myositis update: treatment, autoantibodies and more rare disease visiting professor grand rounds...

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



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


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


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


• 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

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


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


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




• ‘Myositis-specific Abs’ in the absence of myositis



• ‘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


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


Aggarwal, ACR 2010


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%)


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

Aggarwal/Oddis, Curr Rheum Rep, 2011

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

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

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




• 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







• 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


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

myositis update: treatment, autoantibodies and more rare disease visiting professor grand rounds...

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