Four Major Types of Inflammatory Myopathy

Skin Findings (May Precede or Accompany Weakness)

Systemic Associations

• ILD: 20–40% of DM; especially with antisynthetase and MDA5 antibodies; can be rapidly fatal (RP-ILD with MDA5)
• Cardiac: Myocarditis, arrhythmias, conduction defects (uncommon but serious)
• Malignancy: 10–15% in adults >40 years; ovarian, lung, GI, breast, lymphoma — risk highest in first 3 years after diagnosis
• Amyopathic DM (CADM): Classic skin findings WITHOUT significant weakness; still at risk for ILD and malignancy

Myositis-Specific Antibodies in DM

Overview

• Definition: Subacute proximal symmetric weakness WITHOUT skin rash or inclusion bodies
• CK: Elevated 10–50× normal
• EMG: Irritable myopathy (fibrillations, positive sharp waves, short-duration polyphasic MUAPs, early recruitment)
• Pathology: Endomysial CD8+ cytotoxic T lymphocytes invading non-necrotic muscle fibers; MHC-I upregulation on non-necrotic fibers (also seen in IBM and DM)
• Now rare: True PM accounts for <5% of inflammatory myopathies after reclassification of IMNM and IBM

Diagnostic Requirements (Diagnosis of Exclusion)

• Rule out IBM (check for distal weakness, rimmed vacuoles)
• Rule out IMNM (check SRP, HMGCR antibodies; review biopsy for necrosis pattern)
• Rule out muscular dystrophy (especially LGMD — genetic testing if atypical)
• Rule out DM (no skin findings; no perifascicular atrophy on biopsy)
• Must have endomysial CD8+ T cell infiltrate invading non-necrotic fibers on biopsy

Overview

• Presentation: Acute/subacute severe proximal symmetric weakness
• CK: Very high — often >10,000 IU/L (highest among inflammatory myopathies)
• Pathology: Necrosis and regeneration with minimal or absent inflammatory infiltrate; MAC deposition on capillaries
• Mechanism: Complement-mediated — antibodies target muscle fiber surface proteins

IMNM Antibodies

Treatment

• Aggressive immunosuppression required: Steroids alone often insufficient
• Typical regimen: Prednisone + IVIg + steroid-sparing agent (methotrexate, azathioprine, or mycophenolate)
• Refractory cases: Rituximab; some require triple therapy (steroids + IVIg + rituximab)
• HMGCR-positive: Discontinue statin (but weakness persists — statin removal alone is not sufficient)
• Monitor CK as a treatment response marker (CK normalizes before strength improves)

Overview

• Most common inflammatory myopathy in patients >50
• Male predominance (M:F ratio 3:1)
• Insidious onset over years (not weeks–months like DM/PM/IMNM)
• CK: Mild elevation (1–10× normal) — CK may even be normal

Characteristic Weakness Pattern

• Asymmetric involvement is characteristic (unlike DM/PM/IMNM)
• Combined proximal + distal weakness (unlike DM/PM which are purely proximal)

Pathology

• Rimmed vacuoles (on modified Gomori trichrome stain) — hallmark finding
• Intracellular inclusions: amyloid-β, phosphorylated tau, TDP-43, p62
• Endomysial CD8+ T cells (similar to PM) + degenerative features (unique to IBM)
• Combined inflammatory + degenerative pathology — explains treatment resistance

Diagnostics

• Anti-cN1A (anti-cytosolic 5′-nucleotidase 1A): Positive in ~33–50% of IBM (up to 60% in some series); supports diagnosis but not 100% specific (can be positive in Sjögren syndrome, SLE)
• EMG: Mixed myopathic + neuropathic features (long-duration MUAPs in a myopathy = IBM clue)
• MRI: Selective atrophy/fatty replacement of quadriceps and forearm flexors

Treatment

• No proven effective immunotherapy — steroids, IVIg, methotrexate, and rituximab have all failed in trials
• Exercise and physical therapy — the most important intervention; resistance training slows functional decline
• Dysphagia management: Speech therapy, dietary modifications, cricopharyngeal dilation or myotomy for severe cases
• Assistive devices for mobility and ADLs

Clinical Features

• Classic hexad: Myositis + ILD + arthritis + Raynaud phenomenon + mechanic’s hands + fever
• Not all features need to be present — ILD or arthritis may be the dominant/presenting manifestation
• ILD may dominate over myositis — some patients have minimal weakness but severe lung disease

Antisynthetase Antibodies

Treatment

• Steroids (prednisone 1 mg/kg) as initial therapy
• Steroid-sparing agent: Mycophenolate preferred for ILD component; azathioprine or methotrexate for myositis-predominant disease
• Rituximab for refractory cases (especially ILD)
• Avoid methotrexate if significant ILD (risk of pulmonary toxicity)

Key Biopsy Findings by Disease

Granulomatous Myositis (Sarcoid Myopathy)

• Setting: Muscle involvement in systemic sarcoidosis (clinically symptomatic in ~1.4%; subclinical on biopsy in up to 50–80% of sarcoid patients)
• Phenotypes: Chronic myopathic (proximal weakness, atrophy), nodular (palpable muscle nodules), or acute myositis-like
• Biopsy: Non-caseating granulomas within muscle (epithelioid histiocytes, multinucleated giant cells, surrounding lymphocytes)
• Differential: Other granulomatous causes — tuberculosis, fungal infection, foreign body, IBM (rare granulomatous variant)
• Treatment: Corticosteroids (prednisone) first-line; steroid-sparing agents (methotrexate, azathioprine) or anti-TNF (infliximab) for refractory cases

Eosinophilic Myositis

• Causes: Hypereosinophilic syndrome, parasitic infection (trichinosis, cysticercosis), drug reactions (DRESS), eosinophilic granulomatosis with polyangiitis (EGPA), idiopathic
• Presentation: Myalgia, proximal weakness, peripheral eosinophilia; may have skin or systemic features
• Biopsy: Eosinophilic inflammatory infiltrate within muscle (endomysial or perimysial); fiber necrosis variable
• Treatment: Treat underlying cause (antiparasitic for trichinosis, withdraw offending drug, etc.) plus corticosteroids for inflammatory component

Toxic Statin Myopathy (Distinct from Anti-HMGCR IMNM)

• Mechanism: Direct toxic effect of statins on muscle (mitochondrial dysfunction, CoQ10 depletion) — NOT autoimmune
• Presentation: Myalgia, cramps, mild proximal weakness; CK usually mildly elevated (rarely rhabdomyolysis)
• Antibodies: No autoantibodies (anti-HMGCR negative)
• Biopsy: Mild necrosis or essentially normal; no significant inflammation or MAC deposition
• Course: Self-limited — resolves on statin withdrawal within weeks
• Treatment: Discontinue statin; NO immunosuppression needed
• Key distinction from anti-HMGCR IMNM: Toxic statin myopathy resolves with drug withdrawal alone; anti-HMGCR IMNM persists/progresses after statin withdrawal and requires immunosuppression

Hydroxychloroquine / Chloroquine Vacuolar Myopathy

• Mechanism: drug accumulates in lysosomes (cationic amphiphilic) → impaired autophagy → vacuolar myopathy. Distinct from the postsynaptic NMJ-blocking effect that worsens MG.
• Setting: long-term antimalarial/rheumatology therapy (SLE, RA, dermatomyositis); often coexists with hydroxychloroquine retinopathy and cardiomyopathy.
• Presentation: slowly progressive proximal weakness; CK normal or only mildly elevated.
• Biopsy: vacuolar myopathy with autophagic/rimmed vacuoles. Electron microscopy: curvilinear bodies (pathognomonic) and myeloid (concentric lamellar) bodies.
• Course: reversible on drug discontinuation; cardiac involvement may persist.

Overlap Myositis

• Definition: Myositis occurring in the context of another connective tissue disease (CTD)
• Associated CTDs: SLE, systemic sclerosis (scleroderma), mixed connective tissue disease (MCTD), Sjögren syndrome, rheumatoid arthritis
• Key antibodies:
  • Anti-PM/Scl — PM-scleroderma overlap; myositis + sclerodermatous skin changes + ILD
  • Anti-U1-RNP — MCTD (overlap of SLE, scleroderma, PM); Raynaud, swollen hands, myositis
  • Anti-Ku — PM-scleroderma or PM-SLE overlap; ILD common
• Treatment: Corticosteroids + steroid-sparing agent tailored to CTD features (e.g., MMF for ILD/scleroderma overlap)

ENMC Criteria (Reference)

• Lloyd et al. 2014 (ENMC): Clinico-pathologic diagnostic criteria for inclusion body myositis — categories of clinico-pathologically defined IBM, clinically defined IBM, and probable IBM based on weakness pattern (finger flexors, quadriceps), age, duration, CK, and biopsy features
• Allenbach et al. 2018 (ENMC): Clinico-sero-pathologic classification of immune-mediated necrotizing myopathies — three subgroups (anti-SRP, anti-HMGCR, seronegative) defined by clinical features, CK level, and necrotizing biopsy pattern
• Both criteria sets are the current standards referenced in board exams and clinical trials

Treatment by Disease

Steroid-Sparing Agents

Cancer Screening in DM (2023 IMACS Guideline — Risk-Stratified)

• All adult-onset IIM (especially DM) warrant cancer screening, but per the 2023 IMACS guideline this is now risk-stratified rather than universal extensive
• Risk stratification: high-risk = adult-onset DM with anti-TIF1γ (especially age >40), anti-NXP2, or other high-risk clinical features (dysphagia, cutaneous necrosis, older age, male sex); intermediate/standard-risk = other adult DM/IIM
• Basic screening (history/exam, basic labs, age-appropriate sex-specific screens such as mammography/colonoscopy/cervical screening) at diagnosis and annually for 3 years for all adult DM/IIM
• Enhanced screening for HIGH-RISK patients at diagnosis — CT chest/abdomen/pelvis, transvaginal pelvic ultrasound (women), CA-125, age-appropriate evaluation; PET-CT is reserved for selected high-risk patients (not universal)
• Highest cancer-risk antibodies: TIF1-γ (~35–40% malignancy in adults >40) and NXP-2 (~20–30%); low-risk antibodies (Mi-2, MDA5, antisynthetases, SAE) do NOT mandate the enhanced screening tier