Myositis Update: Treatment, Autoantibodies and More

Transcript Myositis Update: Treatment, Autoantibodies and More

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 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

Anti-Synthetases PL-7 PL-12

Mi-2 Jo-1 PM/NM HMGCR SRP TIF-1γ PM-Scl MDA-5 SAE 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

Mi-2 Jo-1 PM/NM HMGCR SRP TIF-1γ PM-Scl MDA-5 SAE 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; O 2 saturation 90% (100% O 2 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

Mi-2 Jo-1 PM/NM HMGCR SRP TIF-1γ PM-Scl MDA-5 SAE MJ DM Overlap U1RNP Ku

Anti-synthetase Autoantibodies Antibody Jo-1 PL-7 PL-12 OJ EJ KS Tyr Zo Antigen (tRNA synthetase) histidyl threonyl alanyl isoleucyl glycyl asparaginyl tyrosyl phenylalanyl Prevalence in IIM (%) 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

Raynaud’s Fatigue 4% 7%* Fever 2% Rash 4% Fatigue Fever 4% 3% Rash 4% Muscle 14%* Pulmonary 22% Muscle 30%* Raynaud’s 25%* Joint 13%* 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

Jo-1 (n=122) non-Jo-1 (n=80) p value Mean Age at Symptom Onset (yrs) % Female % Caucasian 45 46 NS 67 70 NS 86 79 NS Diagnoses at First Visit (%) Myositis Overlap or UCTD SSc 83 17 0 Median Delay in Dx from 1 st CTD Symptom (years; IQR) 0.4

(0.2-0.8) 40 48 13 1.0 (0.4-5.1) 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% Infection 6% Cancer 9% CTD kidney 3% CTD heart 5% Pulmonary HTN 11% Unknown 6% Pulmonary fibrosis 49% - 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 Jo-1 (n=122) non-Jo-1 (n=80) p value 16/36 16/30 NS 3/36 4/30 5 year 90 75 10 year p<0.005

70 47 Median Survival (yrs) 15 9 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

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

histidine his tRNA syn 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 + 100/199 (50%) Anti-CytAb + p value 142/196 (72%) p < 0.001

Aggarwal, ACR 2010

Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients

ANA + Anti-CytAb + Anti-Syn patients

All Jo-1 All non-Jo-1

100/199 (50%) 142/196 (72%)

62/119 (52%) 38/80 (48%) 77/116 (66%) 65/80 (81%)

p value p < 0.001

p = 0.026

p < 0.001

Aggarwal, ACR 2010

Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients

ANA + Anti-Syn patients

All Jo-1 All non-Jo-1

SSc 100/199 (50%)

62/119 (52%) 38/80 (48%) 1935/1946

(99%) Anti-CytAb + 142/196 (72%)

77/116 (66%) 65/80 (81%) 180/1946 (9%)

p value p < 0.001

p = 0.026

p < 0.001

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 CADM-140 Jo-1 Other anti-Syn Mi-2 Target MDA-5 ARS NuRD Subset DM PM/DM Phenotype Amyopathic, ILD Anti-synthetase syndrome DM Shawl, V-neck, Gottron’s

Myositis Autoantibodies

Antibody CADM-140 Jo-1 Other anti-Syn Mi-2 SAE MJ p155/140 SRP 200/100 kD Target MDA-5 ARS NuRD SUMO NXP-2 TIF1-

Signal recognition particle 72, 54 kDa HMGCR Subset DM PM/DM DM DM JDM DM, JDM PM IMNM Phenotype Amyopathic, ILD Anti-synthetase syndrome Shawl, V-neck, Gottron’s ILD, dysphagia Calcinosis, ulceration Severe skin, malignancy 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

0.0046

<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 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 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, 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 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 IFN α/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 • IFN gene/protein signatures and serum IL-6 levels correlated with DM disease activity and with each other 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” Screen Rtx Early Rtx Late Wks 0/1 Rituximab Placebo Wks 8/9 Placebo Rituximab Weeks 12 – 44 Monthly Assessments • 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)

100% 80% 60% 40% 20% 0%

Patients Meeting DOI During Trial

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

25 20 15 10 5 0

21 p < 0.001

13.8

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 MAA = myositis associated antibody

Future Directions: Anti-Jo-1 as Biomarker

Jo-1 levels decreased after rituximab and strongly correlated with disease activity

Rho = - 0.68

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

Median Jo1

700 Abstract #750, ACR 2012