However, accurate in-vivo investigations
of the TF joint mechanics in patients with knee OA have been difficult to
perform due to limitations of conventional techniques. This study sought
to accurately characterize TF joint kinematics and the interactions of the
articulating joint surfaces using high-speed dynamic stereo x-ray (DSX)
technology during the loading phase of downhill walking in older adults
with and without knee OA.
Methods: Eleven subjects with knee OA and 10 subjects without OA
participated in this study. Subjects with knee OA were included if they
demonstrated a Kellgren and Lawrence radiographic OA severity of at
least grade II or higher. High speed DSX images were acquired during the
loading phase of a moderately declined walking condition (7% grade, 0.75
m/s) on an instrumented treadmill. Computerized tomography images
were also taken to create subject-specific 3D bone models of the distal
femur and proximal tibia. A previously validated model-based tracking
algorithm was employed to determine 3D joint motion by matching the
radiographic images with projections through the volumetric bone models.
The anterior/posterior (AP) and medial/lateral (ML) positions of the TF
joint contact points were estimated using the distance-weighted centroids
of the region of closest bony proximity in both the medial and lateral TF
compartments. ML and AP contact path lengths were determined by
subtracting the minimum from the maximum AP and ML contact
positions. In addition, the total contact path was determined as the
algebraic summation of the ML and AP translations of the contact points
in each compartment.
Results: Compared to the control group, subjects with knee OA
contacted the ground with more knee flexion but moved through less
flexion range of motion. Conversely, subjects with knee OA moved
through more knee adduction range of motion despite contacting the
ground with a near neutral frontal plane knee alignment. Additionally,
the OA group demonstrated longer ML and total contact path lengths for
the medial TF compartment and a longer ML contact path for the lateral
TF compartment. rate of OA progression. Intervention strategies to
improve knee flexion during loading while limiting excessive frontal plane
motion and joint translations should be considered.
1126
Comparison between Osteoartritis Initiative and CHECK study (Cohort
Hip & Cohort Knee); Development of pain and function during 4 years
follow-up. Janet Wesseling1, Sita M.A. Bierma-Zeinstra2, Margreet Kloppenburg3, Johannes WJ Bijlsma1 and CHECK steering group4. 1University
Medical Center Utrecht, Utrecht, Netherlands, 2Erasmus MC - University
Medical Center, Rotterdam, Netherlands, 3Department Rheumatology and
Department of Clinical Epidemiology, Leiden University Medical Centre,
Leiden, The Netherlands, Leiden, Netherlands, 4Utrecht
Background/Purpose: Pain and disability related to osteoarthritis (OA)
may generally be considered to be chronic, but it is known that its course can
be very different between patients. In this study, it is investigated whether
there is a difference in course of pain, physical function and radiographic
damage during follow-up between two OA cohorts: Osteoarthritis Initiative
(OAI) and Cohort Hip & Cohort Knee study (CHECK).
Methods: For the current study, longitudinal data of four years
follow-up of the CHECK study and OA Initiative were used. The CHECK
study is a Dutch prospective 10-year follow-up study, initiated by the
Dutch Arthritis Association, to study progression of OA in participants
with early symptomatic OA of knee or hip. Individuals were eligible if
they had pain of knee or hip, were aged 45–65 years, and had not yet
consulted their physician for these symptoms. In the same time in the U.S.
an observational 4-year follow-up study was started to create a public
archive of data, biological samples and joint images to study the natural
history of, and risk factors for, the onset and progression of knee OA. The
WOMAC was utilized to measure pain during activities (range 0–20) and
physical functioning (range 0–68). For comparison with CHECK a
subgroup of the OAI Incidence cohort was selected which was comparable
with the CHECK cohort. Generalized estimating equations (GEE) were
used to account for correlations within individuals and all models were
adjusted for gender, BMI, age, amount of working hours and baseline
radiographic joint damage. Interaction terms were investigated to measure
Disclosure: J. Wesseling, None; S. M. A. Bierma-Zeinstra, None; M. Kloppenburg,
None; J. W. Bijlsma, None;
1127
Dynamic Stereo X-Ray Evaluation of Knee Joint Mechanics During
Downhill Walking in Subject with Knee Osteoarthritis. Shawn Farrokhi,
Carrie A. Rainis, G. Kelley Fitzgerald and Scott Tashman. University of
Pittsburgh, Pittsburgh, PA
S483
Monday, November 12
Methods: Five-year follow-up data from a sample of 713 participants
with early symptomatic knee OA from the Cohort Hip and Cohort Knee
(CHECK) were used. Activity limitations were measured yearly with the
physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Latent class growth analyses
(LCGA) were used to identify trajectory classes of activity limitations.
Multivariable logistic regression analyses were used to examine differences in demographic, clinical and psychological characteristics between
the trajectory classes.
Results: The LCGA yielded 3 trajectory classes for activity limitations. Participants in class 1 (‘slight limitations’; n ⫽ 336) reported
permanent low levels of activity limitations, or moved from moderate or
high levels at baseline to low levels of activity limitations over 5 years.
Participants in class 2 (‘moderate limitations’; n ⫽ 261) reported
permanent moderate levels of activity limitations, or moved from fairly
high or fairly low levels to moderate levels of activity limitations over 5
years. Participants in class 3 (‘severe limitations’; n ⫽ 116) reported
permanent high levels of activity limitations, or moved from low or
moderate levels of activity limitations to high levels of activity limitations
over 5 years. Participants in class 1 (‘slight limitations’) were more likely
to have a lower BMI, to have less than 3 comorbidities, to report a lower
level of knee pain, no to have hip pain, not to have joint space narrowing,
and to feel more vital, compared with participants in class 2 (‘moderate
limitations’) (AUC: 0.75). Participants in class 3 (‘severe limitations’)
were more likely to report a higher level of knee pain, to have bilateral
knee pain, to have osteophytosis, to feel less vital, and to avoid physical
activities (AUC: 0.76).
Conclusion: Three trajectory classes of activity limitations were identified using 5-year follow-up data of 713 participants with early symptomatic
knee OA: ‘slight limitations’; ‘moderate limitations’; and ‘severe limitations’.
The ‘slight limitations’ group was characterized by a lower BMI, a lower
comorbidity count, lower levels of knee pain, not having hip pain, not having
joint space narrowing, and high vitality. The ‘severe limitations’ group was
characterized by higher levels of knee pain, bilateral knee pain, osteophytosis,
low vitality, and avoidance of physical activities.
Table 1. Means and standard deviations for subject demographics, knee joint
kinematics and tibiofemoral compartment contact path translations during the
loading phase of downhill gait.
Monday, November 12
Control (n ⴝ 10)
Age (years)
67.8 ⫾ 5.1
Sex (% female)
60%
2
BMI (Kg/m )
25.0 ⫾ 2.2
Knee Flexion
Position @ Heel Contact (degrees)
0.01 ⫾ 3.8
Total Joint Excursion (degrees)
10.2 ⫾ 5.1
Knee Adduction(ⴚ)/Abduction(ⴙ)
Position @ Heel Contact (degrees)
0.5 ⫾ 3.6
Total Joint Excursion (degrees)
0.9 ⫾ 0.4
Knee External Rotation (ⴚ)/Internal Rotation (ⴙ)
Position @ Heel Contact (degrees)
⫺2.2 ⫾ 5.9
Total Joint Excursion (degrees)
4.3 ⫾ 2.0
Medial Compartment Contact Path
Anterior/Posterior Distance (mm)
3.0 ⫾ 1.9
Medial/Lateral Distance (mm)
0.4 ⫾ 0.3
Total Distance (mm)
4.0 ⫾ 1.9
Lateral Compartment Contact Path
Anterior/Posterior Distance (mm)
3.5 ⫾ 2.4
Medial/Lateral Distance (mm)
0.6 ⫾ 0.3
Total Distance (mm)
4.2 ⫾ 2.6
OA (n ⴝ 11)
69.6 ⫾ 8.0
72%
30.4 ⫾ 5.3*
7.7 ⫾ 8.7*
7.0 ⫾ 4.5*
⫺0.6 ⫾ 8.3
2.0 ⫾ 1.6*
combined. Comparison of differences between the larger subgroups was then
performed.
Results: Group 1a and Group 1b, Group 2a and Group 2b, Group 3a and
Group 3b were no different from each other (p-values ⬎ 0.1). Each of these
pairs was then collapsed into three respective subgroups. The results between
remaining subgroups are summarized in Table 1 below. There were significant differences in the adjusted mean WOMAC pain scores at each OAI visit
between the referent group (i.e., unchanging no/some pain) and the unchanging frequent pain subgroup, the worsening pain subgroups and the improving
pain subgroups.
Table 1. Comparisons of Adjusted Mean WOMAC Pain Scores of the Knee Pain
Trajectories
Knee Pain Frequency
⫺1.4 ⫾ 9.3
4.1 ⫾ 2.6
Baseline
M12
3.2055*
2.2147
M24
M36
M48
P for change over time
between groups
Unchanging Pattern
4.2 ⫾ 2.6
1.3 ⫾ 1.4*
6.2 ⫾ 2.9*
2.9 ⫾ 1.6
1.2 ⫾ 0.9*
4.6 ⫾ 2.0
*Statistically significant differences (p ⬍ 0.05)
Conclusion: Consistent with previous reports, subjects with knee OA
contacted the ground with more knee flexion. However, findings from this
study further suggest that individuals with knee OA also move through less
knee flexion range of motion which can adversely affect shock absorption.
Additionally, individuals with knee OA demonstrated signs of frontal plane
TF joint instability (excessive adduction motion and ML translation) and a
longer medial TF compartment translation which can negatively impact the
Disclosure: S. Farrokhi, None; C. A. Rainis, None; G. K. Fitzgerald, None; S.
Tashman, None.
1128
Different of Patterns Knee Pain Trajectories: Longitudinal Data From
the Osteoarthritis Initiative (OAI). Joseph Devich Jr.1, Michael J. Hannon2, Zhijie Wang2, Robert M. Boudreau3 and C. Kent Kwoh4. 1UPMC
Shadyside, Pittsburgh, PA, 2University of Pittsburgh School of Medicine,
Pittsburgh, PA, 3University of Pittsburgh, Pittsburgh, PA, 4University of
Pittsburgh and VA Healthcare System, Pittsburgh, PA
Background/Purpose: Knee osteoarthritis (KOA) is one of the most
common forms of arthritis and the most common cause of disability
among the elderly. Knee pain is the presenting symptom of KOA, and
symptomatic knee KOA is defined as “frequent knee pain” (pain on most
days of at least one month in the past 12 months) and radiographic KOA.
There is little data, however, on changes in knee pain over time. The
purpose of this study was to identify whether there were different patterns
of knee pain trajectories over four years of follow-up using data from the
Osteoarthritis Initiative (OAI).
Methods: We studied 7,543 knees from OAI from baseline to 48 months
(OAI public use data sets 2.1 and 2.2). Knee pain trajectories were based on
the following knee pain reports at each visit: “No Pain” (no pain or aching in
the past 12 months)⫽0, “Some Pain” (pain but not frequent pain)⫽1, or
“Frequent Pain” (as above)⫽2. Unchanging subgroups had knees with same
pain report at each visit: Group 1a, always 0; Group 1b, always 1; and Group
1c, always 2. Worsening subgroups had knees with consistent progression to
worse pain: Group 2a for knees going 0--⬎(1)--⬎2; Group 2b 1--⬎2; and
Group 2c 0--⬎1. Improving subgroups had knees with consistent progression
to less pain: Group 3a for knees going from 2--⬎(1)--⬎0; Group 3b 2--⬎1;
and Group 3c 1--⬎0. Fluctuating knee pain patterns (i.e., alternating between
0, 1 or 2 from visit to visit) were excluded from this analysis. To reduce the
chances that a fluctuating knee was misclassified, for the worsening and
improving subgroups, knees had to have two time points at the initial level of
lower/higher pain or two time points at the final lower/higher level, respectively. Knee-specific WOMAC pain scores across the five visits were
compared within each knee pain group using GEE (STATA 11.2) with each
model adjusted for age, sex, race, educational level, depression, hand OA, and
BMI. Subgroups within a group that were not distinct from each were
Always 0 (n ⫽ 717) or Always 1
(n ⫽ 434)
Always 2 (n ⫽ 606)
2.4398
2.4167
2.2598
28.5385* 28.1584*
29.8006*
29.7471*
29.1578*
0.332, 0.004, 0.001,
0.031
reference
9.2034* 10.374*
12.1654
14.7872*
17.5806*
⬍ 0.001 all time points
2.3214
3.2002
4.1065*
0.247, 0.146, ⬍ .001, ⬍
.001
Worsening Pain
03(1)32 (n ⫽ 200) or 132
(n ⫽ 231)
031 (n ⫽ 316)
Improving Pain
23(1)30 (n ⫽ 171) or 231
(n ⫽ 291)
130 (n ⫽ 220)
2.3465*
1.788
15.8499* 12.7436*
4.4188*
2.3249
11.5562
9.2976*
7.3585*
⬍ 0.001 all time points
2.1787
1.3796
0.7486
0.005, ⬍ .001, ⬍ .001,
⬍ .001
*Different at p ⬍ .05 from all other groups, Tukey pairwise adjustment.
Where:
0 ⫽ “No Pain”
1 ⫽ “Sometimes Pain”
2 ⫽ “Frequent Pain”
Conclusion: We have been able to define distinct knee pain trajectories of
unchanging, worsening and improving knee pain. Further work is underway
to better characterize these groups. Better understanding of these knee pain
trajectories may help to identify subgroups to target for specific interventions.
Disclosure: J. Devich Jr., None; M. J. Hannon, None; Z. Wang, None; R. M.
Boudreau, None; C. K. Kwoh, AstraZeneca, 2, Beverage Institute, 2.
1129
Prevalence of Symptomatic Basilar Thumb Joint Osteoarthritis in the
General Population. Jennifer Moriatis Wolf1, Aleksandra Turkiewicz2,
Isam Atroshi3 and Martin Englund2 1University of Connecticut Health
Center, Farmington, CT, 2Department of Orthopedics, Clinical Sciences
Lund, Lund University, Lund, Sweden, 3Lund University, Hässleholm,
Sweden
Background/Purpose: While the radiographic prevalence of basilar
thumb osteoarthritis (OA) is well described, little is known about whether this
translates to clinically symptomatic arthritis. The purpose of this study is to
determine the prevalence of physician-diagnosed thumb carpometacarpal
(CMC) arthritis.
Methods: Using healthcare register data from Skåne County, in southern
Sweden (predominantly Caucasian population 1.3 million), we identified all
adults aged 20 years or older who consulted a physician at least once and were
given a diagnosis code for OA of the first CMC joint (ICD-10 code M18).
Data were analyzed over the 13-year period between 1999 and 2011. Using
cross-referencing with the Swedish population register to exclude subjects
who were deceased or had relocated out of the county by end of year 2011,
we obtained frequencies and point prevalence estimates by age and gender.
The population was reduced with 20% to compensate for the loss of patients
seen by the private care practitioners exclusively (ICD-10 codes partially
forwarded to the register).
Results: The point prevalence of physician-diagnosed symptomatic OA
of the basilar thumb joint in adults was estimated to 1.3% overall (2.0% in
women and 0.57% in men). The prevalence peaked in women aged 65–74
with prevalence of 5.3%. The corresponding peak in men was in men aged
75–84 with a prevalence of 1.7%.
Conclusion: In a well-defined population, the clinically important prevalence of basilar thumb OA is substantially higher in women than men, with
peak prevalence in women between 60–79 years of age. Thumb base OA can
have a large impact on function and activities of daily living, and the high
prevalence in elderly women and men is a health and economic concern in an
aging population.
S484
1131
Intraarticular Infliximab for Knee Osteoarthritis: High Baseline
Levels of Synovial Cellularity and High MRI Cartilage Injury At the
Lateral Tibial Plateau Predict Improvement in Total WOMAC Score.
Jeremy R. Schue1, Ossama Tawfik1, Rebecca Bolce2, Donald D. Smith1,
Gary Hinson1, Jo A. Wick1 and Herbert B. Lindsley1. 1Kansas University
Med Ctr, Kansas City, KS, 2Crescendo Bioscience Inc., South San
Francisco, CA
1130
The Effect of Age On the Number of Osteoarthritis Flares with Continuous Versus Intermittent Celecoxib Treatment. George H. Sands. Pritha
Bhadra and Margaret Noyes Essex, Pfizer, Inc, New York, NY
Background/Purpose: Continuous nonsteroidal anti-inflammatory drug
(NSAID) treatment is significantly more efficacious than intermittent dosing1
during 22-weeks in preventing flares in patients with osteoarthritis (OA) of
the knee or hip who have successfully treated an initial flare. The objective
was to characterize the effect of age on efficacy, as measured by the number
of flares, of continuous daily celecoxib treatment versus intermittent celecoxib
treatment.
Methods: An exploratory analysis of a multinational, randomized clinical
trial1was conducted to determine if the number of OA flares during the
blinded postrandomization period was different for patients aged ⬍ or ⱖ 60
years. In the trial, 858 patients aged 18 to 80 years with OA of the knee or hip,
meeting American College of Rheumatology criteria, were randomized to
receive celecoxib 200 mg qd either as “continuous” (daily) or “intermittent”
(celecoxib 200 mg qd when needed to treat OA flare meeting predefined
criteria) treatment. Analyses were performed on the intention-to-treat (ITT)
population (ⱖ 1 dose of study medication post-randomization) and flaremodified ITT population (all patients meeting criteria for ITT population plus
having flare durations ⱕ 14 ⫹ 2 days), using a 2-sided type I error rate of
0.05.
Results: Mean ages were 51.3 and 67.2 years in the 2 continuous
treatment groups (n ⫽ 236 and n ⫽ 195, respectively) and 51.2 and 66.7 years
in the 2 intermittent treatment groups (n ⫽ 220 and n ⫽ 207, respectively).
For patients aged ⬍ 60 years, 0.50 flares/month (SD 0.60) were reported in
the group receiving continuous treatment, while 0.89 flares/month (SD 0.98)
were observed in those receiving intermittent treatment (P ⬍ 0.0001). For
patients aged ⱖ 60 years, the continuous treatment group had 0.59 flares/
month (SD 0.87) compared with 0.97 flares/month (SD 1.04) in the intermittent group (P ⬍ 0.0001). These results are consistent with the primary
results.1
In the flare-modified ITT population, patients aged ⬍ 60 years receiving
continuous treatment had 0.45 flares/month (SD 0.61) vs 0.87 flares/month
(SD 1.15) for the intermittent group (P ⬍ 0.0001). The older flare-modified
ITT population (ⱖ 60 years) had similar results: 0.55 flares/month (SD 1.02)
vs 1.02 flares/month (SD 1.22) for the continuous and intermittent groups,
respectively (P ⫽ 0.001). The mean number of flares was significantly lower
in the continuous group than in the intermittent group irrespective of whether
the patients were aged ⬍ or ⱖ 60 years.
Conclusion: Daily celecoxib treatment was significantly more efficacious, as assessed by the number of flares/month, than intermittent use,
irrespective of whether the patients were aged ⬍ or ⱖ 60 years. These data
may be useful in considering the treatment of OA patients aged ⱖ 60 years.
Reference
1. Strand V, et al. J Rheumatol. 2011;38:2625-34.
Conclusion: BL characteristics of the subjects responsive to IA
anti-TNF therapy included those with higher WOMAC scores, more
abnormal cartilage MRI scores at the lateral compartment, and higher
levels of inflammatory cells, including T lymphocytes and macrophages,
as well as more blood vessels, Cox 2 and IL-1␤ expression. In subjects
with higher WOMAC scores and higher levels of synovial inflammation
IA IFX offers promise as a symptomatic intervention.
Disclosure: G. H. Sands, Pfizer Inc, 3; P. Bhadra, Pfizer Inc, 3; M. Noyes Essex,
Pfizer Inc, 3.
Disclosure: J. R. Schue, None; O. Tawfik, None; R. Bolce, Janssen Services, LLC, 3;
D. D. Smith, None; G. Hinson, None; J. A. Wick, None; H. B. Lindsley, Janssen
Services, 2.
S485
Monday, November 12
Disclosure: J. M. Wolf, None; A. Turkiewicz, None; I. Atroshi, None; M. Englund,
None.
Background/Purpose: Synovial tissue from patients with OA often
demonstrates inflammation. We hypothesized that a single intraarticular
(IA) injection of an anti-TNF drug would decrease inflammatory cell
infiltration (primary outcome) and ultimately reduce articular injury.
These data were drawn from the infliximab (IFX) group, part of a larger
study presented previously (ACR Ann Mtg, Chicago 2011; EULAR Ann
Mtg, Berlin 2012). The results noted below represent new findings.
Methods: The original pilot study was a single center, 2:1:1 (IFX:
MP:P) randomization, double-blind, placebo-controlled IA treatment of
knee OA: infliximab (IFX) 100 mg, methylprednisolone (MP) 80 mg or
saline (P) on Day 0. Subjects (n⫽16) had to have knee pain and show
minimal to moderate OA on knee radiographs. Demographics for IFX
group: Age 54 (IQR 44–62) Race AA/C⫽3/5; Gender F/M⫽5/3; BMI
28.9 (IQR 23.1–31.4). Closed needle synovial biopsies and PBMCs for
flow cytometry were obtained on Days 0 and 28. Total WOMAC scores
and blood samples were obtained on Days 0, 14, 28 and 56. MRI of the
target knee was obtained before Day 0. Statistics: nonparametric Wilcoxon test and Spearman correlation coefficient.
Results: Total WOMAC score improved significantly only for Group
IFX, comparing baseline (BL) to Day 56 (p⬍0.05). The BL total
WOMAC scores were greater in the high vs low cellularity subgroups.
When comparing subjects with high vs low cellularity (4 each), significant
improvement (p⬍0.05) occurred only in the high cellularity subgroup
(See Fig). The high cellularity subgroup had higher scores (p⬍0.02) for
inflammatory intensity, mononuclear cells (CD68⫹ cells, CD3⫹ cells),
blood vessels, Cox-2 expression and IL-1␤ expression. No significant
baseline differences between the high and low subgroups were noted for
synovial TNF␣, IL-6, IL-17, or CD54⫹ cells, or serum levels of CRP,
SAA, IL-6, TNF␣, MMP-3 or COMP. BL PBMC biomarkers were
compared for differences between high and low cellularity subgroups; two
cell subsets trended higher (p⫽0.097) in the high cellularity subgroup: B
cells and low-MFI CD14 CXCR3 monocytes. Higher BL Total WOMAC
scores correlated with lower CD14 MFI (p⫽0.067, R⫽-0.67); no such
correlation was noted with TNF␣, MMP-3 or COMP. Circulating levels of
IFX peaked at Day 4 with a Cmax of 6.1 ug/ml in 6 subjects; two subjects
with detectable anti-IFX Ab had a lower Cmax of 1.6 ug/ml; Cmax did not
differ between the two subgroups (5.5 vs 4.3 ug/ml).
1132
1
Monday, November 12
Prevalence of Knee Pain in Ultramarathon Runners. Victoria M. Kelly ,
Martin Hoffman2, Bharathi Lingala1, Mihoko Bennett1 and Eswar Krishnan1.
1
Stanford University, Palo Alto, CA, 2Department of Veteran’s Affairs,
Northern California Health Care System and University of California Davis
Medical Center, Sacramento, CA
Background/Purpose: Approximately one in four Americans suffer from
frequent knee pain. While some studies have linked long-distance running
with the risk for knee pain, others have not observed such associations. Since
the proposed mechanism of such a link involves mechanical stress to the
joints, greater lifetime running miles should be associated with a greater risk
for knee pain and an earlier age of onset. We tested these expectations by
cross sectional analysis of data from the baseline questionnaire of a new
cohort of ultramarathon runners.
Methods: The ULTRA study is a cohort of runners who have participated
in at least one ultramarathon race (ⱖ50 kilometers) in their lifetime. This
study has been enrolling participants since November 2011. For the purposes
of this analysis, “knee pain” was defined as “any knee pain in the past 6
months”, as there were almost no individuals with chronic-frequent knee pain
in this cohort of high functioning individuals. To assess the impact of mileage
on knee pain, we performed a logistic regression model, where the dependent
variable was knee pain and independent variables were quartiles of lifetime
running distance, age, body mass index (BMI) and current running status.
Ex-runners were defined as those who have not run regularly in the preceding
12 months.
Results: Of the 1,083 runners included in the present analysis, 68% were
men and 6% were classified as ex-runners. The mean age, and BMI were 44
years and 27 kg/square meters respectively. After adjusting for age, gender
and BMI, the prevalence of knee pain was higher in those with lower lifetime
mileage, both in runners and ex-runners. Overall rates of knee pain did not
differ between runners and ex-runners (47% vs. 48%), and confidence
intervals overlapped significantly for knee pain within each mileage group
(see Figure). In the logistic regression model, runners in the highest distance
quartile (⬎25,000 miles) were the least likely to report knee pain, OR 0.5 (CI
0.4–0.8), suggesting that lifetime running distance is inversely correlated with
knee pain.
Methods: 25 subjects with mild radiographic hip OA (KellgrenLawrence grade 2) were identified from an IRB approved repository of gait
and radiographic data. 12 had been enrolled in a study of subjects with
symptomatic unilateral hip OA and 13 came from a database of asymptomatic
subjects. Demographics and BMI were similar between the two groups
(Table). Gait analysis was performed with standard published methods:
participants completed 3 trials per limb walking at a self-selected normal
speed. Kinematics and kinetics were calculated from marker positions and
ground reaction forces. Standard inverse dynamics methods were used. The
variables of interest were speed, dynamic hip range of motion, and peak 3D
external moments normalized to body weight times height (%BWxHt). Data
were averaged for the 3 trials. T-tests were used to compare gait variables
between the two groups.
Results: Walking speeds were not significantly different between the two
groups (Table). The peak adduction and internal rotation moments were 17%
and 29% lower in the symptomatic OA group compared to the asymptomatic
group (p⫽0.017 and p⫽0.044, Table). The external rotation moment was
26% lower in the symptomatic group (trend p⫽0.059). No other comparisons
were statistically significant.
Table. Comparisons between subjects with mild radiographic hip OA who are
symptomatic vs. asymptomatic
Variable
Symptomatic
Asymptomatic
p Value
Age (years)
BMI (kg/m2)
Sex
‘Normal’ walking speed (m/s)
Dynamic sagittal plane hip
range of motion (degrees)
Peak Flexion Moment (%BW
⫻ Ht)
Peak Extension Moment
(%BWxHt)
*Peak Adduction Moment
(%BWxHt)
Peak Abduction Moment
(%BWxHt)
*Peak Internal Rotation
Moment (%BWxHt)
Peak External Rotation
Moment (%BWxHt)
53 ⫾ 6
26 ⫾ 3
9 Female/3 Male
1.16 ⫾ 0.20
29.2 ⫾ 7.4
58 ⫾ 10
28 ⫾ 5
11 Female/2 Male
1.20 ⫾ 0.11
30.8 ⫾ 6.3
0.166
0.198
0.548
0.615
0.568
5.15 ⫾ 1.48
5.85 ⫾ 1.30
0.221
2.37 ⫾ 0.61
2.64 ⫾ 0.99
0.427
3.53 ⴞ 0.84
4.27 ⴞ 0.60
0.017
1.84 ⫾ 0.81
2.05 ⫾ 1.02
0.587
0.53 ⴞ 0.19
0.75 ⴞ 0.29
0.044
0.44 ⫾ 0.13
0.60 ⫾ 0.26
0.059
* bold text indicates p⬍0.05.
Conclusion: Subjects with mild symptomatic radiographic hip OA had
different gait than subjects with mild radiographic OA alone. Notably,
walking speeds were similar between groups. Thus gait differences observed
were not attributable to slower speeds in the symptomatic group. The
adduction, internal rotation, and external rotation moments, which each reflect
aspects of hip abductor function, were reduced in the symptomatic group.
This suggests that this muscle group plays an important role in early
symptomatic OA. Further, these results support previous speculations that
pain may be an initial stimulus that initiates joint loading alterations in hip and
knee OA1,2.
Conclusion: Knee pain was more common among low mileage runners;
the causal direction of this association can be ascertained in prospective
studies. There was no difference in overall knee pain between current and
ex-runners.
References
1
Shakoor et al., Osteoarthritis Cartilage 18(Supp 2): S67, 2010.
2
Thorp et al., Arthritis & Rheumatism. 57: 1254–60, 2007.
Disclosure: V. M. Kelly, None; M. Hoffman, None; B. Lingala, None; M. Bennett,
None; E. Krishnan, None.
Acknowledgement: Rush Translational Science Consortium/Searle Foundation Pilot
Projects Grant
1133
Disclosure: S. S. Chabra, None; N. Shakoor, None; K. C. Foucher, None.
Gait Differences Are Present in Subjects with Symptomatic Vs. Asymptomatic Mild Radiographic Hip Osteoarthritis. Samir S. Chabra1, Najia
Shakoor2 and Kharma C. Foucher2. 1University of Illinois at Chicago,
Chicago, IL, 2Rush University Medical Center, Chicago, IL
1134
Background/Purpose: It is known that joint mechanics are involved in
the hip osteoarthritis (OA) disease process. In a previous study1, several gait
variables were lower in subjects with symptomatic hip OA compared to
asymptomatic controls. In the OA subjects gait variables were significantly
correlated with radiographic OA severity but not pain. It remains unclear,
however, whether structural changes or clinical symptoms initiate the gait
changes associated with hip OA. In this study we tested the hypothesis that
gait variables are different in people with symptomatic radiographic hip OA
compared to those with radiographic changes but no symptoms.
What Are the Levels of Physical Activities and Their Associations with
Quality of Life in Patients with Symptomatic Hip and/or Knee Osteoarthritis? Irawati Lemonnier1, Anne Vuillemin2 and Anne-Christine Rat3.
1
Lorraine Université Paris Descartes University, EA 4360 Apemac, Nancy,
France, Nancy, France, 2Universite de Lorraine, Paris Descartes University,
EA 4360 Apemac, Nancy, France, Nancy, France, 3Université de Lorraine,
Paris Descartes University, APEMAC, EA 4360, F- 54 000, Nancy, France
Background/Purpose: Physical activities (PA) practice is recommended
by numerous public health organizations. According to international recommendations, patients with hip and knee osteoarthritis (OA) should be
encouraged to undertake more specific activities: regular aerobic, muscle
S486
Disclosure: I. Lemonnier, None; A. Vuillemin, None; A. C. Rat, None.
1135
Combined Glucosamine and Chondroitin Sulfate, Once of Three Times
Daily, Provide Clinically Relevant Analgesia in Knee Osteoarthritis. Jose
R. Provenza1, Samuel K. Shinjo2, Joyce M. Silva3, Carla RGS. Peron4 and
Francisco AC Rocha5. 1Pontifı́cia Universidade Católica de Campinas,
Campinas, Brazil, 2Faculdade de Medicina da Universidade de São Paulo,
Sao Paulo, Brazil, 3Sao Paulo, Brazil, 4Laboratórios Aché Ltda, Sao Paulo,
Brazil, 5Federal University of Ceara, Fortaleza, Brazil
Background/Purpose: The analgesic efficacy of combined glucosamine
and chondroitin sulfate (CS) in knee osteoarthritis (OA) remains controversial. Criticism to previous studies includes small sample size, short term
evaluation and lack of intent-to-treat (ITT) analysis. Glucosamine sulfate
(GS) or hydrochloride (GH) formulations and dosing schedule relevance are
also not clearly defined.
Methods: 1,120 subjects with radiographic knee OA (Kellgren/Lawrence
grades 2–3) and moderate-severe knee pain flare after analgesic washout were
randomized (1:1:1) at 16 centers in Brazil to receive GS 500mg/CS 400mg
three times daily capsules (GI) or once daily sachet (GII), or GH 500mg/CS
400mg three times daily capsules (GIII) for a 16 week trial. Acetaminophen
up to 3,750mg daily was a rescue medication. Primary outcome (ITT) was
patient reported pain intensity in the affected knee and variation of
Lequesne’s index (LI) at 16 weeks. Monthly secondary outcomes were mean
changes from baseline in patient reported pain and LI, patient and physician
global assessments of disease activity, acetaminophen consumption, and
adherence. Sample size calculation considered a non-inferiority evaluation
allowing a difference of less than 1.7 points in the LI and a decrease of pain
less than 18mm in GI and GII, as compared to GIII. Safety evaluations were
done at each monthly visit.
Results: The ITT population comprised 302, 301, and 306 patients in GI,
GII and GIII, respectively, and 911 patients for safety. Demographic data
were equally comparable in all groups. The criterion for non-inferiority
analysis of GI and GII in relation to GIII, based on confidence interval (95%),
was met for pain intensity and LI. The mean of pain reduction (GI:
⫺30.9⫾1.5; GII: ⫺28.7⫾1.5; GIII: ⫺29.7⫾1.5 mm) was significant for all
groups at week 16 (P⬍0.001). Similarly, the mean of LI decrease was
significant in all groups (GI: ⫺3.8⫾0.2; GII: ⫺3.7⫾0.2; GIII: ⫺3.9⫾0.2)
(P⬍0.001). Moreover, reduction of acetaminophen consumption (⫺5, ⫺3,
and ⫺5 weekly tablets for GI, GII, and GIII, respectively) was also significant
in all groups (P⬍0.005). Withdrawal rate was 18.2%, 19.3%, and 19.3% for
GI, II, and III. Patients that did not complete the study were 77 (44.8%) for
lack of adherence, 16 (9.3%) consent withdrawal, 11 (6.4%) adverse events,
8 (4.7%) lost to follow-up, and 17 (9.9%) for other causes.
Conclusion: This is the largest study showing that GS/CS and GH/CS
provide clinically meaningful and sustained analgesia in knee OA regardless
of dose fractionation. GS/CS (capsule or sachet) and GH/CS formulations are
equally effective and safe to treat symptomatic knee OA.
Disclosure: J. R. Provenza, None; S. K. Shinjo, Federico Foundation, 2; J. M. Silva,
None; C. R. Peron, None; F. A. Rocha, None.
1136
Aesthetic Dissatisfaction in Hand Osteoarthritis Patients, Its Impact
and Risk Factors. R. Liu, L.J.J. Beaart-van de Voorde, T.W.J. Huizinga and
M. Kloppenburg. Leiden University Medical Center, Leiden, Netherlands
Background/Purpose: Hand osteoarthritis (HOA) leads to aesthetic
damage and is rarely studied. We aim to investigate in HOA patients the
prevalence of dissatisfaction with the appearance of their hands, the impact
and its risk factors.
Methods: Cross-sectional data were used of the ongoing HOSTAS (Hand
OSTeoArthritis in Secondary care) study, in which consecutive patients are
included, that are diagnosed by the treating rheumatologist with primary
HOA. Participants underwent physical examination to assess number of joints
with bony joint enlargements (0–30), deformities (0–22) and limitation in
mobility (0–22).
The Michigan Hand Outcomes (MHQ) questionnaire involves a pain
(range 0–100, higher scores⫽more pain) and an aesthetic scale, which
measures satisfaction (range 1–5, lower scores⫽more dissatisfaction) with the
appearance of the hands and its impact, namely discomfort in public,
depression and/or the interference with normal social activities (range 3–12,
lower scores ⫽ more impact). A score of ⬍3 was considered as dissatisfaction
and a score of ⬍9 as experiencing impact. Scores for right and left hand were
averaged.
Disability was assessed by the functional index for HOA (FIHOA)
(0–30). Anxiety (0–21), depression (0–21) and illness perceptions were
assessed with the Hospital Anxiety and Depression scales (HADS) and Illness
Perception Questionnaire (IPQ), respectively.
Odds Ratio (OR) with 95% confidence intervals (CI) were calculated
using multivariate logistic regression as measures of relative risk for reporting
dissatisfaction with appearance or impact due to dissatisfaction of the
appearance, adjusted for age, sex and BMI.
Results: Of 226 patients (87% women, mean age 61.5 yrs, median
symptom duration 5.2(range 0.1– 58.7) yrs) 93% met ACR criteria for HOA.
25% were aesthetically dissatisfied and only 4% reported impact due to
dissatisfaction. Mean pain score was 44 (SD 19) and median FIHOA score
was 8 (range 0–24). Median depression and anxiety scores were 4 (range
0–18) and 2 (range 0–17), respectively.
Pain (OR 1.02 (1.00–1.04)), disability (OR 1.07 (1.01–1.12)), deformities
(OR 1.24 (1.11–1.37)), number of joints with limitation in mobility (OR 1.05
(1.01–1.08) and the illness perception scale which involves negative feelings
towards OA (OR 1.08 (1.02–1.15)) were associated with dissatisfaction, as
well as with impact.
Bony joint enlargements (OR 1.09 (1.01–1.17)) and illness perception
(belief in OA as a chronic disease) (OR 1.12 (1.01–1.23)) were associated
with dissatisfaction, but not with impact.
Depression (OR 1.32 (1.13 –1.55)), anxiety levels (OR 1.37 (1.14 –1.64))
and illness perceptions (the belief in more severe consequences as a result of
OA, less understanding of OA and attributing more psychological factors to
their disease) were associated with impact.
Conclusion: HOA patients who consult secondary care report regularly
aesthetic dissatisfaction with their hands. However, this dissatisfaction has
negative impact only in a small group of patients, who also experiences more
S487
Monday, November 12
strengthening and range of motion exercises. However, the level of PA
practice in patients with symptomatic hip and/or knee OA in a real setting is
not well known and associations between PA practice and quality of life
(QoL) should be clarified. The aim of the study was to study 1.the level of PA
practice in patients with symptomatic hip and/or knee OA in a real setting 2.
the associations between PA practice and QoL in patients with symptomatic
hip and/or knee OA.
Methods: The 878 patients of the KHOALA (Knee and Hip OsteoArthritis Long term assessment) cohort were included in the study. KHOALA
cohort is a multiregional population based study of patients aged 45–75 years
with symptomatic knee or/and hip OA. The MAQ (modifiable activity
questionnaire) was used to measure the PA during the past year. It includes 2
scores: the numbers of hours spend weekly for physical activities in leisure
activities (PAL) and in professional activities (PAP). QoL was measured by
a generic questionnaire, the SF-36; pain, function, and clinical data by the
Index of Severity for Knee (ISK) and the Harris hip score. All measures were
completed at baseline. Multivariate linear-regression models were constructed
to identify the associations between PA and QoL. The models were adjusted
on OA functional and pain scores, age, sex, BMI, current smoking status,
current employment status and occupation during their life.
Results: Among the 878 patients, 222 had hip OA, 607 knee OA and 49
both. Patients with hip and knee OA were slightly older (64.7⫹8) than those
with knee (62⫹8.5) or hip OA only (61.2⫹8.8). The average body mass
index was 26.9⫹4.4 and 30.3⫹6.2 for patients with hip and knee OA
respectively. 67 and 71% of the patients were women in hip and knee OA
respectively. The level of PAP was of 25 hours a week in patients with hip or
knee OA only and was lower (20 hours a week) in patients with both hip and
knee OA. The level PAL was of 5.6, 6.2, 6.5 hours a week for hip OA, knee
OA and both respectively. No relation was observed between physical
activities level and QoL in patients with hip OA. For patients followed for
knee OA, more hours spend on leisure activities were associated with better
mental health (p⫽0.001), role emotional (p⫽0.02), social functioning
(p⫽0.04) and vitality (p⬍0.001) scores in multivariate analyses. The number
of hours spent on professional activities by patients who suffered from both
hip and knee OA were associated with lower role emotional (p⫽0.03) and
social functioning (p⫽0.04) scores.
Conclusion: These results suggest that more hours spend weekly on
leisure activities may positively affect patients with symptomatic knee and/or
hip OA independently of pain, function and sociodemographic variables. The
associations are found for mental state and social functioning. On the other
hand, physical activities for professional reasons seemed to be associated with
more difficulties in social functioning of patients with both hip and knee OA.
pain, depression and anxiety and negative illness perceptions. These results
have implications for management strategies in patients with HOA.
Disclosure: R. Liu, None; L. J. J. Beaart-van de Voorde, None; T. W. J. Huizinga,
None; M. Kloppenburg, None.
1137
Monday, November 12
Clinimetric Properties of a New Outcome Measure: the HandOsteoarthritis Aesthetic Damage Index. N. Bellamy and Joan Hendrikz.
The University of Queensland, Herston, Queensland, Australia
Background/Purpose: The 2006 OARSI Guidelines for hand OA clinical trials, recognised the potential value of an aesthetic damage assessment,
but acknowledged the absence of any existing instrument to perform the
measurement. In order to address this deficiency, a measure termed the
Hand-Osteoarthritis Aesthetic Damage Index(HADIX) has been developed
and its clinimetric properties explored. HADIX is a hexadimensional, Patient
Reported Outcome Measure (PROM) of the aesthetic impact of hand OA
(HADIX 1–6).
Methods: This study forms part of a larger longitudinal initiative
involving clinical profiling, digital photography and radiography. The development of HADIX has been reported previously (1). In the current study,
test-retest reliability (TRR) and construct validity of re-test HADIX data
(except HADIX 4 which is a relative measure) using the Michigan Hand
Outcomes Questionnaire - MHOQ, were evaluated using Pearson’s rho or
Kendall’s tau-b. Time to completion was also examined.
Results: The study involved 28 subjects with hand OA 25 females and 3
males), who fulfilled the Altman Criteria for hand OA, with mean age last
birthday70 yrs (min ⫽ 52 yrs; max ⫽ 87 yrs; SD ⫽ 9.5). TRR correlation
coefficients were: HADIX1 ⫽ 0.89: HADIX2 ⫽ 0.77: HADIX3 ⫽ 0.86:
HADIX4 ⫽ 0.68: HADIX5 ⫽ 0.76: HADIX6 ⫽ 0.87. Correlations between
the re-test HADIX and MHOQ scores were HADIX1 ⫽ 0.55: HADIX2 ⫽
0.52: HADIX3 ⫽ 0.44: HADIX5 ⫽ 0.72: HADIX6 ⫽ 0.45. Mean time to
completion for HADIX on first presentation was 8.6 mins (min ⫽ 2.33 mins;
max ⫽ 22.22 mins; SD ⫽ 4.57 mins). On the second occasion information
was available for 5 patients who were 34 seconds faster on average.
Conclusion: HADIX provides a novel approach to the evaluation of the
aesthetic impact of hand OA. These observations suggest that the HADIX
Index is reliable, valid and feasible, and may have a role in the evaluation of
structure modifying interventions in hand OA.
(1) Bellamy N. Osteoporosis International 2012;23(Suppl 2):S60.
Disclosure: N. Bellamy, None; J. Hendrikz, None.
1138
Nonpharmacologic and Pharmacologic Therapy Utilization by Primary
Care Providers for Hand Osteoarthritis-Comparative Review by Electronic Health Record Data Mining and in-Home Visit Verification. Gale
A. McCarty, President. Rheum.Ed Consulting, Harborside, ME
Background/Purpose: To compare current utilization of usual nonpharmacologic (NP) and pharmacologic (P) therapies for hand osteoarthritis (OA)
by primary care providers (PCPs) and patients (Pts) based on American
College of Rheumatology (ACR) 2012 Recommendations in 2 age- and
gender-matched populations.
Methods: From voluntary in-home health visit (problem list, history,
exam, medication reconciliation) with electronic health record assessment
over 3 yrs for ascertainment of Medicare Advantage general health maintenance and quality benchmarking (Cty 1-Sacramento County CA, N ⫽ 50,
and Cty 2-Cumberland County ME, N ⫽ 50), age- and gender-matched pts
were identified. Pts were unaware the examiner was a rheumatologist.
Discussion vs. Use vs. Source (PCP or pt) of NP recommendations (Activities
of Daily Living, ADLs/Jt Protection/Assistive Device Provision for ADLs/
Thermal Modalities/TrapezioMCP Splints) and P recs (Top. Capsaicin/Top.
NSAIDs/PO NSAIDs/Tramadol) were queried. Descriptive statistics and/or
SPlus were used where applicable: p value significance was ⬍/⫽ 0.05.
Results: Results: Behavior Risk Factor Surveillance System 2009/10 data
confirmed no significant differences (nsd) from Cty 1 vs Cty 2 in: population
(281,674 vs 265,012), % pop. ⬎ 65 (10.6 vs 11.2%), white ethnicity (78% vs
80%), female gender (70 vs 72%), mean age (72.4 vs 74.1 yrs-range 65–98),
no. of pts. w/doctor-diagnosed arthritis b/w ages of 65 and 74 (45 vs 53%), no.
of pts. w/activity limitation due to arthritis (48 vs 44%), no. of pts w/social
participation restriction due to arthritis (17 vs 14%), no. of pts w/severe pain
due to arthritis-non-site specified (27 vs 21%), obesity by BMI (32 vs 33%),
the no. of Rheumatologists available for referral in network (6 vs 7), and the
% of benchmarks attained for major health metrics (96 vs 95% capture).
Latino ethnicity was statistically different (16.6 vs 1.9%). No significant
differences from Cty 1 vs Cty 2 were noted for: Dx of OA-Hands (88 vs
92%); all had discussed OA as an issue with their PCPs at least once in the
prior 3 yrs. Presence of hand OA was confirmed by Rheumatology exam in
88 vs 92% of pts. At least 1 NP Rec (Thermal Modalities) and 1 P Rec (Top
NSAIDS) had been discussed at least once for all pts. by PCPs (100 vs 100%),
but utilization was significantly different (44 vs 22%). Jt Protection and ADLs
had not been discussed or utilized (80 vs 80%); only Assistive Device
Provision (cane/walker) had been done (33 vs 30%). PO NSAIDs were
actively discouraged even in low dose/Cox2 selective/H2 blocker usage by
providers (80% vs 80%).
Conclusion: Current NP and P recommendations from OA experts are
variably implemented with pts, despite confirmed presence of OA by their
own PCPs as an Active Problem, and pts. reporting pain and social restriction
due to arthritis.
Disclosure: G. A. McCarty, None.
ACR/ARHP Poster Session B
Pediatric Rheumatology - Clinical and Therapeutic Aspects:
Juvenile Idiopathic Arthritis
Monday, November 12, 2012, 9:00 AM–6:00 PM
1139
Inhaled Nitrous Oxide Facilitates Access to Intra-Articular Corticosteroid Injections in Children with Juvenile Idiopathic Arthritis. Mercedes
O. Chan1, Ruth Wyllie2 and H. E. Foster3. 1University of British Columbia
and British Columbia’s Children’s Hospital, Vancouver, BC, 2Newcastle
Hospitals, NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom,
3
Newcastle Hospitals NHS Foundation Trust, Great North Children’s Hospital and Newcastle University, Newcastle Upon Tyne, United Kingdom
Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most
common rheumatic disease of childhood affecting 1 in 1000 children.
Medical management for arthritis often includes intra-articular corticosteroid
injections. The inhalation of nitrous oxide (N2O) in painful procedures is
widely recognised in adults, yet is underused in children and young people
(CYP). N2O is quickly absorbed, having low solubility in water and fat, and
rapidly eliminated from the body when inhalation stops. It is safe, fast-acting,
and non-invasive, reducing apprehension and anxiety. The use of N2O has
increased access for CYP requiring painful procedures such as joint injections
(JIs) that may have previously required a general anaesthetic. We aimed to
describe a population of children receiving JIs with N2O at our center and the
wait time for JIs with N2O once a decision to inject was made.
Methods: Data was collected retrospectively from available charts of
children receiving JIs with N2O from January 2002 to April 2012 at our
centre. Demographics, number of JIs (including types of joints injected), and
number of repeat JIs within a year were recorded. Time from decision point
(DP) to JI was calculated for JIs performed in 2011–2012.
Results: 397 JIs with N2O on 292 occasions (140 males, 152 females)
were performed from 2002–2012. The median age at time of JI was 13.78
(range 6.38 to 18.97 years). The median number of JIs performed with N2O
per year was 24 (range 14–53). On 48 occasions JIs were performed
subsequent to one done earlier that calendar year. The median number of
repeat JIs per patient requiring them was 1.
From 2011–2012, 79 JIs were performed with N2O. The median number
of days from a DP to a JI with N2O was 0 (range 0–87 days). 62 patients had
JIs within 2 weeks; 11 between 2 and 4 weeks; 2 between 4 to 6 weeks; and,
3 after 6 weeks from DP. One patient receiving a JI after 6 weeks (87 days)
from DP required imaging to confirm synovitis before proceeding with the
procedure. Reasons for other JIs performed after 6 weeks from DP were
unable to be elicited from charts. Documentation of a DP for JIs with N2O
was present in 77/79 patients (97.5%).
Joints most commonly injected were: knees (80.05%), ankles (14.4%),
elbows (3.28%), wrists (1.26%), subtalar (0.5%), fingers (0.31%) and shoulders (0.20%). There were no major adverse events (including septic arthritis)
reported. An increase in trainee procedures was seen after 2009 consistent
with the introduction of a paediatric rheumatology (PRh) training program.
S488
Conclusion: Use of N2O for JIs in children with JIA allows for
expeditious, safe and efficient sedation and analgesia. At our centre, children
assessed in clinic and who need JIs may be offered one at that visit, performed
by the PRh team (clinician and nurse specialist). This has benefits for clinical
care (rapid access to the procedure); the patient and family (less time off
school/college or work, no anaesthetic risk); health care costs (reduced need
for day case access and theatre time); and, optimal use of resources
(preferential access to general anaesthetic lists for younger children; or those
requiring multiple JIs or use of image intensifiers; or, quick procedures
reducing PRh time).
Disclosure: M. O. Chan, None; R. Wyllie, None; H. E. Foster, None.
1140
Background/Purpose: To assess the efficacy and safety of treatment
with adalimumab therapy in patients with refractory Juvenile Idiopathic
Arthritis (JIA)-associated uveitis.
Methods: Multicenter study on 40 patients diagnosed as having
JIA-associated uveitis refractory to treatment with corticosteroids therapy
and at least other systemic immunosuppressive drug. Standard adalimumab therapy was started (40 mg subcutaneously every-other-week); for
children aged between 4 and 12 years, the recommended dose was 24
mg/m2 body surface area up to a maximum single dose of 40 mg sc every
other week. The associated immunosuppressive therapy and the prednisone dose were reduced if there was no evidence of inflammation. Degree
of anterior and posterior chamber inflammation (SUN criteria), corticosteroid dose, and macular thickness (optical coherence tomography) were
assessed. Definite outcomes were assessed at six months in all patients.
All expressed comparisons are between baseline and after 6 months of
adalimumab therapy (Wilcoxon test).
Results: Forty patients (11 males, 29 females), mean age of 11,4⫾7,9
years (range: 4 to 44 years), with active intraocular inflammation at baseline
were studied. Thirty-six of 40 patients had inflammation in the anterior
camera, and treatment with adalimumab achieved a significant improvement
in mean tyndall from 1,8⫾1,1 to 0,41⫾0,6; p ⫽0.000001.
Also, 17 (42,5%) patients had macular thickness with Optic Coherence
Tomography (OCT)⬎250 microns. These cases had a significant improvement in OCT from 370,8⫾133,9 to 249,3⫾28,0 microns; p⫽0,0007. In
addition, 9 patients with Cystoid Macular Edema (CME) (OCT⬎300) also
had a significant improvement in OCT (463,1⫾123,8 to 254,4⫾30,2,
p⫽0,007). The dose of corticosteroids also was decreased from 0.26⫾0.4 to
0.004⫾0.02 mg/day (p⫽0.00061).
Adalimumab was usually well tolerated, and only local minor side-effects
at the injection site were observed. Twelve patients (30%) had a mild relapse
during the 6 months of therapy whereas only 2 patients (5%) had a
moderate-severe relapse.
Conclusion: Adalimumab appears to be an effective and safe drug for the
treatment of refractory JIA-associated uveitis and may reduce steroid requirement. Further controlled studies are warranted.
Disclosure: V. Calvo-Rı́o, None; R. Blanco, None; M. Dı́az-Llopis, None; D. Salom,
None; C. Garcı́a-Vicuña, None; M. Cordero-Coma, None; N. Ortego, None; M.
Suarez-de-Figueroa, None; J. C. Fernandez-Cid, None; A. Fonollosa Calduch,
None; M. Garcı́a-Aparicio, None; J. M. Benı́tez-del-Castillo, None; J. L. Olea, None;
J. Loricera, None; M. A. González-Gay, None.
Safety of Celecoxib and Non-Selective Non-Steroidal Anti-Inflammatory
Drugs in Juvenile Idiopathic Arthritis. Rachel E. Sobel1, D. J. Lovell2,
Hermine I. Brunner3, Jennifer E. Weiss4, Paula W. Morris5, Beth S. Gottlieb6,
Elizabeth C. Chalom7, Lawrence K. Jung8, Karen Onel9, Lisa Petinoit10,
Donald P. Goldsmith11, Staci Abramsky-Risman12, James P., Young13 and
Edward H. Giannini14. 1Pfizer, Inc., New York, NY, 2Cincinnati Children’s
Hospital, Cincinnati, OH, 3Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH, 4Hackensack Univ Med Ctr, Hackensack, NJ, 5Univ of
Arkansas for Med Sci, Little Rock, AR, 6Cohen Children’s Medical Center of
New York, New Hyde Park, NY, 7St. Barnabas Medical Center, Livingston,
NJ, 8Children’s National Medical Center, Washington, DC, 9University of
Chicago, Chicago, IL, 10’Specially for Children, Dell Children’s Medical
Center, Austin, TX, 11St Christopher’s Hospital for Children/Drexel College
of Medicine, Philadelphia, PA, 12Pfizer Inc, New York, NY, 13United
BioSource Corporation, Ann Arbor, MI, 14PRCSG-Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH
Background/Purpose: Celecoxib, a selective COX-2 inhibitor, was
approved by the FDA for the treatment of the signs and symptoms of JIA in
children aged 2–17 years in December, 2006. As a condition of approval,
Pfizer conducted a Phase IV study, the Safety in Idiopathic Arthritis: NSAIDs
and Celebrex Evaluation Registry (SINCERE), to collect longer-term safety
and developmental data on patients with JIA treated in routine clinical
practice with celecoxib or non-selective NSAIDs (nsNSAIDs).
Methods: Children aged between 2 and 18 years with RF(⫹) or RF(⫺)
polyarthritis, persistent or extended oligoarthritis, or systemic juvenile arthritis (without features of extra-articular features for ’6 months) were enrolled
into this prospective, observational, multi-centered, standard-of-care registry.
To be eligible, patients had to be receiving newly or recently prescribed (ⱕ6
months) nsNSAID or celecoxib. Duration of previous nsNSAID or celecoxib
exposure, or use of concomitant DMARD or biologic therapy did not affect
eligibility. Once enrolled, patients were to remain in the study whether they
continued on the original NSAID, switched, or discontinued NSAIDs altogether. Visits were scheduled at 0, 4, 8, 12 months, and at 6 month intervals
thereafter for a minimum of 2 years. All adverse events (AEs) regardless of
severity were captured in the SINCERE database.
Results: A total of 274 patients (219 in the nsNSAID and 55 in the
celecoxib group) were observed for 410 patient-years of observation (PYO) at
study termination. Sixty percent of patients in the celecoxib group, and 53%
in the nsNSAID group had oligoarthritis. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib
group had numerically longer disease duration, was older, and had a higher
median weight and height. This is consistent with the practice of using
celecoxib as the second or third NSAID in JIA. A numerically higher
proportion of celecoxib patients had a history of intolerance to nsNSAIDs,
mostly due to gastrointestinal side effects. The analysis of AEs reported
during the study showed a similar incidence of AEs across groups (44 and
53/100 PYO for nsNSAID and celecoxib respectively, and 50/100 PYO for
those off-NSAID [ⱖ29 days after final dose]). AEs were those frequently
observed with NSAID treatment. Two patients on nsNSAID and 2 offNSAID experienced AEs of special interest. Twelve unique patients experienced a total of 18 serious adverse events (SAEs), the most frequent of which
were infections; none were attributed to NSAID. Incidence rates (95% CI) of
SAEs per 100 PYO were 3.4 (1.2, 5.6) and 2.9 (0, 7.0) for the nsNSAID and
celecoxib group respectively, and 4.0 (0, 8.6) for the off-NSAID cohort.
Overall, the study results indicate no important difference in the safety
profiles between celecoxib and nsNSAIDs.
Conclusion: The total study population of 274 patients followed for a
total of 410 PYO is one of the largest JIA NSAID cohorts, and adds
substantially to the safety experience of NSAID treatment of JIA. The safety
profile of celecoxib appears similar overall to that of nsNSAIDs and the
benefit-risk for celecoxib treatment in JIA remains positive.
Disclosure: R. E. Sobel, Pfizer Inc, 3; D. J. Lovell, Centocor, Inc., 5, AstraZeneca, 5,
Wyeth Pharmaceuticals, 8, Amgen, 9, Bristol-Myers Squibb, 5, Abbott Immunology
Pharmaceuticals, 5, Pfizer Inc, 5, Regeneron, 5, Hoffmann-La Roche, Inc., 5, Novartis
Pharmaceutical Corporation, 5, Forest Laboratories, 9, horizon pharmaceuticals, 5; H. I.
Brunner, None; J. E. Weiss, None; P. W. Morris, None; B. S. Gottlieb, Pfizer Inc, 5;
E. C. Chalom, None; L. K. Jung, None; K. Onel, None; L. Petinoit, None; D. P.
Goldsmith, None; S. Abramsky-Risman, None; J. P. Young, None; E. H. Giannini,
None.
S489
Monday, November 12
Response to Adalimumab in 40 Patients with refractory juvenile Idiopathic Arthritis-Associated Uveitis. A Multicenter Study. Vanesa CalvoRı́o1, Ricardo Blanco1, Manuel Dı́az-Llopis2, David Salom3, Carmen Garcı́aVicuña4, Miguel Cordero-Coma5, Norberto Ortego6, Marta Suarez-deFigueroa7, J. Carlos Fernandez-Cid8, A. Fonollosa Calduch9, Ángel M.
Garcı́a-Aparicio10, Jose M. Benı́tez-del-Castillo11, Jose L. Olea12, Javier
Loricera13 and Miguel Angel González-Gay13. 1Hospital Universitario Marqués de Valdecilla-IFIMAV, Santander, Spain, 2Hospital Universitario La Fe
de Valencia, Valencia, 3Hospital Universitario La Fe de Valencia, Valencia,
Spain, 4Hospital Sant Joan de Déu, Barcelona, Barcelona, 5Hospital de León,
León, Spain, 6Hospital Santa Cecilio, Granada, Spain, 7Hospital Ramon y
Cajal, Madrid, Spain, 8Hospital de Pontevedra, Pontevedra, Spain, 9Hospital
de Cruces, Barakaldo, Spain, 10Hospital Virgen Salud, Toledo, Toledo,
11
Hospital Clı́nico San Carlos, Madrid, 12Hospital Son Dureta, Palma de
Mallorca, Spain, 13Hospital Universitario Marqués de Valdecilla. IFIMAV,
Santander, Spain
1141
1142
Monday, November 12
Efficacy of Biologic Agents in Juvenile Idiopathic Arthritis: A Systematic
Review Using Indirect Comparisons. Janneke Anink1, Marieke H. Otten1,
Sandra Spronk2 and Lisette W.A. Van Suijlekom-Smit1. 1Erasmus MC
Sophia Children’s Hospital, Rotterdam, Netherlands, 2Erasmus MC, Rotterdam, Netherlands
Background/Purpose: During the last decade the availability of biologic agents for the treatment of juvenile idiopathic arthritis (JIA) increased
substantially. Because direct head-to-head trials comparing biologics are
lacking, physicians face difficulties to choose between these agents. In order
to provide some scientific guidance, we indirectly compared the short-term
efficacy of biologic agents.
Methods: In a systematic review, all available efficacy data from
randomized controlled trials performed in JIA were retrieved. The following
biologics were included: etanercept, adalimumab, infliximab, abatacept,
anakinra, rilonacept, canakinumab and tocilizumab. Indirect between-drug
comparisons (based on the Bucher’s method) were conducted only if trials
were comparable with regard to design and patients’ characteristics related to
treatment outcome.
Results: Eleven trials that evaluated biologic agents in JIA were selected.
Quality of trials varied greatly: earlier trials for registration gained best scores,
trials evaluating treatment strategies performed worst. For 5 trials, no match
for an indirect comparison could be found due to design and patient
characteristics. The remaining trials could be divided into two networks of
evidence. Network 1 included withdrawal trials that evaluated etanercept,
adalimumab and abatacept in poly-articular course juvenile idiopathic arthritis. Indirect comparisons identified no significant differences in short-term
efficacy. Etanercept seemed superior to adalimumab (relative risk (RR)
disease flare, etanercept vs. adalimumab, 0.59, 95% CI 0.28–1.24) and
abatacept better than adalimumab (RR disease flare, abatacept vs. adalimumab, 0.64, 95% CI 0.34–1.23), especially considering the case-mix of
adalimumab-treated patients, associated with better outcomes. Network 2
indirectly compared anakinra, tocilizumab and canakinumab in systemic
juvenile idiopathic arthritis and no differences could be identified. Canakinumab tended to be superior to tocilizumab (RR 2.44, 95% CI 0.81–7.37).
Conclusion: The short-term efficacy of etanercept, adalimumab and
abatacept seemed similar for poly-articular course JIA and anakinra, canakinumab and tocilizumab seemed similar for systemic JIA. Because of the
observed differences between trials, head-to-head trials comparing 2 biologic
agents directly are highly needed. For now, the pediatric rheumatologist has
to rely on these indirect comparisons supplemented by observational data
derived from cohort studies and safety, practical, and financial arguments.
Disclosure: J. Anink, None; M. H. Otten, Pfizer Inc, 9, Pfizer Inc, 9, Abbott
Immunology Pharmaceuticals, 9, Roche Pharmaceuticals, 9, Novartis Pharmaceutical
Corporation, 9; S. Spronk, None; L. W. A. Van Suijlekom-Smit, Pfizer Inc, 2, Abbott
Immunology Pharmaceuticals, 2, Pfizer Inc, 5, Pfizer Inc, 9.
1143
Tocilizumab Therapy in Children with Systemic Onset Juvenile Idiopathic Arthritis. Russian Experience. Ekaterina Alekseeva, Rina Denisova,
Saniya Valieva, Tatyana Bzarova, Kseniya Isayeva, Alexandra Chomakhidze, Evgeniya Chistyakova, Tatyana Sleptsova and Elena Mitenko.
Scientific Center of Children’s Health, Moscow, Russia
Background/Purpose: Systemic Juvenile Idiopathic Arthritis (sJIA) is
classified as an acquired autoinflammatory disease. The interleukin-1 and
interleukin-6 play a pivotal role in pathogenesis of this disease. The systemic
manifestations as well as arthritis in sJIA are related to interleukin-6 action.
Tocilizumab is promising drug for the treatment of systemic arthritis refractory to immunosuppressive drugs.
Objectives: To evaluate safety and efficacy of tocilizumab treatment in
children with systemic juvenile idiopathic arthritis.
Methods: A prospective observational study in patients with sJIA taking
tocilizumab. A total of 94 patients (49 boys and 45 girls) were included in this
study. Median age was 5,5 years (range; 2 to 15 years) and median disease
duration was 3,5 years (range; 0.5 to 12 years). Tocilizumab was administrated intravenously at a dose of 8–10 mg/kg every 2 weeks during 2 months
then every 4 weeks. All patients received DMARDs. Efficacy end points
included the American College of Rheumatology (ACR) Pediatric criteria for
improvement 30 (ACR30), ACR50, ACR70 and criteria of inactive disease
and remission.
Results: 39 of 94 patients (41%) entered 52 weeks and 69 patients - 24
weeks of continuous tocilizumab treatment. Tocilizumab treatment was
discontinued in 15 patients. 40 patients continue to receive Tocilizumab
therapy and have not entered 52 weeks yet. The ACR Pedi 30, 50 and 70
improvement were achieved by 100%, 100% and 75% of patients at Week 24
(n⫽69) and by 100%, 100% and 87% of patients at Week 52 (n⫽39),
respectively. Inactive disease was achieved by 55% of patients at week 24
(n⫽69) and by 65% of patients at week 52 (n⫽39). Remission was achieved
by 59% of patients (n⫽39). The mean dose of oral glucocorticoid was
decreased from 0,6 (0,4; 0,5) mg/kg (n⫽45) to 0,2 (0,1-0,3) mg/kg (n⫽20) at
week 52. The frequently observed non-severe adverse events were nasopharyngitis, upper respiratory tract infections and gastroenteritis. No cases of
opportunistic infections, malignancies or death were reported. There were
three cases of pneumonia and cellulitis. 30 patients had incidences of
neutropenia. Tocilizumab treatment was discontinued in 15 patients. The
causes for cancellation were relapse of disease (n⫽7), inefficacy (n⫽3),
remission (n⫽1), parent’s refusal (n⫽1), infusion reaction (n⫽2) and Crohn’s
disease (n⫽1).
Dynamics in systemic features
Number of systemic features per
patient
Background
1m
6m
12 m
3,1
1,1
0,5
0,2
Conclusion: The results of the annual prospective observational study have shown
the high efficiency of tocilizumab in patients with the severe sJIA. Drug induced
remission of extra-articular manifestations, arthritis and normalized laboratory
parameters of the disease activity without initiation of treatment with oral prednisolone and increase its dose, thus avoiding severe irreversible complications of
glucocorticoid therapy. Tocilizumab induced disease remission in 59% of patients at
Week 52.
Disclosure: E. Alekseeva, None; R. Denisova, None; S. Valieva, None; T. Bzarova,
None; K. Isayeva, None; A. Chomakhidze, None; E. Chistyakova, None; T.
Sleptsova, None; E. Mitenko, None.
1144
Phenotypic Characterization of Childhood Onset Rheumatoid Arthritis.
Emily G. Ferrell1, Lori Ponder2, Lauren Minor3, Sheila T. Angeles-Han3,
Christine W. Kennedy2, Kelly A. Rouster-Stevens4, Mina Pichavant2, Larry
B. Vogler4 and Sampath Prahalad2. 1Emory University School of Medicine,
Atlanta, GA, 2Emory Children’s Center, Atlanta, GA, 3Emory University,
Atlanta, GA, 4Emory Univ School of Medicine, Atlanta, GA
Background/Purpose: Rheumatoid Factor positive polyarthritis (RF⫹
poly) is the JIA subtype that resembles adult seropositive RA. However, the
ILAR classification criteria for RF⫹ polyarthritis do not capture all children
with childhood onset RA due to specific exclusion criteria: lack of 2 (⫹) RF
tests, ⬍5 active joints in the first 6 months, family history of psoriasis, and
(⫹) HLA-B27 in boys with onset after age 6. The ACR/EULAR criteria used
for diagnosing adult RA do not have these exclusions, and they include the
highly specific anti-CCP antibodies (ACPA). The current ILAR classification
system does not include ACPA. Hence, children who are RF (⫺) but ACPA
(⫹) may be treated less aggressively and develop complications secondary to
undertreated disease. Our objectives are to 1) determine whether RF and/or
ACPA (⫹) children meet ILAR criteria for RF⫹ poly JIA and 2) assess for
significant differences between children who meet RF⫹ poly criteria and
those who are classified as other subtypes.
Methods: Demographic and disease-related data were collected from
charts of RF and/or ACPA (⫹) children. Each child was classified using
ILAR criteria, and the ACR/EULAR classification was used to determine
whether each child met criteria for adult RA. Children with RF⫹ poly JIA
were compared to those with other subtypes. Nominal variables were
compared using Chi square or Fisher’s exact tests, and continuous variables
were compared using Student’s T test.
Results: Of 49 children with RF and/or ACPA (⫹) JIA, 29 (59%) met
criteria for RF⫹ poly JIA (Table 1). Of the 20 who did not, 9 (45%) met
criteria for undifferentiated JIA, 6 (30%) for RF- polyarthritis, 3 (15%) for
persistent oligoarthritis, and 2 (10%) for extended oligoarthritis. All children
with undifferentiated JIA were ACPA (⫹); 7 had presentations consistent
with oligoarthritis, but had 2 positive RF tests; 1 had a father with psoriasis;
1 was an HLA-B27 (⫹) boy with onset after age 6. Comparison of children
who met criteria for RF⫹ poly JIA to those who did not revealed significant
differences in subtype distribution, number meeting ACR/EULAR criteria for
RA, and use of steroids. All other features were not significantly different.
S490
The ACR/EULAR criteria for RA captured more children with RF and/or
ACPA (⫹) JIA than the ILAR RF⫹ poly classification (92% vs. 59%).
Table 1. Characteristics of ACPA and RF positive children with JIA*
Non-RF positive
polyarticular JIA
P value**
29 (59)
10.3 ⫾ 3.4
20 (41)
9.3 ⫾ 3.9
0.34
22 (76)
7 (14)
9 (18)
3.4 ⫾ 0.5
174.5 ⫾ 100.0
15 (75)
1 (5)
8 (40)
3.3 ⫾ 0.5
163.2 ⫾ 100.2
0.95
0.08
0.52
0.60
0.70
29 (100)
0 (0)
0 (0)
0 (0)
0 (0)
29 (100)
0 (0)
6 (30)
2 (10)
3 (15)
9 (45)
16 (80)
<0.0001
0.002
0.09
0.03
<0.0001
0.01
18 (62)
13 (5-30)
7 (35)
11 (1-48)
0.07
0.48
20 (69)
28 (97)
19 (66)
7 (35)
17 (85)
8 (40)
Biologic Patients
Characteristic, med(IQR)
or n(%)
0.02
0.15
0.08
* All values are N(%) of those tested/reporting data for particular variables,
except as indicated.
ACPA: anti-citrullinated protein antibody.
** P⬍0.05 was considered statistically significant
Conclusion: A significant number of children (41%) with RF and/or
ACPA (⫹) JIA did not meet criteria for RF⫹ poly JIA, though many of their
demographic features and disease measures were similar to children who did.
The ACR/EULAR criteria allow a positive RF or ACPA to qualify as positive
serology, and these criteria capture more children with RF and/or ACPA (⫹)
JIA. We propose the inclusion of ACPA in future revisions of the JIA
classification criteria to improve the specificity of diagnosing childhood onset
RA, and we suggest replacing RF⫹ polyarthritis with RF/ACPA⫹ JIA.
Disclosure: E. G. Ferrell, None; L. Ponder, None; L. Minor, None; S. T. AngelesHan, None; C. W. Kennedy, None; K. A. Rouster-Stevens, None; M. Pichavant,
None; L. B. Vogler, None; S. Prahalad, None.
1145
Use of Non-Etanercept Biologics in Children with Juvenile Idiopathic
Arthritis: Results From the Biologics for Children with Rheumatic
Diseases Study. Lianne Kearsley-Fleet1, Eileen Baildam2, Michael Beresford3, Rebecca Davies1, Helen E. Foster4, Katy Mowbray1, Taunton R.
Southwood5, Wendy Thomson1 and Kimme L. Hyrich6. 1Arthritis Research
UK Epidemiology Unit, Manchester Academic Health Science Centre,
Manchester, United Kingdom, 2Alder Hey Children’s Foundation NHS Trust,
Liverpool, United Kingdom, 3Institute of Translational Medicine (Child
Health), Alder Hey Children’s Foundation NHS Trust, Liverpool, United
Kingdom, 4Musculoskeletal Research Group, Newcastle upon Tyne, United
Kingdom, 5University of Birmingham and Birmingham Children’s Hospital,
Birmingham, United Kingdom, 6Arthritis Research UK Epidemiology Unit,
University of Manchester, Manchester Academy of Health Sciences, Manchester, United Kingdom
Background/Purpose: The management of juvenile idiopathic arthritis
(JIA) has been revolutionised by the introduction of biologic therapy,
although the majority remain unlicensed for children. Until recently, etanercept (ETN) was the only choice of licensed therapy in the UK, with recent
additions of adalimumab (age ⱖ 4 years), abatacept (age ⱖ 6 years) and
tocilizumab (systemic arthritis). It is not yet known how and when non-ETN
biologics are being prescribed in JIA. The purpose of this analysis was to
describe the pattern of use of non-ETN biologics in children with JIA.
Methods: Since 2010, the Biologics for Children with Rheumatic
Diseases (BCRD) study, an ongoing prospective observational cohort study,
has been collecting detailed information on children ⬍18 years newly starting
n
Age at Registration,
years
Female
ILAR subtype
Systemic arthritis
Oligoarthritis: persistent
Oligoarthritis: extended
Polyarthritis: RF
Negative
Polyarthritis: RF
Positive
Enthesitis Related
Arthritis
Psoriatic arthritis
Undifferentiated arthritis
Not Recorded
Biologic Drug at
Registration
Adalimumab
Infliximab
Tocilizumab
Abatacept
Anakinra
Rituximab
Licensed Use
Prior Biological
Treatment
1 previous
2 previous
3 previous
5 previous
Ever had Chronic
Anterior Uveitis
Active Chronic Anterior
Uveitis at
Registration
Disease activity
Active joint count
Limited joint count
Physician Global
Assessment (10cm
VAS)
Parent Global
Assessment of Wellbeing (10cm VAS)
CHAQ
Pain (10cm VAS)
ESR, mm/hr
CRP mg/L
First Line
Subsequent
Total
p-value
64 (47.1)
8.5 (4.5-12)
72 (52.9)
11.5 (8-14)
136
10 (6-13.5)
0.0006
37 (57.8)
51 (70.8)
88 (64.7)
0.113
19 (29.7)
16 (25.0)
9 (14.1)
11 (17.2)
17 (23.6)
1 (1.4)
14 (19.4)
26 (36.1)
36 (26.5)
17 (12.5)
23 (16.9)
37 (27.2)
0.001
1 (1.6)
6 (8.3)
7 (5.2)
4 (6.3)
2 (2.8)
6 (4.4)
2 (3.1)
1 (1.6)
1 (1.6)
5 (6.94)
0
1 (1.4)
7 (5.2)
1 (0.7)
2 (1.5)
25 (39.1)
18 (28.1)
11 (17.1)
1 (1.6)
9 (14.1)
0
31 (48.4)
25 (34.7)
14 (19.4)
20 (27.8)
9 (12.5)
1 (1.4)
3 (4.2)
47 (65.3)
50 (36.8)
32 (23.5)
31 (22.8)
10 (7.4)
10 (7.4)
3 (2.2)
78 (57.4)
0.047
0
0
0
0
31 (48.4)
51
17
3
1
19 (26.4)
50 (36.8)
0.028
25 (39.1)
17 (23.6)
42 (30.9)
0.141
2 (0-6)
1 (0-6)
3.1 (1.5-4.9)
3 (1-8.5)
3 (1-8)
3 (1.8-6)
2 (0-7)
2 (0-7)
3 (1.8-5.5)
0.1030
0.0061
0.5603
3 (0.8-5)
4.4 (2-6)
4 (1.1-5.9)
0.3414
1 (0.3-2)
3.8 (0.5-6.1)
10 (6-42)
5 (3-20)
1.3 (0.3-1.6)
3.7 (1-6.6)
14 (5-52)
5 (4-28)
1.1 (0.3-1.8)
3.7 (0.8-6.5)
12 (6-50)
5 (3-20.4)
0.8697
0.7833
0.6820
0.7292
0.002
Conclusion: Many children are now receiving non-ETN biologics in the
UK, although almost half of these are being prescribed off-license. Ongoing
S491
Monday, November 12
Total number
Age at symptom onset
(mean⫾SD)
Demographic features
Female gender
Hispanic ethnicity
African ancestry
Birth weight (kg; mean⫾SD)
ACPA value (mean⫾SD)
ILAR subtype
RF ⫹ poly
RF - poly
Oligo extended
Oligo persistent
Undifferentiated
Meets 2010 ACR/EULAR
criteria for RA
Imaging evidence of damage
Number of affected joints in
first 6 months (mean &
range)
Treatment
Use of systemic steroids
Use of DMARD
Use of biologic
RF positive
polyarticular JIA
a non-ETN biologic therapy for JIA. There are no other exclusion criteria. At
baseline, detailed demographic and disease information, including details of
past biologic therapies, are collected. The use of non-ETN therapy as a
first-line or subsequent biologic therapy was compared, including patterns of
prescription, use under licensed indications, ILAR subtypes and disease
activity/severity using non-parametric descriptive statistics.
Results: To 06/21/2012, 136 children across the UK had been recruited:
median age 10 years, 65% female. The most common ILAR subtypes were
systemic arthritis (26.5%) and rheumatoid factor (RF) negative polyarthritis
(27.2%) (see Table). Sixty four patients (47.1%) were starting a non-ETN
biologic as first-line biologic therapy, of which 33 (51.6%) were prescribed
off-license. Off-license use was more common among first-line users
(p⫽0.047), largely accounted for by infliximab and anakinra. All patients on
anakinra had systemic arthritis, whereas only 67.7% of those were prescribed
tocilizumab. Forty-eight percent of first line users versus 26% of subsequent
users had a history of chronic anterior uveitis (p⫽0.028). Of those registered
at the point of starting a subsequent biologic, 71% had received prior ETN.
The majority had received only 1 prior biologic although 17 children had
received 2 prior biologics, 3 children had received 3 and 1 child (RF negative)
had received 5 previous biologics. Disease severity was moderate to high and
largely comparable between first-line and subsequent biologic users, although
subsequent biologic users had a higher limited joint count.
follow-up will help to address the question of best choice of biologic therapy
for children with JIA, both as first-line and subsequent use, as well as
determine the safety of these drugs in children, for which limited clinical
experience exists.
Disclosure: L. Kearsley-Fleet, None; E. Baildam, None; M. Beresford, None; R.
Davies, None; H. E. Foster, None; K. Mowbray, None; T. R. Southwood, None; W.
Thomson, None; K. L. Hyrich, None.
Monday, November 12
1146
Choice of Systemic JIA Treatment Among Childhood Arthritis and
Rheumatology Research Alliance (CARRA) Rheumatologists. Jennifer E.
Weiss1, Esi M. Morgan DeWitt2, Timothy Beukelman3, Laura E. Schanberg4,
Rayfel Schneider5 and Yukiko Kimura1. 1Joseph M. Sanzari Children’s
Hospital, Hackensack University Medical Center, Hackensack, NJ, 2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 3Univ of AlabamaBirmingham, Birmingham, AL, 4Duke University Medical Center, Durham,
NC, 5The Hospital for Sick Children, Toronto, ON
Background/Purpose: Despite recent advances in identifying effective
treatments for systemic Juvenile Idiopathic Arthritis (sJIA), many pediatric
rheumatologists continue to use corticosteroids and methotrexate. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed
standardized consensus treatment plans (CTPs) for sJIA with the goal of
comparing their effectiveness using data collected for the CARRA Registry.
Since physicians will select CTPs without randomization, each CTP must be
used with sufficient frequency to allow for meaningful comparisons of
efficacy. We aimed to ascertain the current anticipated frequency of CTP use
by CARRA pediatric rheumatologists, and whether a clear standard of care
exists for sJIA treatment.
Methods: An electronic survey was sent to voting members of CARRA
regarding CTP choice for new-onset sJIA which has failed NSAID therapy
alone. Respondents were asked to select one or more of the following CTPs
for each clinical case scenario: (a) systemic corticosteroids (CS) only; or
(b) methotrexate, (c) anti-IL1 or (d) anti-IL6 therapy, each with or without
CS. Respondents could choose more than one CTP if factors such as
insurance limitations or family preference might affect treatment. Features of
the clinical case scenarios are summarized in the Table.
Table. Clinical Cases
Case
Case
Case
Case
1
2
3
4
Systemic
symptoms
Arthritis
Anemia
Acute
Phase
Reactants
Disability
⫹
⫹⫹
⫹
⫹⫹⫹
⫹
⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹
⫹⫹⫹
⫹
⫹⫹⫹⫹
⫹⫹
⫹⫹⫹
⫹
⫹⫹⫹⫹
⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹⫹
Results: 134 of 247 (54%) CARRA members responded. The figure
depicts treatment selections sorted by case, demonstrating wide variability in
preferred treatment for new-onset sJIA. IL1 and IL6 inhibitors have become
important treatment choices. Methotrexate use increases with more prominent
arthritis features; however, methotrexate and CS usage are frequent regardless
of presenting disease features. Overall, concurrent CS use was indicated by
the majority of respondents across all CTPs (Case 1: 74%; Case 2: 87%, Case
3: 66%; Case 4: 91%).
Conclusion: There is still significant variability in sJIA treatment approaches and no clear standard of care among CARRA members, with
widespread use of methotrexate and CS. There is likely to be sufficient
utilization of each of the CTPs for new-onset sJIA to establish comparative
treatment effectiveness using the observational CARRA Registry.
Disclosure: J. E. Weiss, None; E. M. Morgan DeWitt, None; T. Beukelman, Pfizer
Inc, 2, Novartis Pharmaceutical Corporation, 5, Genentech and Biogen IDEC Inc., 5;
L. E. Schanberg, UCB, 5, AstraZeneca, 5, Pfizer Inc, 2; R. Schneider, Hoffmann-La
Roche, Inc., 5, Hoffmann-La Roche, Inc., 8, Innomar Strategies, 5; Y. Kimura,
Novartis Pharmaceutical Corporation, 5, Genentech and Biogen IDEC Inc., 5.
1147
Definition of Improvement Thresholds in Juvenile Idiopathic Arthritis
Using the JADAS. Gerd Horneff1 and Ingrid Kaul2. 1Centre of Pediatric
Rheumatology, Sankt Augustin, Germany, 2Institute of Medical Statistics,
Informatics and Epidemiology, University of Cologne, Cologne, Germany
Background/Purpose: Evaluation of disease activity in JIA is fundamental in clinical assessment. The ACR paediatric response measure used in
clinical trials are validated to analyse the response to a treatment in
comparison to a baseline disease activity but does not judge about the
absolute disease activity or the absolute improvement.
Methods: The JADAS has been calculated in patients of the BIKER
registry newly starting treatment with etanercept or MTX. The JADAS10 was
preferred because it values all 4 domains equally. Physicians ⫹ parents were
requested to judge on treatment efficacy as very good, good, weak, none or
worse. Improvement was assumed if judgement of both were very good or
good. No improvement was assumed if at least one judgement was for none
or poor. Inconclusive judgements or those with a difference ⬎1 point were
excluded from analysis.
Results: Initially, ANOVA of JIA categories showed no significant
differences of mean DJADAS in all baseline classes and IQRs also showed
good overall limits. So, all JIA categories were combined for a joint cutoff.
Analysis was restricted to the 3 month evaluation because of a time
dependence of the judgement of improvement in terms of the JADAS.
Restriction to the 3 month results left 1340 patients. JADAS at baseline was
finally put into 4 classes, class 0 for JADAS ⬍5, “low” for 5ⱕJADAS⬍15,
“moderate” for 15 ⱕJADAS⬍25 and ”high” for 25ⱕJADASⱕ40. An initial
JADAS of ⬍5 was assumed as only minor or no disease activity. An
improvement cutoff was only defined for baseline classes “low”, “moderate”
and “high”. Cutoffs for defining improvement were chosen by calculating
interquartile ranges (IQR) of the judgement groups and considering accuracy
as well as sensitivity/specificity of the resulting model. Analysis by baseline
class revealed clear cutoff points. According to the baseline JADAS class the
following minimum decreases of the JADAS (DJADAS) are proposed for
definition of improvement: For baseline class “low”: DJADAS of 4, for
baseline class “moderate”: DJADAS of 10, for baseline class “high”:
DJADAS of 15. Alternatively a relative decrease of the JADAS by 42% for
JADAS class “low”, by 51% for JADAS Class “moderate” and 56% for
JADAS class “high” were found to define improvement (table 1).
Table 1. Inter quartile ranges of variable DJADAS10 by improvement and
baseline class, absolute and relative values. Chosen cutoff for improvement and
goodness-of-fit parameters. Higher DJADAS10 indicate better treatment efficacy.
Only integer cutoffs were considered.
Low
(5-15)
Improvement
Yes
No
Cutoff for
improvement
Accuracy [%]
Sensitivity
Specificity
Improvement
Yes
No
Cutoff for
improvement
Accuracy [%]
Sensitivity
Specificity
S492
4.1-9.5 (502)
-31.-3.7 (85)
4
76.2
75.9
76.5
45-86
-32-42
42
76.8
77.1
75.3
JADAS10 baseline class
Moderate
(15-25)
High
(25-40)
DJadas10 absolute values IQR (n)
10.4-17.2 (450)
17.8-27.2 (148)
1.5-10.2 (94)
4.6-15.0 (35)
10
15
74.8
85.8
76.2
88.5
73.4
74.3
DJadas10 relative values [%] IQR
55-88
65-94
8-50
18-49
51
50
53
78.5
78.4
78.7
88.0
90.5
77.1
87.4
88.5
82.9
56
87.4
87.2
88.6
Conclusion: Disease improvement on therapy can efficiently be defined by
the decrease of the JADAS depending on the initial JADAS score defining low,
moderate or high disease activity. Our model demonstrates clear cut off values.
After cross validation these cutoffs may be used in clinical trials and for decisions
in clinical practice.
Disclosure: G. Horneff, None; I. Kaul, None.
1148
Adalimumab — Effective Control under Refractory JIA Associated Uveitis.
Ekaterina Alekseeva, Elena Mitenko, Tatyana Bzarova, Saniya Valieva, Kseniya
Isayeva, Alexandra Chomakhidze, Evgeniya Chistyakova, Tatyana Sleptsova and
Rina Denisova. Scientific Center of Children’s Health, Moscow, Russia
Disclosure: E. Alekseeva, None; E. Mitenko, None; T. Bzarova, None; S. Valieva,
None; K. Isayeva, None; A. Chomakhidze, None; E. Chistyakova, None; T.
Sleptsova, None; R. Denisova, None.
1149
Long-Term Safety of Etanercept in Patients with Juvenile Idiopathic Arthritis (JIA). Kirsten Minden1, Martina Niewerth2, Jens Klotsche3, Michael
Hammer4, Johannes Peter Haas5, Gerd Ganser6 and Gerd Horneff7. 1German
Rheumatism Research Center, a Leibniz Institute, Berlin, Germany, 2German
Rheumatism Research Centre, Berlin, Germany, 3German Rheumatism Research
Center, a Leibniz institute, Berlin, Germany, 4St. Josef-Stift, Sendenhorst, Germany, 5German Center for Pediatric and Adolescent Rheumatology, GarmischPartenkirchen, Germany, 6Sankt Josef Stift, Sendenhorst, Germany, 7Centre of
Pediatric Rheumatology, Sankt Augustin, Germany
Reference
1 - Horneff G, Foeldvari I, Minden K, Moebius D, Hospach T. Report on
malignancies in the German juvenile idiopathic arthritis registry. Rheumatology
(Oxford) 2011;50:230-6.
Disclosure: K. Minden, Pfizer Inc, 2, Pfizer Inc, Abbott, Novartis, Chugai, Roche,
Medac, 5; M. Niewerth, None; J. Klotsche, None; M. Hammer, None; J. P. Haas,
Abbott, Novartis, Chugai, 5; G. Ganser, Pfizer, Abbott, Chugai, Actelion, 5; G.
Horneff, Abbott, Pfizer, 2, Abbott, Pfizer, Novartis, Chugai, Swedish orphan, 5.
1150
Adverse Events in Juvenile Idiopathic Arthritis: Results From the Enhanced
Drug Safety Surveillance (EDSS) Pilot Project. Sarah Ringold1, Audrey F.
Hendrickson1, Carol A. Wallace2 and Rachel E. Sobel3. 1Seattle Children’s
Hospital, Seattle, WA, 2Seattle Childrens Hospital, Seattle, WA, 3Pfizer, Inc.,
New York, NY
Background/Purpose: There are few data available regarding the rates of
serious and important medical events (SAEs and IMEs) for most of the
medications used to treat JRA/JIA (Juvenile Rheumatoid Arthritis/Juvenile
Idiopathic Arthritis), including nonsteroidal anti-inflammatory drugs. These data
are of particular importance as the use of biologic disease modifying antirheumatic drugs (DMARDs) in JRA/JIA has increased significantly over the past
several years along with the number of medications that are FDA-approved for
the treatment of these diseases. While the FDA has a voluntary MedWatch
reporting system in place, only a small proportion of physicians fill out these
reports and these data cannot be used to calculate SAE/IME rates. The Enhanced
Drug Safety Surveillance (EDSS) Pilot Project was developed in partnership with
Pfizer, as one of the US FDA post-marketing commitments for celecoxib in JIA,
to implement a pilot process to capture of SAEs and IMEs, and to calculate
SAE/IME rates in children with JRA/JIA utilizing the CARRA (Childhood
Arthritis and Rheumatology Research Alliance) physician network. The objective
of this analysis is to summarize the data resulting from the 4-year (2008–2012)
EDSS Pilot Project.
Methods: Physicians at participating sites were surveyed monthly to determine whether any of their JIA/JRA patients had experienced a SAE or IME
during the prior month. MedWatch forms were subsequently completed for each
event, including attribution to medication(s). SAEs and IMEs were categorized by
the primary organ system and/or the dominant symptoms (e.g. disease flare,
infusion reaction). Each site was surveyed every 6 months regarding the number
S493
Monday, November 12
Background/Purpose: Treatment of juvenile idiopathic arthritis (JIA)associated uveitis is one of the serious problems of paediatric rheumatology. JIA
associated uveitis often is refractory to MTX, CiA and topical NSAIDs and GC.
Humanised anti-TNF␣ monoclonal antibody (adalimumab) may be effective
drug for the treatment of JIA-associated uveitis refractory to immunosuppressive
drugs.
Objectives: To evaluate clinical efficacy and safety of adalimumab therapy in
patients with JIA-associated uveitis.
Methods: It was prospective, observational trial. 48 patients with uveitis were
enrolled in the study, 8 boys and 40 girls, 32-with bilateral and 16-with unilateral
uveitis, 27 had poly-, 21-oligoarthritis. Mean age of patients was 11,8 (range 4-18)
y; mean of disease duration-5,7 (range 1-16) y. Before adalimumab therapy 10
patients were treated with MTX (range of dose 15–25 mg/m2/w), 38-with MTX
in combination with CiA (range of dose 4-4,5 mg/kg/d), 5—with oral GC (range
of dose 5–12 mg/kg/d), all of them-with topical GC drops, NSAID drops, 27
-received retrobulbar injections of GC. Adalimumab was administrated by
subcutaneous injection at dose 40 mg every 2 w during 1y. Adalimumab use was
approved by the Local Ethics Committee. The efficacy of therapy was measured
by ACR-pedi criteria. Changes in ocular inflammation were graded by
M.J.Hogan’s criteria. The main target—remission of uveitis and arthritis.
Results: Prior to administration of adalimumab, injection of conjunctiva,
edema of iris, corneal precipitations, areas of inflammation in lens and optical
nerve disk edema were found in all children with uveitis. After 8 w of treatment
complete management of conjunctiva injection, iris edema and optical nerve disk
edema were reported in 55% (44/80) of the affected eyes—corneal precipitations
disappeared in 45% (36/80); inflammation-associated changes of lens—in 18%
(14/80) of eyes. Treatment-associated improvement of vision was found in 63 of
80 of the affected eyes; no changes of vision acuity were reported in 33 (41%) of
the affected eyes. GC eye drops were discontinued in 45% (22/48) of patients,
NSAIDs eye drops—in 50% (24/48) of children; the dose of GC eye drops was
reduced in 86% (41/48) of patients. The exacerbation of uveitis was persisting in
10% (8/80) of the affected eyes, subacute uveitis—in 25%(20/80); remission was
found in 65%(52/80) of the affected eyes. After 24 w of treatment the cases of
uveitis were not reported; subacute disease was observed in 22%(21/96) of eyes;
remission was diagnosed in 78%(62/80) of the affected eyes. After 52 w of
treatment remission was diagnosed in 83% of the affected eyes (66/80) The
ACR-Pedi 30, 50, 70 were achieved 100%, 80%, 60% of patients at w 4,
respectively. After 24 w of therapy ACR-Pedi 30,50,70 and 90 improvements
rates was registrated in 100 %,92 %,78 % of patients. The remission was achieved
by 63% of patient at w 52. Serious adverse events were not found.
Conclusion: Adalimumab is effective in patients with JIA associated uveitis.
Reduction in uveitis activity and remission were reported in 83% of affected eyes.
Remission of disease—in 63% of patients.The high efficacy of adalimumab
allowed avoiding oral prednisolone and discontinuing topical GC therapy in
patients with uveitis.
Background/Purpose: Etanercept (Eta) has been the most frequently used
biologic drug in patients with JIA. In Germany, about one in three patients with
polyarticular JIA received Eta in 2010. However, published data on its long-term
safety are limited. The data of the German JIA biologic registers BiKeR and
JuMBO were used to determine the rates of serious adverse events or events of
special interest in order to assess the long-term safety of Eta.
Methods: Patients who were included at start with Eta in the BiKeR registry
until March 2007 and have been half-yearly observed into adulthood were
considered for this analysis. All adverse events recorded by physicians over the
whole observation period (mean 7.5 years) were categorized on the basis of
MedDRA. Total exposure-adjusted rates for serious adverse events (SAEs) and
for events of special interest (i.e., deaths, malignancies, medically important
infections [MII], and newly emerged other immune-mediated inflammatory
diseases [IMID]) per 100 patient years (PY) were calculated.
Results: During the 1,815 years of Eta exposure in 386 patients (mean age 23
years, mean disease duration 14 years) 77 SAEs were recorded (4.2 SUEs/100
PY), of which 8% were possibly related to therapy. The SAE rates for each year
of Eta exposure per 100 PY varied somewhat over the first nine years of
treatment, but did not differ significantly (p⫽0.312). The JIA-associated mortality
rate was 1% in this study population. Two deaths occurred in patients treated with
Eta within the last three months before death, but no patient died in suspected
causal relationship to Eta. Two malignancies were reported (that were already
published1), resulting in 0.11 event per 100 PY of exposure. Twenty MII were
recorded which led to drug discontinuation in five patients. 75% of the MII
occurred within the first three years of Eta treatment. The exposure-adjusted MII
rate was 1.1 per 100 PY. Tuberculosis or other opportunistic infections were not
registered. A total of 17 incident IMID (0.9/100 PY) were reported: among them
were eight cases with new onset inflammatory bowel disease (0.44/100 PY) and
eight cases with uveitis (0.44/100 PY).
Conclusion: The hitherto most comprehensive study of the long-term safety
of Eta confirms the good tolerability of the substance. SAEs with possible
relationship to therapy occur only rarely (0.3/100 PY). However, reliable risk rates
for events of particular interest can only be calculated in larger patient cohorts.
Moreover, a comprehensive control group is necessary to put the results into
perspective.
Monday, November 12
of JRA/JIA patients per site, to provide a denominator for the SAE/IME rates.
Reporting rates were calculated per 100 person-years (p-y) and 95% CI were
calculated based on a Poisson distribution.
Results: 37 sites with 115 physicians contributed at least one year of data. The
overall response rate to the monthly surveys was 65% and the overall response to
the 6 month surveys was 86%. There were a total of 139 total SAEs and 139
IMEs. The largest proportion of SAEs and IMEs occurred in children with
polyarticular JIA (39% and 38%, respectively). The majority of SAEs and IMEs
were reported for patients receiving biologic DMARDs (73% and 68%, respectively). NSAIDs and non-biologic DMARDs were the next most commonly
reported medications, with 1 SAE and 2 IMEs attributed to celecoxib, and 12
SAEs and 11 IMEs attributed to other NSAIDs. Infection accounted for the
largest proportion of both SAEs and IMEs (52% and 20%). The next most
common categories of SAE were disease flare and macrophage activation
syndrome. The next most common categories of IME were neurologic and
elevated liver function tests. The total event rate for SAEs and IMEs combined
was 1.2 SAE/IME per 100 p-y (95% CI: 1.1–1.4). The rate for SAEs was the
same as IMEs (0.6 per 100 p-y; 95% CI: 0.5–0.7).
Conclusion: The EDSS provided a simple and effective tool for SAE/IME
reporting. These data support the development of a long-term registry of children
with JRA/JIA in North America to continue the collection of these critical data.
Disclosure: S. Ringold, None; A. F. Hendrickson, None; C. A. Wallace, Pfizer Inc,
1, Amgen, 2, Pfizer Inc, 2, Genentech and Biogen IDEC Inc., 5, Novartis Pharmaceutical Corporation, 5; R. E. Sobel, Pfizer Inc, 3.
1151
Low-Dose Methotrexate and the Selective Accumulation of Intracellular
Aminoimidazolecarboxamide Ribotide. Ryan S. Funk, Leon van Haandel,
Mara L. Becker and J.S. Leeder. Children’s Mercy Hospital, Kansas City, MO
Background/Purpose: Current evidence suggests that the anti-folate
methotrexate (MTX) mediates its anti-inflammatory effects through inhibition of the purine synthesis pathway causing the accumulation of aminoimidazolecarboxamide ribotide (AICAR). Meanwhile, the anti-proliferative effects of MTX have primarily been attributed to inhibition of the pyrimidine
synthesis pathway, marked by the accumulation of deoxyuridine monophosphate (dUMP). Therefore, identification of factors that affect MTX selectivity
for purine synthesis pathway inhibition may be important in predicting and
enhancing drug response in immuno-inflammatory diseases.
Methods: K562 erythroblastoid cells (2.5 ⫻ 105 cells/mL) were exposed to
0, 10, 100 and 1000 nM MTX under normal culture conditions for up to 24 hr.
Cell samples (2.5 ⫻ 106 cells) were harvested after 1, 2, 4, 8 and 24 hr of MTX
exposure. Cell lysates were analyzed for AICAR, dUMP, MTX and six different
oxidation/methylation
states
of
tetrahydrofolate,
including
5-methyltetrahydrofolate (5mTHF); the polyglutamate distribution was also
determined for each folate species and MTX. Mean concentrations and standard
deviations from three independent experiments are reported. Statistical evaluations were conducted by unpaired Student’s t-tests and statistical significance was
defined by a P-value ⬍ 0.05.
Results: The primary effect on intracellular folates was a depletion of 5mTHF
to levels at 24 hr that were 80%, 3% and 1% of control (0 nM MTX) in response
to 10, 100 and 1000 nM MTX challenge, respectively with no effect on cell
viability. Similarly, intracellular dUMP accumulated to levels 29-, 343- and
486-fold greater than control after a 24 hr exposure to 10, 100 and 1000 nM
MTX, respectively. In the presence of 10 nM MTX, AICAR accumulated 93-fold
compared to vehicle treated cells at 24 hr, however, increasing [MTX] had a
paradoxical effect, resulting in lower AICAR concentrations. Across all experimental conditions intracellular [MTX] correlated with the intracellular accumulation of dUMP (r2⫽0.854) and depletion of 5mTHF (r2⫽0.860), but poorly with
intracellular AICAR accumulation (r2⫽0.122).
Conclusion: Under these experimental conditions, increasing concentrations of MTX beyond 10 nM did not result in concentration-dependent
increases in AICAR accumulation, and higher doses of MTX appeared to
minimize the effects on the purine pathway, despite having profound effects
on pyrimidine synthesis. Although the mechanism for this paradoxical effect
on AICAR accumulation is currently under investigation, these findings
support the hypothesis that low-dose MTX selectively targets the purine
biosynthesis pathway and may result in improved anti-inflammatory effects.
Disclosure: R. S. Funk, None; L. van Haandel, None; M. L. Becker, None; J. S.
Leeder, None.
1152
Improvement in Health-Related Quality of Life for Children with
Juvenile Ideopathic Arthritis After Start of Treatment with Etanercept.
Jens Klotsche1, Kirsten Minden2 and Gerd Horneff3. 1German Rheumatism
Research Center, a Leibniz institute, Berlin, Germany, 2German Rheumatism
Research Center, a Leibniz Institute, Berlin, Germany, 3Centre of Pediatric
Rheumatology, Sankt Augustin, Germany
Background/Purpose: The concept of Health-related quality of life (HrQoL)
has been widely accepted as a burden of disease measure in recent years. The
improvement in HrQoL is an important therapy goal in the treatment of patients
with juvenile idiopathic arthritis (JIA). We investigated the 12-month course of
HrQol in an unselected cohort of patients with JIA after therapy start with
Etanercept and identified its associated factors.
Methods: Children were enrolled in the BiKer (Biologics in Paediatric
Rheumatology) registry. A random subset of children completed the Pediatric
Quality of Life Inventory (PedsQL) after the start of Etanercept treatment and was
followed-up monthly for 6 monthly and bimonthly thereafter for up to one year.
The 12-month course of the PedsQL total score and predictors for the change in
HrQoL were investigated by growth curve modeling. The role of the depending
predictor variables of an inactive disease and level of pain were studied in the
course of HrQoL. The criteria by Wallace (2004) were applied to define inactive
disease, the level of pain was assessed on a visual analogue scale (0–100) and
functioning was measured by the CHAQ.
Results: Data were available for 61 patients with a mean age of 10.5 years
(sd⫽3.9) and a mean disease duration of 3.2 years (sd⫽3.2). At baseline, the
mean PedsQL total score was 75.5 (sd⫽16.7), mean number of swollen joints
was 7.2 (sd⫽6.2), the mean rating of disease activity was 56.9 (sd⫽19.5) and
80% of the children reported functional restrictions indicated by a CHAQ above
0. A lower HrQol for patients at baseline was significantly associated with the
number of swollen joints (beta⫽-1.1, p⫽0.016), functional restrictions (beta⫽18.9, p⬍0.001), a high disease activity (beta⫽-0.31, p⫽0.002) and the existence
of at least one comorbid condition (beta⫽11.5, p⫽0.021). The PedsQL total score
increased at a rate of 2.8 units per month (p⬍0.001) in the first 6 months of
treatment up to a level of 89.7 (sd⫽10.7), whereas the increase flattened (0.3 units
per month, p⫽0.144) from 6-month to 12-month follow-up. A total of 16 (26%)
children were already in remission after one year Etanercept treatment. The
achievement of remission at the second month (beta⫽6.7, p⬍0.001) and fourth
month (beta⫽5.2, p⫽0.029) yielded a significant increase in HrQoL. A high level
of pain was associated with a lower HrQoL at each occasion.
Conclusion: HrQoL significantly improved after starting an Etanercept
therapy in children with JIA. Adequate disease control and a low level of pain
predicted a higher HrQoL in the 12-month course. But, both time dependent
predictor variables did not fully explain the improvement in HrQoL.
Disclosure: J. Klotsche, None; K. Minden, Pfizer Inc, 2, Pfizer Inc, Abbott, Novartis,
Chugai, Roche, Medac, 5; G. Horneff, Abbott Immunology Pharmaceuticals, 2, Pfizer Inc,
2.
1153
Perceived Health-Related Quality of Life and Its Determining Factors in
Children with Recent-Onset JIA. Jens Klotsche1, Ina Liedmann1, Martina
Niewerth2, Gerd Horneff3, Johannes Peter Haas4 and Kirsten Minden5.
1
German Rheumatism Research Center, a Leibniz institute, Berlin, Germany,
2
German Rheumatism Research Centre, Berlin, Germany, 3Centre of Pediatric Rheumatology, Sankt Augustin, Germany, 4German Center for Pediatric
and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany, 5German
Rheumatism Research Center, a Leibniz Institute, Berlin, Germany
Figure. Intracellular dUMP and AICAR in K562 cells following a 24 hr exposure
to MTX (**, P-value ⬍ 0.01; ***, P-value ⬍ 0.001).
Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most common
chronic rheumatic disease and a major cause of chronic disability in children aged
below 16 years. Health-related quality of life (HrQoL) has become an important
S494
Disclosure: J. Klotsche, None; I. Liedmann, None; M. Niewerth, None; G. Horneff,
Abbott Immunology Pharmaceuticals, 2, Pfizer Inc, 2; J. P. Haas, None; K. Minden,
Pfizer Inc, 2, Pfizer Inc, Abbott, Novartis, Chugai, Roche, Medac, 5.
1154
Impact of FokI VDR and TNFalpha-308 Polymorphism On Disease Severity and Long Term Outcome in JIA Patients On Anti-TNF Treatment.
Jelena Vojinovic1, Jelena Basic2, Gordana Susic3, Dragana Lazarevic2 and
Nemanja Damjanov4. 1Prof, Nis, Serbia, 2Dr, Nis, Serbia, 3Dr, Belgrade, Serbia,
4
Prof, Belgrade, Serbia
Background/Purpose: Genetic contribution of SNP (single nucleotide polymorphism) of TNF␣-308 promoter and FoxI for VDR (vitamin D receptor)
polymorphism on disease severity and outcome in JIA is not yet well established.
VDR polymorphisms correlations with different autoimmune diseases have been
implicated and found to be different in some populations but data for JIA are
missing. Primary endpoint of this study was to evaluate influence of these
promoter polymorphisms, as possible biomarkers, on disease severity and long
term outcome in JIA patients on anti-TNF treatment.
Methods: Genomic DNA was extracted and TNF␣-308 promoter and FokI
VDR polymorphism was evaluated using the PCR-RFLP method in 60 JIA
patients included in Serbian JIA registry who donated blood samples before
commencement of etanercept treatment. Time cut of point for outcome data
analysis was 4 years after first dose of anti-TNF agent (etanercept).
Results: At enrolment JIA patients mean age was 14.7⫾4.22, disease
duration 6.59⫾2.76, and average dose of MTX 11.91⫾6.68 mg/m2/week.
Disease subtype distribution was 6.78% systemic, 54.24% polyRF- and extended
oligo, 18.64% polyRF⫹, 16.95% ERA and 3.38 PsA. The distribution of
TNF␣308 and VDR genotypes was not significantly different among JIA
subtypes. TNF␣308 genotypes distribution was 6.78% AA, 30.51% GG and
62.71% GA. After 4 years treatment could be stopped (remission) in 35.14%, had
to be reintroduces due to disease worsening in 16.22%, disease was in remission
under medication in 21.62% or still active in 24.32% GA patients while
respectively in 38.9%, 16.7%, 27.8% and 11.1% in GG patients. Average
duration of etanercept treatment was 34.61⫾12.11 months and there was
significantly shorter need for treatment duration if GG polymorphism group.
VDR genotypes distribution was 51.6% FF, 38.7% Ff and 9.7% ff while in 20
healthy controls only FF (wild type) genotype was present. Presence of ff
genotype significantly correlated with worse outcome and disease severity. We
have found significant correlations with disease severity and presence of
TNF␣308 and/or FokI VDR genotypes.
Conclusion: Our results indicate that JIA patients, more frequently than
healthy controls, have Ff or ff VDR FokI polymorphism. Heterozygote or
homozygote presence of f variant for FokI polymorphism of VDR in JIA patients
was associated with more severe disease and worse outcome. JIA patients with
GG TNF␣308 genotype can achieve better outcome and etanercept treatment can
be stopped earlier compared to GA genotype. Both genotypes could be useful
clinical predictive biomarker for disease severity and treatment response.
Disclosure: J. Vojinovic, None; J. Basic, None; G. Susic, None; D. Lazarevic, None;
N. Damjanov, None.
1155
A New Measure of Visual Function for Children with Juvenile Idiopathic
Arthritis-Associated Uveitis. Sheila T. Angeles-Han1, Steven Yeh1, Courtney
McCracken1, Larry B. Vogler1, Kelly A. Rouster-Stevens1, Christine W. Kennedy2, Kirsten Jenkins3, Matthew Kent1, Scott Lambert1, Carolyn Drews-Botsch4
and Sampath Prahalad2. 1Emory Univ School of Medicine, Atlanta, GA, 2Emory
Children’s Center, Atlanta, GA, 3Children’s Healthcare of Atlanta, Atlanta, GA,
4
Emory University School of Public Health, Atlanta, GA
Background/Purpose: Studies on outcomes of children with juvenile idiopathic arthritis-associated uveitis (JIA-U) focus on the clinical ocular exam and
physical disability secondary to arthritis. This assessment could improve by
including measures of the impact of uveitis on daily life. However, until recently,
there were no instruments that measured visual function in this population. Our
objective is to validate a measure of visual function, the “Effects of Youngsters’
Eyesight on Quality of Life (QOL)” (EYE-Q), in children with uveitis.
Methods: Focus groups were held to modify the old EYE-Q for children with
uveitis. The new EYE-Q contains items specific to uveitis. A parent-proxy version
was also developed. Children with JIA, JIA-U, and idiopathic uveitis (I-U)
participated. Medical record reviews were performed. Questionnaires were completed on QOL (Pediatric QOL Inventory - PedsQL), physical function (Childhood Health Assessment Questionnaire - CHAQ), and visual function (EYE-Q).
Results: Participants were 104 children with JIA, 19 with JIA-U and 9 with
I-U (Table 1). There were significant differences in the child and parent EYE-Q
scores in children with uveitis compared to children with JIA (Table 2). For the
child report, there were mild correlations between EYE-Q scores and logmarVA
(r ⫽ ⫺0.35) and moderate correlations with the PedsQL (r ⫽ 0.50) and CHAQ
(r ⫽ ⫺0.53) (Table 3). Similar results were found with the parent report. There
were strong correlations between the parent and child EYE-Q (r ⫽ 0.74), and the
old and new versions of the EYE-Q (r ⫽ 0.96, r ⫽ 0.94).
Table 1. Characteristics of children with JIA-associated uveitis, JIA alone, and
idiopathic uveitis
Demographic Characteristics
Age, mean years ⫾SD
Gender, female, N (%)
Hispanic, N (%)
Disease characteristics
Age at arthritis onset, mean years ⫾SD
Age at uveitis onset, mean years ⫾SD
Duration of JIA, mean years ⫾SD
Duration of uveitis, mean years ⫾SD
Ophthalmology exam, most recent
LogMarVA mean⫾SD, worse eye
Intraocular pressure, worse eye
Slit lamp exam, worse eye
Cells
0 (⬍1 cell in field)
0.5⫹ (1-5 cells in field)
1⫹ (6-15 cells in field)
2⫹ (16-25 cells in field)
3⫹ (26-50 cells in field)
4⫹ (⬎50 cells in field)
Complications, N (%)
Cataracts
Glaucoma
Synechiae
Band keratopathy
Cystoid macular edema
Other complications
Surgeries, N (%)
Cataract extraction
Periocular steroid injection
Other ocular surgeries
S495
JIA alone
N ⴝ 104
JIA-U
N ⴝ 19
I-U
Nⴝ9
11.6 ⫾ 4.8
74 (71.8)
10 (9.7)
10.5 ⫾ 4.5
16 (84.2)
4 (22.2)
11.7 ⫾ 4.9
5 (55.6)
0 (0)
7.4 ⫾ 4.5
4.0 ⫾ 4.6
6.8 ⫾ 5.1
6.48 ⫾ 3.74
3.68 ⫾ 3.56
N ⫽ 15
0.24 ⫾ 0.22
19.0 (7.5)
3.65 ⫾ 3.12
N⫽7
0.74 ⫾ 0.98
18.7 (8.6)
114
2
1
2
0
0
N ⫽ 17
5 (29.4)
0 (0)
6 (36.3)
2 (11.8)
0 (0)
3 (17.7)
2
0
0
0
0
N⫽9
6 (66.7)
2 (22.2)
7 (77.8)
5 (55.6)
3 (33.3)
4 (57.1)
0 (0)
2 (11.8)
1 (5.9)
3 (33.3)
3 (33.3)
2 (22.2)
3.99 ⫾ 3.51
N ⫽ 34
0.17 ⫾ 0.24
11.5 (7.8)
34
0
0
0
0
0
8.0 ⫾ 4.4
Monday, November 12
outcome measure for the perceived burden of disease and therapy effectiveness in
the field of pediatric rheumatology. There is little knowledge about its diversification and determining factors in children with recently diagnosed JIA.
Methods: The diversification and determining factors of HrQoL were
investigated by latent class analyses (LCA) in the ICON (Inception Cohort Of
Newly-diagnosed patients with JIA) study, a prospective controlled observational
multicentere study for long-term observation of patients diagnosed as JIA within
the last 12 months. The evaluation comprised a self assessment by patients and
parents via standardized questionnaires and clinical examinations by pediatric
rheumatologists and ophthalmologists. HrQoL was measured by the Pediatric
Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and the PedsQL 3.0
Rheumatology Module. The PedsQL was completed by patients above an age of
eight years and parents. The difference between both ratings and determining
factors for the difference were investigated.
Results: Information about HrQoL was available for 426 patients. Differences in the patients and parents ratings could be investigated for 198 children
aged above 8 years. More than half of the children (58.4%) were assigned to a
group characterized by high PedsQL scores (range: 79.4, 95% CI: 76.3;82.5 for
treatment problems to 98.3, 95% CI: 97.5;99.2 for daily activity) by LCA. Only
9% of the children were classified into a group with low HrQoL scores (mean
total score 50.6, 95% CI: 45.3;55.9) and were diagnosed with polyarthrits. High
HrQoL scores were associated with the ILAR category oligoarthritis (p⬍0.001)
and a low disease activity (mean 2.7 on NRS 0–10, p⬍0.001). Patients with high
HrQoL scores had significantly less emotional difficulties as measured by the
Strength and Difficulties questionnaire. Interestingly, parents of patients with
higher HrQoL scores had more likely a higher educational level (57% with more
than 10 years of schooling). In general, the parents rating of HrQoL was lower
than the rating of the children (difference in total score ⫽ 4.1, 95%CI: 2.5;5.7).
The most pronounced differences were observed in the rating of emotional
problems (⌬⫽8.3, 95%CI: 5.3;11.2) within the age groups (⌬⫽6.0 for age group
8–12 years versus 1.8 for age group 13–16 years, p⬍0.001). Children in the two
ILAR categories systemic arthritis (⌬⫽8.8, 95%CI: 3.6;14.1) and psoriatic
arthritis (⌬⫽6.6; 95%CI: 1.2;13.5) reported better HrQoL compared to the
parents report.
Conclusion: More than half of the children report high HrQoL scores at the
beginning of JIA. Disease related parameters as well as social and personal factors
independently affect the patients⬘ overall well-being. Parents of younger children
rated HrQoL remarkably lower than the children themselves, both patient- and
proxy-reporting is therefore required to get a full picture of the burden of illness.
Table 2. Mean scores on standard quality of life and function measures in JIA
JIA
N ⴝ 102
Child Reports⫹
EYEQa (range 0-4)**
CHAQb (range 0-3)⫹⫹
PedsQLc Physical scale
(range 0-100)**
PedsQL Psychosocial scale
PedsQL Total scale
Parent Reports
EYEQa (range 0-4)**
CHAQb (range 0-3)⫹⫹
PedsQLc Physical scale
(range 0-100)**
PedsQL Psychosocial scale
PedsQL Total scale
JIA-U
N ⴝ 19
I-U
Nⴝ9
P value
3.64 ⫾ 0.44
0.59 ⫾ 0.61
70.3 ⫾ 24.4
3.31 ⫾ 0.44
0.72 ⫾ 0.67
60.47 ⫾ 24.7
3.37 ⫾ 0.79
0.00 ⫾ 0.00
91.5 ⫾ 5.3
0.043*
0.046*
0.023*
74.5 ⫾ 18.8
73.1 ⫾ 19.5
69.0 ⫾ 17.9
65.98 ⫾ 18.90
81.8 ⫾ 18.4
85.31 ⫾ 18.89
0.334
0.102
3.78 ⫾ 0.37
0.57 ⫾ 0.63
69.48 ⫾ 25.44
3.37 ⫾ 0.57
0.56 ⫾ 0.62
67.29 ⫾ 22.57
3.33 ⫾ 0.89
0.08 ⫾ 0.17
98.2 ⫾ 3.54
0.002*
0.077
0.010
76.29 ⫾ 20.15
73.83 ⫾ 20.49
67.75 ⫾ 19.99
67.64 ⫾ 19.50
84.29 ⫾ 23.80
89.13 ⫾ 15.42
0.135
0.061
Disclosure: K. Geitz, None; I. Foeldvari, None.
Monday, November 12
1157
The Phenotypic Characterization of Juvenile Idiopathic Arthritis in African
American Children. Lauren Minor1, Lori Ponder2, Emily G. Ferrell1, Sheila
Angeles-Han1, Christine W. Kennedy2, Kelly Rouster-Stevens1, Mina Pichavant2, Larry B. Vogler1 and Sampath Prahalad1. 1Emory University School of
Medicine, Atlanta, GA, 2Emory Children’s Center, Atlanta, GA
⫾ data are missing
ANOVA, *p-value ⬍0.05
a
Effects of Youngsters Eyesight on QOL; bChildhood Health Assessment Questionnaire;
c
Pediatric Quality of Life Inventory
** Greater scores indicate better QOL; ⫹⫹Greater scores indicate worse QOL
Table 3. Correlations of the EYEQ with standard measures of quality of life and
function in JIA
EYEQa child
LogmarVAb
CHAQc
PedsQLd Total scale
EYEQ parent
New EYE-Q
EYEQa parent
LogmarVAb
CHAQc score
PedsQLd total
New EYEQa
49%, 70% and by 76%.The CHAQ score decreased at 3,6 and 9 months by 45%,
63% and 62%, the pain-score by 38%, 62% and 51% and the well-being score by
52%, 66% and 49% and the physician global by 58%, 65% and 65%.
Conclusion: In this retrospective chart review we could demonstrate the
effectivity of MTX for peripheral joint involvement and for enthesitis. Interestingly only after 6 months of MTX therapy was the highest rate of improvement
reached. Prospective controlled trial would be important to prove our results.
R [95% CI]**
P value
-0.35 [-0.60 – (-0.03)]
-0.53 [-0.78 – (-0.57)]
0.50 [0.33-0.63]
0.74 [0.63 – 0.81]
0.96 [0.94 – 0.97]
0.029*
⬍0.0001*
⬍0.0001*
⬍0.0001*
⬍0.0001*
-0.22 [-0.46 – 0.046]
-0.34 [-0.48 – (-0.18)]
0.43 [0.28 – 0.57]
0.94 [0.916 – 0.96]
0.101
⬍0.001*
⬍0.001*
⬍0.001*
Spearman’s correlation coefficients, *p-value ⬍0.05
** Mild correlations: R ⬍0.3; Moderate correlations: R ⫽ 0.3 - 0.7; Strong
correlation: R ⫽ ⬎0.7
a
Effects of Youngsters Eyesight on QOL; b Logmar visual acuity; c Childhood
Health Assessment Questionnaire; d Pediatric Quality of Life Inventory
Cronbach’s ␣ for the old EYE-Q child and parent reports was 0.89.
Cronbach’s ␣ for the new EYE-Q child report was 0.91 and for the parent report
was 0.90.
Conclusion: The new EYE-Q, with items specific to uveitis, is a valid
measure of visual function in children with uveitis. There were differences in child
and parent perception of disease hence the inclusion of both perspectives in
disease assessment is important. The EYE-Q may be an important measure in the
assessment of outcomes in this population and a better measure than the clinical
exam and arthritis specific measures alone. Longitudinal studies examining the
performance of the EYE-Q in children with JIA-U and I-U are ongoing.
Disclosure: S. T. Angeles-Han, None; S. Yeh, None; C. McCracken, None; L. B. Vogler,
None; K. A. Rouster-Stevens, None; C. W. Kennedy, None; K. Jenkins, None; M. Kent,
None; S. Lambert, None; C. Drews-Botsch, None; S. Prahalad, None.
1156
Background/Purpose: JIA, a common childhood arthropathy, with an
estimated prevalence of 1 in 1000 in children under the age of 16, affects children
of all ages and races. There is limited data describing the characteristics of JIA in
African-American (AA) children. The purpose of this study was to compare
phenotypic characteristics of AA and Non-Hispanic White (NHW) JIA patients
in our rheumatology clinic.
Methods: Charts of children with JIA, who were enrolled in a genetic study
between June 2009 and June 2012 were reviewed. At time of enrollment,
demographic and disease-related data were collected. Patients who identified as
Hispanic or multi-racial were excluded. Disease characteristics compared between AA and NHW children included: age at onset and diagnosis, family
history, JIA subtype, laboratory tests, associated features, medications, and
radiographic changes. Fischer’s exact test or Chi-Square tests were used to
compare nominal variables, and student’s T test was used to compare continuous
variables.
Results: 150 NHW children and 62 AA children with JIA were studied.
Table 1 compares demographic and disease characteristics of NHW and AA
children. AA children with JIA were significantly older both at disease onset and
presentation to a pediatric rheumatologist. JIA subtypes differed significantly
between AA children and NHW children, with the AA being predominantly
polyarticular RF⫹, and NHW being predominantly persistent oligoarticular. Both
groups had a female predominance. Significantly more AA children had Medicaid and lived closer to their rheumatologist. AA children were less likely to have
a family history of autoimmunity. Laboratory studies demonstrated that AA
children were more likely to have positive RF and CCP antibodies. AA children
were more likely to be treated with methotrexate at diagnosis, and more likely to
have received systemic steroids during the course of their disease. These children
were also more likely to have joint space narrowing and osteopenia on x-ray than
NHW children. AA children were more likely to have rheumatoid nodules and
chronic anemia as manifestations of their disease. The prevalence of uveitis was
not significantly different between AA and NHW children with JIA. Even
excluding the polyarticular RF⫹ subtype, AA children were older at onset and
had more cumulative joints affected.
Table 1. Characteristics of NHW and AA children with JIA*
Effectivity of Methotrexate in Therapy of Juvenile Idiopathic EnthesitisRelated Arthritis. Katharina Geitz and Ivan Foeldvari. Hamburger Zentrum
Kinder-und Jugendrheumatologie, Hamburg, Germany
Background/Purpose: Juvenile idiopathic enthesitis related arthritis
(enthJIA) represents 5 to 10% of children with JIA. Most patients present with
peripheral arthritis and enthesitis. Methotrexate was not formally studied regarding effectivity for the peripheral joint involvement of this subset. Aim of our study
was to assess the effectivity of methotrexate in peripheral joint involvement of
enthesitis related JIA.
Methods: We conducted a chart review of patients with juvenile idiopathic
enthesitis related arthritis, who have been treated at least for 3 months with MTX
since 2005. The clinical and demographic parameters of the patients were
assessed.
Results: We identified 73 patients with confirmed diagnosis of enthJIA, who
were treated at least for 3 months with MTX. At the initiation of the therapy the
average active joint count was 2,5 and the number of active enthesitis sites were
0,9. The mean CHAQ value was 0,55 and the mean pain score was 1,20 and the
mean well being score was 1,26. The mean physician global was 1,74. At 3,6 and
9 months the active joint count was reduced by 18%, 44% and 53%, the number
of painful joints by 22%, 36% and 47% and the number of swollen joints by 70%,
70% and 65%. The number of active enthesitis sites were reduced by 3,6 and 9
months by 44.5%, 61% and 50%. The CRP was reduced at 3,6 and 9 months by
Total Number
Age at onset (mean ⫾SD)
Including RF⫹ poly JIA
Excluding RF⫹ poly JIA
Age at baseline visit (mean ⫾SD)
Including RF⫹ poly JIA
Excluding RF⫹ poly JIA
Gender: females
Insurance type
Medicaid
Private
Both
Distance from rheumatologist
⬍ 30 miles
⬎ 30 miles
Management prior to rheumatology
Managed by Pediatrician
Seen by Orthopedics
Alternate diagnosis
Family history of autoimmunity
JIA subtype
ERA
Oligoarticular extended
Oligoarticular persistent
Polyarticular RFPolyarticular RF⫹
Psoriatic
Systemic-onset
Undifferentiated
Uveitis
S496
NHW
AA
150
62
P value
6.6 ⫾ 4.4
6.5 ⫾ 4.4
8.7 ⫾ 4.4
8.0 ⫾ 4.4
1.8 ⫻ 10⫺3*
0.05*
7.5 ⫾ 4.7
7.2 ⫾ 4.7
102 (68)
9.4 ⫾ 4.4
8.5 ⫾ 4.4
48 (73)
6.9 ⫻ 10⫺3*
0.10
0.19
43 (29)
105 (70)
2 (1)
37 (60)
24 (39)
1 (1)
1.9 ⫻ 10⫺5*
1.7 ⫻ 10⫺4*
0.44
35 (23)
115 (77)
44 (71)
18 (29)
⬍1.0 ⫻ 10⫺4*
⬍1.0 ⫻ 10⫺4*
12 (8)
56 (37)
16 (11)
39 (26)
8 (13)
6 (10)
9 (15)
9 (15)
0.1
1.7 ⫻ 10⫺5*
0.13
0.03*
19 (13)
20 (13)
45 (30)
37 (35)
9 (6)
7 (5)
8 (5)
5 (3)
20 (13)
6 (10)
10 (16)
6 (10)
12 (19)
18 (29)
1 (2)
7 (11)
2 (3)
7 (11)
0.16
0.14
6.8 ⫻ 10⫺4*
0.1
1.4 ⫻ 10⫺5*
0.21
0.07
0.32
0.4
Joint involvement (excluding RF⫹
polyarticular JIA)
Joints at onset
Cumulative joints involved
JADAS-27 joint count ever
Laboratory tests
Positive ANA
Positive HLA-B27
Confirmed RF positive
Anti-CCP positive
Radiographic findings
Osteopenia
Joint space narrowing
Treatment
Use of systemic steroids
Use of DMARD ever
Use of biologic ever
5.2 ⫾ 6.4
8.4 ⫾ 8.3
6.5 ⫾ 5.7
7.2 ⫾ 9.5
11.9 ⫾ 11.0
9.3 ⫾ 8.2
than the cut-off was 85.6% among nonresponders and 23.8% among
responders. Evidence of predictive ability of the cut-offs was obtained by
demonstrating that in the longitudinal patient sample, the percentage of
patients with inactive disease or with a C-HAQ score of 0 at final visit was
significantly lower among patients who had a JADAS above the cut-off
value at first visit than among those who did not.
Conclusion: We developed the JADAS cut-offs for HDA in JIA. The
cut-offs revealed strong discriminative and predictive ability in a clinical trial
and are, therefore, potentially applicable in clinical practice, observational
investigations, and therapeutic studies.
0.08
0.01*
4.9 ⫻ 10⫺3*
43 (29)
17 (16)
12 (8)
13 (9)
19 (32)
3 (6)
18 (30)
18 (36)
0.9
0.6
8.3 ⫻ 10⫺4*
1.8 ⫻ 10⫺3*
31 (21)
18 (12)
20 (32)
16 (26)
0.08
8.5 ⫻ 10⫺3*
62(41)
113 (75)
73 (49)
43 (69)
51 (83)
36 (58)
1.2 ⫻ 10⫺4*
0.08
0.06
* All values are N(%) of those tested/reporting data for particular variables, except as indicated.
Significant P- values considered ⬍0.05.
Disclosure: L. Minor, None; L. Ponder, None; E. G. Ferrell, None; S. Angeles-Han,
None; C. W. Kennedy, None; K. Rouster-Stevens, None; M. Pichavant, None; L. B.
Vogler, None; S. Prahalad, None.
1158
Development of Cut-off Values for High Disease Activity in Juvenile
Idiopathic Arthritis Based On the Juvenile Arthritis Disease Activity
Score. Alessandro Consolaro1, Stefano Lanni1, Sara Verazza1, Maria C.
Gallo1, Marta Bertamino1, Giulia C. Varnier1, Serena Calandra2, Nicolino
Ruperto3, Alberto Martini2 and Angelo Ravelli4. 1Istituto Giannina Gaslini,
Genova, Italy, 2University of Genova, Genova, Italy, 3Paediatric Rheumatology International Trials Organisation [PRINTO], Genova, Italy, 4Paediatric
Rheumatology International Trials Organization (PRINTO), Istituto Giannina
Gaslini, Genova, Italy
Background/Purpose: In the last decade, there have been major advances in the management of juvenile idiopathic arthritis (JIA), including the
shift towards early aggressive interventions and the development of new
therapeutic agents and combination treatment strategies. A reliable documentation of the advances in therapeutic effectiveness creates the need for
validated and clinically useful criteria that describe precisely the clinical state
of the patient. The study was aimed to determine cut-off values for the state
of high disease activity (HDA) in JIA based on the Juvenile Arthritis Disease
Activity Score (JADAS).
Methods: For the selection of cut-offs, data from a clinical database
including 618 children with JIA followed between 2007 and 2011 were used.
Patients were defined as being in HDA when one of the following therapeutic
interventions was prescribed: 1) start of methotrexate; 2) intraarticular
corticosteroid therapy; 3) start of a biologic medication; 4) start of systemic
corticosteroid therapy. Patients were defined as having low disease activity
(LDA) when they were receiving no therapy or had therapy discontinued,
tapered or left unchanged for ⬎ 1 year. For each patient, 1 visit in HDA and
1 visit in LDA were retained. Optimal JADAS cut-offs were determined by
calculating the 25thpercentile of cumulative score distribution in patients with
HDA and by assessing their ability to discriminate between the states of HDA
and LDA through ROC curve analysis (including calculation of Youden
index and fixed 90% specificity). Cross-validation of cut-offs was performed
in 490 JIA patients enrolled in the PRINTO methotrexate trial (Ruperto et al,
A&R 2004;50:2191-201) and on 358 patients followed longitudinally at study
centers for a median of 1.7 years, and was based on assessment of
discriminative and predictive validity.
Results: The cut-offs were calculated separately for patients with
oligoarticular and polyarticular course of joint disease (irrespective of
ILAR category) owing to the different severity of these 2 JIA phenotypes.
Complete clinical data were available for 258 visits of patients with
oligoarthritis and 289 visits of patients with polyarthritis. JADAS-10 and
JADAS-71 cut-offs were 7.6 for oligoarthritis and 10.6 for polyarthritis.
JADAS-27 cutoffs were 7.7 for oligoarthritis and 8.9 for polyarthritis.
Validation analyses showed that at baseline visit of methotrexate trial
94.7% of patients had a JADAS higher than the proposed cut-off for
JADAS. At 6-month visit, the percentage of patients with a JADAS higher
1159
Reasons and Predictors of Methotrexate Discontinuation in Children
with JIA: Results From the Childhood Arthritis Prospective Study
(CAPS). Suzanne Verstappen1, Lucy R. Wedderburn2, H. E. Foster3, Eileen
Baildam4, Janet Gardner-Medwin5, Joyce Davidson5, Alice Chieng6, Wendy
Thomson7 and Kimme L. Hyrich8. 1University of Manchester, Manchester
Academic Health Sciences Centre, Manchester, United Kingdom, 2University
College London (UCL), London, United Kingdom, 3Newcastle Hospitals
NHS Foundation Trust and Great North Children’s Hospital, Newcastle Upon
Tyne, United Kingdom, 4Alder Hey Children’s Foundation NHS Trust,
Liverpool, United Kingdom, 5Royal Hospital for Sick Children, Glasgow,
United Kingdom, 6Manchester Children’s Hospital, Manchester, United
Kingdom, 7Arthritis Research UK Epidemiology Unit, Manchester, United
Kingdom, 8Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academy of Health Sciences, Manchester, United
Kingdom
Background/Purpose: Methotrexate (MTX) is the DMARD of first
choice in patients with juvenile idiopathic arthritis (JIA). However, limited
data is available on MTX survival, including reasons for stopping MTX, and
predictors for stopping MTX.
Objectives: The objectives of this study were to i) describe survival time
and reasons for stopping MTX and ii) to identify possible predictors for
stopping MTX due to adverse events (AE) or inefficacy.
Methods: Consecutive children with JIA treated with MTX from the
Childhood Arthritis Prospective Study (CAPS), a large prospective
longitudinal inception cohort study, were included. At baseline, 6 months
and at annual follow-up visits a clinical examination was performed including the physician’s global assessment (PGA) and number of
active and limited joints. The CHAQ, was completed by the parent or the
child. Start and stop dates and reasons for stopping MTX were also
collected. For the present study the following definitions were applied:
1) AE, stopped due to AE and MTX not restarted for at least one month;
2) inefficacy, stopped MTX due to inefficacy or added a biologic;
3) efficacy, stopped MTX because of efficacy and MTX not restarted for
at least one year; 4) other. Kaplan Meier survival curves were calculated
to determine the survival probability at two years for overall, AE,
inefficacy or efficacy survival. Patients were included until the date of
stopping MTX or until the last follow-up date when MTX treatment was
continued. Cox proportional hazards regression analyses were applied to
assess the predictive ability of demographic and clinical variables assessed at time of starting MTX treatment with AE or inefficacy. Since data
on disease activity were not always collected at time of MTX therapy
start, disease activity and CHAQ-score assessed for a maximum of
three months prior to MTX start was used, otherwise data was defined
missing.
Results: 501 children (median [IQR] age at MTX start was 8.3 [4.012.2] yrs) received MTX after a median time since symptom onset of
7.1 [3.5-19.1] months. 244 (49%) stopped MTX, reasons: AE (n⫽58),
inefficacy (n⫽121), efficacy (n⫽34) and other reasons (n⫽31). Overall
median survival time was 2.4 [1.1-4.4] yrs. The estimated survival rates at
two yrs were 0.87 (95%CI 0.83 to 0.90) for AE, 0.75 (95%CI 0.70 to 0.79)
for inefficacy and 0.93 (95%CI 0.88 to 0.95) for efficacy. Older children
were more likely to stop MTX medication because of AE (HR 1.08,
95%CI 1.01 to 1.14) or inefficacy (HR 1.06, 95%CI 1.01 to 1.10) and a
high PGA score measured at MTX start (HR 1.21, 95%CI 1.04 to 1.42
(n⫽236)) was associated with MTX related AE survival. No other
associations with AE or inefficacy survival were found, probably due to
lack of power, respectively: female gender (HR, 95%CI; 0.83 (0.48 to
1.43) and 0.98 (0.66 to 1.44)), active joint count (HR, 95%CI; 0.99 (0.95
S497
Monday, November 12
Conclusion: Using a large cohort of AA and NHW children with JIA, we
confirm reports of the differences in disease characteristics reported in smaller
earlier studies. AA children with JIA demonstrate significant differences in
disease characteristics; they are older at disease onset, more likely to have
RF/CCP ⫹ polyarthritis, more likely to use systemic steroids, more likely to
have a higher joint count involvement, and more likely to have radiographic
evidence of disease. These observations support earlier observations that the
phenotype of JIA is different in AA children.
Disclosure: A. Consolaro, None; S. Lanni, None; S. Verazza, None; M. C. Gallo,
None; M. Bertamino, None; G. C. Varnier, None; S. Calandra, None; N. Ruperto,
None; A. Martini, None; A. Ravelli, None.
to 1.03) and 1.02 (0.99 to 1.04) (n⫽323)), limited joint count (HR,
95%CI, 0.99 (0.95 to 1.04) and 1.02 (0.99 to 1.04) (n⫽321)), and
CHAQ-score (HR, 95%CI, 0.71 (0.36 to 1.41) and 1.03 (0.64 to 1.66)
(n⫽147)).
Conclusion: In this cohort of patients with JIA starting MTX we
found that children stayed on MTX therapy for a median of 2.5 years.
Older age was a predictor for stopping MTX due to AE and inefficacy.
Disclosure: S. Verstappen, None; L. R. Wedderburn, None; H. E. Foster, None; E.
Baildam, None; J. Gardner-Medwin, None; J. Davidson, None; A. Chieng, None;
W. Thomson, None; K. L. Hyrich, None.
Monday, November 12
1160
Assessment of Subclinical Synovitis by Power Doppler Ultrasonography
in Patients with Juvenile Idiopathic Arthritis. Maria Teresa Terreri1,
Vanessa M. Bugni2, Claudio A. Len2, Sônia de A.V. Mitraud3, Rita NV.
Furtado4 and Jamil Natour5. 1Universidade Federal de São Paulo/UNIFESP,
Sao Paulo, Brazil, 2Universidade Federal de São Paulo/UNIFESP, São Paulo,
Brazil, 3Universidade Federal de São Paulo/UNIFESP, São Paulo, 4Universidade Federal de Sao Paulo, Sao Paulo, Brazil, 5Universidade Federal de São
Paulo, São Paulo, Brazil
Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most
common chronic rheumatic disease in childhood, leading to physical disability and poor quality of life. Advances in the treatment of JIA have led to
higher remission rates. However despite clinical remission articular ultrasonography (US) can sometimes detect subclinical synovitis (SS). The aim of this
study was to evaluate patients with JIA in remission and healthy controls for
the presence of SS by US Power Doppler (PD), and evaluate its association
with demographic and clinical variables.
Methods: Cross-sectional study of patients with JIA in remission and
healthy controls, matched for age and gender. Inclusion criteria: oligoarticular and polyarticular JIA, clinical and laboratory remission (Wallace et
al), between the ages 5 to 18 years. Clinical assessment: active/limited
joint count, functional capacity by the Childhood Health Assessment
Questionnaire (CHAQ), physician global visual analogue scale (VAS),
patient global VAS, medications in use. US assessment evaluated 17 joints
bilaterally. Ultrasonographic parameters included synovitis and synovial
blood flow in PD. A moderate to severe degree of synovitis and/or any
synovial flow present at the PD indicated the presence of SS. P-values
were calculated based on the chi-square test, Fisher’s exact test, student’s
T test and Mann-Whitney U test.
Results: Thirty-six patients (mean age 11.5 ⫾ 3.7 years) and 36
controls (mean age 11.3 ⫾ 3.7 years) were included and a total of 2448
joints were assessed. There were 36 JIA patients, 29 were girls, with a
mean age at assessment of 11.5 ⫾ 3.7 years and a mean age at disease
onset of 4.3 ⫾ 3.2 years. Sixteen patients had persistent oligoarticular JIA,
11 extended oligoarticular and 9 polyarticular with negative rheumatoid
factor. Nine patients were off medication and 27 were on medication, with
an average time of remission of 1.8 ⫾ 2.2 years. SS was present in
46/2448 (1.8%). SS was more common in patients (41.6%) than in
controls (13.9%) (p⫽0.009). The most frequently affected joints were the
wrists (15), followed by elbows (9), ankles (8), toes (7), knees (4) and
fingers (3). There were differences between patients and controls related
to the presence of SS in elbows (p⫽0.033) and ankles (p⫽0.006). On
ultrasonographic evaluation of JIA patients, 38/1224 (3.1%) had SS joints.
Patients with JIA polyarticular/extended oligoarticular subtypes and age at
onset older than 6 years old had more SS (p⫽0.026 and p⫽0.018,
respectively). There were no differences in terms of gender, age at
evaluation, presence of antinuclear antibodies, type of remission, duration
of remission, type of medication, previous uveitis, previous intra-articular
injections, physician VAS, patient VAS and CHAQ.
Conclusion: SS was present in 3.1% of joints from JIA patients
considered to be in remission especially in wrists, elbows, ankles, knees,
fingers and toes. Although SS was shown to be more frequent in all JIA joints
than in controls, we only observed significant difference in elbows and ankles
joints. SS was more common in patients with polyarticular involvement
(polyarticular and extended oligoarticular) and later age of JIA onset (greater
than 6 years old).
Disclosure: M. T. Terreri, None; V. M. Bugni, None; C. A. Len, None; S. D. A. V.
Mitraud, None; R. N. Furtado, None; J. Natour, None.
1161
Current Evidence of Anti-TNF␣ Treatment Efficacy in Childhood
Chronic Uveitis: A Systematic Review and Meta-Analysis Approach
Comparing the Different Drugs. Gabriele Simonini1, Kate Druce2, Rolando
Cimaz1, Gary J. Macfarlane2 and Gareth T. Jones2. 1Anna Meyer Children’s
Hospital-University of Florence, Firenze, Italy, 2University of Aberdeen,
Aberdeen, United Kingdom
Background/Purpose: To summarize evidence regarding the effectiveness of anti-TNF␣ treatments in childhood autoimmune chronic uveitis
(ACU), non responder and/or failure to previous DMARD course.
Methods: A systematic search of articles between January 2000 and June
2012 was conducted using EMBASE, Ovid MEDLINE, Evidence Based
Medicine Reviews-ACP Journal Club, Cochrane libraries, and EBM Reviews. Studies were eligible for inclusion if they investigated the efficacy of
anti-TNF␣ therapy as the first biologic modifier immunosuppressant medication, among children (’16 yrs) naı̈ve to any anti-TNF␣, therapy in the
treatment of ACU, refractory to therapy with topical treatment and/or
systemic treatment and at least one immunosuppressive treatment (MTX,
and/or Azathioprin and/or CSA and/or Clorambucil and/or Micofenolate
Mofetil). The primary outcome for this review was the proportion of patients
classified as having improved intraocular inflammation, expressed as Tyndall,
as defined by the Standardization of Uveitis Nomenclature (SUN) working
group criteria. We determined a combined estimate of the proportion of
children in the eligible studies responding to anti-TNF␣ treatment: Etanercept
(ETA), Infliximab (INF), or Adalimumab (ADA).
Results: The initial search identified 959 articles, of which 144 were
potentially eligible. 26 eligible articles, all retrospective chart reviews, but one
RCT, remained in the analysis. 245 children were included in the analysis
(ADA n⫽27; ETA n⫽62 and INF n⫽156) and the number of children in
studies ranged from 1 to 47. The pooled analysis suggested that INF and ADA
have favorable effects in the improvement of intraocular inflammation: the
proportion of responding subjects was 82% (95% CI: 68–96%) and 68%
(61–76%) for ADA and INF respectively. In contrast, only 28% (16–40%)
showed improvement with ETA. There was no difference in the proportion of
responders between ADA and INF (␹2 2.17,p⫽0.14), although both showed
superior efficacy compared to ETA (ADA vs ETA ␹2 ⫽21.1, p⬍0.001; INF
vs ETA ␹2⫽25.5, p⬍0.001)
Conclusion: Although randomized controlled trials are needed, the
available evidence does not support the use of ETA in the treatment of
childhood ACU.; ADA and INF seem instead reliable approach for their
treatment.
Disclosure: G. Simonini, None; K. Druce, None; R. Cimaz, None; G. J. Macfarlane,
None; G. T. Jones, None.
1162
Patients with Juvenile Idiopathic Arthritis From a Low Socio-Economic
Background Perceive Their Disease Activity and Physical Limitations
Higher Than Patients from a High Socio-Economic Background. Suzanne Verstappen1, Joanna Cobb2, H. E. Foster3, Eileen Baildam4, Lucy R.
Wedderburn5, Janet Gardner-Medwin6, Alice Chieng7, Joyce Davidson6,
Wendy Thomson8 and Kimme L. Hyrich9. 1University of Manchester,
Manchester Academic Health Sciences Centre, Manchester, United Kingdom, 2Arthritis Research UK Epidemiology Unit, University of Manchester,
Manchester, United Kingdom, 3Newcastle Hospitals NHS Foundation Trust
and Great North Children’s Hospital, Newcastle Upon Tyne, United Kingdom, 4Alder Hey Children’s Foundation NHS Trust, Liverpool, United
Kingdom, 5University College London (UCL), London, United Kingdom,
6
Royal Hospital for Sick Children, Glasgow, United Kingdom, 7Manchester
Children’s Hospital, Manchester, United Kingdom, 8Arthritis Research UK
Epidemiology Unit, Manchester, United Kingdom, 9Arthritis Research UK
Epidemiology Unit, University of Manchester, Manchester Academy of
Health Sciences, Manchester, United Kingdom
Background/Purpose: It has been suggested that socio-economic status
(SES) may be associated with delayed to access to rheumatology care and with
worse disease severity in patients with juvenile idiopathic arthritis (JIA). The
objectives of this study were to examine the association between SES and delay
to rheumatology clinic and disease severity in patients with JIA in England.
Methods: Consecutive children from the Childhood Arthritis Prospective
Study (CAPS), a large prospective longitudinal inception cohort study, were
included. At baseline, a clinical examination was performed including the
physician’s global assessment (PGA), number of active and limited joints and
S498
Therefore, the risk factors for radiologic progression during the biologic
therapy were investigated by evaluating the CL in polyarticular JIA patients.
Methods: Forty-six polyarticular JIA patients initiating biologics were
followed up prospectively for mean 3.1 years. RF was positive in 36 out of 46,
and all had active arthritis in the wrist at starting biologic therapy. Duration
from the onset to initiating biologics was mean 3.1 years, and the 1st biologic
agents used were etanercept in 21, adalimumab in 7, infliximab in 9, and
tocilizumab in 9. CL was measured from radiographs of the wrist obtained at
baseline (n⫽46), at 1year (n⫽36), and at 3 year (n⫽20), and the standard
deviation (SD) of CL calculated by Poznanski’s formula established from
healthy children1) was analyzed.
Results: 1) Changes in CL (SD) from baseline (Figure).
Monday, November 12
JADAS71. The CHAQ, pain score, the parental general evaluation (PGE) and the
CHQ, including several physical and psychosocial concepts (higher scores
indicate better functioning and well-being), were completed by the child or parent.
Using postcode data, SES was determined by calculating the Index of Multiple
Deprivation score (IMD). Based on the ranking of the IMD score, patients were
included in the low SES group (lowest quartile), middle SES group (two middle
quartiles) and high SES (highest quartile). Differences in demographic and
disease characteristics between these three groups were statistically tested applying the Kruskal-Wallis test or Chi-square test for gender.
Results: 934 JIA patients with a median age of 6.8 [IQR 2.9-10.9] yrs at
baseline were included in this study. At baseline the percentage of patients
according to the ILAR subtypes for the low, middle and high SES classes were,
respectively: systemic (3.6%, 6.8%, 8.0%), oligoarthritis (54%, 51%, 48%),
extended oligoarthritis (1.6%, 2.4%, 2.5%), polyarthritis RF- (13.6%, 18.4%,
19.0%), polyarthritis RF⫹ (4.2%, 2.9%, 2.5%), enthesitis related arthritis (4.2%,
5.8%, 5.5%), psoriatic arthritis (6.1%, 4.2%, 5.5%), undifferentiated (7.2%, 5.8%,
4.9%), other (5.5%, 3.2%, 4.3%). There was no difference in delay to first
rheumatology consultation between the three SES groups. Although no significant differences in diseases activity scores assessed by the rheumatologist were
observed between the three SES groups, children and/or parents of children with
JIA in the low SES group recorded higher pain scores, disease activity scores and
lower physical function scores than those in the high SES group. SES did not
seem to impact on psycho-social outcomes as measured in the CHQ.
Table. Demographic clinical and self-reported outcomes of disease related factors
in JIA patients from low, middle and high socio-economic background
Middle SES group
N ⴝ 419
High SES
group
N ⴝ 338
P-value
6.1 [2.5–10.8]
6.3 [2.8–10.3]
0.0103
211 (62%)
265 (63%)
112 (63%)
0.843
Delay to 1st rheumatology consultation, yrs
0.37 [0.19–0.86]
0.41 [0.19–0.86]
0.35 [0.17–0.91]
0.3929
JADAS71
PGA, mm
12.2 [5.6–16.7]
28 [17–50]
10.8 [6.0–18.1]
29 [15–51]
20.3 [5.5–16.0]
29 [13–53]
0.6620
0.9744
Low SES group
N ⴝ 177
Age at onset, yrs
Gender, female
No. limited joints
No. active joints
CHAQ-score
7.6 [3.5–115]
1 [1–3]
2 [1–5]
0.875 [0.312–1.625]
1 [1–3]
1 [0–3]
2 [1–5]
2 [1–4]
0.625 [0.125–1.375] 0.375 [0–0.875]
0.8891
0.7333
0.0001
Pain score, mm
39 [14–64]
30 [6–55]
18 [4–49]
0.0003
PGE, mm
30 [7–52]
20 [3–50]
15 [4–36]
0.0013
CHQ score
Physical functioning
56 [28–89]
72 [33–94]
89 [39–100]
0.0016
Role social limitations
50 [33–100]
75 [33–100]
86 [67–83]
0.0043
Bodily pain/discomfort
Behaviour
40 [20–60]
73 [56–83]
50 [20–70]
68 [56–83]
50 [30–80]
77 [60–85]
0.0081
0.3698
Mental health
75 [55–85]
75 [60–85]
75 [65–85]
0.3379
Self esteem
73 [54–88]
71 [50–83]
75 [67–88]
0.1167
General health perception
Parental impact-emotional
Parental impact - time
Family activities
Family cohesion
60 [43–75]
67 [33–83]
89 [56–100]
71 [48–88]
85 [60–85]
64 [52–73]
58 [33–83]
89 [56–100]
79 [50–96]
85 [60–85]
70 [60–81]
67 [42–83]
89 [67–100]
83 [58–96]
85 [60–85]
0.0028
0.4277
0.3193
0.0176
0.9630
Scores are median [IQR] or %
Conclusion: Patients from lower SES background score their disease
activity and functional disability higher than patients from higher SES
background, whereas no differences were found in disease activity scores
obtained in clinic between the different SES groups. This study suggests that
it is important to take SES background into account when patients with JIA
present to the clinic for the first time.
Disclosure: S. Verstappen, None; J. Cobb, None; H. E. Foster, None; E. Baildam,
None; L. R. Wedderburn, None; J. Gardner-Medwin, None; A. Chieng, None; J.
Davidson, None; W. Thomson, None; K. L. Hyrich, None.
1163
Risk Factors for Radiologic Progression in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Biologic Agents. Tomohiro
Kubota1, Tsuyoshi Yamatou1, Yukiko Nonaka1, Harumi Akaike2, Tomokazu
Nagakura3, Yuichi Yamasaki1, Tomoko Takezaki1, Yasuhito Nerome1, Hiroyuki Imanaka1 and Syuji Takei1. 1Kagoshima University, Kagoshima City,
Japan, 2Kagoshima University, Kagoshima, Japan, 3House of Meguminoseibo, Usuki, Japan
Background/Purpose: Progression of joint damage is sometimes observed in JIA patients during the biologic therapy. However, it is difficult to
evaluate the radiographic progression by simple radiographs because the
width of joint space and ossification varies with age. Carpal length (CL) is a
useful measure component for identifying joint space narrowing due to
cartilage damage of the wrist in children1–2).
At 1 year after starting biologics, incidence of patients with increased
(improved) or sustained CL(SD) was 61%, which indicated that 61% patients
had no radiographic progression of joint damage of the wrist during the first
year of biologic therapy. At 3 year from baseline, 70% of patients showed no
radiographic progression of joint damage.
2) Risk factors for progression of joint damage.
Background, clinical features, disease activity by DAS28ESR, and the
biologic therapy were compared between two groups of patients with
improved/sustained CL(SD) and with non-improved CL(SD) to determine the
risk factors for radiologic progression after 1 year biologic therapy.
As the result, incidence of the patients showed no statistical difference
between the two groups as to sex (male, female), onset age (⬍10 y, ⱖ10 y),
RF (positive, negative), disease duration at initiating biologic therapy (⬍1 y,
1-⬍3 y, ⱖ3 y), 1st biologic agent used, and episode of switching to the 2nd
biologic agent. However, the incidence of patients who attained DAS28⬍2.6
remission was significantly higher in improved/sustained CL(SD) group
(100%) than that of non-improved CL(SD) group (46%) (Qui square⫽7.038,
P⫽0.0080).
Conclusion: Biologics can prevent the radiologic progression of wrist in
only patients who attained the DAS28⬍2.6 remission during the first year
treatment. Switching to the 2nd biologic agent may be needed in polyarticular
JIA patients who failed to complete the DAS28⬍2.6 remission.
1) Poznanski AK et al. Radiology 1978;129:661-8.
2) Ravelli A, et al. J Pediatr 1998; 133:262-5
Disclosure: T. Kubota, None; T. Yamatou, None; Y. Nonaka, None; H. Akaike,
None; T. Nagakura, None; Y. Yamasaki, None; T. Takezaki, None; Y. Nerome,
None; H. Imanaka, None; S. Takei, Chugai, Eisai, Takeda, Brystol-Mayers Japan, 2.
1164
Orofacial Anomalies in Children with Confirmed Juvenile Idiopathic
Arthritis. Bernd Koos1, Franka Stahl de Castrillon2, Robert Ciesielski1 and
Nikolay Tzaribachev3. 1University Medical Center Schleswig-Holstein,
Campus Kiel, Kiel, Germany, 2Department of Orthodontics, University of
Rostock, Germany, Rostock, Germany, 3Center for Rheumatic Diseases, Bad
Bramstedt, Germany
Background/Purpose: In children with juvenile idiopathic arthritis (JIA)
temporomandibular joints (TMJ) are affected in up to 96% of the patients,
S499
Monday, November 12
where TMJ arthritis is frequently asymptomatic. Despite that, orofacial
anomalies occur in many patients and tend to be correlated with dysfunction
and excessive mechanical strain, which may complicate treatment and
aggravate TMJ destruction.
To examine the prevalence and severity of relevant orofacial anomalies in
patients with JIA compared to healthy children and to assess the correlation
with Gadolinium (Gd) enhanced MRI.
Methods: TMJ data of 216 consecutive JIA patients (69% female, median
age 12.9 years) were compared to TMJ data of 3756 healthy children (Stahl,
Grabowski et al., 2007; Hirsch et al., 2009). JIA patients were divided into
group I (2-10 years) and group II (10-18 years). The following measurements
were taken: occlusal relations, mandibular position, deep and open bite (group
I) and TMJ noise, tenderness to palpation of the TMJ or the masticatory
muscles, reduced mouth opening (group II). In a subgroup (37 consecutive
JIA patients, 57% female, median age 11.1 years) Gd MRI examinations were
analyzed and compared to functional measurements. Sensitivity and specificity of the functional measurements were determined.
Results: Mandibular asymmetry was found in 35% of patients (15%
right, 20% left; no correlation with sex; p ⫽ 0.76). Inhibited mandibular
growth (distocclusion) was seen in 59% of patients (no correlation with sex;
p⫽ 0.57). Open bite was seen in 6.5%, deep bite in 33% of the children.
TMJ arthritis was demonstrated in 81% of the children from the MRI
subgroup. Pathological TMJ sounds were present in 26% of the patients, but
showed no statistical significance (p⫽ 0.16). TMJ and masticatory muscles
tenderness were present in 46.8% and 40.2%, respectively. Limitation of the
interincisal opening was found in 14.4% of the patients. A positive statistical
correlation was found for these functional measures (tenderness to palpation
p ⱕ 0.001 and limitation of interincisal opening p ⫽ 0.002), but sensitivity
was low at 53% (specificity: 89%).
Conclusion: The prevalence of orofacial abnormalities is noticeably
increased in JIA patients compared to healthy children, particularly inhibition
of the mandibular growth and mandibular asymmetries. Clinical findings and
inflammatory state of TMJ does not reliable correlate. This mandates
interdisciplinary TMJ treatment including orthodontics especially with respect to the high prevalence of TMJ dysfunction.
Disclosure: B. Koos, None; F. Stahl de Castrillon, None; R. Ciesielski, None; N.
Tzaribachev, None.
1165
Factors Associated with Achievement of Inactive Disease in Children
with Juvenile Idiopathic Arthritis Treated with Etanercept. Nicoletta
Solari1, Elena Palmisani1, Alessandro Consolaro1, Sara Dalprà1, Benedetta Schiappapietra1, Giulia Bracciolini1, Silvia Rosina1, Giorgia Negro1,
Alberto Martini2 and Angelo Ravelli3. 1Istituto Giannina Gaslini, Genova,
Italy, 2University of Genova, Genova, Italy, 3Paediatric Rheumatology
International Trials Organization (PRINTO), Istituto Giannina Gaslini,
Genova, Italy
Background/Purpose: The advent of new therapies for juvenile idiopathic arthritis (JIA), particularly the introduction of biologic medications, has
increased considerably the potential for treatment benefit, with clinical
remission being now a realistic goal for a substantial proportion of patients.
However, the assessment of remission has seldom been incorporated in
clinical trials of biologics in JIA. Moreover, little information exists on
predictors of the effectiveness of biologic medications. The study aim was
two-fold: 1) to evaluate the rate of inactive disease (ID) in children with
juvenile idiopathic arthritis (JIA) treated with etanercept (ETN); 2) to identify
clinical characteristics associated with attainment of ID.
Methods: The clinical chart of all consecutive JIA patients who were
given ETN between 2002 and 2011, and had a follow-up of at least 6
months after ETN start were reviewed. For each patient, all visits made
from ETN initiation to the last follow-up evaluation in which the patient
was still receiving ETN were examined to establish whether the patient
had reached the state of ID, defined by the Wallace criteria (J Rheum
2004;31:2290-4), and to identify the first visit in which ID was documented. Clinical characteristics associated with achievement of ID were
sought for by means of univariate analyses and Cox regression procedures. Predictive factors included sex, age at disease onset, age and
disease duration at treatment baseline, interval between first observation at
study center and start of ETN, ILAR category, antinuclear antibody status,
JIA outcome measures at ETN start, joints affected before ETN start, and
medications administered before ETN start and administered concomitantly during ETN therapy.
Results: A total of 173 patients who received ETN for a median of 2.2
years (range 0.5–10.5 years) were included in the study. Eighty-seven
patients (50.3%) achieved ID a median of 0.6 years (range, 0.1–2.5 years)
after the initiation of ETN therapy. The rate of ID was much lower in
children with systemic JIA than in those with non-systemic categories
altogether (29.6% vs. 54.1%). At last follow up visit, 0.5 to 10.5 years
after ETN start (median, 2.2 years), 85 patients (49.1%) still had ID and
70 patients (40.5%) met the criteria for clinical remission on medication.
The probability of achievement of ID after 6, 12 and 24 months of therapy
was 24%, 46% and 57%, respectively. On Cox regression analysis, the
attainment of ID was associated with lack of wrist involvement [HRAdj
(95% CI): 2.19 (1.38-3.48), p⫽0.0006] and an age at onset ⬍ 3.6 years
[HRAdj (95% CI): 1.61 (1.04- 2.49), p⫽0.03]. A secondary analysis made
after the exclusion of the 27 children with systemic JIA led to identify the
same predictors
Conclusion: Around half of our JIA patients treated with ETN in standard
clinical care were able to achieve the state of ID. Children who lacked wrist
involvement and had a younger age at disease onset had a greater likelihood
of achieving ID during ETN administration. Thus, the presence of wrist
disease and an older age at disease presentation may constitute an indication
for the earlier introduction of ETN or its administration in combination with
methotrexate.
Disclosure: N. Solari, None; E. Palmisani, None; A. Consolaro, None; S. Dalprà,
None; B. Schiappapietra, None; G. Bracciolini, None; S. Rosina, None; G. Negro,
None; A. Martini, None; A. Ravelli, Pfizer Inc, 2.
1166
Clinical and Therapeutic Features of 312 Patients with Macrophage
Activation Syndrome Enrolled in a Multinational Survey. Sergio Davı̀1,
Francesca Minoia1, Erkan Demirkaya2, Chiara Suffia1, Mario Abinun3,
Amita Aggarwal4, Nuray Aktay Ayaz5, Maria Alessio6, Jordi Anton5, Maria
Apaz5, Tadej Avcin7, Patrizia Barone8, Blanca E. Bica9, Isabel Bolt10,
Luciana Breda11, Vyacheslav Chasnyk12, Rolando Cimaz5 Fabrizia Corona5,
Ruben Cuttica13, Gianfranco D’Angelo14, AnnaCarin Horne15, Nicola Ruperto1, Alberto Martini1, Randy Q. Cron16 and Angelo Ravelli5. 1Istituto di
Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy, 2International Investigator Consortium for MAS Diagnostic Criteria, Ankara, Turkey,
3
International Investigator Consortium for MAS Diagnostic Criteria, Newcastle upon Tyne, United Kingdom, 4Sanjay Gandhi Postgraduate Institute of
Medical Sciences, Lucknow, India, 5Paediatric Rheumatology International
Trials Organization (PRINTO), Istituto Giannina Gaslini, Genova, Italy,
6
University of Naples Federico II, Naples, Italy, 7International Investigator
Consortium for MAS Diagnostic Criteria, Ljubljana, Slovenia, 8International
Investigator Consortium for MAS Diagnostic Criteria, Catania, Italy, 9International Investigator Consortium for MAS Diagnostic Criteria, Rio de
Janeiro, Brazil, 10International Investigator Consortium for MAS Diagnostic
Criteria, Zurich, Switzerland, 11International Investigator Consortium for
MAS Diagnostic Criteria, Chieti, Italy, 12International Investigator Consortium for MAS Diagnostic Criteria, Saint-Petersburg, Russia, 13International
Investigator Consortium for MAS Diagnostic Criteria, Buenos Aires, Argentina, 14International Investigator Consortium for MAS Diagnostic Criteria,
Ancona, Italy, 15Karolinska Institutet, Karolinska University Hospital Solna,
Stockholm, Sweden, 16Univ of Alabama-Birmingham, Birmingham, AL
Background/Purpose: A multinational collaborative effort aimed to
develop a new set of criteria for macrophage activation syndrome (MAS)
complicating systemic juvenile idiopathic arthritis (sJIA) has been recently
started. The first step of the project, based on a Delphi survey, has been
completed (Davı̀ S et al. J Rheumatol 2011;38:764-8). The second step,
whose goal is to collect the data of a sizable sample of children with MAS and
with potentially ‘confusable’ conditions, is currently under way. The study
aim is to describe the demographic, clinical, laboratory, histopathologic,
therapeutic and prognostic features of children with MAS collected so far in
the data-collection phase of the project.
Methods: Investigators who participated in the Delphi survey were asked
to enter the information of their patients with MAS collected retrospectively
in a web-based database, developed by the Pediatric Rheumatology International Trials Organization (PRINTO).
Results: At the 31st of May, 2012, 312 patients with sJIA-associated
MAS have been entered in the study website by 87 investigators from 27
countries. 181 (58%) patients were females and 131 (42%) were males. The
age at onset of sJIA ranged from 0.2 to 15,9 years (median 5,1 years) and the
disease duration from onset of sJIA and onset of MAS ranged from 0 to 15,6
years (median 0,3 years). MAS occurred at onset of sJIA in 50 (20,2 %)
S500
patients. The frequency of the clinical, laboratory and histopathologic features
of MAS is reported in the Table. The most frequently reported trigger of MAS
was active disease (35,3%), followed by infection (26,3%) and medication
toxicity (3,7%). 69 (37,1%) patients were admitted in the ICU. Therapeutic
interventions included iv steroids (88.0%), oral steroids (74.1%), cyclosporine
(65.5%), other immunosuppressants (13.8%), iv Ig (36.3%), etoposide
(11.1%), anakinra (6.8%), and plasma exchange (5.4%). The mortality rate
was 8.2%.
Table. Frequency of clinical, laboratory, histopathologic features of 312 patients
with MAS.
No. with info
available
Percentage
Falling platelet count (ⱕ 262 ⫻109/l)
Hyperferritinemia (ⱖ 500 ng/ml)
Bone marrow hemophagocytosis
Increased liver enzymes (AST ⬎ 59UI/L)
Falling leukocyte count (⬍ 4⫻109/l)
Persistent continuous fever ⱖ 38°C
Hypofibrinogenemia (ⱕ 2,5 g/l)
Hypertrigliceridemia (ⱖ 265 mg/dl)
Central nervous system dysfunction
Increased D-dimer (ⱖ 500 ng/ml)
Hemorrhagic manifestations
Liver enlargement
Spleen enlargement
286
256
214
275
285
302
250
221
302
105
301
305
301
74.8
91.4
60.7
74.9
21.1
63.9
48.4
43.9
36.1
88.6
20.9
70.5
59.5
Disclosure: I. Pontikaki, None; O. De Lucia, None; M. Gattinara, None; A.
Salmaso, None; P. L. Meroni, None; V. Gerloni, None.
1168
Conclusion: Hyperferritinemia, increased liver enzymes and falling
platelet count were the most frequently observed laboratory abnormalities.The frequency of falling leukocyte count was unexpectedly low. Also
unexpectedly, liver and spleen enlargement were recorded more frequently
than persistent continuous fever. Hemophagocytosis was noticed in around
two third of patients who underwent bone marrow aspirate. As expected,
corticosteroids and cyclosporine were the most commonly administered
medications.
Disclosure: S. Davı̀, None; F. Minoia, None; E. Demirkaya, None; C. Suffia, None;
M. Abinun, None; A. Aggarwal, None; N. Aktay Ayaz, None; M. Alessio, None; J.
Anton, None; M. Apaz, None; T. Avcin, None; P. Barone, None; B. E. Bica, None;
I. Bolt, None; L. Breda, None; V. Chasnyk, None; R. Cimaz, None; F. Corona, None;
R. Cuttica, None; G. D’Angelo, None; A. Horne, None; N. Ruperto, None; A.
Martini, None; R. Q. Cron, None; A. Ravelli, None.
1167
Golimumab in 25 Young Adults Affected by Juvenile Idiopathic
ARTHRITIS NON Responders to OTHER Biological Agents: Preliminary DATA. Irene Pontikaki1, Orazio De Lucia1, Maurizio Gattinara1,
Alessandra Salmaso1 Pier Luigi Meroni2 and Valeria Gerloni1. 1Orthopedic Institute Gaetano Pini, Milano, Italy, 2Istituto G. Pini, University of
Milan, Milano, Italy
Background/Purpose: Biological agents licensed in JIA have demonstrated a favourable benefit-to-risk profile. Nevertheless, intolerance,
loss and lack of efficacy or adverse events have led to try other therapeutic
options. Ultrasound can help in the assessment of active synovitis. The
purpose of this study was to evaluate efficacy and safety of Golimumab in
young adults affected by JIA with active polyarthritis (with or without
uveitis), non responders to MTX, antiCD20 and anti-IL-1 and intolerant to
the first generation of antiTNF (Infliximab, Etanercept and Adalimumab)
by EULAR criteria and power Doppler ultrasound (PDUS).
Methods: In our Centre, since november ‘99 to dicembre 2011, 288
patients affected by refractory JIA were treated with TNF inhibitors and
since May 2011, 25 patients (16 F, 9 M) affected by refractory JIA, non
responders to other biologic agents, were enrolled in Golimumab (Simponi).
Patients had failed MTX as monotherapy, previous TNF inhibitors,
Rituximab and anti-IL1 therapy. Two patients had been treated with 8
different biologic agents, 1 patient with 7, 2 patients with 6, 5 patients
with 5, 3 with 3, 7 with 2 and 3 patients with just one previous biologic
agent.
Two patients had a Systemic onset of JIA, 4 polyarthritis RF negative,
3 enthesitis related arthritis, 1 psoriatic arthritis, 6 oligoarthritis persistent
and 9 oligoarthritis extended. Median age was of 28.7 years, median onset
age 7.3 years, median disease duration 19.8 years. All patients had active
Cost-Effectiveness Analysis of Early Biologic Treatment in Polyarticular Juvenile Idiopathic Arthritis. Nadia Luca1, Heather Burnett2,
Wendy Ungar2, Timothy Beukelman3, Brian M. Feldman2, Gwen
Schwartz4 and Ahmed Bayoumi5. 1Hospital for Sick Children, Toronto,
ON, 2The Hospital for Sick Children, Toronto, ON, 3Univ of AlabamaBirmingham, Birmingham, AL, 4St. Michael’s Hospital, Toronto, ON,
5
Keenan Research Centre of the Li Ka Shing Knowledge Institute of St.
Michael’s Hospital, Toronto, ON
Background/Purpose: The optimal timing of high cost biologic therapies in
the treatment of polyarticular juvenile idiopathic arthritis (JIA) is uncertain. We
evaluated the economic and health outcomes of initial compared with step-wise
use of anti-tumor necrosis factor (TNF) agent, etanercept (ETN), in this setting.
Methods: We conducted a cost-utility analysis of two strategies from a
Canadian health care payer perspective. In one strategy, initial therapy was with
methotrexate (MTX) alone. ETN was added in a step-wise fashion for patients
who did not respond to MTX. In the other strategy, initial therapy was with MTX
in combination with ETN; patients who did not respond switched to another
anti-TNF agent. In both strategies, third and fourth line therapies were modeled
with additional biological agents. Our base case was a 12-year-old child (weight
40 kg) with newly diagnosed polyarticular JIA naı̈ve to disease-modifying and
biological agents. We simulated the course of the disease over 5 years using a
Markov model with a cycle length of 1 month. Treatment response was defined
as achieving an ACR Ped 70 response or better after 4 months of therapy. If this
response was sustained over 12 months, without flare, patients entered a remission
state. We derived model parameters, including treatment efficacy, disease flares,
adverse events, costs, and quality of life weights from the medical literature.
Effects were calculated as quality-adjusted life years (QALYs); costs and QALYs
were discounted at a rate of 3% per year. We conducted sensitivity analyses on
all model parameters to assess the robustness of our results and used a
$50,000/QALY threshold for cost-effectiveness.
Results: Our model predicted that the proportion of patients entering
remission after 5 years was 89% with initial MTX and 93% with initial MTX
and ETN combination. Median time to remission was 20 months in the MTX
monotherapy group and 16 months in the combination group. The combination of initial MTX and ETN, compared to MTX alone, resulted in a
discounted incremental cost of $14,498 per patient over 5 years and yielded
a discounted incremental effect of 0.15 QALYs, for an incremental costeffectiveness ratio of $97,517 per QALY. The results were sensitive to the
cost of ETN and estimates of the efficacy of initial combination therapy.
Conclusion: Our model suggests that using initial combination therapy of
MTX and ETN is unlikely to be cost-effective compared to using MTX alone,
but more research is needed on key model parameters, including efficacy of
initial anti-TNF agents and their impact on quality of life. A reduction in the
cost of ETN by 33% would make initial use of this drug cost-effective.
Disclosure: N. Luca, None; H. Burnett, None; W. Ungar, None; T. Beukelman,
Pfizer Inc, 2, Novartis Pharmaceutical Corporation, 5, Genentech and Biogen IDEC Inc.,
5; B. M. Feldman, Bayer, 2, Baxter, 9, Pfizer Inc, 9, Novartis Pharmaceutical
Corporation, 9; G. Schwartz, None; A. Bayoumi, None.
S501
Monday, November 12
Feature
disease according to EULAR criteria, 8 patients had a previous history of
chronic Iridocyclitis. Patients received Golimumab at the dose of 50 mg
subcutaneously every month, as in RA. Fifteen patients receive Golimumab in association with MTX. All patients underwent basal assessment
of DAS 28 and after 4 months DAS 28 and PDUS assessment of the same
28 joints. Presence of synovitis at PDUS examination was considered in
presence of at least one between joint effusion, synovial thickening and
power Doppler signal detected in accordance to OMERACT criteria.
Results: Seventeen patients (68%) were responders according both to
DAS 28 and PDUS, 5 patients were not evaluable because of follow-up
less than 12 weeks and 3 patients were non responders (1 of these 3 pts
dropped-out). In non responder patients PDUS showed a higher number of
joints involved. No adverse events were observed. No adverse events
occured.
Conclusion: Golimumab seems to be effective and wel