myositis update: treatment, autoantibodies and more rare disease visiting professor grand rounds...
TRANSCRIPT
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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
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Disclosures
Questcor: Advisory Board
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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
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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)
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Gottron Papules
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Rashes of Dermatomyositis
Gottron Sign
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Heliotrope Rash
Rashes of Dermatomyositis
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Rashes of Dermatomyositis
Facial Rash
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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)
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Endocrine myopathies• hyper/hypothyroid
Drug or toxic myopathiesMetabolic myopathiesMitochondrial myopathies Muscular dystrophiesInfectious myositisNeuropathies/neurologic syndromesParaneoplastic syndromesOther connective tissue disordersMiscellaneous
• amyloid, sarcoid
Polymyositis Mimics
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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
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We can classify pathologically
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DM
PM
IBM
NM
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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
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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
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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
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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)
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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”
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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
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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
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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
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Anti-CADM-140
• Novel cutaneous phenotype of palmar papules and cutaneous ulcerations – severe vasculopathy
• Rapidly progressive ILD
Fiorentino, J Am Acad Derm, 2011
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• 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
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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
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Percutaneous needle muscle biopsy
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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
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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
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Anti-synthetase Syndrome
• Defines a clinically homogeneous patient population– Fever– Myositis– Arthritis (misdx as RA)– Raynaud phenomenon– Mechanic’s hands– ILD
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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
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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
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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
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Making the Diagnosis of Autoimmune ILD?
Not everyone will present with
the classic anti-synthetase
syndrome
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Making the Diagnosis of Autoimmune ILD?
• Recognize ‘incomplete’ clinical syndromes ILD alone or ILD with subtle CTD findings
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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A Negative ANA Does Not Imply Antibody Negativity
Dimitri, Muscle and Nerve, 2007
Homogeneous, diffuse cytoplasmic staining
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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
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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
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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
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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
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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
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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
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Myositis Treatment:
Beyond Steroids, Methotrexate
and Azathioprine
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Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
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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
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Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
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Aggarwal/Oddis, Curr Rheum Rep, 2011
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Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
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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
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IS Agents Beyond Mtx and Aza…
• Mycophenolate mofetil
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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
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IS Agents Beyond Mtx and Aza…
• Mycophenolate mofetil• Cyclosporine/tacrolimus• Cyclophosphamide
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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
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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)
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Is Anti-T cell Therapy Rational in Myositis-
associated ILD?
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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
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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
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Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
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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
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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
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Pharmacologic Therapy of IIM
• Corticosteroids• Immunosuppressive
Agents• Combination regimens• IVIg • Biologic agents
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Biologic Targets
• TNF – alpha
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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
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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
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Biologic Targets
• TNF – alpha
• B cell
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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
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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
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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)
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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
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Biologic Targets
• TNF – alpha
• B cell
• Other – Interleukin – 6
– Type 1 IFN
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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
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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
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• 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
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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
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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
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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
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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
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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
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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
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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
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B cell Numbers Before and After Rituximab
Early Rtx
Late Rtx
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Primary Outcome: Entire Cohort
Median time to DOI: Early Rtx = 20.0 weeks Late Rtx = 20.2 weeks p = 0.74 (log rank)
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Primary Outcome: JDM
Median time to DOI: Early Rtx = 11.7 weeks Late Rtx = 19.6 weeks p = 0.32 (log rank)
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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
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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
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Kaplan Meier: Myositis Autoantibody Subsets
MAA = myositis associated antibody
Pro
babi
lity
of N
ot M
eetin
g D
OI
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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