EULAR 2011 Medical Passport
Highlights of EULAR 2011
London, United Kingdom
June 2011
1
Faculty
Lillian Barra, MD
Majed Khraishi, MD
George Ecker, MD
Liam Martin, MD
Isabelle Fortin, MD
Wojciech Olszynski, MD
Jacob Karsh, MD
Janet Pope, MD
Nader Khalidi, MD
Anthony Russell, MD
Medical Passport Program-EULAR 2011
2
Disclosure
•Copyright 2011 STA HealthCare Communications
Inc. All rights reserved. This program is published
by STA HealthCare Communications Inc. as a
professional service funded by Bristol-Myers Squibb
Canada Co. The information and opinions contained
herein reflect the views and experience of the
authors and not necessarily those of Bristol-Myers
Squibb Canada Co., or STA HealthCare
Communications Inc. Any products mentioned
herein should be used in accordance with the
prescribing information contained in their respective
product monograph.
3
Outline
Gums, joints and inflammation
Lillian Barra, MD
Cytokines with a double edge sword
Lillian Barra, MD
From bench to bedside: New insights into
pathogenesis and pathophysiology of AS
George Ecker, MD
Clinical aspects of SpA – What is new?:
Abstract session
George Ecker, MD
Osteoporosis: Selected posters
George Ecker, MD
RA - A life without biologics: Abstract session Isabelle Fortin, MD
4
Outline
RA: Nothing is working! What to do?
Isabelle Fortin, MD
RA: Selected posters
Isabelle Fortin, MD
Bone and crystal diseases
Jacob Karsh, MD
Inflammasomes as sentinels
and enemies from within
Jacob Karsh, MD
RA & advanced therapeutics: selected
posters
Jacob Karsh, MD
Vasculitis: abstract session
Nader Khalidi, MD
Last but not least: The orphans
Nader Khalidi, MD
5
Outline
Pathogenesis of ANCA-associated
vasculitis
Nader Khalidi, MD
Psychiatric disease in rheumatology
practice
Liam Martin, MD
Tight control: theory and practice
Liam Martin, MD
The earliest phase of RA
Liam Martin, MD
Fibromyalgia: selected posters
Liam Martin, MD
Genomics, genetics, epigenetics
Wojciech Olszynski, MD
Epigenetic regulation of inflammation
Wojciech Olszynski, MD
6
Outline
Osteoporosis: Abstract session
Wojciech Olszynski, MD
Too much immunoglobulin - diseases
relevant for the rheumatologist
Anthony Russell, MD
Myositis and myopathies
Anthony Russell, MD
Update in RA therapeutics: targeting
intracellular signalling
Anthony Russell, MD
RA – Non-TNF biologics: Abstract
session & selected posters
Janet Pope, MD
Late-breaking abstracts
Majed Khraishi, MD
7
Gums, joints and inflammation
Highlights of the EULAR Basic
and Translational Science
Session held Wednesday, May 25
Summarized by Dr. Lillian Barra
8
List of Presentations in this Session
Abstract # (if
applicable)
Speaker
Title
De Pablo, P
The epidemiology of RA and tooth loss
NA
Venables, P
The biology of citrullination in
periodontal disease and RA
NA
Bartold, M
The relationship between
periodontitis and RA
SP0026
Potemper, J
The corruption of innate immunity
by bacterial proteases
SP0027
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
9
Periodontitis: Background
• Caused by bacterial infection.
• Causative agent is P. gingivalis
• Leads to inflammatory response in the gum
endothelium
• Endothelium ulcerates and the cumulative
surface area of involved tissue is significant
enough to cause systemic inflammation
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Periodontitis and RA
• Both are systemic inflammatory diseases that
have similar:
Inflammatory mediators
Erosive bone disease
Associations
– Smoking
– HLA-DR4
– CAD
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Are Patients with RA At Risk
of Periodontitis and Vice Versa?
• De Pablo et al, J Rheum 2008:
N = 4461
OR = 4.13 (PD in RA patients)
OR = 1.5 (RA in PD patients)
• De Smit et al [EULAR 2011: Abstract THU0289]
N = 98 RA patients, 51% with PD
PD had higher DAS, increased smoking,
increased ACPA
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Are Patients with RA At Risk
of Peridontitis and Vice Versa?
• Nurse’s Health Study (Arkema et al, J Rheum
2010):
N = 81132
No association between PD and RA
PD associated with smoking
• Why the difference between studies????
Classification of disease
Patient population
Confounders
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Does PD cause RA and vice versa?
The Role of Citrulline
• Anti-Citrullinated Protein Antibodies (ACPA)
appear to be pathogenic
Mice immunized with citrullinated enolase
produce anti-citrullinated enolase antibodies
and develop arthritis
Other mouse models support this
Citrullinated proteins and ACPA complexes
are found in the joints of RA patients
• Citrulline is produced by an enzyme called
Peptidyl Arginine Deiminase (PAD)
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Peptidyl Arginine Deiminase (PAD):
Therapeutic Target?
• PADs thought to be important for RA include:
Human PAD2, human PAD4, P. gingivalis PAD
(PPAD)
– PPAD can citrullinate both bacterial and human
proteins which can lead to autoimmunity
– 2-Chloracetamidine can inhibit PPAD but is too
toxic for clinical use
– Other inhibitory molecules are being developed
that may have therapeutic benefit
Which PAD to inhibit?
What is physiologic role of citrullination?
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Importance of P. gingivalis:
Observations from Mouse Models
• Mice were infected with P. gingivalis and CIA
was induced in these mice:
1. CIA + P. gingivalis have more severe arthritis
than CIA alone and more severe PD than P.
gingivalis alone
2. These mice had citrullinated proteins
present in the gums
3. CIA mice not injected with P. gingivalis also
had PD whereas WT mice did not
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Importance of P. gingivalis:
Observations From Mouse Models (cont'd)
• Mice preinjected with any infectious organism
will have similar results
• Therefore:
Any inflammatory process in pre-arthritis
stage worsens arthritis
Other factors are clearly at play – multiple hit
hypothesis
IA appears to predispose to PD
Basic & Translational Science session:
Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.
Cytokines with a
Double-edged Sword
Highlights of the EULAR Basic
and Translational Science
Session held Wednesday, May 25
Summarized by Dr. Lillian Barra
18
List of Presentations in this Session
Abstract # (if
applicable)
Speaker
Title
Brusewitz, M
The problems I have experienced from
my RA and how health professionals
have intervened to assist me in
resolving them
NA
Opava, C
Reflections on the limitations of
traditional measures in clinical studies
NA
Oesch, P
The influence of language and literacy
on the use of patient reported
outcomes and consequences for
health care research
OP0099
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
19
IL-22: Pathogenic vs. Protective
• Elevated in Psoriasis, IBD, RA
• Produced by Th17 cells and NK cells
• Binds to IL-22R, which are found on epithelial
cells
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
Evidence for IL-22 Pathogenesis
• Experiments done in a mouse model of IBD
1.
Mice deficient in IL-22 were produced
2.
Acute IBD-like disease induced in these mice
• Results:
Mice had more severe epithelial ulceration
• Conclusions:
IL-22 has an important role in epithelial repair
in acute inflammation
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
Evidence for IL-22 Pathogenesis (Cont'd)
3.
Chronic IBD-like disease induced in IL-22
deficient mice:
• Results:
Less epithelial hyperplasia
• Conclusions:
In chronic disease, no epithelial erosions
Elevated IL-22 whose role is to repair leads to
pathologic hyperplasia
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
IL-22: Implications for RA
• Cytokines may have different functions at
different stages of disease; in the case of IL-22
Synovial damage acutely or in pre-RA?
Synovial hyperplasia chronically?
• Therapeutic targets therefore may need to be
different depending of disease stage
• Current mouse models are more consistent
with acute vs. chronic RA
Should we be developing chronic RA models?
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
IL-33: Protective?
• Produced by Mast cells
• Binds ST2 on Th2 cells (stimulatory) and soluble
ST2 (inhibitory)
• Mouse model of CAD:
Give high levels of IL-33 decreased plaque and
obesity
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
IL-33: Importance in RA?
• RA patients have very high IL-33 so why do RA
patients have increased CAD???
They also have high levels of soluble ST2
which inhibits IL-33 protective function
Smokers have lower levels of IL-33
• Take home message:
Balance of cytokines and their receptors must
be considered when identifying therapeutic
targets
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
BAFF and TACI
• Tolerance requires deletion of self-reactive B cells
• This is an imperfect process:
If recognizes self with high affinity, all are deleted
If recognizes self with low affinity, deletion occurs
infrequently
• Therefore, in all people there is a pool of low-affinity B
cells that have the potential to self-react
• Most of these are marginal zone B cells
• These cells can be activated without T-cell help via TLR
• Why doesn’t autoimmunity always occur after
infection??
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
BAFF and TACI, cont'd
• Low affinity MZ B cells upregulate TACI expression during
infection
• Findings from TACI knock-out:
MZ B cell hyperplasia
SLE-like disease
• Proposed mechanism during infection:
TLR4 activation leads MZ B cell to produce low-affinity Abs
as first defense against microbes
Infection leads to macrophage and DC production of BAFF
BAFF binds TACI and, in presence of TLR4 activation, leads
to upregulation of FasL
Low-affinity MZ B cells undergo apoptosis and are deleted
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
Implications of BAFF and TACI Observations
• New mechanism of disease in SLE and/or other
antibody-mediated autoimmune conditions?
• How do we identify and target the right B cells?
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
From Bench to Bedside: New
Insights into Pathogenesis and
Pathophysiology of Ankylosing
Spondylitis
Highlights of the EULAR Clinical
Science Session held
Wednesday, May 25
Summarized by Dr. George Ecker
29
List of Presentations in this Session
Abstract # (if
applicable)
Speaker
Title
Heiner, A
New insights into AS pathophysiology
based on bone histology studies
SP0018
Rik, L
Mechanisms of new bone formation in
animal models of AS
NA
Brown, W
The evolving role of genes and gene
expression profiles in AS
SP0019
Yeremenko, N
Identification of robust and diseasespecific stromal alterations in
spondyloarthritis synovitis
OP0005
Basic & Translational Science session:
Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.
30
Ankylosing Spondylitis from Bench to
Bedside: Key Points from the Session
• AS is more than T-cell disease
• There is crosstalk between inflammation and
new bone formation
• T- and B-cell aggregates close to cartilage in
active AS facet joints
• There is no major response seen with abatacept
in AS
Sanget, et al: Ann Rheum Dis 2011; 70:1108.
• Rituximab has a positive effect in TNF-naïve AS,
but not in TNF failures
Clinical Science session: From Bench to Bedside – New Insights into
Pathogenesis and Pathophysiology of AS. EULAR 2011; Wed., May 25.
Ankylosing Spondylitis from Bench to Bedside:
Key Points from the Session (Cont'd)
• Active inflammation repair new bone
formation
• WNT is a pathway of new bone formation
• DKK1 is an inhibitor of the WNT pathway
• Mechanisms that interfere with WNT pathway
may present potential therapeutic option to
prevent new bone formation in AS
Clinical Science session: From Bench to Bedside – New Insights into
Pathogenesis and Pathophysiology of AS. EULAR 2011; Wed., May 25.
Clinical Aspects of
Spondyloarthritis – What is
New?
Highlights of the EULAR Abstract
Session held Thursday, May 26
Summarized by Dr. George Ecker
33
List of Presentations in this Session
Abstract # (if
applicable)
Speaker
Title
Maksymowych,
W
The Echospa MRI module for early spondyloarthritis (SpA): Which features are
sufficiently reliable for evaluation of diagnosis?
OP0041
Sieper, J
Comparing 2 referral strategies to diagnose axial spondyloarthritis: RADAR study
OP0042
Weber, U
Anterior chest wall inflammation by MRI in patients with spondyloarthritis:
Frequency of involvement and association between clinical and imaging findings
OP0043
Fagerli, K
The role of CRP and peripheral disease in achieving ASDAS response to antiTNF therapy in 308 patients with ankylosing spondylitis
OP0044
Plasencia, C
Influence of immunogenicity on the efficacy of long-term treatment with infliximab
in spondyloarthrities
OP0045
LafranchiDebra, M –A
Comparison of axial spondylarthropathy (ASPA) and non ASPA patients
rheumatologist diagnosis among an recent inflammatory back pain patients
cohort? The DESIR cohort
OP0046
Weber, U
Erosions on MRI of the sacroiliac joints in patients with ankylosing spondylitis:
Can they be reliably detected?
OP0047
Vossen, M
Improvement in deployment of MR-SI in patients suspected for spondyloarthritis
in a large clinical practice using a targeted intervention: A case study
OP0048
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
34
Clinical Aspects of Spondyloarthritis –
What is New? Highlights of the Session
• MRI (Maksymowych, Abstract #OP0041)
Bone edema reliable despite minimal contribution
Erosions moderately reliable: capsulitis, joint
space narrowing can be reliably detected, lesions
in ligamentus compartment NOT reliably detected
• Referrals (Sieper, Abstract #OP0042)
IBP, B27, sacroilitis as good as more complex
strategies, IBP best PPV
• Chest wall inflammation (Weber, Abstract #OP0043)
May start earlier than disease, poor agreement
between clinical and MRI inflammation
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
Clinical Aspects of Spondyloarthritis –
What is New? Highlights of the Session
• Immunogenicity (Plasencia, Abstract #OP0045)
Anti-infliximab-antibody-positive (anti-INFAb+) patients have higher disease activity
than antibody-negative
Anti-INF-Ab+ was associated with:
– Decreased treatment survival
– Higher rate of infusion reactions
– Shortened infusion interval
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
Clinical Aspects of Spondyloarthritis –
What is New? Highlights of the Session
• Early anti-inflammatory therapy may be key in AS
• Phase 3 study, N=76, adalimumab 40 mg eow vs. placebo
• Results
Ankylosis more likely to occur at sites with more advanced
as compared with acute inflammatory lesions
Ankylosis evident at these "sites of advanced inflammation"
despite resolution of inflammation by anti-TNF
In contrast, acute lesions that resolve completely with
treatment are not followed by development of ankylosis
Inflammation and ankylosis become increasingly uncoupled
as inflammatory lesions mature
• Conclusion: Treat early
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
Clinical Aspects of Spondyloarthritis –
What is New? Highlights of the Session
• MRI (Weber, Abstract #OP0047)
New bone formation more likely in complex
inflammatory lesions characterized by fat
metaplasia where it may be uncoupled from
inflammation
• Prognostic significance of spinal inflammation on
MRI (Vossen, Abstract #OP0048)
Effective suppression of inflammation on MRI
important objective beyond signs and symptoms
Early and effective anti-inflammatory may be
disease modifying
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
Importance of Smoking in AS
• DESIR cohort (Lafranchi-Debra, Abstract
#OP0046)
Smokers more likely to have:
– Earlier onset of inflammatory back pain
– Greater disease activity
– Increased axial inflammation
– Increased axial structural damage
– Poorer function and worse QoL
Abstract session: Clinical Aspects of Spondyloarthritis – What is New?
EULAR 2011; Thurs., May 26.
Osteoporosis
Highlights of EULAR Poster
Sessions held Thursday, May 26
Summarized by Dr. George Ecker
40
Efficacy and Safety of Denosumab in
Osteoporosis: Lit. Review & Meta-analysis
• Denosumab increases BMD and reduces bone
remodelling
Greater effects than alendronate, placebo
• Denosumab demonstrated ability to reduce
vertebral, non-vertebral fractures
• Tolerability concerns
Increased incidence of urinary tract infection
and rash
Silva L, et al: Presented at EULAR 2011; Poster #THU0166.
Intravenous Zoledronic Acid after Subcutaneous
Teriparatide in Postmenopausal Osteoporosis
• Sequential s.c. teriparatide i.v. zoledronic
acid was associated with:
Stability of BMD at both lumbar spine and hip
Increased BMD at lumbar spine: statistically
significant in comparison to oral
bisphosphonate
Carlino G, et al: Presented at EULAR 2011; Poster #THU0158.
A Life Without Biologics
Highlights of a EULAR Abstract
Session held Thursday, May 26
Summarized by Dr. Isabelle Fortin
43
List of Presentations in this Session
Speaker
Title
Balsa, A
New drugs and new strategies for rheumatoid arthritis. A step forward
Weinblatt,
ME
Improved health-related quality of life in patients with active rheumatoid arthritis
receiving fostamatinib (R788)
OP0057
Mohamed, W
Daily vs. weekly supplementation of folate in rheumatoid arthritis patients receiving
weekly low-dose methotrexate (MTX)
OP0058
Fleischmann,
R
The oral S1P lyase inhibitor LX3305 (aka LX2931) demonstrates favorable safety
and potential clinical benefit at 12 weeks in a phase 2, proof-of-concept trial in
patients with active rheumatoid arthritis on stable methotrexate therapy
OP0059
Hetland, M
Short- and long-term effect of unguided, intra-articular injections with
betamethasone in early rheumatoid arthritis. Impact of joint area, repeated
injections, MRI findings, anti-CCP, IgM-RF and CRP
OP0060
Saleem, B
Prediction of flare and long-term outcome in DMARD-treated RA patients in
remission: The value of imaging and new remission criteria
OP0061
Buttgereit, F
Integrated summary of safety for modified-release prednisone compared to
immediate-release prednisone: Results from the Circadian Administration of
Prednisone in Rheumatoid Arthritis (CAPRA) studies
OP0062
Strand, V
Oral Solo (A3921045): Effects of the Oral JAK inhibitor tofacitinib (CP-690,550)
monotherapy on patient-reported outcomes in a phase 3 study of active
rheumatoid arthritis
OP0063
Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.
Abstract #
NA
44
A Life Without Biologics
• Many advances in RA treatment
New drugs
New ways of treating patients
• Methotrexate is the anchor drug for the
treatment of RA
Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.
Combination Treatment
Yes
No
SWEFOT
TEAR
COBRA
FIN-RACo
• EULAR does not recommend combination
treatment
• The most important recommendation is
Treat to Target
Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.
What About Biologics?
Advantages
Disadvantages
Efficacy to control symptoms
Very high costs
Efficacy to control radiographic
progression
Adverse events
Still patients with active disease
With or without MTX
Not available for everyone
Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.
Novel Treatments:
Signal Transduction Inhibitors
• SYK: spleen tyrosine kinase
• JAK: Janus kinase
tofacitinib
• NFkB
• MAPk
Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.
fostamatinib
RA: Nothing is working!
What to do?
Highlights of a EULAR Challenges
in Clinical Practice Session held
Thursday, May 26
Summarized by Dr. Isabelle Fortin
49
For Patients with a Disease Activity Score
(DAS) > 5
• Are you calculating DAS?
Or CDAI, SDAI?
• The only association proven better than
monotherapy is MTX + cyclosporine
• Prednisone is good!
Challenges in Clinical Practice Session:
RA: Nothing is working! What to do?. EULAR 2011; Thurs., May 26.
Considerations for Choosing
an Anti-TNF Agent
• Which one is the best?
• What are the patient characteristics that you
consider?
• Why not tocilizumab or abatacept?
Challenges in Clinical Practice Session:
RA: Nothing is working! What to do?. EULAR 2011; Thurs., May 26.
Options for Patients Who Have Failed on
Anti-TNF Therapy
• Another anti-TNF
• Tocilizumab
• Abatacept
• Rituximab
Challenges in Clinical Practice Session:
RA: Nothing is working! What to do?. EULAR 2011; Thurs., May 26.
Non-biologic Alternatives to Keep in Mind
• Leflunomide
• Cyclosporine (CIMESTRA)
• Gold salts
• Intra-articular injections
Challenges in Clinical Practice Session:
RA: Nothing is working! What to do?. EULAR 2011; Thurs., May 26.
Inflammasomes as Sentinels and
Enemies from Within
Highlights of a EULAR Basic and
Translational Science Session
held Thursday, May 26
Summarized by Dr. Jacob Karsh
54
List of Presentations in this Session
Abstract
#
Speaker
Title
Cawston, T
Connective tissue components = immunostimulators
Distler, J
What do animal models tell us?
SP0069
Lafyatis, R
Immune dysregulation in systemic sclerosis
SP0070
Shiozawa, S
IFN alpha as a cause of systemic lupus erythematosis and
its implication to self-organized criticality theory of
autoimmunity
OP0143
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
NA
55
The Innate Immune System
• Activation of the inflammasome appears to be
the fundamental step in the pathogenesis of
gout
It may also play a role in the development of
atherosclerosis, type 1 diabetes, RA and other
immune diseases
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
56
Immune System: PAMPs and DAMPs
• PAMPs: Pathogen-associated molecular patterns
• DAMPs: Damage-associated molecular patterns
• PAMPs and DAMPs intersect with cells of innate
immunity via:
a)
Toll-like receptors (TLRs): cell surface
b)
NOD-like receptors (NLRs): cytoplasm
c)
RIG-like receptors (RLRs): RNA from bacteria /
viruses
d)
Cytosolic dsDNA Sensors (CDSs): DNA from
bacteria / viruses
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
57
Four Known Inflammasome Proteins
• NLRP 1
• NLRP 3
• iPAK
• AIM2
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
58
Inflammasomes in Non-myeloid Cells
• Myeloid cells are the best studied
• Non-myeloid cells with inflammasomes
Keratinocytes
Astrocytes
Adiopocytes
Islet cells
• Acne
• Contact dermatitis
• Psoriasis
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
59
Inflammasomes Can Be
Activated by Non-biologic Substances
• NLPR3
Nanoparticles: sunscreen, inhaled
Alum: vaccines
Asbestos
Amyloid Alzheimer's
Amylin: Islet cells
Cholesterol crystals
– Ubiquitous, and may enhance atherosclerosis via NLPR3
• HDL cholesterol inhibits cholesterol crystals
• May be a more fundamental mechanism than
previously thought
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
60
Inflammasomes and Uric Acid
• Uric acid activates inflammasomes
• Uric acid is monosodium urate (MSU) crystals
Most of crystal is sodium
When MSU is phagocytosed, high amounts of sodium are
introduced into the cell
The phagocytic vesicle (lysoome) needs to acidify to release
MSU into the cytoplasm; this in turn leads to high
intracellular Na+
– To deal with this, the cell ingests H20, which leads to
dilution of K+, which is required to activate NLPR3
HCQ / chloroquine prevents lysosomal acidification
Basic and Translational Science Session:
Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.
61
Bone and Crystal Diseases
Highlights of a EULAR Abstract
Session held Thursday, May 26
Summarized by Dr. Jacob Karsh
62
List of Presentations in this Session
Speaker
Title
Schlesinger, N
Efficacy of canankinumab vs. triamcinolone acetonide in preventing recurrent
flares in acute gouty arthritis patients contraindicated, intolerant or
unresponsive to NSAIDs and/or colchicine: Results from two pivotal studies.
OP0107
So, A
A controlled trial of canakinumab vs. triamcinolone acetonide in acute gouty
arthritis patients: Results of the ?-RELIEVED study (response in acute flare
and in prevention of episodes of re-flare in gout).
OP0108
Ottaviani, S
Ultrasonography findings in gouty patients: A case-control study.
OP0109
Richette, P
Effect of massive weight loss on serum uric acid levels
OP0110
Perez-Ruiz, F
Efficacy and safety of lesinurad (RDEA594), a novel uricosuric agent, given in
combination with allopurinol in allopurinol-refractory gout patients:
Randomized, double-blind, placebo-controlled, phase 2B study
OP0111
Nuki, G
Chronic gout in Europe in 2010: Clinical profile of 1,380 patients in the UK,
Germany, France, Italy and Spain
OP0112
Lipsky, P
Safety and efficacy of long-term pegloticase (Krystexya?) treatment in adult
patients with chronic gout refractory to conventional therapy
OP0113
Lee, Y-A
Tight serum urate control may improve renal dysfunction in patients with gout
OP0114
Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.
Abstract #
63
Common Themes in the Abstract Session
• Hyperuricemia / gout is poorly treated
Goal should be to bring uric acid below level
where urate is soluble – 6 mg/dL or 360 μM/L
• Global increase in gout
Prevalence of gout is 1.4% in UK
Treatment is 7% of men and 3% of women >
75 years
Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.
64
Common Themes in the Abstract Session:
Undertreatment
• Few patients on allopurinol have dose > 300
mg/d
Best was UK, where 19% had > 300 mg,
ascribed to NICE recommendations
• <2% used uricosurics
• Only 1/3 of patients had serum uric acid < 360
μM/L
• Overall, 18% received > 300 mg/d allopurinol or
> 80 mg febuxostat and still had uncontrolled
gout
• A treat-to-target approach is needed
Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.
65
Common Themes in the Abstract Session:
Undertreatment
• Reasons for reticence in higher doses of allopurinol
Renal insufficiency
Fear of AEs, especially hypersensitivity
– Hypersensitivity reactions found to be related
to baseline renal function and allopurinol
starting dose
• Nephros / rheums were no better than family
doctors: urged to be more aggressive
In patients with normal renal function, increasing
allopurinol dose to as high as 600 mg/d led to 95%
success in reducing SUA to < 360 μM/L
Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.
66
Effect of Massive Weight Loss on Serum Uric Acid
• EULAR recommends weight loss as part of
treatment
However, weight loss of 10 kg results in only a
very small reduction in UA
• In an investigation of the effects of bariatric surgery
(n=152 patients, mostly women, without gout):
Patients lost 20-30 kg
Change in serum uric acid: from mean of 331
μM/L to 299 μM/L
Best correlate of reduced UA was reduced TG
Richette P, et al: Presented at EULAR 2011; Presentation #OP0110.
67
Effect of Lesinurad in Allopurinol-refractory Gout
• Lesinurad inhibits URAT1 in the proximal tubule, OAT4
transporter
• In two separate studies, investigated in combination with
allopurinol or with febuxostat versus either agent in
monotherapy
Doses studied: 400 & 600 mg: in combination with stable
allopurinol 200 – 600 and febuxostat 40 and 80
Lesinurad was found to be:
– Very effective at achieving normal SUA levels in
combination with allopurinol or febuxostat
• Febuxostat combination better than the allopurinol
combination
• Patients receiving concomitant HCTZ fared better
than those not receiving HCTZ
Perez-Ruiz F, et al: Presented at EULAR 2011; Presentation #OP0111.
68
Novel Agents: BCX4208
• BCX 4208 is a novel enzyme inhibitor of Purine
Nucleoside Phosphorylase (PNP)
Blocks the generation of precursors of uric
acid at a higher level in the metabolic pathway
than xanthine oxidase inhibitors
• When added to allopurinol, synergistic
reduction in serum UA, with 100% of patients
achieving SUA < 6 mg/dL
Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.
69
Novel Agents: Pegloticase
• Placebo-controlled study, followed by openlabel extension
85 patients treated with 8 mg i.v. q 2 weeks in
6-month placebo-controlled phase
– 36 entered the open-label extension
• For those capable of continuing, SUA
was reduced < 2 mg/dL with significant
reduction in flares, tophi, tender &
swollen joints
• Infusion reactions 0.4% in persistent
responders, 4.2% in those with
antibodies
Lipsky P, et al: Presented at EULAR 2011; Presentation #OP0113.
70
Uric Acid and Kidney Disease
• High uric acid is an independent risk factor for
kidney disease
There is too much worry regarding the use of
allopruinol in patients with renal insufficiency
• Study of 370 patients with gout investigated the
prevalence of renal insufficience
92 had GFR 30-59 (moderate)
29 had GFR 15-29 (severe)
Tight control of serum UA (≤ 6 mg/dL) was
associated with improvement in renal function
Lee Y-A, et al: Presented at EULAR 2011; Presentation #OP0114.
71
Canakinumab for Treatment of Acute Gout
• B-RELIEVED and B-RELIEVED 2
Parallel, 12-week studies in patients with
gout, intolerant of, unresponsive to or with
contraindication for NSAIDs and/or colchicine
Subjects treated with single injection of
canakinumab 50 mg s.c. or triamcinolone 40
mg i.m.
Schlesinger N, et al: Presented at EULAR 2011; Presentation #OP0107.
So S, et al: Presented at EULAR 2011; Presentation #OP0108.
72
Canakinumab for Treatment of Acute Gout
• Results of BELIEVE & BELIEVE 2:
High completion rate (>90%)
Flares reduced 55-68% at 12 weeks
Pain significantly reduced at 72 hours
– Reduction of 40 mm on a 100 mm VAS with
canakinumab vs. 28 mm with triamcinolone
– Decrease in joint tenderness
– No major side effects
– Higher number of infections with canakinumab
Schlesinger N, et al: Presented at EULAR 2011; Presentation #OP0107.
So S, et al: Presented at EULAR 2011; Presentation #OP0108.
73
Vasculitis
Highlights of a EULAR Abstract
Session held Thursday, May 26
Summarized by Dr. Nader Khalidi
74
Long-term Efficacy of Rituximab in ANCAassociated Vasculitis (RAVE trial)
•
Objectives: To evaluate efficacy and safety of one course of RTX in
comparison to CYC followed by AZA over the course of 18 months
•
Methods:
Multicenter, randomized, double-blind, placebo-controlled trial
RTX (375 mg/m2 iv weekly x 4) versus CYC (2 mg/kg/d po)
Followed for a minimum of 18 months
Patients received 1-3 g iv methylprednisolone followed by
prednisone 1 mg/kg/d, tapered over 5.5 months
CYC was replaced by AZA between months 3-6 if remission was
achieved, and AZA was continued through 18 months
The RTX group received placebo after 3-6 months if remission had
been achieved
All data shown were based on intention-to-treat analyses with
worst case imputation
Stone J, et al: Presented at EULAR 2011; Oral Presentation #OP0054.
Long-term Efficacy of Rituximab in ANCAassociated Vasculitis (RAVE trial)
• Results:
197 ANCA-positive patients were enrolled
Mean follow-up: 35 months (SD, 14.6).
The primary outcome at 6 months (BVAS/WG and
prednisone=0) was achieved by
• 64% of the patients assigned to RTX
• 53% in the CYC arm (p = 0.13)
At 12 and 18 months,
• 42% and 36% in the RTX arm versus 38% and 31% in the
CYC arm remained in remission off glucocorticoids (p =
NS)
The number flares, the number of patients suffering at least
one flare, and the flare rates did not differ between
treatment arms over 18 months (p = NS)
Stone J, et al: Presented at EULAR 2011; Oral Presentation #OP0054.
Long-term Efficacy of Rituximab in ANCAassociated Vasculitis (RAVE trial)
• Results (cont'd):
Relapses were more common among PR3-ANCA positive
patients than MPO-ANCA positive patients
Average cumulative glucocorticoid dose was significantly
lower in the RTX arm by 12 months (RTX 3270 mg versus
control 3678 mg, p = 0.031), but no longer by 18 months
(RTX 3541 versus control 3956, p = 0.088)
There was no difference in overall, serious or selected
adverse events rates between the treatment arms at 18
months or through common close-out
• Conclusions:
In patients with severe AAV, a single course of RTX is as
effective as 18 months of standard therapy for remission
induction and maintenance
Stone J, et al: Presented at EULAR 2011; Oral Presentation #OP0054.
Two-year Follow-up Results From a Randomized Trial of RTX
Vs. CYC for ANCA-associated Renal Vasculitis: RITUXVAS
•
•
Background:
CYC-based induction regimens are standard therapy for ANCAAAVr; however, associated mortality and adverse event rates are
high and safer regimens are required
RTX-based regimens are a potential alternative to CYC induction
Methods:
2-year results of a randomized trial comparing a RTX-based
induction regimen with a standard intravenous CYC regimen for
new AAVr
All patients had newly diagnosed AAVr and ANCA positivity.
44 patients were randomized:
• 33 to RTX 4 × 375 mg/m2 and 2 × 15 mg/kg i.v. CYC; and
• 11 to i.v. CYC 6–10 × 15 mg/kg.
Both groups received the same i.v. and oral prednisolone regimen
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Two-year Follow-up Results From a Randomized Trial of RTX
Vs. CYC for ANCA-associated Renal Vasculitis: RITUXVAS
•
Results:
At entry, median age was 68 years; GPA 50%, MPA 50%; CRP 28;
BVAS 18; PR3-ANCA 57%, MPO-ANCA 43%, GFR 18 ml/min; 20%
required dialysis.
At 2 years:
– The primary composite outcome of relapse, death or ESRF
occurred in 14 of 33 (42%) RTX vs. 4 of 11 (36%) CYC (p = 1.00)
– Relapse occurred in 7 of 33 (21%) RTX vs. 2 of 11 (18%) CYC (p =
1.00)
– Death occurred in 6 of 33 (18%) RTX vs. 3 of 11 (27%) CYC (p =
0.67)
– ESRF occurred in 2 of 33 (6%) RTX vs. 0 of 11 (0%) CYC (p = 0.57)
Median estimated GFR was 20 and 44 mL/min/m2 in RTX patients at
0 and 24 months, respectively, vs. 12 and 31 mL/min/m2 in CYC
patients
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Two-year Follow-up Results From a Randomized Trial of RTX
Vs. CYC for ANCA-associated Renal Vasculitis: RITUXVAS
• Results (Cont'd):
Serious adverse events (SAEs) occurred in
– 61% RTX (50 events, 20 of 33 patients)
– 36% CYC (15 events, 4 of 11 patients)
• Incidence rate ratio 1.16; 95% CI 0.64–
2.22) (p = 0.64)
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Two-year Follow-up Results From a Randomized Trial of RTX
Vs. CYC for ANCA-associated Renal Vasculitis: RITUXVAS
• Conclusions:
RTX-based induction therapy is efficacious,
but is not superior to i.v. CYC at 2 years in
terms of combined relapse, mortality and
ESRF outcome
Further strategies to reduce mortality and
SAEs and prevent relapse should be
considered
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Long-term Renal Outcome of Patients Enrolled in the
CYCAZAREM Trial
• Objective:
Long-term renal outcome of patients enrolled
in the CYCAZAREM trial
• Methods:
Long term follow-up data of CYCAZAREM
patients were acquired from a questionnaire
completed by all participating physicians
Berden A, et al: Clin Exp Immunol 2011; (suppl.1):51.
Long-term Renal Outcome of Patients Enrolled in the
CYCAZAREM Trial
• Results: Data on ESRD were available for 130 of 155
patients enrolled originally in the trial.
Mean ± s.d. follow-up was 7.09 ± 3.14 years
In the oral CYC treatment arm, 6 of 65 (9%)
developed ESRD during follow-up, compared to 8
of 65 (12%) in the AZA arm (n.s.)
Mean ± s.d. eGFR at 5 years was 49.0 ± 29.9
mL/min in the AZA arm compared to 50.9 ± 25.1
mL/min in the oral CYC arm (n.s.)
• Conclusion: Azathioprine is as effective as oral CYC
maintenance therapy in ANCA-associated vasculitis
when regarding long-term renal outcome,
supporting its use
Berden A, et al: Clin Exp Immunol 2011; (suppl.1):51.
Pulse Versus Daily Oral CYC for Induction of Remission in ANCAassociated Vasculitis. A European, Multi-centre Randomized Controlled
Trial: Long-term Follow-up (CYCLOPS)
• Objective:
Describe the long-term patient survival and relapse rates of
patients recruited to the CYCLOPS study
• Methods:
Questionnaire was sent to the CYCLOPS participating
physicians
Data on survival, renal survival, relapse rate,
immunosuppressive therapy, cancer rate, bone fractures,
thromboembolic disease and cardiovascular morbidity were
recorded
Returns were received on 134 of 149 patients recruited to
the original study
Analyses were performed by intention-to treat
Harper L, et al: Clin Exp Immunol 2011; (suppl.1):56.
Pulse Versus Daily Oral CYC for Induction of Remission in ANCAassociated Vasculitis. A European, Multi-centre Randomized Controlled
Trial: Long-term Follow-up (CYCLOPS)
• Results:
Median duration of follow-up was 4.3 years (IQR
2.95–5.44 years), with no difference between the
two arms (p = 0.5)
12 patients in the daily oral and 13 in the pulse
arm died during follow-up; median time to death
was 813 days (IQR 117–1143), with no difference
between the two arms (p = 0.94)
44 patients (29 pulse and 15 daily oral) had 67
relapses, 28 of which were renal
The time to relapse was significantly longer in the
daily oral arm (HR = 0.51, 95% CI: 0.27–0.95; p =
0.033)
Harper L, et al: Clin Exp Immunol 2011; (suppl.1):56.
Pulse Versus Daily Oral CYC for Induction of Remission in ANCAassociated Vasculitis. A European, Multi-centre Randomized Controlled
Trial: Long-term Follow-up (CYCLOPS)
• Results (cont'd):
Patients who were PR3-anti-ANCA positive at
diagnosis were more likely to relapse than those
who were not PR3-ANCA-positive (HR = 0.49, 95%
CI: 0.27–0.91)
Despite a reduced time to relapse there was no
difference in renal function (pulse median 116, IQR
89–185, DO median 119, IQR 102–143; P = 0.84),
adverse events, total dose of immunosuppression
or VDI between the two arms
• Conclusion: Pulse cyclophosphamide is associated
with a higher relapse rate than daily oral
cyclophosphamide; however, this is not associated
with increased death or worse renal function
Harper L, et al: Clin Exp Immunol 2011; (suppl.1):56.
Protocolized Versus Non-protocolized RTX Treatment
for Refractory ANCA-AAV
• Objective:
Single-centre study comparing 6-monthly,
protocolized RTX retreatment and nonprotocolized RTX retreatment according to
clinical need for refractory AAV
• Methods:
49 patients received a protocolized RTX regimen:
– 1 g × 2 followed by 1 g × 1 q 6 months for 2
years (5 g total) with early immunosuppression
and corticosteroid withdrawal
34 received non-protocolized RTX; either 1 g × 2
or 375 mg/m2 × 4 only repeated at relapse
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Protocolized Versus Non-protocolized RTX Treatment
for Refractory ANCA-AAV
•
Results:
At first RTX, median disease duration was 55 months: previous
cyclophosphamide exposure was 14 g
RTX indication was relapsing disease in 90% of protocol and 82%
of non-protocol patients; the remainder had grumbling disease
while receiving continuous high-dose corticosteroids or
immunosuppression
Median follow-up was 25 (4–46) months for protocol patients,
versus 22 (6–84) months for non-protocol patients
Response to RTX occurred in 47 of 49 (96%) protocol patients
(90% full remission, 6% partial) and 32 of 34 (94%) non-protocol
patients (82% full remission, 12% partial)
In protocol patients only 3 of 48 (6%) were still receiving
immunosuppression at 6 months, and by 24 months 22% had
withdrawn from prednisolone (4.25 mg/ day median)
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Protocolized Versus Non-protocolized RTX Treatment
for Refractory ANCA-AAV
• Results (cont'd):
At 2 years, relapse had occurred in:
– 11 of 49 (22%) protocol patients
– 24 of 34 (71%) non-protocol patients
At end of follow-up, relapse had occurred in:
– 3 of 49 (27%) protocol patients
– 26 of 34 (76%) non-protocol patients (p < 0.01)
Serious infections occurred in:
– 14% of protocol patients
– 18% of non-protocol patients
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Protocolized Versus Non-protocolized RTX Treatment
for Refractory ANCA-AAV
• Conclusion:
Six-monthly protocolized RTX retreatment is
effective for relapse prevention, allows
immunosuppression withdrawal and appears safe
in refractory AAV
Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.
Rituximab Provides Stable Long-term
Responses in ANCA-associated Vasculitis
•
•
Background:
Randomized clinical trials have demonstrated that rituximab (RTX)
is an effective treatment for ANCA Associated Systemic Vasculitis
(AASV), with primary clinical outcome at 6 months
Some protocols have specified fixed repeat treatment at 6 months
However, there are fewer data regarding longer term outcomes
after RTX, including duration of response, patterns of relapse and
the basis for the timing of repeat treatment
Objectives:
To identify patterns of response and relapse after RTX for AASV
To identify potential biomarkers of response to guide decisions
regarding timing of repeat cycles of RTX
Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.
Rituximab Provides Stable Long-term
Responses in ANCA-associated Vasculitis
• Methods:
Prospective study of patients with active AASV treated with
RTX 1g and methylprednisolone 100mg x 2 infusions on
Days 1 and 15
• Also received oral prednisolone 60mg daily (1 week) and
30mg (1 week) between infusions to minimise infusion
reactions and incidence of serum sickness
Disease activity was assessed by BVAS 3.0 at baseline and
every 3 months post therapy
Responders were maintained on stable or reducing levels of
immunosuppression (including oral steroid)
Repeat treatment was given on clinical diagnosis of relapse
Follow up after the 2nd cycle of RTX was as for the 1st cycle
Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.
Rituximab Provides Stable Long-term
Responses in ANCA-associated Vasculitis
• Results:
22 patients were treated (18 GPA, 3 pANCA vasculitis, 1
Churg Strauss): all were ANCA positive before RTX
Most common organ systems: ENT (77%), renal (55%) and
arthritis and pulmonary (45% each)
18 patients had received cyclophosphamide previously
(withdrawn in 16 due to lack of efficacy); baseline mean
BVAS score was 9.9 (SD 5.1)
13 patients were maintained on concomitant
immunosuppression with DMARDs
Total patient follow-up was 3288 weeks; median follow up
was 137 weeks (range 35-263 weeks)
Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.
Rituximab Provides Stable Long-term
Responses in ANCA-associated Vasculitis
•
Results:
Mean BVAS at week 26 was 1.2 (SD 0.5, p = 0.003)
At week 26, 11 patients had complete response, 9 patients had
partial response
Relapse:
– Median time to relapse was 89 weeks
– Patients with partial response relapsed earlier than those with
complete response (81 vs 120 weeks, partial vs complete
response, p = 0.03)
The duration of response for cycles 1 and 2 of RTX showed
significant correlation (r = 0.709, p = 0.022)
Median dose of daily oral prednisone was reduced from 15mg
(baseline) to 6.3 mg (week 26) and 4.3 mg (relapse)
No patient relapsed in the absence of peripheral blood B cells
– However, levels of B cell depletion or repopulation did not
predict response or subsequent relapse
Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.
Rituximab Provides Stable Long-term
Responses in ANCA-associated Vasculitis
• Conclusions:
1.
RTX is an effective therapy for severe, active AASV
2.
Responses are long, often considerably greater than 24
weeks and are longer in those with complete clinical
response
3.
Disease activity at relapse is often less than at baseline
4.
This suggests that retreatment with RTX on relapse may be
more appropriate than a fixed retreatment regime eg given
at 6 months. Decisions regarding the timing of retreatment
may be guided more accurately by the duration of response
to the 1st cycle of RTX
5.
A biomarker that predicts response and relapse is still to be
identified
Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.
Retrospective Study of Rituximab in Refractory Granulomatosis with
Polyangiitis (Wegener's): Comparison of Treatment Response in
Vasculitic Versus Granulomatous Manifestations
• Objectives:
To determine the overall efficacy of RTX in
refractory WG in a monocentric retrospective
study of 75 cases
To compare the efficacy of RTX in granulomatous
versus vasculitic manifestations
• Methods:
All patients received RTX with or without
additional conventional immunosuppressants for
refractory GPA from 2002 to 2010 (4x 375 mg/m2
four times in weekly intervals)
Side effects, duration of remission and relapses
were also documented
Holle J, et al: Presented at EULAR 2011; Oral Presentation #OP0055.
Retrospective Study of Rituximab in Refractory Granulomatosis with
Polyangiitis (Wegener's): Comparison of Treatment Response in
Vasculitic Versus Granulomatous Manifestations
• Results:
59 GPA patients received 75 cycles of RTX for
refractory manifestations, 66% due to granulomatous
and/or 39% due to vasculitic manifestations
Follow-up of at least 4 months, 9.33% had a complete
remission, 52% a response, 9.33% an unchanged
activity and 26.66% a disease progression
Prednisolone dose, BVAS and B-cell counts
decreased significantly (p < 0.05) after RTX treatment
Response rates (complete remission plus response)
of vasculitic manifestations were excellent and
significantly higher compared to granulomatous
manifestation such as orbital granuloma and
pachymeningitis (p < 0.05)
Holle J, et al: Presented at EULAR 2011; Oral Presentation #OP0055.
Retrospective Study of Rituximab in Refractory Granulomatosis with
Polyangiitis (Wegener's): Comparison of Treatment Response in
Vasculitic Versus Granulomatous Manifestations
• Results (Cont’d):
In patients with alveolar hemorrhage (n=12) or
refractory active renal disease (n=26), there were
83.3% and 80.1% complete remissions/responses
In 27 patients with orbital granuloma, there were
no complete remissions, 44.4% responses, 22.2%
with unchanged activity and 33.3% with
progression
2 patients died, the infection rate was 21% and
relapse was frequent (40% after a median followup of 13.5 months, range 3-54 months)
Re-treatment after relapse was effective
Holle J, et al: Presented at EULAR 2011; Oral Presentation #OP0055.
Retrospective Study of Rituximab in Refractory Granulomatosis with
Polyangiitis (Wegener's): Comparison of Treatment Response in
Vasculitic Versus Granulomatous Manifestations
• Conclusions:
1.
Overall efficacy of RTX in refractory GPA was
good (around 61.3% complete remissions or
improvement)
2.
Response rates of vasculitic manifestations were
excellent; treatment failure or progress occurred
mainly in granulomatous manifestations,
especially in orbital granuloma
3.
Relapse rates were high (40%)
Holle J, et al: Presented at EULAR 2011; Oral Presentation #OP0055.
Churg-Strauss Syndrome: Description and Long-term
Follow-up of the 383 Patients Enrolled in the FVSG Cohort
• Objective:
To describe the main characteristics and
long-term outcomes of a large cohort of
patients with well-characterized CSS
diagnoses
• Methods:
Characteristics and outcomes of CSS patients
especially according to ANCA status and the
year of diagnosis (≤ or >1996, when the fivefactor score (FFS) was devised) were
analyzed
Pagnoux C, et al: Presented at EULAR 2011; Oral Presentation #OP0051.
Churg-Strauss Syndrome: Description and Long-term
Follow-up of the 383 Patients Enrolled in the FVSG Cohort
•
Results:
383 patients (199 men, 184 women), diagnosed between March 1957 and
June 2009 [128 (33.4%) ≤1996], and followed for a mean ± SD of 67.1±62.8
months.
Mean age at diagnosis: 50.3±15.7 years
Main manifestations:
– Asthma (91.1% of the patients), with mean asthma duration of
111±130 months,
– Weight loss (49.4%),
– Myalgias (38.9%),
– Arthralgias (29.8%),
– ENT manifestations (48.0%),
– Lung infiltrates (38.6%),
– Peripheral neuropathy (51.4%),
– Skin lesions (39.7%; mainly purpura),
– Renal (21.7%), GI (23.2%) and/or cardiac (16.5%) involvement(s)
Pagnoux C, et al: Presented at EULAR 2011; Oral Presentation #OP0051.
Churg-Strauss Syndrome: Description and Long-term
Follow-up of the 383 Patients Enrolled in the FVSG Cohort
• Results (Cont’d):
Mean eosinophil count was 7427±3763/mm3 and 106
(27.7%) patients were ANCA+, mainly with antiMPO-ANCA
(64% of the ANCA+ patients).
CSS was histologically proven for 162 (42.3%).
ANCA-, compared to ANCA+ patients, had significantly:
– More frequent cardiac manifestations (31.1% vs. 17.9%;
p = 0.01)
– Less frequent ENT manifestations, peripheral
neuropathy, renal involvement and lower BVAS (20.6 vs.
18.4; p = 0.04); they received cyclophosphamide less
frequently (43.3% vs. 57.6%; p = 0.01)
Pagnoux C, et al: Presented at EULAR 2011; Oral Presentation #OP0051.
Churg-Strauss Syndrome: Description and Long-term
Follow-up of the 383 Patients Enrolled in the FVSG Cohort
• Results (Cont’d):
Multivariable analysis revealed as
independent mortality risk factors:
– Cardiomyopathy (HR 3.23; 95 CI, 1.55-6.76)
– Age >65 years (HR 3.58; 95 CI, 1.60-8.02)
– Diagnosis ≤1996 (HR=3.81; 95 CI, 1.57-9.21)
– Creatinine >140 μmol/L (HR 18.6; 95 CI,
4.43-78.4)
Pagnoux C, et al: Presented at EULAR 2011; Oral Presentation #OP0051.
Last But Not Least, the Orphans
Highlights of a EULAR Abstract
Session held Friday, May 27
Summarized by Dr. Nader Khalidi
10
4
The Clinical Characteristics of Remitting Seronegative
Symmetrical Synovitis with Pitting Edema (RS3PE) and the
Complication with Neoplasia
• Background: It was previously reported that.;
Serum levels of vascular endothelial growth
factor (VEGF) were markedly elevated in
patients with RS3PE
Serologic variables such as matrix
metalloproteinase 3 (MMP-3) and VEGF were
useful for monitoring the therapeutic efficacy
RS3PE has been reported to be complicated
with solid tumors
Origuchi T, et al: Presented at EULAR 2011; Oral Presentation #OP0267.
The Clinical Characteristics of Remitting Seronegative
Symmetrical Synovitis with Pitting Edema (RS3PE) and the
Complication with Neoplasia
• Results:
45 patients fulfilled the criteria of RS3PE
– 9 patients were excluded owing to a lack of
clinical data, and 35 patients with RS3PE were
included
– Mean age was 78 years (59-89), and they
included 17 men (48.6%) and 18 women (51.4%)
27 (77.1%) patients were diagnosed one week or
more after onset, and 20 (57.1%) patients were
diagnosed more than one month later
All patients had a good response to prednisolone
Origuchi T, et al: Presented at EULAR 2011; Oral Presentation #OP0267.
The Clinical Characteristics of Remitting Seronegative
Symmetrical Synovitis with Pitting Edema (RS3PE) and the
Complication with Neoplasia
• Results (Cont’d):
In 9 patients (25.7%) RS3PE was complicated with
neoplasia
The serum levels of MMP-3 were high in 27
(77.1%) patients with RS3PE
Median MMP level in RS3PE patients complicated
with neoplasia (455.3 ng/mL) was significantly
higher than that in RS3PE patients without
neoplasia (149.0 ng/mL) (p < 0.05)
The mean serum level of VEGF was 1408.9 ng/mL
in 4 patients with RS3PE and 3008.3 ng/mL in 2
paraneoplastic RS3PE patients
Origuchi T, et al: Presented at EULAR 2011; Oral Presentation #OP0267.
The Clinical Characteristics of Remitting Seronegative
Symmetrical Synovitis with Pitting Edema (RS3PE) and the
Complication with Neoplasia
• Conclusions:
1.
RS3PE is associated with a high-frequency
complication of neoplasia
2.
Long time to make a diagnosis of RS3PE
3.
RS3PE patients had high levels of MMP-3 and
VEGF
4.
Early diagnosis of RS3PE is important
5.
MMP-3 and VEGF were useful for the diagnosis of
paraneoplastic RS3PE
Origuchi T, et al: Presented at EULAR 2011; Oral Presentation #OP0267.
Dosing Requirement and Longer-term effects of Canakinumab for
Treatment of All Phenotypes of Cryopyrin-associated Periodic
Syndrome (CAPS)
• Background:
Longer-term effects of interleukin-1beta blockade
in CAPS ascertained in an open label, phase-3
study of canakinumab in the largest study cohort
to date of pediatric and adult patients with CAPS
phenotypes of all types
• Objectives:
Assess safety and tolerability of canakinumab
– Key efficacy assessments were complete
clinical and serologic response (CR),
maintenance of CR, and proportion of patients
requiring dose adjustments
Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.
Dosing Requirement and Longer-term effects of Canakinumab for
Treatment of All Phenotypes of Cryopyrin-associated Periodic
Syndrome (CAPS)
• Methods:
Canakinumab was administered 8-weekly for up
to 2 years by s.c. injection, 150 mg to adults and 2
mg/kg to patients ≤40 kg
An increase in dose up to 600 mg or 8 mg/kg for
those ≤40 kg, and/or frequency of administration
was allowed in patients who did not
achieve/remain in CR
Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.
Dosing Requirement and Longer-term effects of Canakinumab for
Treatment of All Phenotypes of Cryopyrin-associated Periodic
Syndrome (CAPS)
• Results:
166 patients (119 adult and 47 children) aged 3-91
years with a diagnosis of FCAS (n=30), MWS
(n=103), NOMID/CINCA (n=32) were treated
A greater proportion of children and patients with
NOMID/CINCA required an adjustment of dose
and frequency compared to adults or those with
other phenotypes
Higher doses were required in children vs. adults
and in NOMID/CINCA vs. other phenotypes
Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.
Dosing Requirement and Longer-term effects of Canakinumab for
Treatment of All Phenotypes of Cryopyrin-associated Periodic
Syndrome (CAPS)
Mean dose, mg
Phenotype
(>40 kg / ≤ 40 kg)
Adjustments, n (%)
> 40 kg
≤ 40 kg
Dose or
frequency
Dose
Frequency
FCAS (27/3)
188.9
2.7
5 (16.6)
5 (16.6)
0
MWS (90/13)
199.8
5.5
20 (19.4)
17 (16.5)
11 (10.7)
NOMID / CINCA
(19/13)
228.9
5.8
15 (46.9)
14 (43.8)
8 (25.0)
Total (166)
40 (24.1)
36 (21.7)
19 (11.4)
Adults (119)
23 (19.3)
20 (16.8)
8 (6.7)
Pediatrics (47)
17 (36.2)
16 (34.0)
11 (23.4)
Age group
FCAS = Familial cold auto-inflammatory syndrome
MWS= Muckle Wells syndrome
NOMID= Neonatal Onset Multisystem Inflammatory disease
CINCA= Chronic Infantile Neurological, Cutaneous and Articular Syndrome.
Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.
Dosing Requirement and Longer-term effects of Canakinumab for
Treatment of All Phenotypes of Cryopyrin-associated Periodic
Syndrome (CAPS)
• Conclusions:
Canakinumab administered every 8 weeks was
well tolerated and provided substantial disease
control in adults and children with all phenotypes
of CAPS
Increased doses of canakinumab were efficacious
in younger patients and those with more severe
CAPS disease without evidence of increased AE
rates
Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.
Rituximab as a Therapeutic Tool in Severe Mixed
Cryoglobulinemia: A Long-term Study on 22 Patients
• Background:
Type II mixed cryoglobulinemia (MC) is a systemic vasculitis
sustained by proliferation of oligoclonal cells, associated in
most cases with hepatitis C virus (HCV) infection
Several studies suggest that clinical remission can be
achieved by human/mouse chimeric monoclonal antibody
that specifically reacts with the CD20 antigen (Rituximab)
However, data on the long term effects of Rituximab,
especially when administered alone are lacking
• Objective:
Evaluate the response by assessing the changes in clinical
signs, symptoms, and laboratory parameters after rituximab
therapy in patients with Type II mixed cryoglobulinemia
Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.
Rituximab as a Therapeutic Tool in Severe Mixed
Cryoglobulinemia: A Long-term Study on 22 Patients
• Methods:
Patients were followed for 12-72 months (18 patients for 24
and 10 for 48 months)
22 patients, mean age 61.7 years (range 36-78), 21 with HCV
infection genotype 2a2c (7 cases), 1b (11 cases) and 3 (3
cases) and symptomatic type II MC with systemic
manifestations
– Severe renal involvement in 12 cases (11 biopsy-proven,
having diffuse membrano-proliferative
glomerulonephritis (10 patients) or renal vasculitis) large
necrotizing ulcers (9), severe polyneuropathy (13)
– Considered eligible for rituximab treatment because of
resistance (6 cases) or intolerance (6 cases) to
conventional therapy or important bone marrow
infiltration (5)
Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.
Rituximab as a Therapeutic Tool in Severe Mixed
Cryoglobulinemia: A Long-term Study on 22 Patients
• Methods (Cont'd)
5 patients were given Rituximab as a front-line therapy: 375
mg/m2 i.v. on days 1, 8, 15, and 22
2 more doses were administered 1 and 2 months later
No other immunosuppressive drugs were added
Further infusions were given to 13 patients
– 8 received a re-induction (2 doses in 2 weeks plus 1
monthly infusion for 2 months) after 12-51 months
– 5 were allocated in a maintenance protocol for 1 year
after induction therapy (1 infusion at 3 months interval).
Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.
Rituximab as a Therapeutic Tool in Severe Mixed
Cryoglobulinemia: A Long-term Study on 22 Patients
• Results:
Levels of proteinuria, ESR, cryocrit, rheumatoid factor, and
IgM significantly decreased at 6, 12, 18 and 24 months (p <
0.01)
HCV viral load did not increase during the entire
observation period. Bone marrow abnormalities were found
to reverse to normal in all the 5 re-examined patients
Improvement of polyneuropathy was documented by a
significant increase of the mean motor amplitude CMAP (p <
0.02) and motor conduction velocity (p < 0.05) 12 months
after rituximab therapy
Constitutional symptoms disappeared or ameliorated
No acute or delayed side effects were seen
Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.
Rituximab as a Therapeutic Tool in Severe Mixed
Cryoglobulinemia: A Long-term Study on 22 Patients
• Conclusions:
Based on this experience and a number of reports
published in the last 5 years, Rituximab appears
to be a safe and effective therapeutic option in
patients with HCV-associated MC severe systemic
vasculitis
Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.
Psychiatric Disease in
Rheumatology Practice
Highlights of a EULAR Clinical
Science Session held
Wednesday, May 25
Summarized by Dr. Liam Martin
11
9
Psychiatric Disease in Rheumatology
Practice: Session Overview
• Series of talks with varying degrees of
relevance
• Topics varied from evaluation of NPSLE to
Lyme brain disease to Psychiatric problems in
FM
• Presenters from Italy, France, US, and China
Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Neuropsychiatric SLE (NPSLE)
• NPSLE is well recognized
• Symptoms vary from H/A to cognitive
dysfunction to stroke
• Can be difficult to diagnose
• MRI not always helpful
• However, Spect scan is of value in speaker’s
experience
Castellino G: Presented at EULAR 2011; Presentation #SP0009.
NPSLE: Key Points
• In moderate to severe disease
Spect scan is positive when MRI is negative
• Diffusion weighted technique is used to
distinguish old versus new lesions
• Spect scanning can assess function of brain
tissue
• Problems
Expensive
Not standardized
Lack of availability
Castellino G: Presented at EULAR 2011; Presentation #SP0009.
Psychiatric Evidence in Chronic Fatigue
Syndrome and Fibromyalgia Syndrome
• 1,000’s of papers on both FM and CFS
• None comparing psychiatric involvement
• Both conditions have criteria which involve
excluding other causes of symptoms
• Both conditions have certain similarities and
differences
Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.
Psychiatric Evidence in Chronic Fatigue
Syndrome and Fibromyalgia Syndrome
• Sex, race, symptoms and natural history:
similar
• Low employability, decreased function, high
health care costs
• Emotional disorders; childhood abuse; and
difficult doctor-patient relationship – some
differences
• HPA disorders and treatment – different
Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.
Psychiatric Evidence in Chronic Fatigue
Syndrome and Fibromyalgia Syndrome
• Overlap
24 -42% of FM have CFS
25 – 75% CFS have FM
• Comorbid psychiatric conditions in CFS and FM
30 – 60% in referral centres
Less in general practice
• Depression most common
• Symptoms difficult to diagnose
Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.
Psychiatric Evidence in Chronic Fatigue
Syndrome and Fibromyalgia Syndrome
• Management issues arise CFS and FM
Dysfunctional beliefs
Over exertion cycle
Passive strategies
• Complexities in management
Diagnosis and cure
Time is of the essence
Family and other source of support
Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.
Psychiatric Evidence in Chronic Fatigue
Syndrome and Fibromyalgia Syndrome
• Management
Validate
Assess psychiatric / psychological issues
Abuse issues occur more frequently in FM
Address these issues if present
Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.
Psychiatric Manifestations of Lyme Disease
• Neuroborreliosis – relatively more common in
Europe
• Alsace region in France has most number of
cases in Europe
• 3.3% of blood donors in region have positive
serology; 1% have symptoms
Blanc F: Presented during Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Psychiatric Manifestations of Lyme Disease
• Neuroborreliosis is difficult to diagnose
• Symptoms include
Meningeal / radiculopathy: 7th cranial nerve
Meningitis
Transverse myelitis
Encephalopathy
Optic neuritis
• Ratio of serum Lyme Elisa / CSF Lyme Elisa
Blanc F: Presented during Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Psychiatric Manifestations of Lyme Disease
• Depression most common psychiatric symptom
• 2 cases presented of patients who presented
with no previous history of psychiatric disease
• Both presented with paranoia
• Unresponsive to anti-psychotic meds
• Lyme antibodies positive in both
• Symptoms cleared completely with ceftriaxone
Blanc F: Presented during Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Psychiatric Manifestations of Lyme Disease
• 1 cases of patient who presented with cognitive
dysfunction
• Negative investigations but positive Lyme
serology
• Symptoms cleared completely with ceftriaxone
• Still remains well
Blanc F: Presented during Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Psychiatric Manifestations of Lyme Disease
• Psychiatric involvement in Lyme disease is rare
• Neurologic symptoms are more common
• Hard to diagnose
• Serum / CSF antibody ratio may help
• Tetracyclines are helpful in treatment
Blanc F: Presented during Clinical Science session:
Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.
Neuropsychiatric involvement in SLE in
China
• Report of SLE in Peking from 1990 – 2004 (Peking university
hospital)
• Poor prognosis in patients with widespread systemic disease
or NPSLE
• Steroid therapy helped improve prognosis but dose of steroid
not studied
• Study performed on all NPSLE patients by CRA (n=128)
All patients were confused
32 years, mean age; SLEDAI: high scores
Patients with transverse myelopathy included
All patients treated cyclophosphamide i.v. monthly and
either 200 mg, 500 mg or 1 g weekly
Ye S: Presented at EULAR 2011; Presentation #SP0011.
Neuropsychiatric involvement in SLE in
China
• All patients improved at 4 weeks; no apparent
difference between doses
• 6 with myelopathy still had cord problems
• Treated with rituximab – 4 improved over 6
months, able to move legs
• Investigators measured P selectin, VCAM, IL8
High before, reduced to normal after
treatment
Ye S: Presented at EULAR 2011; Presentation #SP0011.
Neuropsychiatric involvement in SLE in
China
• Found new antibody
Alpha internexin
56 Kd, neurofilament protein
• Conclusions:
NPSLE responds to IV steroids and IV cyclo
May take up to 4 weeks to see response
Poorer outcome for full recovery if patient has
flaccid limbs
Ye S: Presented at EULAR 2011; Presentation #SP0011.
RA – Tight control:
Theory and Practice
Highlights of a EULAR Clinical
Science Session held
Thursday, May 26
Summarized by Dr. Liam Martin
13
6
Tight Control: Overview of Session
• These talks focused on the new way of
managing RA
Tight control
Treat to Target (T2T)
• There were MANY talks which focused on this
area
• The EULAR guidelines were mentioned
constantly regarding the ideal management of
RA
Clinical Science session:
RA – Tight control: Theory and Practice. EULAR 2011; Wed., May 25.
Tight Control: The MASCOT Study
• Step-up design, published in 2007, trial
commenced in 1999
• Patients recruited from clinical practices in
Scotland
• 687 patients recruited – 552 completed 6
months
• SSZ first drug; MTX added or substituted
• Overall response was modest – was not aiming
for remission
Porter D: Presented at EULAR 2011; Presentation #SP0044.
Tight Control: TICORA
• Step-up design; T2T; blinded assessment
• Reviewed every month; Tx changed if DAS not
2.4 or less
• Remission in 65%; EULAR good response in
80%; less X-ray damaged in tight control
• Steroids used freely - ? Role in maintaining
control
Porter D: Presented at EULAR 2011; Presentation #SP0044.
Tight Control: TEAR (UK and US)
• Triple therapy versus step-up therapy
• UK – monthly visits; tight control; T2T
• US – MTX to ETN/MTX versus triple
therapy
Both worked;
Group not responding to triple therapy were
switched to ETN/MTX; no increase in X-ray
damage in this group
• EULAR guidelines – Add biologic if one
DMARD not helpful – no data
Porter D: Presented at EULAR 2011; Presentation #SP0044.
Tight Control: SWEFOT
• Step-up study
MTX for 3 months; 30% DAS good or
remission
– Non smoker, low DAS at initiation
If not, switch to MTX/IFX versus triple therapy
At 12 months:
– MTX/IFX 60% good EULAR versus 45% in
triple therapy
Bratt J: Presented at EULAR 2011; Presentation #SP0045.
Tight Control: SWEFOT
• At 12 months:
MTX/IFX 60% good EULAR versus 45% in 3 therapy
• At 24 months
MTX/IFX 43% good EULAR versus 33% in 3 therapy
Not good response at 12 months no change at 24 months
• X-ray changes in both but less in MTX/IFX
• Risk factors for poor response: High CRP and
erosions at baseline
• MTX responders at 3 months: at 24 months 80% in
remission but X-ray progression on Sharp score
Bratt J: Presented at EULAR 2011; Presentation #SP0045.
Tight Control: CAMERA
• Computer-assisted management in early
RA
• Two studies: 1 and 2
• CAMERA - 2
ERA – treated with MTX (119) or MTX with
prednisone (117)
Monthly visits
X-ray: primary outcome
DAS28, HAQ, Remission: secondary outcome
Bakker M: Presented at EULAR 2011; Presentation #OP0138.
Tight Control: CAMERA
• CAMERA 2 Results
61 MTX and 72 MTX/pred - remission
34 dropped out in MTX, 32 MTX/pred –A/E
Add adalimumab if not in remission at 3 months
Erosions less in MTX/Pred
• CAMERA 1: Conventional versus tight control
MTX is anchor drug
Computer calculated DAS scores for intense
group – DAS <3.2 was target
MTX switched to S.C at 3 months if not DAS not
<3.2
Bakker M: Presented at EULAR 2011; Presentation #OP0138.
Genomics, Genetics &
Epigenetics
Highlights of the EULAR Poster
Session held Thursday, May 26
Summarized by Dr. Wojciech Olszynski
14
5
Genomics in RA:
Key Points from Selected Posters
• Recent genome wide and candidate gene
association = identified >30 confirmed loci
susceptible to RA
• Role of HLA BRB1 early ?, impact on joint damage?
• RA CCP and RF + mainly (Japanese cohort 424)
• 20 found with single nucleotide polymorphism
(SNP) in relation to disease severity, genetic factor
of joint destruction?
• CD40 genetic risk factor for AID (SLE), part of TNF
receptor. CD40 expression and contribution to
aberrant and cellular response in SLE
Suzuki T, et al: Presented at EULAR 2011; Poster #THU0082.
Vazgiourakis V, et al: Presented at EULAR 2011; Poster #THU0084.
The Occurrence of Anti-citrullinated
Autoantibodies in RA Discordant Twin Pairs
• ACPA so far in diagnosis and prognosis – part
of pathogenesis as well?
• Testing mono and dizygotic twins (162 twins)
with RA self reported
• The presence of strongly positive CCP found in
monozygotic twins – genes are regulating the
presence of CCP
Svendsen AJ, et al: Presented at EULAR 2011; Poster #THU0083.
Genomics in OA and RA
• OA and phenotype definition ???
• Similarities of RA based on ACPA studies?
• Based on 3000 individuals. from Sweden, some
overlap between ACPA + and –
• Non major histocompatibility genetic factors
different in RA positive and negative ACPA
Panoutsopoulous K, et al: Presented at EULAR 2011; Poster #THU0085.
Källberg HJ, et al: Presented at EULAR 2011; Poster #THU0086.
Relation between Psoriatic Arthritis and
Psoriasis Vulgaris
• Using genome-wide association studies
(GWAS) many similarities found in Ps V and
those are not confirmed in PsA
• Need for further studies in PsA using GWAS?
Bowes J, et al: Presented at EULAR 2011; Poster #THU0088.
Epigenetic Regulation of
Inflammation
Highlights of the EULAR Basic
and Translational Science
Session held Thursday, May 26
Summarized by Dr. Wojciech Olszynski
15
0
Epigenetics of Inflammation: Key Points
• Bioenergy sensor Sirtiun 1 (Sirt 1) is an
genetic representation involved in
inflammatory checkpoint/expression in
leading to atherosclerosis, sepsis?
• In obesity, atherosclerosis, diabetes – Sirt1
is low what may predispose to chronic
proinflammatory state and sepsis
• Epigenetic modifications are fundamental
events in pathogenesis of RA (number of
processes responsible for pathogenesis)
McCall C: Presented at EULAR 2011; Presentation #SP0103.
Gay S: Presented at EULAR 2011; Presentation #SP0104.
Osteoporosis
Highlights of the EULAR Abstract
Session held Friday, May 27
Summarized by Dr. Wojciech Olszynski
15
2
Denosumab Discontinuation and Bone Remodelling
in Postmenopausal Women with Osteoporosis
• Denosumab effects are reversible after
discontinuation
• From previous studies, 15 patients evaluated
after 12-36 months (markers and biopsies)
• Histomorphic and biochemical data – confirmed
reversibility of denosumab effects
• Clinical implications ?
Brown J: Presented at EULAR 2011; Presentation #OP0197.
Role of RANKL in Osteoporosis
• New anti-RANKL antibody tested in phase I
(ALX-0141)1
Prolonged inhibitory effect after single, low
dose
Effect sustained after 120 days, plan to check
in 9 months
• Osteoprotegerin blocks RANKL-RANK activity2
Osteoprotegerin is reduced in first 5 years
after menopause
Potential role of osteoprotegerin in therapy
1. Van Bockstaele F: Presented at EULAR 2011; Presentation #OP0198.
2. Abaza N: Presented at EULAR 2011; Presentation #OP0202.
Prolonged Bisphosphonate Release After
Treatment in Women with Osteoporosis
• Urinary excretion of risedronate and
alendronate measured after discontinuation of
treatment
• Residual trace of alendronate was detected
much longer than after risedronate (up to 19
months for the first one)
• Clinical implications?
Peris P: Presented at EULAR 2011; Presentation #OP0200.
Strontium Ranelate for Postmenopausal
Osteoporosis
• Prolonged use of Strontium ranelate, not other
form !!!
• Data confirmed good bone strength based on
results from biopsies (microarchitecture) and
BMD
• Not available in Canada (mistakenly other forms
of strontium advised)
Felsenberg D: Presented at EULAR 2011; Presentation #OP0203.
Validity of Fracture Risk Instruments:
Systematic Review
• All instruments that have been used for fracture
risk assessment do not have enough sensitivity
and specificity
No proper validity, reliability and
responsiveness
• Clinical implications !!!
Martinez-Lopez JA: Presented at EULAR 2011; Presentation #OP0201.
Effect of Alcohol Consumption on Bone
Mineral Density
• Alcohol overuse (abuse) result in decreased
BMD
• Of ~500 pts tested, alcohol excess was
correlated with decreased BMD of the spine but
not at the femoral neck
• CaMos is showing up to 4 drinks for men and
two drinks for women – positive effect
• QUESTION – what is too much?
Thomas D: Presented at EULAR 2011; Presentation #OP0204.
Update in RA
Therapeutics
Highlights of Various EULAR
Sessions held Thursday & Friday,
May 26 and 27
Summarized by Dr. Anthony Russell
15
9
Spleen Tyrosine Kinase Inhibition in RA:
Fostamatinib
• Fostamatinib is an oral spleen tyrosine kinase
inhibitor (Syk)
T ½ = 13 hours
Efficacy previously demonstrated (phase II)
– Mean ACR 72% w/ 100 mg b.i.d (vs. 32% for
placebo)
– Significant difference vs. placebo at week 1
– Serum IL-6, MMP-3 fell by 1 week
Weinblatt ME: Presented at EULAR 2011 during Clinical Science Session:
Update in RA therapeutics: targeting intracellular signalling, Friday, May 27.
Spleen Tyrosine Kinase Inhibition in RA:
Fostamatinib Safety Observations
Adverse Event
of Interest
150 mg b.i.d.
100 mg b.i.d.
Placebo
Diarrhea
45%
16%
13%
Neutropenia
30%
10%
0
Increase in BP
6%
6%
0
• For patients experiencing adverse events on
fostamatinib 100 mg b.i.d., cutting the dose led
to their resolution
• No lipid effects reported
Weinblatt ME: Presented at EULAR 2011 during Clinical Science Session:
Update in RA therapeutics: targeting intracellular signalling, Friday, May 27.
JAK Inhibition with Tofacitinib:
Evidence from Phase II & III Trials
• Efficacy of tofacitinib in all reported trials to
date is significant vs. placebo (in 12-24 week
trials)
ACR 20: 58.7-70.5%
ACR 50: consistent 44% range
ACR 70: 24.6-30.7%
• Safety concerns:
Infections were more common vs. controls
Elevations of transaminase enzymes
Increases in LDL cholesterol
Kremer J, et al: Presented at EULAR 2011; Presentation #SP0117.
Oral JAK Inhibitor (Tofacitinib) for RA
• NB: Name changed from tasocitinib
Also known as CP-690,550
• T ½ = 3 hours
• Efficacy previously documented in RA with 5
mg and 10 mg b.i.d.
• New phase III study demonstrated efficacy on
patient-reported outcomes
Strand V, et al: Presented at EULAR 2011; Presentation #OP0063.
Interleukin (IL)-17B in RA
• IL-17 has 5 homologues
• Expression of IL-17B is seen in fibroblast-like
synoviocytes, induced by TNFα
IL-17B + TNF α = ↑ IL-6, etc.
Kouri V-P: Presented at EULAR 2011; Presentation #OP0218.
Interleukin (IL)-17A in RA
• Phase II RCT (n=237) of secukinumab in RA patients
Secukinumab 25, 75, 150 and 300 mg vs. placebo
(s.c. once monthly)
Primary outcome: ACR 20 at 16 weeks
ACR 20 (%)
25 mg
75 mg
150 mg
300 mg
Placebo
35%
45%
45%
54%
36%
By week 12, patients treated with 75, 150 and 300
mg achieved a clinically meaningful DAS28
reduction of >1.2 compared with those on placebo
Overall efficacy was greater among those with ↑
CRP at baseline
Genovese M, et al: Presented at EULAR 2011; Poster #FRI0380.
Effect of Abatacept on Circulating Dendritic
Cells
•
Study in 36 RA patients with inadequate response to TNF inhibitors
•
Treated with abatacept + MTX
•
Assessed by flow cytometry at 0, 3 and 6 months
Baseline
RA patients
Normals
T cells
1.11
2.16
CD4
0.54
1.0
CD8
0.27
0.54
T reg
0.033
0.051
M. Dendritic cells
6829
15003
P. Dendritic cells
4683
7605
All differences statistically significant except T reg
•
Plasmacytoid dendritic cells ↑ at 3 and 6 months with treatment
•
Tregs slightly decreased at month 3
•
No other significant changes
Shipley E, et al: Presented at EULAR 2011; Poster #FRI0353.
Abatacept + Traditional DMARDs Severely Impairs Humoral
Response to H1N1 Vaccination in RA Patients
• Investigators used "epidemic" H1N1
vaccination in RA patients and controls
• Seroconversion (response) was defined as;
Increase of AbT > 4x if prevaccine titer >10
AbT > 40 if prevaccination titers < 10
Seroconversion
Abatacept
(n=11)*
Methotrexate
(n=33)
Healthy controls
(n=33)
0%
19/33 (58%)
21/33 (64%)
*6 abatacept patients were also receiving MTX
Ribiero A, et al: Presented at EULAR 2011; Poster #FRI0342.
RA – Non-TNF Biologics
Highlights of the EULAR Abstract
Session held Thursday, May 26
Summarized by Dr. Janet Pope
16
8
Non-TNF Biologics: Session Overview
• Abatacept s.c. is equal to i.v., with very good response rates in
a large RCT (presented also at ACR)
• Many of the treatments studied are of modest benefit and not
ready for prime time (anti-BAFF, anti-lymphotoxin alpha, antiCD20 [ofatumumab])
• The efficacy of tocilizumab alone seems very favorable to
tocilizumab with MTX
• A second look at exact lipid profiles in TCZ
Tocilizumab may have overall favorable changes in lipid
profile
• Tocilizumab may be effective in amyloid secondary to RA (10
cases presented from Japan, rare in NA, Europe)
Abstract Session: RA – Non-TNF biologics. EULAR 2011; Thurs., May 26.
A Large, Phase IIIb Non-inferiority Trial
of Subcutaneous Abatacept Compared
with Intravenous Abatacept, in Patients
with Rheumatoid Arthritis
M Genovese1, A Covarrubias2, G Leon3, E Mysler4, M Keiserman5, R Valente6,
P Nash7, JA Simon Campos8, W Porawska9, J Box10, C Legerton11, E Nasanov12,
P Durez13, R Aranda14, R Pappu14, I Delaet14, J Teng14, R Alten15
1Stanford
University, Palo Alto, CA, US; 2Centro Medico De Las Americas, Merida, Yucatan, Mexico; 3Instituto De
Ginecologia Y Reproduccion, Lima, Peru; 4Organización Médica de Investigación, Buenos Aires, Argentina;
5Pontificial Catholic University, School of Medicine, Porto Alegre, Brazil; 6Physician Research Collaboration,
Lincoln, NE, US; 7University of Queensland, Brisbane, Australia; 8Centro De Especialidades Médicas, Merida,
Mexico; 9Poznanski Osrodek Medyczny ‘Novamed’, Poznan, Poland; 10The Arthritis Clinic & Carolina Bone & Joint,
Charlotte, NC, US; 11Low Country Rheumatology, Charleston, SC, US; 12Institute of Rheumatology, Moscow,
Russia; 13Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 14Bristol-Myers
Squibb Co., Princeton, NJ, US; 15Schlosspark-Klinik,Charité, University Medicine Berlin, Department of Internal
Medicine II, Rheumatology, Berlin, Germany
170
ACQUIRE Study Design
IV abatacept loading
dose (Day 1)
SC abatacept 125 mg/week plus MTX
(IV placebo)
n=736
Patients with
active RA and an
inadequate response to
MTX (≥3 months)
≥10 SJC, ≥12 TJC
and CRP ≥ 0.8 mg/dL
SC abatacept 125
mg/week plus MTX†
Randomization (1:1)
Stratification by body weight
n=721
IV abatacept ~10 mg/kg plus MTX
(SC placebo)
Day 1
Month 6
Primary endpoint: Non-inferiority of
SC versus IV abatacept by ACR 20
Other endpoints: Efficacy, safety
and immunogenicity
• SC injections administered on Day 1 (with IV loading dose) and weekly thereafter
• IV infusions administered on Day 1, 15 and 29, and monthly thereafter
†Patients
who completed Month 6 could continue into the long-term extension where all patients received SC abatacept 125
mg/week plus MTX (data not shown); SJC=swollen joint count; TJC=tender joint count
171
Baseline Demographics
ITT population
SC abatacept + IV abatacept
MTX
+ MTX
(n=736)
(n=721)
Age, years
PP population
SC abatacept IV abatacept +
+ MTX
MTX
(n=696)
(n=683)
49.9 (13.2)
50.1 (12.6)
49.9 (13.0)
49.9 (12.7)
Gender, % female
84.4
80.4
84.2
80.4
Race, % Caucasian
74.7
74.5
74.1
73.9
72.0 (18.0)
71.8 (17.6)
72.1 (18.1)
71.5 (17.5)
Quartile ≤59.4 kg, %
25.5
24.7
25.4
25.0
Quartile >59.4 to ≤69 kg,
24.5
27.0
24.4
27.2
24.9
24.3
24.7
24.5
25.1
24.0
25.4
23.3
Disease duration, years
7.6 (8.1)
7.7 (7.8)
7.6 (8.0)
7.7 (7.9)
Duration ≤2 years, %
32.6
30.7
32.9
30.2
Duration >2 to ≤5 years,
21.1
20.8
20.7
21.2
22.7
19.3
22.7
Weight, kg
%
Quartile >69 to ≤81.9 kg,
%
Quartile >81.9 kg, %
%
Duration
>5 to deviation,
≤10 years,
19.3
Data are
mean standard
unless otherwise
stated
172
ACR 20, 50 and 70 Responses
Over 6 Months
100
SC (n=693)
ACR 20
IV (n=678)
90
SC (n=693)
Proportion of patients with ACR
20, 50 or 70 response (%)
ACR 50
IV (n=678)
80
SC=76.0%
SC (n=693)
ACR 70
IV=75.8%
IV (n=678)
70
60
SC=51.5%
50
IV=50.3%
40
30
SC=26.4%
20
IV=25.1%
10
0
0.5
1
2
3
4
5
6
Month
Data exclude eight patients due to site non-compliance; PP population included all randomized and treated patients who
received at least one dose of study medication, excluding patients with a protocol deviation; Patients who discontinued were
considered non-responders; Error bars represent 95% CI
173
Overall Safety Summary
Event, n (%)
SC abatacept + MTX
IV abatacept + MTX
(n=736)
(n=721)
Deaths
2 (0.3)
5 (0.7)
SAEs
31 (4.2)
35 (4.9)
8 (1.1)
14 (1.9)
493 (67.0)
470 (65.2)
15 (2.0)
25 (3.5)
234 (31.8)
221 (30.7)
Serious infections
5 (0.7)
10 (1.4)
Malignancies
3 (0.4)
5 (0.7)
Autoimmune events
7 (1.0)
6 (0.8)
Discontinued due to SAEs
AEs
Discontinued due to AEs
Infections
•
Safety profiles were similar across the different weight quartiles (≤59.4
kg, >59.4 to ≤69 kg, >69 to ≤81.9 kg and >81.9)
Safety data are based on all patients who received at least one dose of abatacept and are reported up to 56 days post last
study dose; Deaths occurring >56 days post last study dose are also included
174
Subcutaneous Injection Site Reactions
Event, n (%)
SC abatacept
SC placebo*
(n=736)
(n=721)
19 (2.6)
18 (2.5)
Pruritus
6 (0.8)
1 (0.1)
Erythema
5 (0.7)
1 (0.1)
Hematoma
4 (0.5)
4 (0.6)
Rash
2 (0.3)
1 (0.1)
Pain
1 (0.1)
4 (0.6)
Papule
1 (0.1)
3 (0.4)
Reaction
1 (0.1)
3 (0.4)
Urticaria
0
2 (0.3)
4 (0.5)
0
Total patients with subcutaneous
injection site reactions
Other†
Patients in the SC abatacept group also received IV placebo and patients in the
IV abatacept group also received SC placebo
In the SC abatacept group, subcutaneous injection site reactions were mild in
intensity in 18 out of 19 patients; 1 patient reported moderate reaction
*Patients received IV abatacept; Data are based on all patients who received ≥1 dose of abatacept and are reported up to 56
days post last dose; Reactions were pre-specified; †Individual reactions not reported in more than one patient
175
Conclusions
The ACQUIRE trial has demonstrated that the
efficacy and safety of weekly fixed dosing of
SC abatacept, in patients with moderate-tosevere RA and an inadequate response to
MTX, is comparable to that of IV abatacept
Efficacy benefits were observed
irrespective of patient weight or disease
duration
176
A Phase 2 Study of Monthly Subcutaneous LY2127399 (An
Anti-BAFF Monoclonal Antibody) in Patients with Active RA
Wk24Not
Placebo
10mgmild30mg
60mg
120mg
totally impressive,
high1mg
placebo3mg
response,
reduction
in CRP
n=36
n=30
n=20
n=15
n=18
n=13
n=24
ACR20 Response (%)
44.4
40.0
45.0
46.7
61.1
53.8
70.8*
ACR50 Response (%)
22.2
10.0
10.0
33.3
11.1
7.7
37.5
ACR70 Response (%)
5.6
3.3
0.0
6.7
5.6
0.0
4.2
EULAR Response
(Good/Moderate) %
57.1
64.3
52.6
57.1
76.5
58.3
82.6*
Mean Change in DAS28 (n)
-1.448
(n=35)
-1.539
(n=28)
-1.026
(n=19)
-1.678
(n=14)
-1.536
(n=17)
-1.642
(n=12)
-1.915**
(n=23)
Median Change in CRP
-30.27
19.57
4.26
-13.82
-50.53
-44.23
-31.80
Median Change in ESR
-9.19
-28.68
-9.58
-4.76
-22.02
-34.38
-32.39
*p < 0.05 compared to placebo; **p < 0.05 compared to placebo
Genovese M: Presented at EULAR 2011; Presentation #OP0017.
Anti-Lymphotoxin-alpha Monoclonal Antibody: Results from a Phase I
Randomized, Placebo-controlled Clinical Trial in Patients with Active RA
Very small N, minimal change in DAS vs. placebo
Placebo
(n=7)
MLTA3698A
(n=16)
ACR20 (% patients)
57
75
ACR50 (% patients)
29
56
ACR70 (% patients)
0
25
0.82
1.22
8
28
DAS28-CRP (median reduction from
baseline)
CRP (median % decrease from
baseline)
Emu B: Presented at EULAR 2011; Presentation #OP0018.
Ofatumumab, A Fully Human Anti-CD20 MAb,
in the Treatment of Biologic-naive RA Patients
RF positive and negative seemed to have same response, 24 weeks, n=219
analyzed of 260 patients, modest ACR 20, rash and urticaria frequent
Placebo
Active anti-CD20
ACR 20
27
50
ACR 50
Not given
Not given
ACR 70
Not given
Not given
41
67
<1%
21%/16%
Moderate / Good EULAR Response
Rash/Urticaria
Taylor P: Presented at EULAR 2011; Presentation #OP0019.
Tocilizumab + MTX Does Not Have Superior Clinical Efficacy to
Tocilizumab Alone in RA Patients with Inadequate response to MTX
(ACT-RAY) Study
Randomized to D/C Mtx or continue
starting
TCZ
TCZwhen
8 mg/kg
+
TCZ8mg/kg,
8 mg/kgnon-inferiority
Endpoint
P
study, results at 24 weeks look very
similar
EXCEPT +for
more
in LDAS with MTX
MTX
(n=277)
PBO
(n=276)
DAS28 remission rate (DAS28
40.4 (112)
34.8 (96)
0.189
<2.6) , % (n)
LDAS, % (n) (DAS28 ≤3.2)
61.7 (171)
51.5 (142)
0.028
89.5 (248)
85.8 (237)
0.190
-11.3 (8.07)
-11.7 (9.46)
0.834
-17.2 (13.57)
-17.0 (13.63)
0.945
ACR 20, % (n)
71.8 (199)
70.7 (195)
0.862
ACR 50, % (n)
45.1 (125)
40.9 (113)
0.436
ACR 70, % (n)
24.9 (69)
25.7 (71)
0.679
ACR 90, % (n)
5.8 (16)
5.1 (14)
0.837
EULAR good or moderate
response, % (n)
SJC (mean change from
baseline [SD])
TJC (mean change from
baseline [SD])
Dougados M: Presented at EULAR 2011; Presentation #OP0020.
MEASURE: Effects of Tocilizumab on
Parameters of Lipids and Inflammation
• TCZ induced quantitative changes in lipoprotein
profiles, altered HDL composition, and reduced
the levels of inflammatory and prothrombotic
markers
• These changes may favor improved CV riskbenefit for RA patients treated with TCZ,
although clinical correlates will be required for
validation
McInnes I: Presented at EULAR 2011; Presentation #OP0021.
RA – Abstracts of Interest
Highlights of EULAR Abstract and
Poster Sessions held
Wednesday to Friday,
May 25 to 27
Summarized by Dr. Janet Pope
18
2
Lipids in ERA: Manchester Cohort –
Baseline Characteristics
Variables
Mean (SD) / N (%)
Age (years)
50.7 (19.7)
SBP (mmHg)
142 (22)
DBP (mmHg)
81 (10)
BMI (kg/m2)
26.7 (5)
CRP level (mg/L)
14.6 (20)
ACPA +
81 (27.4%)
RF +
115 (34.6%)
HAQ score
0.89 (0.7)
DAS 28
3.5 (1.2)
Females
223 (65.8%)
Smoker (current)
75 (23.9%)
Al-Husain AZ: Presented at EULAR 2011; Poster #THU0265.
Lipids in ERA: Manchester Cohort –
Conclusions
• In treatment-naive, early inflammatory arthritis
patients, lipid profile remains within normal
limits
• In contrast to other smaller studies, markers of
disease activity (CRP, DAS28) are negatively
associated with TG
• In patients with early arthritis, inflammation
mainly affects TG
• Detailed study of TG subtypes may provide
insight to how inflammation alters CVD risk in
RA
Al-Husain AZ: Presented at EULAR 2011; Poster #THU0265.
PREVALENCE OF REMISSION IN EARLY RA - A COMPARISON OF NEW
REMISSION CRITERIA TO ESTABLISHED CRITERIA
Obviously the proportion of ERA in remission will vary according to definition.
The CATCH data were used for this study.
DAS28 <2.6
DAS28 <2.0
SDAI
</=3.3
CDAI </=2.8
ACR/
EULAR
6 months
148 (45)
88 (27)
79 (24)
75 (23)
57 (17)
12 months
176 (53)
118 (36)
88 (27)
83 (25)
73 (22)
The new criteria from ACR/EULAR have the least in remission and the numbers
are closest to SDAI and CDAI remission at 12 months but not as many at 6
months. The agreement is modest.
Kuriya B, et al: Presented at EULAR 2011; Poster #SAT0405.
Does RF Status Affect Response to Infliximab?
Observational Cohort: RF negative status may be better
8
6
p < 0.05
p < 0.05
RA, RF+
4
RA, RF2
0
0
14
22
Weeks
Pozdnyakova E, et al: Presented at EULAR 2011; Poster #THU0228
54
Comparative Characteristics of the Answer (on EULAR) in
Groups with RF+ and RF- RA Against Therapy by Infliximab
Pozdnyakova E, et al: Presented at EULAR 2011; Poster #THU0228
Validation of Power Doppler
Ultrasound in RA Remission
Most but not all patients with low SDAI had no power doppler
Not sure what the power doppler + means in clinical remission
Absence of PD signal in 28 joints
Sensitivity
Specificity
LR +
LR -
SDAI ≤ 3.3
54
(41.8 – 65.7)
75.7
(59.9 – 86.3)
2.22
(1.20 – 4.09)
0.61
(0.44 – 083)
Boolean
based
61.9
(49.6 – 72.9)
67.6
(51.5 – 80.4)
1.91
(1.15 – 3.16)
0.56
(0.39 – 0.81)
Absence of PD signal in 42 joints
Sensitivity
Specificity
LR +
LR -
SDAI ≤ 3.3
56.1
(43.3 – 68.2)
74.4
(59.8 – 85.1)
2.19
(1.25 – 3.85)
0.59
(0.42 – 0.83)
Boolean
based
63.2
(50.2 – 75.5)
65.1
(50.2 – 77.6)
1.81
(1.15 – 2.85)
0.57
(0.38 – 0.84)
Bertoli AM, et al: Presented at EULAR 2011; Poster #FRI0057
Validation of Power Doppler
Ultrasound in RA Remission
Most but not all patients with low SDAI had no power doppler
Not sure what the power doppler + means in clinical remission
Bertoli AM, et al: Presented at EULAR 2011; Poster #FRI0057
Patterns of Drug Use in a Large US Database
(California Medicaid)
TNF inhibitors at 20%, Coxibs increased then decreased, steroids decreasing
Wong AL, et al: Presented at EULAR 2011; Poster #THU0310.
311, EULAR 2011
Patterns of Drug Use in a Large US
Database (California Medicaid)
Patients Characteristics
Variable
Age, mean (SD)
Female, n (%)
Predictors of RA Drugs Used
Value
Significant predictors
47.4 (11.2)
Age
5,269 (81.5)
Race
White
Race, n (%)
OR (95% CI)
0.99 (0.983 – 0.997)
1.0
White
2,359 (36.5)
Hispanic
0.64 (0.55 – 0.78)
Hispanic
2,156 (33.4)
Black
0.47 (0.35 – 0.63)
Black
784 (12.1)
Others
0.78 (0.64 – 0.96)
Others
1,164 (18.0)
Medi-Cal &
MediCare eligibility
1.20 (1.02 – 1.40)
# of RA drug fills*
2.66 (2.53 – 2.79)
Medi-Cal &
MediCare eligibility, n (%)
2,798 (43.3)
Comorbidities, mean (SD)
1.8 (2.0)
History of RA length
1.33 (1.11 – 1.60)
RA drug classes used, mean (SD)
2.6 (1.0)
# of comorbidities
0.90 (0.86 – 0.94)
Rheumatologist visits, mean (SD)
1.4 (7.7)
*Biologics & DMARDs
Wong AL, et al: Presented at EULAR 2011; Poster #THU0310.
Predictors of RA Medication Use
• Whites received more DMARDs
• Drug access (MediCAL)
• RA disease duration
• Fewer comorbidities
Wong AL, et al: Presented at EULAR 2011; Poster #THU0310.
Patterns of RA Medication Use: Conclusions
• Variations in RA med prescriptions
• TNFi use 20% and seemingly increasing
• Steroids and Coxibs decreasing
• Access issues still exist (insurance plan, by
race /ethnicity)
Wong AL, et al: Presented at EULAR 2011; Poster #THU0310.
Home Monitoring with Computerized RAPID-3
Home monitoring shows flares and improvements
Appeared feasible (Pilot of RA and AS patients)
Not sure of utility as you could ask a patient to call if flaring
Berthelot JM, et al: Presented at EULAR 2011; Poster #THU0349.
Late-breaking Abstracts
Highlights of the EULAR Abstract
Session held Friday, May 27
Summarized by Dr. Majed Khraishi
19
5
Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of
Autologous Tolerising Dendritic Cells Exposed to Citrullinated
Peptides (Rheumavax) in Patients with Rheumatoid Arthritis
• Background:
Bone marrow-derived dendritic cells modified
with the irreversible NF-kappaB inhibitor, Bay117082 (Bay-DCs), exposed to arthritogenic antigen,
transfer antigen-specific suppression of
inflammatory arthritis in mice, through induction
of regulatory T cells
Human peripheral blood (PB) monocyte-derived
DCs derived from healthy controls or RA patients
similarly modified with Bay suppress T cell
responses in vitro
Thomas R, et al: Presented at EULAR 2011; Presentation #LB0004.
Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of
Autologous Tolerising Dendritic Cells Exposed to Citrullinated
Peptides (Rheumavax) in Patients with Rheumatoid Arthritis
•
Objective:
•
•
To demonstrate that autologous PB DC immunotherapy can safely
modify the immune response to specific rheumatoid arthritis (RA)
autoantigens
Methods:
Phase I clinical trial of autologous Bay-DCs exposed to
citrullinated peptide antigens (known as Rheumavax) in HLA-DR
shared epitope (SE)+ anti-citrullinated peptide antibody (ACPA)+
RA patients
Early RA clinic: 11: 9:9 (PBO, 1m, 5M), 2-3 years duration, 1-3
DMARDs
Results
AEs were all grade 1
Only 2 patients did not respond
No flares in patients in remission
Thomas R, et al: Presented at EULAR 2011; Presentation #LB0004.
Tofacitinib (CP-690,550) in Combination with Traditional DMARDS:
Phase 3 Study in Patients with Active RA with Inadequate Response to
DMARDS
• Objective:
To compare efficacy and safety of tofacitinib vs placebo
(PBO) in pts with active RA with inadequate response to ≥1
DMARD
• Methods: 12-month study
Patient on non-biologic background DMARDs were
randomised (2:2:1) to tofacitinib 5 or 10 mg BID or PBO for
six months
At month 3 ‘non-responder’ PBO patients were advanced to
tofacitinib 5 or 10 mg BID
At month 6, remaining PBO patients were advanced to
tofacitinib
Primary endpoints: ACR20 and DAS28-4 (ESR) <2.6
responses at month 6; change in HAQ-DI at month 3
Kremer J, et al: Presented at EULAR 2011; Presentation #LB0005.
Tofacitinib (CP-690,550) in Combination with Traditional DMARDS:
Phase 3 Study in Patients with Active RA with Inadequate Response to
DMARDS
Efficacy
ACR20† (%)
N=777
ACR50† (%)
N=777
ACR70† (%)
N=777
∆HAQ-DI§
Mo 3
N=731
5 mg BID
52.7***
33.8***
13.2***
-0.46***
11.0**
-2.2***
10 mg BID
58.3***
36.6***
16.2***
-0.56***
14.8***
-2.5***
PBO
31.2
12.7
3.2
-0.21
2.7
-1.6
Months 0-3
DAS28-4
Mean ∆
†
(ESR) <2.6
DAS28-4
(%) N=680 (ESR)‡ N=438
Months 3-6
Months 0-6
Safety n (%)
AEs
SAEs
AEs
SAEs
D/C (AEs)
5 mg BID
166 (52.7)
9 (2.9)
121 (38.4)
5 (1.6)
13 (4.2)
10 mg BID
173 (54.4)
8 (2.5)
124 (39.0)
7 (2.2)
15 (4.7)
PBO
97 (61.0)
6 (3.8)
21 (25.9)
0
3 (1.9)
P→5
-
-
16 (42.1)
0
2 (2.5)§
P→10
-
-
18 (45.0)
0
3 (3.8)§
imputation; ‡Mixed-effect longitudinal linear model; §Months 3-6
**p<0.001, ***p<0.0001 vs PBO
Kremer J, et al: Presented at EULAR 2011; Presentation #LB0005.
†Non-responder
Relative Mortality in People with Rheumatoid Arthritis Treated
Alternatively with Etanercept or DMARDs: Long-term Data from a
Large, UK, Observational Cohort Study
•
Objective: To compare mortality in people treated with etanercept (ETN) with
those treated with DMARDs
•
Methods:
The British Society of Rheumatology Biologics Register provided
anonymous, observational data for this analysis, characterizing ETNtreated patients and a DMARD-treated reference group (DMARD-RG)
Patients are followed from baseline via consultant review and patient
survey at 6-month intervals for three years and then annually
Subjects were defined as those with potential for five years follow-up, and
a Disease Activity Score (DAS-28) >4.2
Cases were defined as those recruited to the ETN group
2 extreme, best and worst-case scenarios are reported
– Scenario 1 censored cases 3-months after ETN discontinuation
– Scenario 2 followed patients to the end of their recorded data in an
intention to treat (ITT) analysis
Emery P, et al: Presented at EULAR 2011; Presentation #LB0007.
Relative Mortality in People with Rheumatoid Arthritis Treated
Alternatively with Etanercept or DMARDs: Long-term Data from a
Large, UK, Observational Cohort Study
• Results:
3,431 people were treated with ETN (71.5%) and 1,365
(28.5%) treated with DMARDs
Total follow-up (based on ITT) was 14,194 years in the ETN
group (mean 4.1; median 4.9), and 5,583 years in the
DMARD-RG (mean 4.1; median 4.9)
There were significant differences in baseline
characteristics between the ETN and the DMARD-RG
– Mean age 55.4 versus 59.4, p<0.001
– Duration of RA 13.6 versus 9.6 years, p<0.001
– Mean HAQ 2.1 versus 1.7, p<0.001
– Mean DAS-28 6.7 versus 5.7, p<0.001)
Emery P, et al: Presented at EULAR 2011; Presentation #LB0007.
Relative Mortality in People with Rheumatoid Arthritis Treated
Alternatively with Etanercept or DMARDs: Long-term Data from a
Large, UK, Observational Cohort Study
• Results (Cont'd):
There were 186 deaths in the ETN group and 127 in the DMARD-RG
Crude mortality for the observed period was 13.1 deaths per 1,000
person years (PKPY) in the ETN group and 22.7 PKPY in the
DMARD-RG
Using the Cox models:
– Under scenario 1, HR = 0.64 (95%CI 0.46-0.90, p=0.009)
following adjustment for RA duration, gender, age, non-RA
drugs at baseline, smoking history, systolic blood pressure
(SBP) and baseline HAQ
– In scenario 2, HR = 0.77 (95%CI 0.56-1.05, p=0.094) following
adjustment for age, gender, smoking history, non-RA drugs at
baseline, SBP, BMI, baseline HAQ and baseline DAS-28
– The inclusion of time dependent variables did not substantially
affect the reported HRs
Emery P, et al: Presented at EULAR 2011; Presentation #LB0007.
Evaluation of Rilonacept for Prevention of Gout Flares During Initiation
of Uric Acid-Lowering Therapy: Results of a Phase 3, Randomized,
Double-blind, Placebo-controlled Global Trial
• Background:
Although attaining target serum levels is
critical to the long-term management of gout,
uric acid-lowering therapy (ULT) can elicit
gout attacks during the initial months of
therapy
• Objective:
To evaluate the efficacy and safety of
rilonacept (IL-1 Trap) for the prevention of
gout flares (GFs) during initiation of ULT with
allopurinol
Mitha E, et al: Presented at EULAR 2011; Presentation #LB0001.
Evaluation of Rilonacept for Prevention of Gout Flares During Initiation
of Uric Acid-Lowering Therapy: Results of a Phase 3, Randomized,
Double-blind, Placebo-controlled Global Trial
• Subjects: Adults with gout, serum uric acid levels ≥446
μmol/L, and self-reported history of ≥2 flares in the prior year
• Methods: 16-week trial
Patients were initiated on allopurinol 300 mg daily (lower
dose in those with renal dysfunction) with subsequent
titration to achieve serum uric acid levels <357 μmol/L
Patients were randomized to receive weekly subcutaneous
injections of placebo, rilonacept 80 mg, or rilonacept 160
mg with a double (loading) dose on Day 1
Flares were treated with NSAIDs and/or oral steroids while
continuing study treatments
Primary endpoint: Number of flares per patient
Safety and tolerability were also assessed
Mitha E, et al: Presented at EULAR 2011; Presentation #LB0001.
Evaluation of Rilonacept for Prevention of Gout Flares During Initiation
of Uric Acid-Lowering Therapy: Results of a Phase 3, Randomized,
Double-blind, Placebo-controlled Global Trial
• Results:
248 patients were randomized
Baseline characteristics were similar among groups: 93%
male, mean age 51 years
Placebo
(n=82)
Rilonacept
80 mg (n=82)
Rilonacept
160 mg (n=84)
Number of flares
101
29
28
Mean # of flares
1.23
0.35
0.34
# of patients with flares
46
21
28
Serious adverse events
5
4
3
Endpoint
Mitha E, et al: Presented at EULAR 2011; Presentation #LB0001.
Gout is an Independent Risk Factor for Acute
Myocardial Infarction in Young and Low-risk Patients
• Background:
A high risk of acute myocardial infarction
(AMI) in gout patients has been observed
There was a lack of evidence on the risk of
AMI in younger patients or those with low risk
profiles
• Objective:
To investigate the risk of AMI by comparing
rates of first admission for AMI among gout
and non-gout patients in a representative
sampling cohort of the general population in
Taiwan
Kuo C-F, et al: Presented at EULAR 2011; Presentation #LB0002.
Gout is an Independent Risk Factor for Acute
Myocardial Infarction in Young and Low-risk Patients
• Methods:
The primary data source was the Taiwan
National Health Insurance database
– Adults older than 20 years were included in
the cohort
– The cohort included 704,503 patients (men:
360,432; women: 344,071)
Multivariate Cox proportional hazards models
were used to evaluate the risk of AMI in gout
patients
Kuo C-F, et al: Presented at EULAR 2011; Presentation #LB0002.
Gout is an Independent Risk Factor for Acute Myocardial
Infarction in Young and Low-risk Patients
• Results:
26,556 (3.8%) patients received a gout
diagnosis and treatment during 1996-1999
– 70.3% (n=18,674) were men
– Mean age of patients was 42.7 years
• Gout patients were significantly older
than non-gout patients (55.4 vs. 42.0
years)
– Gout patients were significantly more likely
to have diabetes and hypertension, with
ORs of 4.94 and 7.55, respectively
Kuo C-F, et LB0002.
Gout is an Independent Risk Factor for Acute Myocardial
Infarction in Young and Low-risk Patients
• Results (Cont'd):
Total follow-up since January 2000: 5,622,532
patient-years
During this period, 3718 (gout, n=463; nongout, n=3255) patients were hospitalized due
to AMI, 299 (gout, n=35; non-gout, n=264) of
whom suffered a fatal event
The incidence of AMI was 2.20 and 0.60 per
1000 patient-years among gout and non-gout
patients, respectively (log-rank test, p<0.001).
Kuo C-F, et al: Presented at EULAR 2011; Presentation #LB0002.
Gout is an Independent Risk Factor for Acute Myocardial
Infarction in Young and Low-risk Patients
• Results (Cont'd):
After adjustment for age, sex, diabetes mellitus,
hypertension, coronary heart disease, stroke, and
end-stage renal disease, gout was associated
with all-AMI (hazard ratio [HR], 1.23) and non-fatal
AMI (HR, 1.26)
In patients without cardiovascular risk factors,
gout was associated with all-AMI (HR, 1.84); and
non-fatal AMI (HR, 1.80); after adjustment for age
and sex.
The HRs (95% CI) for AMI in patients aged 20–44,
45–59, and 60 years or older were 1.59 (1.12–2.24),
1.24 (1.08–1.41), and 1.11 (0.94–1.32), respectively
Kuo C-F, et al: Presented at EULAR 2011; Presentation #LB0002.
