CH. 369: POLIOMYOSITIS (PM), DERMATOMYOSITIS (DM) & INCLUSION BODY MYOSITIS (IBM) The inflammatory myopathies, classified into 3 groups: a.) DM, b.) PM, c.

) IBM, represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness. Clinical Features

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DM: children> adults, F> M IBM: M> F, Caucasian> Blacks, persons >50 y/o These disorders present as progressive, symmetric muscle weakness Increasing difficulty with tasks requiring use of proximal muscles (i.e.climbing steps, combing hair) Fine-motor movements that depend on strength of distal muscles: late in PM and DM; early in IBM Falling is common in IBM due to early involvement of quadriceps muscles with buckling of knees Ocular muscles are spared Facial muscles: unaffected in PM and DM; mild weakness in IBM All forms: pharyngeal and neck flexor muscles are involved causing dysphagia or difficulty in holding head up (head drop) Respiratory muscles involved in advanced and rarely acute cases Severe weakness if untreated associated with muscles wasting Sensation: normal Tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles especially in IBM, where atrophy of distal muscles and quads are common Myalgia and muscle tenderness may occur early in disease particularly in DM associated with CT disorders Weakness progression: subacutely over weeks/months, rarely acutely in PM and DM; very slowly (years) stimulating a late-life muscular dystrophy or progressive motor neuron disorder in IBM

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Identified by characteristic rash, accompanying or preceding muscle weakness Rash, which worsens after sun exposure, may present as: o Heliotrope Rash: blue-purple discoloration on upper eyelids with edema o Gottron Rash: erythema on knuckles with raised violaceous scaly eruptions o V sign: erythematous rash on neck and anterior chest o Shawl Sign: rash on back and shoulders o Flat red rash on face and upper trunk, knees, elbows, malleoli Rash may be pruritic, especially on scalp, chest, and back Dilated capillary loops at the base of the fingernails Mechanic’s hands: irregular, thickened and distorted cuticles; lateral and palmar areas of finger are rough and cracked, with irregular “dirt” horizontal lines Muscle strength may appear normal, hence, the term: dermatomyositis sine myositis Usually occurs alone but may overlap with scleroderma and mixed CT disease Fasciitis and thickening of the skin similar to that seen in chronic cases have occurred in patients with eosinophilia-myalgia syndrome associated with ingestion of contaminated L-tryptophan

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C. Inclusion Body Myositis • Most common of the inflammatory myopathies among 50 years old and above • Often misdiagnosed as PM and only suspected later when presumed PM does not respond to therapy • Weakness and atrophy of distal muscles, especially foot extensors and deep finger flexors (clue to early diagnosis) • Knees collapse due to early quadriceps weakness • Weakness in small muscles of the hands leading to inability to hold objects

Specific Features A. Polymyositis • Actual onset not easily determined • Patients delay seeking medical advice • Mimics many other myopathies and is diagnosis of exclusion

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Subacute inflammatory myopathy affecting adults, rarely children, who do not have any of the ff: o Rash o Involvement of extrocular and facial muscles o Family hx of neuromuscular disease o History of exposure to myotoxic drugs or toxins o Endocrinopathy o Neurogenic disease o Muscular dystrophy o Biochemical muscle disorder (muscle enzyme deficiency) o IBM as excluded by muscle biopsy analysis Occurs in association with systemic, autoimmune , or connective tissue disease, or with known viral or bacterial infection Drugs (i.e. D-penicillamine, zidovudine (AZT)) may produce inflammatory myopathy similar to PM

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Occasionally, weakness and atrophy may be asymmetric and selectively involve the quads, iliopsoas, triceps, biceps and finger flexors, resembling LMN disease Dysphagia may occur leading to choking Sensory exam: normal Mildly diminished vibratory sensation at the angles presumable age-related Pattern of distal weakness (resemble motor neuron or peripheral nerve disease) results from myopathic process affecting distal muscles Disease progression is slow Most require assistive devices such as cane, walker Familial Inflammatory IBM: familial aggregation of typical IBM Hereditary IBM (h-IBM): heterogenous group of recessive, less frequently dominant inherited syndrome; non-inflammatory myopathies Subset of h-IBM: spares quadriceps linked to chromosome 9p1 and results from mutations in the GNE gene

Associated Clinical Findings A. Extramuscular Manifestations - may present to varying degree in PM or DM, including: 1. Systemic symptoms: fever, malaise, Raynaud’s phenomenon especially when associated with CT disorder

B. Dermatomyositis

2. Joint contracture, mostly in DM and especially children 3. Dysphagia and GI symptoms due to involvement of oropharyngeal striated muscles and upper esophagus especially in DM and IBM 4. Cardiac disturbances: including AV conduction defects, tachyarrythmas, dilated cardiomyopathy, and low ejection fraction. CHF and myocarditis from diseases itself or from HPN due to use of glucocorticoids 5. Pulmonary dysfunction: due to weakness of thoracic muscles, interstial lung disease, or drug –induced pneumonitis that can cause dyspnea, aspiration pneumonia, nonprod. Cough 6. Subcutaneous calcifications: in DM, extruding on skin and causing ulcerations and infections B. Association with Malignancies • o o o

and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces Occurrence of endothelial cell necrosis, decreased endomysial capillaries, ischemia and muscle-fiber destruction Remaining capillaries have dilated lumens due to ischemia Residual perifascicular atrophy reflects endofascicular hypoperfusion that is prominent in periphery of muscle fascicles

Increased only in patients with DM, not in PM or IBM Most common tumors associated with DM: ovarian CA, breast CA, melanoma, colon CA and nonHodgkin lymphoma Tumors are usually uncovered by abnormal findings in the history and P.E. Common annual P.E. (urinalysis, CBC, CXR, pelvic, breast exam) would suffice Nasopharyngeal CA: common in Asians

PM and IBM o T cell mediated cytotoxicity o CD8 t cells with macrophages invade and destroy healthy muscle fibers that express class I MHC o Cytokines secreted induces MHC-I expression o CD8/MHC-I complex characteristic of PM and IBM o Cytotoxic CD8 T cells contain perforin and granzyme granules directed towards muscle fibers inducing myonecrosis

C. Role of Non-immune Factors in IBM

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C. Overlap Syndromes • Association with CT diseases

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DM can have manifestations of systemic sclerosis or mixed CT disease (i.e. calcium deposits, contractures) Signs of R.A., SLE, or Sjoregren’s syndrome rare in DM DM + systemic sclerosis: have specific ANA, the anti-PM/Scl

Presence of vacuoles with B-amyloid deposits within vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase-negative fibers suggest autoimmune component and degenerative process Amyloid deposits are immunoreactive against amyloid precursor protein (APP), chymotrypsin, apolipoprotein E, and phosphorylated tau. Mitochodrial abnormalities secondary to aging or bystander effect of upregulated cytokines with Viral Infections and Role of

D. Association Retroviruses

Pathogenesis -an autoimmune etiology is indirectly supported by association with other CT diseases; presence of autoantibodies, association with MHC; demonstration of T cell-mediated myotoxicity or complement-mediated microangiopathy; & response to immunotherapy. A. Autoantibodies and Immunogenetics

Coxsackieviruses: autoimmune myositis triggered by molecular mimicry due to structural homology between histidyl-transfer RNA synthetase that is target of Jo-1 antibody and genomic RNA of encephalomyocarditis virus Retroviruses: best evidence of viral connection in PM and IBM; distinguished from toxic myopathy related to long-term therapy with AZT (inhibits yDNA polymerase, an enzyme found in mitochondrial matrix) o AZT-induced myopathy: mitochondrial disorder characterized by “ragged red” fibers

Antibodies to cytoplasmig antigens are directed against riboucleoprotiens involved in protein synthesis (anti-synthetase) or translational transport (anti-signal-recogntion particles) Anti-Jo-1: Ab directed against histidyl-transfer RNA synthetase with majority of patients having interstitial lung disease; accounts for 75% of all anti-synthetases May also have Raynaud’s phenomenon, nonerosive arthritis and MHC molecules DR3 and DRw52

Differential Dx • Skin rash w/ proximal or diffuse muscle weakness has few causes other than DM • Proximal weakness w/ out rash has many causes other than PM or IBM A. Subacute or Chronic Progressive Muscle Weakness • Denervating muscle conditions Spinal musclular atrophies Amytrophic Lateral Sclerosis Weakness followed by UMN signs and denervation on EMG • Muscular Dystrophy Rare over 30 y/o Develop over years no months • Difficult to differentiate chronic PM vs rapidly advancing muscular dystrophy even with biopsy Ex- facioscapulohumeral muscular dystrophy, dsyferlin myopathy, and dystrophinopathies all with early inflammatory cell infiltrate Dx- glucocorticoid trial tx and detection of MHC/CD8 by immunohistochem

B. Immunopathologic Mechanisms • DM o Humoral immune mechanisms, resulting in microangiopathy and muscle ischemia o Endomysial inflammatory infiltrates composed of B cells located in proximity to CD4 T cells and macrophages o Relative absence of lymhocytic invasion of nonnecrotic muscle fibers o Complement C5b-9 membranolytic attack complex activation triggers release of cytokines and chemokines, induce expression of VCAM 1 and ICAM1 on endothelial cells,

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Metabolic myopathies dx via muscle biopsy: glycogen storage disease due to myophosphorylase or acid maltase deficiency lipid storage myopathy due to carnitine deficiency mitochondrial diseases Endocrine myopathy hypercorticosteroidism hyper/ hypothyroidism hyper/ hypoparathyroidism Muscle wasting w/ neoplasm due to cachexia, disuse, rare to paraneoplastic myopathy NMJ diseases myasthenia gravis Lambert Eaton Myasthenic syndrome both with fatiguing weakness, eye and cranial nerve weakness dx- repetitive nerve stimulation and EMG

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associated with Amphotericin B, aminocaproic acid, fenfluramine, heroin Myopathic muscle weakness use of amiodarone, chloroquine, colchicines, carbimazole, emetine, etretinate, ipecac syrup, chronic laxative or licorice use causing hypokalemia, and glucocorticoid or growth hormone administration Pancuronium w/ glucocorticoid cause acute critical illness myopathy Careful drug Hx is necessary Immunosuppressive Tx is NOT necessary


E. Pain on Movement and Muscle Tenderness

Polymyalgia rheumatica and arthritic disorders of adjacent joints cause inflammatory myopathy without myositis Normal Biopsy or Type II muscle fiber atrophy FIbrositis and Fibromyalgia present as: 1. Focal/ diffuse muscle tenderness, fatigue, aching 2. Signs of collagen vascular disorder like increased ESR, antinuclear antibody, or rheumatoid factor 3. Slight but transient increase in serum CK Muscle biopsy Normal and prognosis good Respond to NSAIDS but with continued indolent pain Chronic Fatigue Syndrome Follow viral infection Debilitating fatigue, fever, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, headache No muscle weakness Normal biopsy

B. Acute Muscle Weakness • Guillain Barre Syndrome, transverse myelitis, a neurotoxin, or viral infection such as polio or West nile virus • Acute weakness + painful muscle cramps, rhabdomylosis, myoglobinuria Metabolic disorders including glycogen storage disease such as myophosphorylase deficiency or carnitine palmityltransferase deficiency • Acute viral infection

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Parasites, Parasitic polymyositis protozoa (toxoplasma, trypanosome) cestodes (cysticerci) nematodes (trichinae) with focal or diffuse inflammatory myopathy Anaerobic suppuroative myositis aka Tropical polymyositis Staph Aureus, Yersinia, and Strep Begins in childhood= periodic paralysis developing into recurrent painless acute muscle weakness Chronic Alcoholics present as: 1. Painlful myopathy with myoglobinuria 2. Painless, acute hypokalemic, reversible myopathy 3. Asymptomatic Inc serum CK and myoglobin Diff Dx of acute muscle weakness w/ myoglobinuria is severe hypokalemia or hypophosphatemia (+) hypomagnesia Also common in px w/ parenteral hyperalimentation

C. Macrophagic Myofasciitis • Inflammation w/ diffuse myalgia, fatigue, mild muscle weakness • Biopsy shows connective tissue infiltration with CD8 and PAS positive macrophages • Limited to France and to previous sites of vaccine w/ aluminum containing substrate D. Drug Induced Myopathies • Resembles true PM from D-Penicillamine and procainamide • DM-like with L-tryptophan • AZT causes mitochondrial myopathy • Toxic noninflammatory myopathy is histologically different from PM, DM, or IBM: Cholesterol lowering clofibrate, lovastatin, simvastatin, provastatin esp when combined w/ cyclosporine or gemfibrozil may elicit this reaction • Rhabdomylosis and myoglobinuria

Diagnosis • Dx PM, DM, or IBM by examining muscle enzymes, EMG, and muscle biopsy • Most sensitive enzyme is CK. Increases 50x in active disease Levels parallel disease activity Can be normal in IBM or DM especially with Connective tissue disease Always elevated in PM • EMG findings Short duration, low amp polyphasic units on voluntary activation Fibrillations, complex repetitive discharges, positive sharp waves on increased spontaneous activity Mixed (polyphasic with short and long duration) indicate chronic process or fiber regeneration often seen in IBM Not diagnostic Differentiate chronic vs active Exclude neurogenic disorders • MRI not routine but used to guide during biopsy • Muscle biopsy definitive test for Dx of inflammatory myopathy 1. PM: Primary inflammation with T cell infiltrates, within muscle fascicles (endomysial) surrounding individual healthy fibers causing necrosis and phagocytosis. CD8/MHC-I lesion fundamental for dx. Chronic PM has inc connective tissue and positive reaction with alkaline phosphatase 2. DM: Endomysial inflammation is perivascular or interfascicular septae. Intramuscular blood vessels show endothelial hyperplasia w/ tuboreticular profiles, fibrin thrombi, obliteration of capillaries. Dx for DM, are microinfarcts w/ in muscle resulting to perfascicular atrophy (2 to 10 layers of


atrophy at the periphery) even without inflammation. IBM: Endomysial inflammation with T cell invading MHC-I nonvacuolated fibers. Or basophilic granules around slit like vacuole (rimmed) with filamentous inclusion seen on EM. Normal fibers replaced with connective tissue, hypertrophic fibers, and angulated or round fiber. May have eosinophilic grandules, or abnormal mitochondria with ragged red fibers.


IVIg with minimal benefit. May be used to halt progression of choking episodes due to dysphagia

Treatment • Goal= improve muscle strength, improve functioning via ADL, and ameliorate extramuscular manifestations. • CK levels decrease with improved strength. However do not just decrease levels without improving muscle strength. • Agents for PM and DM: 1. Glucocorticoids Oral is initial tx Use determined by efficacy and side effects High does 1mg/kg/day initially After 3 to 4 weeks taper for 10 weeks to lowest possible - ADL better usually by 3rd month If no response after 3 months, discontinue DM respond better than PM - Steroid therapy is long term use causing increased weakness and normal or unchanged CK levels 2. Other Immunosuppressive drugs 75% require additional tx Occurs w/ prednisone associated complications such as resistance, adverse side effects, relapse, or rapidly progressive disease with respi failure Azathioprine is well tolerated with few side effects. 3mg/kd/day Methotrexate has faster onset. Associated with Jo- 1 anitbody MTX pneumonitis. Cyclophosphamide with significant toxicity Cyclosporine is inconsistent with mild benefit Mycophenolate Mofetil Immunomodulation Good with refractory DM IVIg improve strength and rash Short lived benefit (<8 weeks)

Prognosis • 5 year survival rate for PM and DM is 95% • 10 year survival rate is 84% • Death from cardiac, pulmo, or other systemic causes • Worse prognosis in patients with delayed tx, severe dysphagia or respi conditions, older px, and those with associated cancer • DM responds better and thus better prognosis than PM • 30% with residual weakness even after tx • Relapse may occur at any time • IBM worst prognosis Most require cane, walker, wheelchair within 5 to 10 years of onset Older age of onset of IBM, more rapidly progressive course



Recommended Empirical Approach 1. Step1- high does prednisone 2. Step2- AZT or MTX 3. IVIg 4. Trial with guarded optimism based on patient’s age, degree of disability, tolerance, experience with drug, and general health. Possible are cyclosporine, chlorambucil, cyclophosphamide (px w/ insterstitial lung disease), or mycophenolate. Patient with PM who doesn’t respond to any immunotherapy most likely has IBM. Associated with DM, Calcinosis, is difficult to treat. IBM generally resisitant to immunosuppressive tx. Prednisone with AZT or MTX for a few months in newly diagnosed pax Maintain on low dose, every other day prednisone or weekly MTX

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