Inflammatory Myopathies

Inflammatory myopathies are a group of immune-mediated muscle diseases characterized by inflammation, muscle weakness, and elevated creatine kinase. The major entities are polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), and immune-mediated necrotizing myopathy (IMNM). Each has distinctive clinical, serologic, and histopathologic features that have been refined by the discovery of myositis-specific autoantibodies. Recognition and classification matter because treatment differs substantially across the entities. This page covers the inflammatory myopathies and their pathology.

Classification

• Polymyositis (PM).
• Dermatomyositis (DM).
• Inclusion body myositis (IBM).
• Immune-mediated necrotizing myopathy (IMNM).
• Overlap myositis: with other connective tissue diseases.
• Antisynthetase syndrome: anti-synthetase antibodies + ILD + Raynaud + mechanic’s hands.
• Juvenile dermatomyositis.

Polymyositis (PM)

Pathology

• Endomysial CD8+ T-cell infiltrate: surrounds and invades non-necrotic fibers.
• MHC class I expression on sarcolemma of muscle fibers (normally absent in adult muscle).
• Fiber necrosis and regeneration.
• No vacuolar / inclusion features (distinguishing from IBM).
• Endomysial fibrosis.

Clinical

• Adult onset (often 40s-50s).
• Proximal weakness, often symmetric.
• Dysphagia in some.
• No skin involvement (distinguishing from DM).
• Often associated with antisynthetase antibodies, ILD, Raynaud, mechanic’s hands.
• Sometimes paraneoplastic (especially in older patients).

Antibodies

• Anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, etc. (antisynthetase antibodies).
• Anti-SRP (signal recognition particle): now reclassified as IMNM.

Treatment

• Corticosteroids first-line.
• Steroid-sparing: methotrexate, azathioprine, mycophenolate.
• IVIG.
• Rituximab in refractory cases.

Dermatomyositis (DM)

Pathology

• Perifascicular atrophy: the histologic hallmark; small fibers at fascicle borders.
• Perivascular inflammation: CD4+ T cells and B cells in perimysium and around vessels.
• Complement deposition on capillaries (membrane attack complex, MAC).
• Capillary loss.
• Vasculopathy with vessel changes.
• Type I interferon signature: upregulation of interferon-induced genes (e.g., MxA) in muscle.
• Fiber necrosis and regeneration.

Clinical

• Proximal weakness.
• Heliotrope rash: violaceous discoloration of eyelids.
• Gottron papules: erythematous papules over knuckles.
• V-sign, shawl sign: erythema in V of neck or upper back.
• Mechanic’s hands: fissured, hyperkeratotic skin on fingers.
• Calcinosis cutis: in juvenile DM especially.
• ILD, cardiac involvement.
• Increased malignancy risk (especially ovarian, GI, lung, breast — anti-TIF1γ associated).

Antibodies

• Anti-Mi-2: classic DM with skin findings.
• Anti-MDA5: amyopathic DM + severe ILD.
• Anti-TIF1γ: increased malignancy risk.
• Anti-NXP2: calcinosis.
• Anti-SAE.

Treatment

• Corticosteroids + immunosuppressive (similar to PM).
• IVIG (especially for severe/refractory).
• Hydroxychloroquine for skin.
• Rituximab.
• JAK inhibitors emerging.

Inclusion Body Myositis (IBM)

Pathology

• Endomysial T-cell infiltrate: similar to PM.
• MHC class I expression on sarcolemma.
• Rimmed vacuoles: small intracytoplasmic vacuoles with basophilic granular material lining them.
• Eosinophilic inclusions in some fibers.
• 15-18 nm tubulofilaments on electron microscopy: characteristic.
• p62, TDP-43, LC3 inclusions on IHC: protein aggregation features.
• Increasing congo red positivity (amyloid-like material).
• Fiber necrosis and regeneration variable.

Clinical

• Older patients (often > 50, often male).
• Distal and proximal weakness: classical pattern of finger flexor + quadriceps weakness.
• Dysphagia common.
• Slowly progressive over years.
• CK mildly to moderately elevated (or normal).
• Refractory to immunosuppression: distinguishing clinical feature.

Antibodies

• Anti-cN1A (anti-cytosolic 5′-nucleotidase 1A): highly specific for IBM (60-70%).

Treatment

• Generally refractory.
• Modest trials of immunosuppression and IVIG; benefits limited.
• Physical therapy.
• Falls prevention.

Immune-Mediated Necrotizing Myopathy (IMNM)

Pathology

• Extensive fiber necrosis and regeneration: characteristic.
• Macrophage infiltration: predominant inflammatory cell.
• Minimal lymphocytic infiltration: distinguishes from PM/DM.
• MAC deposition on sarcolemma of non-necrotic fibers.
• Often with marked CK elevation.

Subtypes by Antibody

• Anti-HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase): statin-associated necrotizing myopathy (statin exposure history; persists after statin discontinuation).
• Anti-SRP (signal recognition particle): severe weakness; cardiomyopathy.
• Seronegative IMNM: subset; may have other antibodies or associations.

Clinical

• Subacute severe proximal weakness.
• CK > 5,000-10,000 often.
• Statin exposure history (HMGCR).
• Sometimes paraneoplastic.

Treatment

• Stop statin (for HMGCR myopathy).
• Corticosteroids + steroid-sparing + IVIG.
• Often refractory; rituximab in resistant cases.

Distinguishing Features Summary

Other Inflammatory Conditions

• Sarcoidosis (muscle involvement): granulomatous inflammation.
• Eosinophilic myopathy: eosinophilic infiltration; trichinosis, drug-induced, idiopathic.
• Focal myositis: localized inflammation.
• Infectious myositis: viral (Coxsackie, influenza), parasitic (trichinosis), bacterial (rare).
• Drug-induced: statins (can be inflammatory, necrotizing, or toxic), zidovudine (mitochondrial), colchicine.
• Immune checkpoint inhibitor-related myositis: increasing recognition with PD-1/PD-L1 inhibitors.

🔍 Did You Know?

The discovery of myositis-specific autoantibodies has transformed our understanding and management of inflammatory myopathies. Before specific antibodies were identified, polymyositis and dermatomyositis were lumped together clinically and pathologically — with treatment essentially the same. The recognition of distinct antibody profiles has revealed clinical syndromes that align with specific antibodies more than with the classical PM vs DM distinction. For example: anti-MDA5 antibody dermatomyositis is often amyopathic but associated with severe rapidly progressive interstitial lung disease — and requires aggressive immunosuppression even though muscle weakness may be minimal. Anti-TIF1γ dermatomyositis in adults carries substantially increased cancer risk and prompts cancer screening. Anti-HMGCR necrotizing myopathy from statin exposure persists after statin discontinuation and requires immunosuppression. Anti-SRP necrotizing myopathy has severe muscle weakness and cardiomyopathy. Anti-cN1A antibody is highly specific for inclusion body myositis. Each antibody tells a story about likely clinical features, associated systemic findings, and treatment approach. The modern classification of inflammatory myopathies thus integrates clinical phenotype, antibody status, and histologic pattern into an integrated diagnosis — much like the modern integrated diagnosis of CNS tumors. The lesson: antibody testing should be done routinely in inflammatory myopathies, and the results inform both diagnosis and management.

Pitfalls and Pearls

• PM: endomysial CD8+ T-cell infiltrate + MHC-I sarcolemmal; symmetric proximal; steroid responsive.
• DM: perifascicular atrophy + perivascular CD4+ inflammation + complement + capillary loss; skin findings.
• IBM: rimmed vacuoles + 15-18 nm filaments + p62/TDP-43 inclusions; distal/proximal asymmetric; steroid refractory.
• IMNM: extensive necrosis + macrophages + minimal T-cells; anti-HMGCR or anti-SRP.
• Antisynthetase syndrome: anti-Jo-1 etc + ILD + Raynaud + mechanic’s hands.
• Anti-MDA5 DM: amyopathic + severe ILD.
• Anti-TIF1γ DM: cancer risk; screen.
• Heliotrope rash + Gottron papules: DM.
• Anti-HMGCR myopathy: statin-induced; persists after statin stop; immunosuppression needed.
• Anti-cN1A: highly specific for IBM.
• IBM finger flexor + quadriceps weakness: characteristic pattern.
• MHC-I sarcolemmal expression: marker of inflammatory myopathy (PM, DM, IBM).
• Perifascicular atrophy: DM hallmark.
• Rimmed vacuoles: IBM, OPMD, distal myopathies.
• Immune checkpoint inhibitor myositis: anti-PD-1 era; often severe; immunosuppression needed.

References

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2. Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med. 2016;374(7):664-669.
3. Allenbach Y, Mammen AL, Benveniste O, Stenzel W; Immune-Mediated Necrotizing Myopathies Working Group. 224th ENMC International Workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies. Neuromuscul Disord. 2018;28(1):87-99.
4. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292(7):344-347.
5. Greenberg SA. Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol. 2019;15(5):257-272.
6. Selva-O’Callaghan A, Pinal-Fernandez I, Trallero-Araguás E, Milisenda JC, Grau-Junyent JM, Mammen AL. Classification and management of adult inflammatory myopathies. Lancet Neurol. 2018;17(9):816-828.