What is the etiology of myositis?

Etiology of Myositis

Myositis is primarily caused by autoimmune mechanisms, immune checkpoint inhibitor therapy, infections, medications, malignancies, and connective tissue diseases, with specific antibody profiles often correlating with distinct clinical phenotypes. 1, 2, 3

Primary Etiological Categories

1. Autoimmune Mechanisms

• Idiopathic inflammatory myopathies (IIMs) represent the most common form of myositis
• Characterized by autoimmune responses to nuclear and cytoplasmic autoantigens 4
• Approximately 60% of patients with IIMs have myositis-specific autoantibodies (MSAs) 5:
  • Anti-synthetase antibodies
  • Anti-Mi-2 antibodies
  • Anti-MDA5 antibodies
  • Anti-TIF1 antibodies
  • Anti-SRP antibodies

2. Medication-Induced Myositis

• Immune Checkpoint Inhibitors (ICPis)
  • More common with PD-1/PD-L1 inhibitors than with ipilimumab 1
  • Can present as reactivation of preexisting paraneoplastic polymyositis/dermatomyositis or as de novo myositis
  • Can have a fulminant necrotizing course with rhabdomyolysis and potentially fatal complications
• Other Medications
  • Statins (particularly associated with immune-mediated necrotizing myopathy)
  • Newer classes of medications 6

3. Infectious Causes

• Viral infections:
  • Influenza
  • HIV
  • SARS-CoV2
  • Other viral pathogens 3
• Bacterial and parasitic infections can also trigger myositis

4. Malignancy-Associated Myositis

• Paraneoplastic phenomenon
• Particularly associated with dermatomyositis
• Requires specific screening and management approaches 3

5. Overlap Syndromes

• Myositis occurring in conjunction with other rheumatologic diseases:
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Systemic sclerosis
  • Mixed connective tissue disease 3

Pathophysiological Mechanisms

The pathogenesis varies based on the specific type of myositis:

1. Dermatomyositis:

   • Complement-mediated microangiopathy
   • Perifascicular atrophy
   • CD4+ T cells and B cells predominate 7

2. Polymyositis:

   • Cell-mediated cytotoxicity
   • CD8+ T cells invade non-necrotic muscle fibers 7

3. Immune-Mediated Necrotizing Myopathy:

   • Macrophage-mediated muscle fiber damage
   • Minimal inflammatory infiltrates
   • Often associated with anti-SRP or anti-HMGCR antibodies 2

4. Inclusion Body Myositis:

   • Combination of inflammatory and degenerative processes
   • Rimmed vacuoles and protein aggregates 7

Clinical Correlation with Etiology

The clinical presentation often provides clues to the underlying etiology:

• Proximal muscle weakness with elevated CK levels:

  • Characteristic of most inflammatory myopathies
  • Particularly pronounced in immune-mediated necrotizing myopathy 2

• Skin manifestations:

  • Gottron's papules, heliotrope rash: Dermatomyositis
  • May indicate underlying malignancy or connective tissue disease

• Timing in relation to medication exposure:

  • ICPi-induced myositis can occur at any time during treatment 1
  • Statin-associated myopathy typically develops within months of initiation or dose increase

• Associated symptoms:

  • Interstitial lung disease: Often seen with anti-synthetase syndrome
  • Arthritis: Common in overlap syndromes
  • Dysphagia: Can indicate more severe disease

Diagnostic Approach Based on Etiology

Laboratory evaluation should include:

• Muscle enzymes (CK, LDH, AST)
• Inflammatory markers (ESR, CRP)
• Autoantibody testing (myositis-specific antibodies)
• Screening for underlying infections or malignancies when clinically indicated 2

Imaging with MRI can help differentiate true inflammatory myopathies from mimics such as muscular dystrophies, denervation, or muscle injury 6.

Common Pitfalls and Caveats

1. Misdiagnosis: Many conditions can mimic myositis, including muscular dystrophies, metabolic myopathies, and endocrine disorders 6

2. Overlooking secondary causes: Always consider medications, infections, and malignancies as potential triggers 3

3. Incomplete antibody testing: The presence of specific autoantibodies can provide important prognostic information and guide treatment decisions 5

4. Confusing polymyalgia rheumatica with myositis: Patients with polymyalgia-like syndrome have pain but not true weakness, and CK levels are typically normal 1

5. Delayed recognition of life-threatening complications: ICPi-induced myositis can rapidly progress to involve vital skeletal muscles including the myocardium 1

By understanding the diverse etiologies of myositis, clinicians can implement targeted diagnostic approaches and therapeutic strategies to improve patient outcomes.