Autoantibodies in Myositis

Autoantibodies in Myositis

Pennsylvania Rheumatology Society Annual Meeting

September 23, 2018

Chester V. Oddis, MDDirector, Myositis CenterUniversity of Pittsburgh

Disclosures

• Genentech: Clinical trial support

• Bristol Myers Squibb: Clinical trial support

• Mallinckrodt: Clinical trial support

• Octapharma: Clinical trial support

Lecture Objectives

• Discuss clinical features of myositis classification

• Discuss spectrum of autoantibodies seen in

patients with myositis

Classification of Myositis

• Adult polymyositis

• Adult dermatomyositis

• Juvenile myositis (DM >> PM)

• Malignancy‐associated myositis

• Myositis in overlap with another AI disease

• Inclusion body myositis (IBM)

IIM: Diagnostic CriteriaBohan and Peter (1975)

• Symmetric proximal muscle weakness

• Elevation of serum muscle enzymes: CK, aldolase, AST, ALT, LDH

• Myopathic electromyographic abnormalities: sharp waves,fibrillations, polyphasic motor units, high frequency repetitivedischarges

• Characteristic muscle pathology: myofiberdegeneration/regeneration, MNC infiltrates, perifascicularatrophy

• Cutaneous features (heliotrope, Gottron sign/papules)

IIM: Diagnostic CriteriaBohan and Peter (1975)

• Symmetric proximal muscle weakness

• Elevation of serum muscle enzymes: CK, aldolase, AST, ALT, LDH

• Myopathic electromyographic abnormalities: sharp waves,fibrillations, polyphasic motor units, high frequency repetitivedischarges

• Characteristic muscle pathology: myofiberdegeneration/regeneration, MNC infiltrates, perifascicularatrophy

• Cutaneous features (heliotrope, Gottron sign/papules)

Problems with B&P Criteria• No good way to exclude other myopathies• Misclassification of IBM as PM• Each criterion not explicitly defined

Lundberg et al, Ann RD, 2018

• Candidate variables assembled from publishedcriteria/expert opinion

• Data collected from rheum/derm/neuro/peds clinicsworldwide

• New criteria were derived and each item wasassigned a ‘weighted’ score

• Total score corresponds to a probability of having IIM



• For patients without classic DM rashes, do a musclebiopsy.

• For DM patients without muscle involvement do askin biopsy.

• These criteria provide a score and probability forhaving IIM (for clinical trial purposes)

Rashes of DermatomyositisDermatomyositis Rashes

• 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

Polymyositis Mimics

Muscle Biopsy is a Must in “Polymyositis “(unlike classic DM)

Muscle Biopsy is a Must in “Polymyositis “(unlike classic DM)

And maybe pathologic classification may even be better

than “clinical” classification

Pathologic Myositis Classification

Pestronk, Curr Opin Rheum, 2011

Pathologic Myositis Classification


MyovasculopathyDM


Muscle Biopsy is a Must in Polymyositis (unlike classic DM)

Distinguishing Histologic Features: PM vs. DM

Polymyositis

Lymphocytic invasion of non‐necrotic myofiber

perimysial/perivascular CD4+ Thelper cell

Dermatomyositis perifascicular atrophy perivascular B cells and C5‐C9 (MAC)

deposition endomysial CD8+ T cells perimysial CD4+ T helper cells






• Myositis in overlap with another AIdisease


• Necrotizing myopathy (NM)

What we called PM before, in some cases, is now called NM






• Myositis in overlap with another AIdisease




Neurology, 2003

Medicine, 2005






• Myositis in overlap with anotherAI disease




Case One

• 67 year old Caucasian female with HTN, hyperlipidemia, uterinecancer (1997)

• July, 2004: atorvastatin

• June, 2008: lower extremity weakness

• Spring, 2009: difficulty walking up steps and lifting armsoverhead

• June, 2009: stops atorvastatin on her own but no improvementin weakness

• September, 2009: CK 6473, repeat 9375; ANA 1:320 (H)

• Admitted to hospital; muscle biopsy: myonecrosis, noinflammation or vasculitis

Necrotizing Myopathy

Kassardjian, JAMA Neurol, 2015

Case One

• 67 year old Caucasian female with HTN, hyperlipidemia, uterinecancer (1997)

• July, 2004: atorvastatin

• June, 2008: lower extremity weakness

• Spring, 2009: difficulty walking up steps and lifting armsoverhead

• June, 2009: stops atorvastatin on her own but no improvementin weakness

• September, 2009: CK 6473, repeat 9375; ANA 1:320 (H)

• Admitted to hospital; muscle biopsy: myonecrosis, noinflammation or vasculitis

• Treated with prednisone (60mg/day) and CK and weaknessimprove

Case One

• March, 2010 (1st UPMC visit)

– CK 5800 (increasing as prednisone tapered)

– No other autoimmune manifestations; no FH ofautoimmune diseases

– No rashes of dermatomyositis

– Deltoids 4+/5; neck flexors 4/5; iliopsoas 3+/5

• Statin myopathy

• Pt hesitant to increase prednisone

Immune‐Mediated Necrotizing Myopathy Associated with Statins

• Proximal weakness during or after statin use

• Elevated CK

• Persistent weakness and elevated CK despitestopping the statin

• Improvement with IS agents

• Muscle biopsy showing necrotizing myopathywithout significant inflammation

• 25 patients from 2 centers

Grable‐Esposito, Muscle & Nerve, 2010

Anti‐200/100 kD AutoAb Defines Subgroup of Necrotizing Myopathy (NM)

• 16/38 patient sera with NMhad the doublet

– All were weak with high CK

– 63% had statin exposure priorto weakness

– 83% >age 50 exposed tostatins

– All responded to IS therapyand many relapsed

Christopher‐Stine, Arth Rheum, 2010

Controls in lanes 5 and 10

Statin Necrotizing Myopathy

• HMGCR was identified as the 100‐kd autoantigenic target

• Developed an ELISA for anti‐HMGCR autoAb

– All 16 doublet positive pts were anti‐HMGCR (+)

– 45/750 (6%) of cohort were anti‐HMGCR (+)

Mammen, Arth Rheum, 2011

Case One

• April‐June, 2010: worse weakness; CK 6367

• July, 2010: prednisone increased (60mg/d) and mtx added

• Jan, 2011: added imuran/mtx (25mg/week), pred 30mg/d

• May, 2011: added IVIg; continued other IS agents

• August, 2011: clearly improved with first normal CK in July

• November, 2011: 5/5 strength; taper IVIg (never off completely)

• March, 2012: stopped imuran

• June, 2012: off prednisone

• Progressive rise of CK 2013 – 2017; went back on mtx and IVIg; CKstill elevated

Pt is anti‐HMGCR autoAb positive

Mammen, NEJM, 2015

Suggests IVIg as first‐line therapy for statin‐associated autoimmune,

necrotizing myopathy

Features of Anti‐SRP Subset

• Acute onset of severe weakness withmyalgias; high CK

• Necrotizingmyopathy (or PM phenotype)

– no DM rash; ILD rare

• Poor response to therapy with variableprognosis

Refractory, persistently high CK, “dystrophy‐like”

Muscle Pathology of SRP Antibody Subset

• Necrotizing myopathy without inflammation

Dimitri, Muscle and Nerve, 2007









– Anti‐HMGCR

– Anti‐SRP




– Amyopathic Dermatomyositis






– Anti‐HMGCR

– Anti‐SRP

Clinically Amyopathic DM (CADM)

• A subset of DM patients with cutaneousmanifestations of DM for 6 months or longer

• No proximal muscle weakness

• May have slightly elevated serum muscleenzymes, mild EMG or biopsy abnormalities

CADM = Amyopathic DM (ADM) + Hypomyopathic DM (HDM)

Sometimes the skin

disease can be the most

dominant feature

DM Scalp Rash

Treatment of DM Cutaneous Disease

Sun‐protective measures; avoid photosensitive meds

Topical GC (potency depends on severity)

Topical calcineurin inhibitors (tacrolimus, pimecrolimus)

Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine

Oral glucocorticoids (varying doses)

2nd Line

Methotrexate (oral/SQ)

MMF

3rd Line

IVIGTacrolimusCyclophosphamideRituximab

Taper prednisone by 20‐25% monthly to minimum

effective dose

YesNo

Clinical Response after 1‐3 months?

Treatment of DM Cutaneous Disease

Sun‐protective measures; avoid photosensitive meds

Topical GC (potency depends on severity)

Topical calcineurin inhibitors (tacrolimus, pimecrolimus)

Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine

Oral glucocorticoids (varying doses)

2nd Line

Methotrexate (oral/SQ)

MMF

3rd Line

IVIGTacrolimusCyclophosphamideRituximab

Taper prednisone by 20‐25% monthly to minimum

effective dose

YesNo

Clinical Response after 1‐3 months?

4th Line

Tofacitinib

Apremilast

Anti‐CADM‐140(anti‐MDA‐5)

• 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 similarphenotype

• Target autoantigen is MDA‐5. What is MDA‐5?

– Cytoplasmic protein that “senses” viral RNA and inducesproduction of type I interferon

– Involved in innate immune defense against viruses

Anti‐CADM‐140(anti‐MDA‐5)

• 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 similarphenotype

• Target autoantigen is MDA‐5. What is MDA‐5?

– Cytoplasmic protein that “senses” viral RNA and inducesproduction of type I interferon

– Involved in innate immune defense against viruses

Supports role of a viral trigger

Anti‐MDA‐5

• Novel cutaneous phenotype of palmar papules andcutaneous ulcerations – severe vasculopathy

Fiorentino, J Am Acad Derm, 2011

• 70 year old WM

• “Double pneumonia” in June

• Rash of DM in September

• Vasculitic skin changes in Jan

• No muscle weakness

• Recommended cyclophosphamide

Case Two

• 70 year old WM

• “Double pneumonia” in June

• Rash of DM in September

• Vasculitic skin changes in Jan

• No muscle weakness

• Recommended cyclophosphamide

Case Two

Anti‐ MDA‐5 positive

Case Three

• Summer, 2012: Photosensitive rash in 58 yo WF

• January, 2013: Polyarthritis; mild muscle weakness; rashof DM

– nl CK; Jo‐1, ANA and SSA/B – all negative

– improves on low dose prednisone/mtx

• May, 2013: DM rashes worse; faint basilar crackles onexam (no pulmonary sx); mild weakness

– Recommended 20mg prednisone and MMF

– HRCT/PFTs

June 6

Case Three

• July 1: Presents to local ED “feeling very SOB”

• CXR ‘opacified’

• In one day, she is up to 12 liters/min O2

• Contacted by rheumatologist

– Rash a little different

Case Three

• July 1: Presents to local ED “feeling very SOB”

• CXR ‘opacified’

• In one day, she is up to 12 liters/min O2

• Contacted by rheumatologist

– Rash a little different

• Recommend pulse steroids, cytoxan andrituximab

July 2

July 2

June 6

July 2

June 6

Anti‐ MDA‐5 positive

Anti‐MDA‐5 Positivity is Associated with a Poor Pulmonary Outcome

p<0.001

MDA5 (‐) (n=106)

MDA5 (+) (n=16)

Moghadam‐Kia, Arth Care Rsch, 2016

MDA‐5 Positive ‘Vasculopathy’

3 months

2 months

Myositis specific autoantibodies Clinical phenotypes in adults and children

Myositis‐specific autoantibodies

Anti-synthetases

PL-12OJ

KS

PL-7

EJ

Jo-1

Zo

YRS

Anti-SRP

Anti-HMGCR Anti-MDA-5

Anti-SAE Anti-NXP-2

Anti-Mi-2Anti-TIF1g

Necrotizing

myopathy

High CK

Amyopathic

dermatomyositis

Rash sinemyositis

Hypomyopathic

Rash precedes myositis

Dermatomyositis

Rash

Malignancy

Calcinosis/vasculitis (children)

Anti‐synthetase syndrome

Fever

Raynauds

Lung fibrosis

Myositis

Arthropathy

Mechanics hands

+/‐ DM rash

Slide courtesy of Drs. Chinoy and Gunawardena

X X

Anti‐synthetase Syndrome

• Defines a clinically homogeneous patientpopulation:

– Fever

– Myositis

– Arthritis (misdiagnosed as RA)

– Raynaud phenomenon

– Mechanic’s hands

– ILD

Clinical Features: Anti‐synthetase Syndrome

But … the skin rash(es) and the myositis

may be subtle and the clinical

presentation may be ‘lung dominant’

Case Four

• 1/2001: 39 yo WF admitted to hospital with 5

weeks of fever (103‐1040) and myalgias;

extensive w/u negative except for low titer ANA

and mild basilar fibrosis; leaves hospital with

FUO frustrated by lack of diagnosis

Case Four

• 1/2001: 39 yo WF admitted with 5 weeks of

fever (103‐1040) and myalgias; extensive w/u

negative except for low titer ANA and mild

basilar fibrosis; leaves hospital with FUO

frustrated by lack of diagnosis

• 3/2001 (office): worsening myalgias and

arthralgias, small pleural effusions, fever,

Raynaud phenomenon. Dx as UCTD and given

empiric prednisone

Case Four• 1/2001: 39 yo WF admitted with 5 weeks of fever(103‐1040) and myalgias; extensive w/u negativeexcept for low titer ANA and mild basilar fibrosis;leaves hospital with FUO frustrated by lack ofdiagnosis

• 3/2001 (office): worsening myalgias andarthralgias, small pleural effusions, fever, Raynaudphenomenon. Dx as UCTD and given empiricprednisone

• 4/2001: Increased SOB with more prominentdiffuse pulmonary infiltrates; subtle Gottronchanges; anti‐PL‐12 autoantibody identified

Case Four: Subsequent Course

• Worsening infiltrates and deteriorating PFTs– PFTs: FVC 56%, FEV‐1 52%, DLCO 40%

• Responded to glucocorticoids and tacrolimus

• Skin rash, joint symptoms and fever never return

• Never developed myositis

• Raynaud is mild and most recent PFTs (5/2018)– FVC 75%; FEV‐1 87%; DLCO 78%– Echo with nl PAS (25mmHg)

• Currently on tacrolimus, no prednisone

Making the Diagnosis of Autoimmune ILD

Not everyone will present with

the classic anti-synthetase

syndrome

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

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

Initial CTD Diagnosis in Anti‐Syn Cohort

Aggarwal, Ann Rheum Dis, 2014

DM 24%

17%

Jo‐1n=122

PM 22%

DM 17% Overlap or UCTD 48%

SSc13%

Non‐Jo‐1n=80

PM DM Overlap or UCTD SSc

PM 59%

Initial CTD Diagnosis in Anti‐Syn Cohort


DM 24%

17%

Jo‐1n=122

PM 22%

DM 17% Overlap or UCTD 48%

SSc13%

Non‐Jo‐1n=80

PM DM Overlap or UCTD SSc

PM 59%

Myositis UCTD/Overlap Scleroderma

Jo‐1 83% 17% 0%

Non‐Jo‐1 39% 48% 13%p<0.001

Survival is worse in non Jo‐1 than Jo‐1 patients


Jo‐1

non Jo‐1

Survival is worse in non Jo‐1 than Jo‐1 patients


Jo‐1

non Jo‐1

Jo‐1 non Jo‐1 p value

Diagnosis delay (years)

0.4 (0.2‐0.8) 1.0 (0.4 – 5.1) <0.01

Pulmonary fibrosis49%

Pulmonary HTN11%

CTD heart 5%

CTD kidney 3%

Cancer9%

Infection6%

Atherosclerosis9%

Unknown6%

Cause of Death in Anti‐Synthetase Cohort

In synthetase (+) pts pulmonary disease was most common cause of death


Synthetase Positive Patients: Jo‐1 vs. non‐Jo‐1

• Non Jo‐1 synthetase (+) patients frequentlypresent with non‐myositis symptoms … and maynever manifest them.

• Diagnosis of a specific CTD is delayed in non‐Jo‐1synthetase (+) patients – perhaps leading toworse survival.

• Synthetase (+) patients, whether Jo‐1 or non Jo‐1have increased pulmonary morbidity andmortality.

Antibody Target Subset Phenotype

CADM-140 MDA-5 DM Amyopathic, ILD

Jo-1 and other anti-Syn

Aminoacyl tRNAsynthetases (ARS) PM/DM Anti-synthetase syndrome

Mi-2 NuRD DM Shawl, V-neck, Gottron’s

Myositis Autoantibodies

Shawl Sign V‐neck Sign










– Anti‐HMGCR

– Anti‐SRP

Are there autoantibody markers that

identify patients with malignancy‐

associated myositis?

Antibody Target Subset Phenotype

CADM‐140 MDA‐5 DM Amyopathic, ILD

Jo‐1

Other anti‐SynARS PM/DM Anti‐synthetase syndrome

Mi‐2 NuRD DM Shawl, V‐neck, Gottron’s

p155/140 TIF1‐γ DM, JDM Severe skin, malignancy

Myositis Autoantibodies

Gunawardena, Rheumatol, 2008

Anti‐p155/140 (anti‐TIF1‐γ) Autoantibody

• Adults: Associated with severe cutaneousDM and cancer associated myositis

• JDM: Severe cutaneous involvementincluding ulceration, edema and calcinosis

• But cancer associated myositis is not seen inJDM

Anti‐NXP‐2 is Another Common JDM Autoantibody

• Found in 20‐25% of JDM cohorts

• Associated with increased risk of calcinosisacross all age groups in JDM

• Marker of severe disease in JDM

– Calcinosis

– Skin ulcerations

– ContracturesTansley, Rheumatol, 2014

Anti‐NXP‐2 is Associated with Cancer in Adult DM

• Reactivity against NXP‐2 or TIF1‐γ identified83% of patients with cancer‐associated DM

• Sex stratification revealed anti‐NXP‐2 wasassociated with cancer in males

Fiorentino, Arth Rheum, 2013

Myositis specific autoantibodies Clinical phenotypes in adults and children

Myositis‐specific autoantibodies

Anti-synthetases

PL-12OJ

KS

PL-7

EJ

Jo-1

Zo

YRS

Anti-SRP

Anti-HMGCR Anti-MDA-5

Anti-SAE Anti-NXP-2

Anti-Mi-2Anti-TIF1g

Necrotizing

myopathy

High CK

Amyopathic

dermatomyositis

Rash sinemyositis

Hypomyopathic

Rash precedes myositis

Dermatomyositis

Rash

Malignancy

Calcinosis/vasculitis (children)

Anti‐synthetase syndrome

Fever

Raynauds

Lung fibrosis

Myositis

Arthropathy

Mechanics hands

+/‐ DM rash

Slide courtesy of Drs. Chinoy and Gunawardena










– Anti‐HMGCR

– Anti‐SRP

• Most common myopathy in middle aged ‐ elderly

• Consider IBM when confronted with refractorypolymyositis patient

• Male predominance (elderly)

• Insidious onset of painless muscle weakness with slowprogression

• Distal and asymmetric muscle involvement (foot drop)

• Characteristic pattern of muscle atrophy (forearmflexors, quadriceps, intrinsic muscles of hands)

Inclusion Body Myositis

Inclusion Body Myositis

• Distinctive histology: endomysial inflammation

often called polymyositis rimmed vacuoles

Anti‐Mup44 Autoantibodies in IBM

• Targets cN1A (Cytosolic 5′‐nucleotidase)

– Muscle‐specific enzyme catalyzing AMP to adenosineand inorganic phosphate

– Involved in physiologic control of energy balance

• Detected in 33% of sIBM patient sera

• Low in DM, PM and other NM disorders

• Specificity needs to be established

– found in some Sjogren/SLE patients

Pluk, Ann Neurol, 2013

Summary

• Clinical key: recognize ‘syndromes’ or clusters ofsymptoms to identify autoAb‐associated systemicautoimmune rheumatic diseases

• Watch for autoimmune ILD

• AutoAb markers have clinical and prognosticimportance

• How do you order them?

– RDL laboratories

– OMRF (Ira Targoff has studied these Abs for years)

Thank You

Autoantibodies in Myositis

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