Adult Myopathies

Adult Myopathies

Myositis 101 for PM/DM/NM/ASyS Steven R. Ytterberg, M.D. Emeritus , Division of Rheumatology Mayo Clinic, Rochester, MN The Myositis Association Annual Conference Bloomington, MN Sept. 5 & 6, 2019 Disclosures Consulting: Pfizer Corbus Univ. of Pittsburgh Off-label use: Nothing is FDA approved other than steroids

Division of RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated?

Division of RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated?

Division of RHEUMATOLOGY Muscle http://www.nooruse.ee/e-ope/opiobjektid/lihasfysioloogia/lihasfsioloogia_alused.html Division of RHEUMATOLOGY Myositis = muscle inflammation a) Normal muscle b) PM endomysial inflammation c) DM perifascicular

atrophy Mammen, Nat Rev Neurol 2011; 7:343-54 Division of RHEUMATOLOGY Myositis = muscle inflammation http://www.neuro.wustl.edu/neuromuscular/pathol/inflammation.htm Division of RHEUMATOLOGY Myopathy = muscle abnormality Myopathy: general term for muscle abnormality Myositis: muscle inflammation Most of the muscle disorders discussed are

caused by abnormality of the immune system Autoimmune: immune system directed toward self Sometimes immune system abnormality causes myopathy without inflammation Division of RHEUMATOLOGY Idiopathic Inflammatory Myopathies Polymyositis (PM) Dermatomyositis (DM)

Isolated, adult Juvenile Malignancy Overlap Bohan & Peter, N Engl J Med 292: 344, 405, 1975 Bohan et al., Medicine 56: 255, 1977 Division of RHEUMATOLOGY Idiopathic Inflammatory Myopathies Polymyositis (PM) Dermatomyositis (DM)

Isolated, adult Juvenile Malignancy Overlap Inclusion body myositis (IBM) Antisynthetase syndrome (ASyS) Necrotizing myopathy (NM or IMNM) Division of RHEUMATOLOGY Idiopathic Inflammatory Myopathies Immune-mediated

Isolated, adult Juvenile Polymyositis (PM) Malignancy Dermatomyositis (DM) Overlap Inclusion body myositis (IBM) Antisynthetase syndrome (ASyS) Necrotizing myopathy (NM or IMNM) Division of RHEUMATOLOGY I hope to answer some common questions:

What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY I hope to answer some common questions:

What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY Cause is a difficult term Correlation or association Causation! http://www.benchtobmore.com/wp-content/uploads/2015/09/Chart-Tiff-copy.png Division of

RHEUMATOLOGY Cause is a difficult term Disease triggers Genetic factors Environmental factors Muscle fiber change Disease mechanisms Immune system Inflammation Muscle damage Others? Division of RHEUMATOLOGY Myositis is likely triggered by genetic and

environmental factors Genetic factors Environmental factors Division of RHEUMATOLOGY Genome-wide association study (GWAS) in DM/JDM Genes related to the immune systems recognition of foreign proteins are most highly associated with DM/JDM Strongest association with MHC Non-MHC SNPs: PLCL1

BLK CCL21 Miller et al., Arthritis Rheum 2013; 65: 3239-47 Division of RHEUMATOLOGY GWAS in PM and DM Adult PM Adult and juvenile DM Rothwell et al., Ann Rheum Dis 2016; 75: 1558-66 Division of RHEUMATOLOGY

Classes of environmental exposures Chemical factors Silica Asbestos Metals Pesticides Industrial chemicals and solvents Air pollution

Smoking Personal care products Physical factors Ionizing radiation UV radiation Electric and magnetic fields Biologic factors Infectious agents Foods and dietary contaminants Molds Mycotoxins

Other toxins Miller, et al., J Autoimmun 2012; 39: 259-71 Division of RHEUMATOLOGY Pathogenesis of IIM Feature DM PM Increased MHC I IBM + + +

B-cell mechanisms + - T-cell mechanisms + + + Inclusions - - + Autoantibodies + + + (Myositis specific antibodies) Division of RHEUMATOLOGY MHC I expression in muscle Normal IBM http://neuromuscular.wustl.edu/pathol/ibm.htm Division of RHEUMATOLOGY

Activated T cells (T lymphocytes) invade and damage muscle in IBM and PM Arahata & Engel, Ann Neurol 1984; 16:193 Division of RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis?

What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis?

What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY What does myositis to do patients? It depends On the specific disorder On the individual patient Muscle weakness is the hallmark but not always present Many other things can occur Division of

RHEUMATOLOGY Assessment of Muscle Weakness Patient report of effect on activities Manual muscle strength testing Physiologic testing Functional tests Timed stands 6 minute walk Functional Index-2 Division of RHEUMATOLOGY Evaluation of Muscle Disease: Laboratory Tests

CK Creatine kinase (CPK) Aldolase LDH Lactate dehydrogenase AST aspartate aminotransferase ALT alanine aminotransferase Division of RHEUMATOLOGY Muscle MRI can show inflammation or scarring

Division of RHEUMATOLOGY Motor Unit Action Potentials (MUAPs) Normal MUAPs Myopathy: Low amplitude, short, polyphasic MUAPs Neuropathy: Large, long duration, polyphasic MUAPs Division of RHEUMATOLOGY Dermatomyositis: characterized by rash Heliotrope

Gottrons papules Shawl sign & others Calcinosis cutis Division of RHEUMATOLOGY Heliotrope Division of RHEUMATOLOGY Gottrons papules Division of RHEUMATOLOGY

Gottrons sign Division of RHEUMATOLOGY Shawl sign Division of RHEUMATOLOGY Periungual erythema Division of RHEUMATOLOGY

Calcinosis cutis Division of RHEUMATOLOGY Amyopathic Dermatomyositis (Dermatomyositis sin myositis) Cutaneous features of DM No muscle weakness Maybe elevated muscle enzymes or EMG, but not weak Gerami et al., J Am Acad Dermatol 2006;54:597-613 Division of RHEUMATOLOGY

Other organ system problems Lung interstitial lung disease Gastrointestinal dysphagia, anorexia, reflux Heart inflammation, fibrosis, rhythm Joints arthritis, arthralgia, morning stiffness Raynauds phenomenon Constitutional fatigue, fever Division of RHEUMATOLOGY

Autoimmune Connective Tissue Diseases Other terms: Overlap CTD Undifferentiated CTD Mixed CTD Rheumatoid arthritis Lupus Sjogrens MCTD Scleroderma

PM/DM Division of RHEUMATOLOGY Clinical Features of sIBM Insidious onset ~6 years to diagnosis Weakness generalized or localized to limbs; may be asymmetric Reflexes normal initially, eventually diminished in 40%

Dysphagia in 2/3 late Myalgia uncommon but aching in thighs and knees in some Typical involvement: Finger flexors Wrist flexors Knee extensors Ankle dorsiflexors Needham & Mastaglia, Lancet Neurol 6: 620-31, 2007 Division of RHEUMATOLOGY Anti-synthetase Syndrome

Anti-synthetase antibody Jo-1, others PM/DM Interstitial lung disease Inflammatory arthritis Raynauds phenomenon Mechanics hands Fever Division of RHEUMATOLOGY Mechanics hands

Division of RHEUMATOLOGY Necrotizing myopathy Characterized by muscle biopsy with necrotic muscle fibers without inflammation Specific autoantibodies Anti-SRP Anti-HMGCR Often associated with statin use Christopher-Stine, et al. Arthritis Rheum 2010; 62: 2757-66 Mammen, et al. Arthritis Rheum 2011; 63: 713-21 Division of

RHEUMATOLOGY Epidemiology of IBM and PM Olmsted County, 1981-2000* IBM PM Incidence 0.79 0.41 (0.24-1.35) (0.08-0.73) Prevalence 7.06 3.45 (0.87-13.24) (0.00-7.35) *Age- and sex-adjusted rates per 100,000 population; (95% CI) Wilson et al., J Rheumatol 2008; 35:445-7 Division of RHEUMATOLOGY

Epidemiology of DM Olmsted County, 1976-2007* DM CADM Incidence 0.96 0.21 (0.61-1.32) (0.04-0.38) Prevalence 2.14 (1.31-2.98) *Age- and sex-adjusted rates per 100,000 population; (95% CI) Bendewald et al., Arch Dermatol 2010; 146: 26-30 Division of

RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of

RHEUMATOLOGY I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of

RHEUMATOLOGY PM/DM Classification Criteria Proximal muscle weakness Elevated serum levels of skeletal muscle enzymes Myopathic changes on EMG Muscle biopsy evidence of inflammation Skin rash Definite PM or DM: 4 criteria Probable PM or DM: 3 criteria Possible PM or DM: 2 criteria Bohan & Peter, N Engl J Med 292: 344, 405, 1975 Bohan et al., Medicine 56: 255, 1977

Division of RHEUMATOLOGY PM/DM Classification Criteria Lundberg article/slide Bohan & Peter, N Engl J Med 292: 344, 405, 1975 Bohan et al., Medicine 56: 255, 1977 Division of RHEUMATOLOGY Muscle histopathology a) Normal muscle b) PM endomysial inflammation

c) DM perifascicular atrophy d) Necrotizing myopathy Mammen, Nat Rev Neurol 2011; 7:343-54 Division of RHEUMATOLOGY IBM: Vacuoles Division of RHEUMATOLOGY Antibodies

Immunoglobulin Produced by plasma cells in the immune system Identify and neutralize viruses and bacteria Each recognizes a unique protein (antigen) Division of RHEUMATOLOGY Autoantibodies Antibodies directed toward an individuals normal proteins

Autoantibodies may: Cause disease Simply be markers of disease Autoantibody Target Disorder Antinuclear antibodies (ANA) Contents of cell nuclei

Lupus and related conditions Rheumatoid factor (RF) IgG Rheumatoid arthritis Anti-Jo-1 Histidyl tRNA synthetase Anti-synthetase syndrome

Anti-PR-3 (c-ANCA) Neutrophil proteinase-3 Granulomatosis with polyangiitis Anti-thyroid antibodies TPO Thyroglobulin Hashimotos thyroiditis

Anti-AChR Acetylcholine receptor on muscle Myasthenia gravis Anti-TTG Tissue transglutaminase Celiac disease Division of RHEUMATOLOGY

Non-specific Autoantibodies in Myositis Percent of Patients with Various Autoantibodies Antibody All (n=212) PM (n=58) DM (n=79) CTM (n=36) CAM (n=13)

IBM (n=26) ANA 52 40 62 77 31 23 ds-DNA

5 3 3 11 8 4 SSA/Ro 12 12

11 17 0 12 SSB/La 8 5 6 19 8

8 Sm 3 0 1 17 0 0 U1RNP

11 7 13 25 0 0 PM/Scl 2 0 4

3 0 0 RF 6 5 8 8 0

4 Love et al, Medicine 1991; 70: 360-74 Division of RHEUMATOLOGY Myositis-Specific Antibodies Feature Synthetase SRP Mi-2 Clinical Arthritis, ILD Cardiac Classic DM fever, myalgias; Raynauds black women Rate

Acute Severity Very acute Acute Severe Very severe Mild Season Spring Fall Unknown Response Moderate Poor Good Prognosis Poor (70%) Terrible (25%) Good (~100%) Frequency 20-25% <5%

5-10% Division of RHEUMATOLOGY Antisynthetase antibodies Frequency (%) Antigen tRNA synthetase Any ADM* Non-white 1-5 30 AA 29 Jo1 Histidyl-2-5 25-30 PL12 JDM*

AA13 Alanyl- 1-3 <5 PL7Threonyl- <1 <5 Japanese 17 EJ Glycyl- <1 <5 OJ Isoleucyl- <1 <5 KS Asparagynyl- NA <1 HA Tyrosyl-NA <1

ZA Phenylalanyl- NA <1 *Caucasian Robinson & Reed, Nat Rev Rheumatol 2011; 7: 664-75 Division of RHEUMATOLOGY Serologic Subgroups in IIM 2 Anti-TIF-1 (anti-transcription intermediary factor 1; anti-p155): DM, including JDM, malignancy Targoff et al., Arthritis Rheum 2006; 54: 3682-3689 Trallero-Araguas et al., Medicine 2010; 89: 47-52 Anti-MDA-5 (anti-melanoma differentiation-associated protein 5; anti-CADM): CADM, rapidly progressive ILD

Sato et al., Arthritis Rheum 2005; 52:1571-6 Anti-NXP2 (anti-nuclear matrix protein 2; anti-MJ): JDM, especially with calcinosis, malignancy Gunawardena et al., Arthritis Rheum 2009; 60: 1807-14 Gunawardena et al., Rheumatology 48: 607-12, 2009 Division of RHEUMATOLOGY Myositis Specific Autoantibodies Betteridge & McHugh, J Intern Med 2015; Epub Division of RHEUMATOLOGY

I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY

I hope to answer some common questions: What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY

General Approach to Treatment of Myositis PM, DM, ASyS, Overlap myositis Autoimmune process Inflammation Symptoms Division of RHEUMATOLOGY General Approach to Treatment of Myositis PM, DM, ASyS, Overlap myositis Damage Autoimmune process

Inflammation Symptoms Division of RHEUMATOLOGY General Approach to Treatment of Myositis PM, DM, ASyS, Overlap myositis Damage Autoimmune process Inflammation Immune suppressing

agents Steroids Symptoms Division of RHEUMATOLOGY General Approach to Treatment of Myositis Immune-mediated necrotizing myopathy Damage Autoimmune process Mechanism? Immune

suppressing agents Steroids Symptoms Division of RHEUMATOLOGY General Approach to Treatment of Myositis Cancer-associated myositis Cancer Damage Autoimmune process

Inflammation Immune suppressing agents? Steroids? Symptoms Division of RHEUMATOLOGY Approach to Management Start with high-dose prednisone (e.g., 1 mg/kg/ day)

Consider IV to begin Consider split daily dose Continue about 1 month with slow taper Use an immunosuppressive agent Attention to side effects of therapy (e.g., osteoporosis, infection) Division of RHEUMATOLOGY My Approach to Prednisone Begin 1 mg/kg/d (usually max 80 mg/d) Continue 1 month 2 weeks each: 40 mg/d 30 mg/d 25 mg/d

20 mg/d 17.5 mg/d 15 mg/d 12.5 mg/d 10 mg/d and then decide what next Division of RHEUMATOLOGY My Approach to Immunosuppressives First-line agents Methotrexate Azathioprine (Imuran) Mycophenolate mofetil (CellCept) Second-line agents IVIg Rituximab (Rituxan)

Tacrolimus (Prograf) Cyclosporine A (Neoral, Sandimmune) Leflunomide (Arava) Severe disease Cyclophosphamide (Cytoxan) Studies Abatacept (Orencia) Tocilizumab (Actemra) Belimumab (Benlysta) Never used ACTHAR gel Division of RHEUMATOLOGY Also remember

Pneumocystis pneumonia prophylaxis when on high dose prednisone Influenza, pneumococcal, and other immunizations Osteoporosis attention: calcium and vitamin D; bone density Mobility and assistive devices; fall prevention Dysphagia Exercise Division of RHEUMATOLOGY I hope to answer some common questions:

What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY I hope to answer some common questions:

What is myositis? What causes myositis? What does myositis do to patients? How is myositis diagnosed? How is myositis treated? Division of RHEUMATOLOGY Questions? Division of

RHEUMATOLOGY

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