Myositis Update:
Treatment, Autoantibodies and More
Rare Disease Visiting Professor Grand Rounds
Neurology/Neurosurgery
University of Kansas Medical Center
August 23, 2013
Chester V. Oddis, MD
Division of Rheumatology
and Clinical Immunology
University of Pittsburgh
Disclosures
Questcor: Advisory Board
Lecture Objectives
•
Discuss general myositis classification and
autoantibodies
•
Discuss autoimmune ILD in myositis syndromes
•
Review selected treatments and discuss newer
potential therapeutic options for myositis
Essentially none of the agents discussed today are
“approved” for use in myositis
Conventional Classification of Myositis
•
Adult polymyositis (PM)
•
Adult dermatomyositis (DM)
•
Juvenile myositis (DM >> PM)
•
Malignancy-associated myositis
•
Myositis in overlap with another
autoimmune disease
•
Inclusion body myositis (IBM)
Gottron Papules
Rashes of Dermatomyositis
Gottron Sign
Rashes of Dermatomyositis
Heliotrope Rash
Rashes of Dermatomyositis
Facial Rash
Conventional Classification of Myositis
•
Adult polymyositis (PM)
•
Adult dermatomyositis (DM)
•
Juvenile myositis (DM >> PM)
•
Malignancy-associated myositis
•
Myositis in overlap with another
autoimmune disease
•
Inclusion body myositis (IBM)
Polymyositis Mimics
Endocrine myopathies
•
hyper/hypothyroid
Drug or toxic myopathies
Metabolic myopathies
Mitochondrial myopathies
Muscular dystrophies
Infectious myositis
Neuropathies/neurologic syndromes
Paraneoplastic syndromes
Other connective tissue disorders
Miscellaneous
•
amyloid, sarcoid
Elevated Muscle Enzymes in the Absence of
Muscle Disease
•
Demographics

BM > BF > WM > WF

Racial variation in serum CK

Healthy asymptomatic blacks have higher serum CK
levels than whites or Hispanics
•
Exercise/Manual Labor
•
Idiopathic HyperCKemia
Johnston et al, JRSM, 1996
Prelle et al, J Neurol, 2002
We can classify pathologically
DM
IBM
PM
NM
IIM Serologic Classification
• “Myositis-specific” (MSA)
–
–
–
–
–
–
–
–
ARS (anti-synthetase)
Mi-2
CADM 140 (MDA-5)
SAE
MJ
P155/140 (TIF1-γ)
SRP
HMG CoA reductase (statin NM)
• Myositis-associated (MAA)
– anti-PM/Scl, Ku, U1/U2/U3RNP
• MSA/MAA negative
Myositis Autoantibody Subsets
Anti-Synthetases
PL-7
PL-12
EJ
Mi-2
Jo-1
TIF-1γ
PM/NM
SRP
HMGCR
SAE
MDA-5
PM-Scl
MJ
DM
Overlap
U1RNP
Ku
Classification of Myositis
•
Adult polymyositis
•
Adult dermatomyositis
–
Amyopathic DM (ADM)
•
Juvenile myositis (DM >> PM)
•
Malignancy-associated myositis
•
Myositis in overlap with another
autoimmune disease
•
Inclusion body myositis (IBM)
•
Necrotizing myopathy
–
Statin/anti-SRP
Clinically Amyopathic DM (CADM)
• A subset of DM patients with cutaneous
manifestations of DM for 6 months or longer
• No proximal muscle weakness
• May have elevated serum muscle enzymes,
mild EMG abnormalities/biopsy findings
CADM =
Amyopathic DM (ADM) + Hypomyopathic DM (HDM)
Malignancy and CADM
• Frequency of malignancy probably similar in
CADM and classic DM
– 41/291 (14%) in ADM review series (Gerami, 2006)
– 15% in classic DM (Sigurgeirsson, NEJM, 1992)
• Antibody positivity may not be “protective”
CADM and Lung Disease
• 19/197 (10%) ADM pts had ILD
– review of literature
• Challenge
– They may be missed if the rash of DM is
missed
Gerami, J Am Acad Dermatol, 2006
Myositis Autoantibody Subsets
PL-7
PL-12
EJ
Mi-2
Jo-1
TIF-1γ
PM/NM
SRP
HMGCR
SAE
MDA-5
PM-Scl
MJ
DM
Overlap
U1RNP
Ku
ADM
Anti-CADM-140
• Amyopathic DM with rapidly progressive ILD in
Japanese (Sato, Arth Rheum, 2005 and 2009)
• Acute/subacute interstitial pneumonitis in DM in
Chinese (Chen, Rheum Int, 2011)
• Also described in other Asian populations with
similar phenotype
• Target autoantigen is MDA-5. What is MDA-5?
– Involved in innate immune defense against viruses
Supports role of a viral trigger
Anti-CADM-140
• Novel cutaneous phenotype of palmar papules
and cutaneous ulcerations – severe vasculopathy
• Rapidly progressive ILD
Fiorentino, J Am Acad Derm, 2011
Case One
•
•
•
•
•
•
70 year old WM
“Double pneumonia” in 6/2012
Rash of DM in 9/2012
Vasculitic skin changes in 1/2013
No muscle weakness
Cytoxan for ILD
Case Two
• Pt referred for “Amyopathic DM”
• 44 yo WF with mild Gottron’s rash and
periungual changes
• Normal muscle enzymes (LDH 256)
• Subtle iliopsoas weakness at 4+/5
• “Borderline” myopathic changes in deltoid
Percutaneous needle muscle biopsy
Case Two: Teaching Points
• Careful physical examination is important

no subjective symptoms, nl CK, essentially nl EMG
• Normal-CK, active myositis occurs!


particularly dermatomyositis (juvenile and adult)
other enzymes may also be normal
• Muscle biopsy still helpful
Case Three
•
41 y.o. white male with HTN, dyslipidemia
•
3/20: periorbital edema
•
3/27: acute polyarthritis
•
4/7: dyspnea, fever
•
4/11: admitted to outside hospital with bilateral pulmonary infiltrates
•
4/26: worsening dyspnea; unresponsive to antibiotics and steroids and
transferred to UPMC
•
4/27: Post bronchoscopy and BAL/biopsy; dyspneic male with no
history of muscle or lung problems; O2 saturation 90% (100% O2
mask/nasal cannula)

ROS: no Raynauds, mild joint pain

Exam: drug rash but no heliotrope or Gottron’s sign; diffuse rales;
no synovitis; normal muscle strength
Labs: CK 657; ANA negative; other labs essentially normal

Anti-synthetase
Syndrome
• Defines a clinically
homogeneous patient
population
–
–
–
–
–
–
Fever
Myositis
Arthritis (misdx as RA)
Raynaud phenomenon
Mechanic’s hands
ILD
Myositis Autoantibody Subsets
Anti-synthetases
PL-7
PL-12
EJ
Mi-2
Jo-1
TIF-1γ
PM/NM
SRP
HMGCR
SAE
MDA-5
PM-Scl
MJ
DM
Overlap
U1RNP
Ku
Anti-synthetase Autoantibodies
Antibody
Jo-1
PL-7
PL-12
OJ
EJ
KS
Tyr
Zo
Antigen
(tRNA synthetase)
Prevalence in
IIM (%)
histidyl
threonyl
alanyl
isoleucyl
glycyl
asparaginyl
tyrosyl
phenylalanyl
20-30
<5
<5
<5
<5
<1
<1
<1
Myositis-Associated ILD
• 30-40% IIM patients have ILD
– most commonly involved extramuscular organ
• Significant contribution to morbidity/mortality
Strong association of ILD with all
anti-synthetase autoAbs
Making the Diagnosis of Autoimmune ILD?
Not everyone will present with
the classic anti-synthetase
syndrome
Making the Diagnosis of Autoimmune ILD?
• Recognize ‘incomplete’ clinical syndromes

ILD alone or ILD with subtle CTD findings
University of Pittsburgh
Anti-synthetase Cohort
Autoantibody
Jo-1
PL-12
PL-7
EJ
OJ
KS
Total Synthetases
Number (% synthetases)
140 (60%)
36 (16%)
27 (12%)
11 (5)
6 (3)
9 (4)
229
University of Pittsburgh
Anti-synthetase Cohort
Autoantibody
Jo-1
PL-12
PL-7
EJ
OJ
KS
Total Synthetases
Number (% synthetases)
140 (60%)
36 (16%)
27 (12%)
11 (5)
6 (3)
9 (4)
229
Initial CTD Symptom in Anti-syn Cohort
Rash
Fatigue Fever
2% 4%
Raynaud’s 4%
7%*
Fever
Fatigue 4%
3%
Muscle
30%*
Pulmonary
22%
Rash
4%
Muscle
14%*
Joint
13%*
Raynaud’s
25%*
Joint
27%*
Pulmonary
29%
* p<0.02
Jo-1
(n=122)
Other Anti-synthetases
(n=80)
- Raynaud’s more common as initial symptom in non-Jo-1 subset
- Muscle and joint less frequent initial symptom in non-Jo-1 subset
Aggarwal, Ann RD, 2013
Jo-1 vs. Other Synthetases: Clinical Presentation
Mean Age
at
%
%
Symptom
Female Caucasian
Onset
(yrs)
Diagnoses at First Visit
(%)
Myositis
Overlap
or UCTD
SSc
Median
Delay in Dx
from 1st
CTD
Symptom
(years; IQR)
Jo-1
(n=122)
45
67
86
83
17
0
0.4
(0.2-0.8)
non-Jo-1
(n=80)
46
70
79
40
48
13
1.0
(0.4-5.1)
p value
NS
NS
NS
p<0.001
p<0.001
• In 60% of cases, non-Jo-1 pts did NOT have a myositis Dx at their initial visit
• Non-Jo-1 patients had a longer delay in Dx than Jo-1 patients
Aggarwal, Ann RD, 2013
Cause of Death in Anti-synthetase Cohort
Atherosclerosis
9%
Unknown
6%
Infection
6%
Pulmonary
fibrosis
49%
Cancer
9%
CTD
kidney
3%
CTD heart
5%
Pulmonary
HTN
11%
- In synthetase (+) pts pulmonary disease was most common cause of death
Aggarwal, Ann RD, 2013
Jo-1 vs. Other Anti-synthetases: Outcome
Pulmonary Cause of
Death
Cumulative Survival
%
Fibrosis
PAH
5 year
10 year
Jo-1
(n=122)
16/36
3/36
90
70
15
non-Jo-1
(n=80)
16/30
4/30
75
47
9
p value
NS
p<0.005
Median
Survival
(yrs)
p<0.01
• Pulmonary cause of death was similar between groups
• Non-Jo-1 pts had decreased survival compared to Jo-1 pts
Aggarwal, Ann RD, 2013
Making the Diagnosis of Autoimmune ILD?
• Recognize ‘incomplete’ clinical syndromes

ILD alone or ILD with subtle CTD findings
• ‘Myositis-specific Abs’ in the absence of
myositis
Making the Diagnosis of Autoimmune ILD?
• Recognize ‘incomplete’ clinical syndromes

ILD alone or ILD with subtle CTD findings
• ‘Myositis-specific Abs’ in the absence of
myositis
• Negative ANA
Case Three
•
41 y.o. white male with HTN, dyslipidemia
•
3/20: periorbital edema
•
3/27: acute polyarthritis
•
4/7: dyspnea, fever
•
4/11: admitted to outside hospital with bilateral pulmonary infiltrates
•
4/26: worsening dyspnea; unresponsive to antibiotics and steroids and
transferred to UPMC
•
4/27: Post bronchoscopy and BAL/biopsy; dyspneic male with no
history of muscle or lung problems; O2 saturation 90% (100% O2
mask/nasal cannula)

ROS: no Raynauds, mild joint pain

Exam: drug rash but no heliotrope or Gottron’s sign; diffuse rales;
no synovitis; normal muscle strength
Labs: CK 657; ANA negative; other labs essentially normal

Anti-Jo-1 Autoantibody
•
•
Directed against
histidyl-tRNA
synthetase
histidine
his tRNA syn
Ag
Ag: enzyme that
catalyzes binding of
an amino acid to its
tRNA in process of
protein synthesis
tRNA for histidine
A Negative ANA Does Not Imply
Antibody Negativity
Homogeneous, diffuse
cytoplasmic staining
Dimitri, Muscle and Nerve, 2007
Frequency of ANA and Cytoplasmic Staining in
Anti-synthetase Patients
Anti-Syn
patients
ANA +
Anti-CytAb +
p value
100/199 (50%)
142/196 (72%)
p < 0.001
Aggarwal, ACR 2010
Frequency of ANA and Cytoplasmic Staining in
Anti-synthetase Patients
Anti-Syn
patients
All Jo-1
All non-Jo-1
ANA +
Anti-CytAb +
p value
100/199 (50%)
142/196 (72%)
p < 0.001
62/119 (52%)
77/116 (66%)
p = 0.026
38/80 (48%)
65/80 (81%)
p < 0.001
Aggarwal, ACR 2010
Frequency of ANA and Cytoplasmic Staining in
Anti-synthetase Patients
Anti-Syn
patients
All Jo-1
All non-Jo-1
SSc
ANA +
Anti-CytAb +
p value
100/199 (50%)
142/196 (72%)
p < 0.001
62/119 (52%)
77/116 (66%)
p = 0.026
38/80 (48%)
65/80 (81%)
p < 0.001
1935/1946 (99%)
180/1946 (9%)
Aggarwal, ACR 2010
How Can You Miss Autoimmune ILD?
• Failure to recognize ‘incomplete’ clinical
syndromes
• ‘Myositis-specific Abs’ in the absence of
myositis aren’t ordered or not detected
• Reassured by the negative ANA
Myositis Autoantibodies
Antibody
Target
Subset
Phenotype
CADM-140
MDA-5
DM
Amyopathic, ILD
Jo-1
Other anti-Syn
ARS
PM/DM
Anti-synthetase syndrome
Mi-2
NuRD
DM
Shawl, V-neck, Gottron’s
Myositis Autoantibodies
Antibody
Target
Subset
Phenotype
CADM-140
MDA-5
DM
Amyopathic, ILD
Jo-1
Other anti-Syn
ARS
PM/DM
Anti-synthetase syndrome
Mi-2
NuRD
DM
Shawl, V-neck, Gottron’s
SAE
SUMO
DM
ILD, dysphagia
MJ
NXP-2
JDM
Calcinosis, ulceration
p155/140
TIF1-g
DM, JDM
Severe skin, malignancy
SRP
Signal
recognition
particle
72, 54 kDa
200/100 kD
HMGCR
PM
IMNM
Severe/refractory
necrotizing myositis
Necrotizing myopathy
Myositis Treatment:
Beyond Steroids, Methotrexate
and Azathioprine
Pharmacologic Therapy of IIM
•
•
•
•
•
Corticosteroids
Immunosuppressive Agents
Combination regimens
IVIg
Biologic agents
Corticosteroids in Myositis
•
Empirically remain initial treatment of choice
•
Begin divided dose prednisone at 60 mg daily
(30 mg bid)
•
Continue until serum CK falls to normal
•
Consolidate to single morning dose
•
Taper by 25% existing dose q 3-4 weeks to 5-10 mg
daily maintenance dose
•
Continue until active disease suppressed one year
•
Improvement in strength lags behind CK improvement
Pharmacologic Therapy of IIM
•
•
•
•
•
Corticosteroids
Immunosuppressive Agents
Combination regimens
IVIg
Biologic agents
Aggarwal/Oddis, Curr Rheum Rep, 2011
Pharmacologic Therapy of IIM
•
•
•
•
•
Corticosteroids
Immunosuppressive Agents
Combination regimens
IVIg
Biologic agents
Combination Therapy in Myositis
•
Multiple reports of combination therapy in
treatment of refractory PM and DM
•
Literature support for combination of
methotrexate and azathioprine in IIM
[Villalba, Arthritis Rheum, 1998]
–
effective in treatment-resistant myositis
–
beneficial in those who had failed either mtx or
aza alone
IS Agents Beyond Mtx and Aza…
•
Mycophenolate mofetil
Mycophenolate Mofetil in Myositis
•
6 of 10 patients with DM successfully tapered CS with MMF
[Rowin, Neurology, 2006]
–
•
3 developed opportunistic infections (other risk factors)
Improvement in cutaneous features in 10/12 DM patients
[Edge, Arch Derm, 2006]
•
IVIg as add-on therapy to MMF effective in 7 severe and
refractory pts (4PM/3DM) [Danielli, Autoimmunity Rev, 2009]
–
•
Safe and steroid-sparing
Retrospective review of 50 JDM pts using MMF for 12
months [Rouster-Stevens, Arth Care Rsch, 2010]
–
Improved skin and muscle and steroid-sparing; well-tolerated
IS Agents Beyond Mtx and Aza…
•
Mycophenolate mofetil
•
Cyclosporine/tacrolimus
•
Cyclophosphamide
Treatment of ILD in Myositis Patients
•
Corticosteroids remain the initial treatment
•
Cyclophosphamide and azathioprine used early
or in CS resistant cases with variable results

•
Intermittent IV ctx pulse
[Okada, Mod Rheumatol, 2007]
MMF in CTD-associated ILD
[Swigris, Chest, 2006;
Fischer, J Rheum, 2013]
•
Cyclosporine and tacrolimus used in both adult
and pediatric patients with promising results
Tacrolimus in Myositis and ILD
Parameter
FVC
FEV-1
DLCO
CK
MMT
CS Dose
p-value
<0.0001
<0.0001
0.0046
<0.0001
0.06
<0.0001
Retrospective study of 13 synthetase (+) pts
(12 with Jo-1)
Wilkes, Arth Rheum, 2005
Is Anti-T cell Therapy Rational
in Myositis-associated ILD?
T cells as Therapeutic Targets in MyositisAssociated ILD
•
Pathology: abundant lymphocytes and plasma cells in
the lung of PM/DM pts (form lymphoid follicles)
•
Infiltrating lymphocytes in myositis NSIP pts revealed
“activated” CD8+ T-cells [Yamadori, Rheumatol Int, 2001]
•
CD8+ and “activated” T-cells increased in BAL fluid of
PM/DM pts (n=22) [Kurasawa, Clin Exp Immunol, 2002]
•
Decrease in regulatory T cells in IP of CTD-ILD [Katigiri,
Mod Rheumatol, 2008]
Implicates activated CD8+ T-cells in myositis-associated ILD
Anti-T cell Therapy in Myositis-associated ILD
• Accumulating data on efficacy of tacrolimus/CsA
– Wilkes, Arth Rheum, 2005
– Takada, Autoimmunity, 2005
– Takada, Mod Rheumatol, 2007
– Guglielmo, Eur Respir J, 2009
 ARDS reversed with tacrolimus
– Ando, Clin Rheumatol, 2010
 ADM pt refractory to CsA responded to tacrolimus
A
Abatacept should also be studied in AILD
Pharmacologic Therapy of IIM
•
•
•
•
•
Corticosteroids
Immunosuppressive Agents
Combination regimens
IVIg
Biologic agents
IVIg in Myositis
• Randomized, double-blind, placebocontrolled study of 15 treatment-resistant
DM patients demonstrated efficacy [Dalakas,
NEJM, 1993]
– No significant side effects; felt to be safe and
effective for refractory DM
IVIg in Myositis
• Literature review of 308
adult patients
– 14 articles
– only 2 RCT
• Safe with tolerable
adverse events
• Steroid-sparing in
setting of infection
• Effective in esophageal
involvement
• “Acute” complications
or rapidly progressive
disease
• Effective for refractory
rash
Wang, Clin Rheumatol, 2012
Pharmacologic Therapy of IIM
•
•
•
•
•
Corticosteroids
Immunosuppressive Agents
Combination regimens
IVIg
Biologic agents
Biologic Targets
• TNF – alpha
Anti-TNF-α Therapy in Myositis
•
TNF-α and other proinflammatory
cytokines are increased in muscle tissue of
myositis patients [Lundberg, RDCNA, 2002]
•
TNF-α is toxic to myofibers and prevents
their regeneration
•
TNF-α enhances other inflammatory
cytokines in DM and PM
A Randomized, Pilot Study of
Etanercept in Dermatomyositis
Anthony A. Amato, M.D.
Brigham and Women’s Hospital
Harvard Medical School
&
THE MUSCLE STUDY GROUP
Amato, Ann Neurol, 2011
Biologic Targets
• TNF – alpha
• B cell
Rituximab in Myositis
• Open label study uncontrolled pilot trial in 7 adult refractory
DM pts
– Levine, Arth Rheum, 2005
• Effective in antisynthetase syndrome
– Brulhart, Ann Rheum Dis, 2006
– Sem, Rheumatol, 2009
• Effective in refractory myositis and DM rash (some
longstanding remission)
– Mok, J Rheumatol, 2007
– Dinh, J Am Acad Derm, 2007
• Ineffective for DM rash
– Chung, Arch Dermatol, 2007
Rituximab in Myositis
Rituximab in the Treatment of Refractory Adult and
Juvenile Dermatomyositis and Adult Polymyositis
Chester V. Oddis, MD
Ann M. Reed, MD
and the RIM Study Group
Participating Centers
Adult Sites
 Alabama (Fessler)
 Boston (Narayanaswami)
 Cedars Sinai (Venuturupalli/Weisman)
 Czech Republic (Vencovsky)
 Dallas (Olsen)
 Kansas City (Barohn/Latinis)
 Kentucky (Crofford)
 London (Isenberg)
 Mayo Clinic (Ytterberg)
 Miami (Sharma)
 Michigan (Seibold/Schiopu)
 Michigan State (Martin/Eggebeen)
 Milwaukee (Cronin)
 New York: North Shore (Marder)
 New York: HSS (DiMartino)
 NIH (Miller)
 Philadelphia (Kolasinski)
 Phoenix (Levine)
 Pittsburgh (Oddis/Ascherman)
 Stanford (Chung/Fiorentino)
 Sweden (Lundberg)
Pediatric Sites
 Boston (Kim)
 Cincinnati (Lovell)
 Duke (Rabinovich)
 Mayo Clinic (Reed)
 Miami (Rivas-Chacon)
 Michigan State (Martin/Eggebeen)
 NIH (Rider)
 Nova Scotia (Huber)
 Philadelphia (Sherry)
 Pittsburgh (Kietz)
 Stanford (Sandborg)
 Toronto (Feldman)
RIM Trial Summary
• Primary and secondary endpoints were not
achieved
• 83% of refractory adult and juvenile myositis
patients met the Definition of Improvement in this
trial
• There was a significant corticosteroid sparing
effect noted in this trial between the baseline dose
and the dose at study conclusion
• Rituximab was generally well tolerated
Biologic Targets
• TNF – alpha
• B cell
• Other
– Interleukin – 6
– Type 1 IFN
IL-6 Blockade in Murine Model of PM
• IL-6 critically involved in development of
myositis and muscles expressed IL-6
• Treatment with tocilizumab was effective in
amelioration of myositis
• IL-6 blockade is potential new approach to
treatment of myositis
• Anti-IL-6 effective/approved for RA
Okiyama, Arth Rheum, 2009
Microarrays of DM and Normal Muscle
•
Cluster of genes known
to be induced by IFNα/β
–
DM: genes were highly
over-expressed
compared to controls
Greenberg, Ann Neurol, 2005
Gene expression: Red: high; black: intermed; green: low
DM patients
Type I IFN Gene Expression
in DM
• Results essentially duplicated with
blood IFN signature correlating
with disease activity
• Also, multiplex ELISAs
demonstrate increased levels of
IFN-regulated chemokines that
also correlated with disease
activity
 IP-10, MCP-1, MCP-2
IFN signature, IFN-related cytokines
both correlated with disease activity
Baechler, Mol Med, 2007
Type I IFN Genes, Chemokines and IL-6 in DM
• Blood IFN gene expression, ELISA-based IFN-regulated
chemokines and IL-6 in adult DM and JDM (n=56 pts)
Bilgic, Arth Rheum, 2009
Type I IFN Genes, Chemokines and IL-6 in DM
• Blood IFN gene expression, ELISA-based IFN-regulated
chemokines and IL-6 in adult DM and JDM (n=56 pts)
• Elevated levels of IL-6 and type I IFN–regulated
transcripts and proteins in blood of adult DM and JDM
Bilgic, Arth Rheum, 2009
Type I IFN Genes, Chemokines and IL-6 in DM
• Blood IFN gene expression, ELISA-based IFN-regulated
chemokines and IL-6 in adult DM and JDM (n=56 pts)
• Elevated levels of IL-6 and type I IFN–regulated
transcripts and proteins in blood of adult DM and JDM
• IFN gene/protein signatures and serum IL-6 levels
correlated with DM disease activity and with each other
Bilgic, Arth Rheum, 2009
Type I IFN Genes, Chemokines and IL-6 in DM
• Blood IFN gene expression, ELISA-based IFN-regulated
chemokines and IL-6 in adult DM and JDM (n=56 pts)
• Elevated levels of IL-6 and type I IFN–regulated
transcripts and proteins in blood of adult DM and JDM
• IFN gene/protein signatures and serum IL-6 levels
correlated with DM disease activity and with each other
• Suggests that coordinated dysregulation of type I IFN
signaling and IL-6 production may contribute to DM
pathogenesis
Bilgic, Arth Rheum, 2009
Summary
• Myositis is heterogeneous and autoAbs help
in classification and treatment
• Lung disease is a critical prognostic
determinant
• Exciting time for therapeutic intervention in
myositis
– Temper our enthusiasm with a respect for all of
these novel agents and their short and longterm side effects
RIM Study: Trial Design
“Randomized Placebo Phase”
Wks 0/1
Screen
Rituximab
Wks 8/9
Placebo
Weeks 12 – 44
Monthly Assessments
Rtx Early
Rtx Late
Placebo
Rituximab
• 200 myositis patients: 76 adult polymyositis (PM), 76 adult
dermatomyositis (DM) and 48 Juvenile dermatomyositis (JDM) patients
• Subjects randomly assigned, double-blind, to ‘Rtx Early’ or ‘Rtx Late’
• Patients were followed for 44 weeks
• Myositis Core Set Measures (CSM) were assessed monthly
Oddis, Arthritis Rheum, 2013
Primary Endpoint and Hypothesis
•
Primary Endpoint: Compare the time to DOI
between the ‘Rtx Early’ and ‘Rtx Late’ groups
•
Hypothesis: The time to DOI will be statistically
less (shorter) in early vs. late treatment groups
B cell Numbers Before and After Rituximab
Early Rtx
Late Rtx
Primary Outcome: Entire Cohort
Median time to DOI:
Early Rtx = 20.0 weeks
Late Rtx = 20.2 weeks
p = 0.74 (log rank)
Primary Outcome: JDM
Median time to DOI:
Early Rtx = 11.7 weeks
Late Rtx = 19.6 weeks
p = 0.32 (log rank)
Patients Meeting DOI During Trial
100%
80%
60%
40%
20%
0%
Early Rtx
Late Rtx
80%
85%
Overall, 83% (161/195) of subjects met the DOI
during the course of the 44-week clinical trial
Corticosteroid Sparing Effect
Mean Total Daily Dose (mg)
25
p < 0.001
20
21
15
13.8
10
5
0
wk 0
wk 44
Timepoint
There was a significant difference in the mean
corticosteroid dose at baseline compared to the final visit
Kaplan Meier: Myositis Autoantibody Subsets
Probability of Not Meeting DOI
MAA = myositis associated antibody
Future Directions: Anti-Jo-1 as Biomarker
Rho = - 0.68
Median MMT
Median Jo-1 Levels
Jo-1 levels decreased after rituximab and
strongly correlated with disease activity
600
500
400
300
200
100
0
8
16
24
32
40
Weeks from rituximab
Median Rho = 0.68
95
90
85
80
75
300
400
500
600
700
Median Jo1
Abstract #750, ACR 2012