Post on 16-Oct-2021
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
Lundberg et al, Ann RD, 2018
Lundberg et al, Ann RD, 2018
• 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
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)
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)
• 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
Pestronk, Curr Opin Rheum, 2011
MyovasculopathyDM
Pestronk, Curr Opin Rheum, 2011
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
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with another AIdisease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
What we called PM before, in some cases, is now called NM
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with another AIdisease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
What we called PM before, in some cases, is now called NM
Neurology, 2003
Medicine, 2005
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with anotherAI disease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
What we called PM before, in some cases, is now called NM
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
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)
• Necrotizing myopathy (NM)
– Anti‐HMGCR
– Anti‐SRP
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
– Amyopathic Dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with another AI disease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
– 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
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%
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
Aggarwal, Ann Rheum Dis, 2014
Jo‐1
non Jo‐1
Survival is worse in non Jo‐1 than Jo‐1 patients
Aggarwal, Ann Rheum Dis, 2014
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
Aggarwal, Ann Rheum Dis, 2014
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
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
– Amyopathic Dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with another AI disease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
– 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
Classification of Myositis
• Adult polymyositis
• Adult dermatomyositis
– Amyopathic Dermatomyositis
• Juvenile myositis (DM >> PM)
• Malignancy‐associated myositis
• Myositis in overlap with another AI disease
• Inclusion body myositis (IBM)
• Necrotizing myopathy (NM)
– 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