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, MDDivision of Rheumatology and Clinical ImmunologyUniversity 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
Heliotrope Rash
Rashes of Dermatomyositis
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)
Endocrine myopathies• hyper/hypothyroid
Drug or toxic myopathiesMetabolic myopathiesMitochondrial myopathies Muscular dystrophiesInfectious myositisNeuropathies/neurologic syndromesParaneoplastic syndromesOther connective tissue disordersMiscellaneous
• amyloid, sarcoid
Polymyositis Mimics
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
PM
IBM
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
DM
Overlap
SRP
U1RNP
PM-Scl
Ku
Mi-2
MJ
PL-12
Jo-1
PL-7
PM/NM
EJ
TIF-1γ
HMGCR
MDA-5
SAE
Anti-Synthetases
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
DM
Overlap
SRP
U1RNP
PM-Scl
Ku
Mi-2
MJ
PL-12
Jo-1
PL-7
PM/NM
EJ
TIF-1γ
HMGCR
MDA-5
SAE 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
• 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 One
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
DM
Overlap
SRP
U1RNP
PM-Scl
Ku
Mi-2
MJ
PL-12
Jo-1
PL-7
PM/NM
EJ
TIF-1γ
Anti-synthetases
HMGCR
MDA-5
SAE
Anti-synthetase Autoantibodies
Antibody Antigen (tRNA synthetase)
Prevalence in IIM (%)
Jo-1
histidyl
20-30
PL-7 threonyl <5 PL-12 alanyl <5
OJ isoleucyl <5 EJ glycyl <5 KS asparaginyl <1 Tyr tyrosyl <1 Zo phenylalanyl < 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 Number (% synthetases)
Jo-1 140 (60%)
PL-12 36 (16%)
PL-7 27 (12%)
EJ 11 (5)
OJ 6 (3)
KS 9 (4)
Total Synthetases 229
University of Pittsburgh Anti-synthetase Cohort
Autoantibody Number (% synthetases)
Jo-1 140 (60%)
PL-12 36 (16%)
PL-7 27 (12%)
EJ 11 (5)
OJ 6 (3)
KS 9 (4)
Total Synthetases 229
Muscle 30%*
Joint 27%*
Pul-monary
22%
Ray-naud’s
7%*
Fatigue 4%
Fever 2% Rash
4%Muscle 14%* Joint
13%*
Pulmonary 29%
Ray-naud’s 25%*
Fatigue 3%
Fever 4% Rash
4%
Initial CTD Symptom in Anti-syn Cohort
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
* p<0.02
Aggarwal, Ann RD, 2013
Mean Age at
Symptom Onset (yrs)
% Female
% Caucasian
Diagnoses at First Visit(%) Median
Delay in Dx from 1st
CTD Symptom
(years; IQR)Myositis Overlap
or UCTD SSc
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
Jo-1 vs. Other Synthetases: Clinical Presentation
Aggarwal, Ann RD, 2013
Pul-monary fibrosis
49%
Pulmonary HTN11%
CTD heart 5%
CTD kidney 3%
Cancer9%
Infection6%
Athero-sclerosis
9%
Unknown6%
Cause of Death in Anti-synthetase Cohort
- In synthetase (+) pts pulmonary disease was most common cause of death
Aggarwal, Ann RD, 2013
Pulmonary Cause of Death
Cumulative Survival% Median
Survival (yrs)
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 p<0.01
• Pulmonary cause of death was similar between groups• Non-Jo-1 pts had decreased survival compared to Jo-1 pts
Jo-1 vs. Other Anti-synthetases: Outcome
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
• Ag: enzyme that catalyzes binding of an amino acid to its tRNA in process of protein synthesis tRNA for
histidine
histidine
his tRNA syn
Ag
A Negative ANA Does Not Imply Antibody Negativity
Dimitri, Muscle and Nerve, 2007
Homogeneous, diffuse cytoplasmic staining
ANA + Anti-CytAb + p value
Anti-Syn patients
100/199 (50%) 142/196 (72%)
p < 0.001
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients
Aggarwal, ACR 2010
ANA + Anti-CytAb + p value
Anti-Syn patients
100/199 (50%) 142/196 (72%)
p < 0.001
All Jo-1 62/119 (52%) 77/116 (66%) p = 0.026
All non-Jo-1 38/80 (48%) 65/80 (81%) p < 0.001
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients
Aggarwal, ACR 2010
ANA + Anti-CytAb + p value
Anti-Syn patients
100/199 (50%) 142/196 (72%)
p < 0.001
All Jo-1 62/119 (52%) 77/116 (66%) p = 0.026
All non-Jo-1 38/80 (48%) 65/80 (81%) p < 0.001
SSc 1935/1946 (99%) 180/1946 (9%)
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients
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
Antibody Target Subset Phenotype
CADM-140 MDA-5 DM Amyopathic, ILD
Jo-1Other 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-1Other 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 particle72, 54 kDa
PMSevere/refractory
necrotizing myositis
200/100 kD HMGCR IMNM Necrotizing myopathy
Myositis Autoantibodies
Myositis Treatment:
Beyond Steroids, Methotrexate
and Azathioprine
Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
Corticosteroids in Myositis
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 p-valueFVC <0.0001
FEV-1 <0.0001
DLCO 0.0046
CK <0.0001
MMT 0.06
CS Dose <0.0001
Wilkes, Arth Rheum, 2005
Retrospective study of 13 synthetase (+) pts (12 with Jo-1)
Is Anti-T cell Therapy Rational in Myositis-
associated ILD?
T cells as Therapeutic Targets in Myositis- Associated 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
AAbatacept should also be studied in AILD
Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
IVIg in MyositisIVIg in Myositis
• Randomized, double-blind, placebo-controlled 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 CentersAdult 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 IFN-α/β – DM: genes were
highly over-expressed compared to controls
Gene expression: Red: high; black: intermed; green: low
Greenberg, Ann Neurol, 2005
• 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
DM patients
Baechler, Mol Med, 2007
Type I IFN Gene Expression in DM
IFN signature, IFN-related cytokines both correlated with disease activity
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 long-
term side effects
RIM Study: Trial Design“Randomized Placebo Phase”
Rituximab
Placebo
Wks 0/1 Wks 8/9
Placebo
Rituximab
ScreenWeeks 12 – 44Monthly Assessments
Rtx EarlyRtx Late
• 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
0%
20%
40%
60%
80%
100%
Overall, 83% (161/195) of subjects met the DOI during the course of the 44-week clinical trial
80%85%
Early Rtx Late Rtx
21
13.8
0
5
10
15
20
25
wk 0 wk 44Me
an
To
tal D
aily
Do
se
(mg
)
Timepoint
Corticosteroid Sparing Effect
p < 0.001
There was a significant difference in the mean corticosteroid dose at baseline compared to the final
visit
Kaplan Meier: Myositis Autoantibody Subsets
MAA = myositis associated antibody
Pro
babi
lity
of N
ot M
eetin
g D
OI
Future Directions: Anti-Jo-1 as BiomarkerJo-1 levels decreased after rituximab and strongly correlated with disease activity
Abstract #750, ACR 2012
Median Rho = 0.68Rho = - 0.68
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