Acquired Myopathies January 30, 2017 Christina M. Ulane, MD, PhD Neuromuscular Medicine EMG Laboratory

Acquired Myopathies Inflammatory/Immune Toxic/Drug-induced Infectious Dermatomyositis Polymyositis Inclusion body myositis Necrotizing Toxic/Drug-induced Infectious

Dermatomyositis (DM)-clinical Rash Purplish discoloration of cheeks, eyelids: blanches (heliotrope) Periorbital edema Gottron’s papules (mimics psoriasis) V- sign/shawl sign Weakness Symmetric weakness, proximal >distal Often relapse-remit Pain not prominent

Dermatomyositis (DM)-clinical Associated cancer (10-15%) Breast, lung, ovarian, gastric, lymphoma Other vascular manifestations Raynaud’s Cardiac Interstitial lung disease Smooth muscle involvement (GI) Juvenile form Clinically amyopathic dermatomyositis

Bohan and Peter Criteria for Myositis Definite PM: 4 criteria Definite DM: 3 or 4 criteria plus rash Possible PM: 2 criteria Possible DM: 1 criterion plus rash PM=Polymyositis, DM=Dermatomyositis Criterion Description Symmetric proximal weakness (over weeks to months) Neck flexors, limb-girdle musculature Consistent muscle biopsy findings Necrosis, regeneration, phagocytosis, atrophy, mononuclear cell infiltrates Elevated muscle enzymes Creatine kinase, aldolase, transaminases, lactate dehydrogenase Electromyographic evidence for myopathy Muscle fiber irritability (positive sharp waves, fibrillations), short duration, small amplitude, polyphasic motor unit potentials, with spontaneous bizarre high-frequency discharges Characteristic skin rash Gottron’s sign, Gottron’s papules, heliotrope

DM-rash

Myositis specific antibodies Antibody Clinical features Antisynthetase antibodies Anti Jo-1 Anti PL-7 Anti PL-12 Anti EJ Anti OJ Anti KS Anti Zo Anti Ha Seen in Polymyositis, Dermatomyositis and Interstitial Lung Disease Dermatomyositis specific antibodies   Anti Mi-2 Treatment responsive Anti MDA5 (CADM-140) Minimal myopathy; ILD Anti 155/140 Cancer associated Anti 140 Juvenile dermatomyositis, calcinosis Anti SAE Amyopathic DM Antibodies in immune mediated necrotizing myopathy Anti SRP Severe, acute presentation, resistant to treatment Anti HMGCR Related to statin use Adapted from: Albayda, J and Mammen, AL. Is statin-induced myositis part of the polymyositis disease spectrum? Curr Rheumatol Rep 2014;16:433.

DM-Pathology EMG: spontaneous activity, myopathic motor units Laboratory CK normal or mildly elevated (aldolase) Antibodies tRNA synthetases (Jo-1 assoc w/ interstitial lung dsease) Anti- Mi-2 (20%) Other myositis specific antibodies May have ANA, RF positive if part of overlap syndrome EMG: spontaneous activity, myopathic motor units

DM-Pathology Vasculitis Perivascular and perimysial inflammation Capillaries and small blood vessels Perivascular and perimysial inflammation No inflammatory cell invasion of non-necrotic fibers Increased expression of IFN1- inducible proteins Humoral response CD4+ cells and B-cells Complement and immunoglobulin deposition on capillaries

DM-perimysial inflammation (a–f) Immune myopathy with perimysial pathology (IMPP): (a) Perimysial pathology includes fragmented connective tissue with rounded clear regions (blue arrow) and abnormal cells with large nuclei and abundant cytoplasm (black arrows) (H&E stain). (b) Many of the cells in the perimysium stain red with acid phosphatase. (c) Perimysial cells often appear elongated with extended processes (Esterase stain). (d) Small muscle fibers at the edge of fascicles may be necrotic or regenerating [large nuclei with basophilic cytoplasm (arrows)] (H&E stain). (e) Perimysial connective tissue between fascicles stains darkly (alkaline phosphatase stain). (f) Muscle fibers, often histologically normal, at the edge of fascicles have abnormal expression ofMHCclass I around their rimand in cytoplasm. (

DM-perivascular inflammation

Polymyositis 1863-Wagner 1950s-1970s: Rowland, Eaton, Bohan and Peter Clinical: Proximal > distal weakness May have systemic symptoms at onset CPK always elevated

PM-endomysial inflammation (g–i) Immune polymyopathy: (g) scatteredmuscle fibers, early in the disease course, are necrotic (large blue arrow) or regenerating (small black arrow) (H&E stain); (h) necrotic muscle fibers contain cells that stain red (acid phosphatase stain); (i) rapid accumulation of endomysial connective tissue (within 7 months of onset of weakness) (H&E stain). (j, k) Immune myopathy with endomysial pathology: (j) endomysial deposition of C5b-9 complement (brown) around muscle fibers; (k) control muscle with no deposition of C5b-9 complement.

MRI in myositis

DM and PM Treatment Glucocorticoids Immunosuppressive/steroid-sparing High dose for at least 4-6wks, taper over 1yr 80mg or 1mg/kg No RCTs, NIH series with 39% normalized CPK, 25% regained full strength Immunosuppressive/steroid-sparing Azathioprine Randomized trial vs prednisone alone, better functional outcome at 3yrs Methotrexate (pulmonary fibrosis) Can be started simultaneously Hydroxychloroquine (skin disease but not muscle)

Treatment resistant Consider alternative diagnosis (IBM) Rituximab IVIG Other: CSA, tacrolimus, MMF

Features differentiating dermatomyositis from polymyositis Typical dermatologic manifestations May be associated with malignancy   Not generally associated with systemic rheumatologic disease, except sometimes scleroderma Childhood form exists Muscle biopsy findings (perimysial and perivascular inflammation) Polymyositis No rash unless lupus associated Not typically associated with malignancy Often associated with a systemic rheumatologic disease, including lupus, systemic sclerosis, vasculitis Adult disease Muscle biopsy findings (endomysial inflammation)

Differential Diagnosis of Polymyositis Mimic Differentiating characteristics Dermatomyositis Associated rash, specific pathological findings on muscle biopsy, Myositis specific antibodies Necrotizing myopathy Specific pathological findings on muscle biopsy, drug/statin exposure, more resistant to immunosuppressant therapy Inclusion body myositis Slower progression, older age of onset, distribution of muscle weakness, specific pathological findings on muscle biopsy, lack of response to immunosuppressants Overlap syndrome Associated rheumatologic diagnosis (e.g. lupus, rheumatoid arthritis) Muscular dystrophy Age of onset, slower progression, family history, specific pathological findings on muscle biopsy, genetic testing, lack of response to immunosuppressants Metabolic myopathy Age of onset, slower progression, family history, pathology, genetic testing, lack of response to immunosuppressants Fibromyalgia Prominent pain, no weakness, normal muscle biopsy Polymyalgia rheumatica High ESR/CRP, normal CK, normal EMG

Inclusion body myositis Most common myopathy >50yrs Men>women Clinical: Distal predominence FF, WF, quads, anterior tibial atrophy Asymmetrical 1/3 with dysphagia, facial weakness

Differential diagnosis for Inclusion Body Myositis (IBM) Dermatomyositis Associated skin findings Muscle pathology Polymyositis Assosciated autoantibodies Hereditary distal myopathies Family history Early age of onset Genetic testing Drug induced (toxic) myopathies History of toxic or medication exposure Motor neuron disease Upper motor neuron findings Electrodiagnostic testing Muscle biopsy – neurogenic changes Myasthenia gravis Ocular and prominent bulbar symptoms Acetylcholine receptor or muscle specific kinase (Musk) antibodies Abnormal repetitive stimulation Response to immunotherapy

Diagnostic criteria for IBM from the European Neuromuscular Center (ENMC) Workshop, 2011 Adapted from Barohn et al 2014/Machado P, Brady S, Hanna MG. Update in inclusion body myositis. Curr Opin Rheumatol 2013;25(6):763–71; Classification Clinical Features Pathologic Features Clinicopathologically defined IBM Duration over 12 months Age at onset over 45 years Quadricep weakness greater than hip flexor weakness and/or finger flexor weakness greater than shoulder abductor weakness Serum CK not greater than 15x the upper limited of normal Endomysial inflammation and Rimmed vacuoles and Protein accumulation (amyloid or other proteins) Or Filaments 15–18 nm Clinically defined IBM One or more of the following: or Increased MHC-1 staining or Rimmed vacuoles or Protein accumulation (amyloid or other proteins) or Filaments 15–18 nm Probable IBM Endomysial exudate or increased MHC-1 staining

IBM

IBM-pathology CPK may be normal or mildly elevated EMG: myopathic, spontaneous activity, may have small and large polyphasic MUPs Muscle biopsy Similar to PM Rimmed vacuoles (with amyloid deposits) EM: tubuloreticular aggregates Plasma cells, MHCI, CD8+ Nondx bx in 20-30%

IBM-endomysial inflammation

IBM-inclusions

IBM treatment Relatively resistant Prednisone, methotrexate, azathioprine IVIG

Other Immune Myopathies Necrotizing Often with anti-SRP antibodies HMGCR antibodies U1-snRNP Anti-MAS Sarcoid GVHD Brachio-cervical inflammatory myopathy

Key Features of Inflammatory and Necrotizing Autoimmune Myopathies   Dermatomyositis Polymyositis Inclusion body myositis Necrotizing autoimmune myopathy Autoantibodies Antisynthetase antibodies (anti-Jo-1 and others) Dermatomyositis specific antibodies (anti-Mi-2 and others) Antibodies of systemic rheumatologic disease Possibly anti-cytosolic 5’-nucleotidase 1A (cN1A) Anti-SRP Anti-HMGCR Muscle enzymes Up to 50x ULN Up to 15x ULN Often >10x ULN Associated disorders Interstitial lung disease (antisynthetase) Malignancy (ovarian, lung, others) Systemic rheumatologic disorders None HMGCR – statin use Treatment Prednisone  Azathioprine Methotrexate Rituximab IVIG Others Prednisone

Toxic Myopathies Necrotizing: Amphiphilic drug myopathy: Cholesterol lowering agents Cyclosporine, tacrolimus Amphiphilic drug myopathy: Chloroquine Amiodarone Antimicrotubular myopathy: colchicine Non-specific: Steroids (type 2 atrophy) Drug-induced mitochondrial myopathy: Zidovudine (RRF)

SUSPECTED STATIN RELATED NEUROTOXICITY Statins: Highest risk: cerivastatin (withdrawn from market) and atorvastatin Intermediate risk: simvastatin, lovastatin, pravastatin, red yeast rice (similar to lovastatin) Lowest risk: fluvastatin Additional history: Is the patient taking a CYP3A4 inhibitor? (most common: clarithromycin, verapamil, diltiazem, cyclosporine A) Is the patient taking a fibrate? Could the patient be an asymptomatic carrier for a metabolic myopathy or mitochondrial disorder? Is the patient taking a proton pump inhibitor? (increased risk for polymyositis and dermatomyositis) CLINICAL SYNDROMES : Myalgias Cramps Asymptomatic hyperCKemia Rare: necrotizing myopathy, acute rhabdomyolysis/myoglobinuria/acute renal failure

TREATMENT OF STATIN-INDUCED MYOPATHY: Asymptomatic or mild hyperCKemia Can continue statin, monitor closely Drug cessation: most will resolve in 2-3 months Switch to a lower-risk statin If the symptoms persist or progressmuscle biopsy to look for underlying neuromuscular disorder or myositis Retrial with lower dose or less potent statin after period of recovery Acute rhabdomyolysis/myoglobinuria/renal failure: hospital admission, IV hydration, supportive measures, hemodialysis if needed Other: Risk/benefit analysis regarding need for statin Potential role for vitamin D, Coenzyme Q10

Critical Illness Myopathy First described 1980s Affects 1/3 to ½ of all critically ill Profound residual weakness (months to years) Often with CIP Criteria: Critically ill Limb weakness Difficulty weaning from vent Cardiac/pulm causes excluded CMAP amp <80% LLN without CB Normal SNAPs Myopathic EMG +/- fibs, PSWs No decrement on RNS Biopsy: myosin loss or necrosis CMAP duration prolonged

CIM-risk factors Sepsis SIRS MOF ARDS >1 wk ICU stay Prolonged mechanical ventilation Other: duration of vasopressor support, hyperglycemia, female sex, renal failure/ replacement therapy, TPN, low albumin

Copyright © 2014 American Medical Association. All rights reserved. From: Acute Skeletal Muscle Wasting in Critical Illness JAMA. 2013;310(15):1591-1600. doi:10.1001/jama.2013.278481 Figure Legend: outline) for green, and 4',6-diamidion-2-pheylidole (a nuclear marker) for blue. Date of download: 3/11/2014 Copyright © 2014 American Medical Association. All rights reserved.

Infectious Myopathies Bacterial Viral Mild, myalgias Severe with rhabdo: influenza, cocksackievirus, EBV, HSV, HIV, measles, dengue Chronic: echovirus w/ hypogammaglobulinemia, HIV Pathophysiology: direct muscle invasion vs cytokine response Parasitic