What are the causes of necrotizing myopathy?

Causes of Necrotizing Myopathy

Necrotizing myopathy is primarily caused by immune-mediated mechanisms, medications (especially statins), viral infections, malignancies, and connective tissue diseases, with immune-mediated necrotizing myopathy (IMNM) being the most clinically significant form requiring aggressive immunosuppressive therapy to prevent irreversible muscle damage. 1, 2

Immune-Mediated Causes

Autoantibody-Associated IMNM

• Anti-HMGCR antibodies:

  • Most commonly associated with statin exposure (Statin-Induced Necrotizing Autoimmune Myopathy or SINAM)
  • Can persist and progress despite statin discontinuation 3
  • Typically requires aggressive immunosuppression

• Anti-SRP (Signal Recognition Particle) antibodies:

  • Associated with severe necrotizing myopathy
  • Often presents with acute onset
  • Can involve dilated cardiomyopathy
  • Poor response to standard immunosuppression 1

Other Autoimmune Associations

• Connective tissue diseases (overlap syndromes)
• Antisynthetase syndrome (rarely presents as necrotizing myopathy)
• Anti-Mi2 dermatomyositis (can have necrotizing features)
• Antimitochondrial antibody-associated myositis 4

Medication-Induced Causes

• Statins (HMG-CoA reductase inhibitors) - most common drug cause 3
• Checkpoint inhibitors used in cancer treatment 4
• Other medications with toxic effects on muscle tissue 5

Malignancy-Associated

• Paraneoplastic necrotizing myopathy
• The American College of Physicians recommends screening for underlying malignancy in all patients with NAM 2

Infectious Causes

• Viral infections:
  • HIV
  • Hepatitis C
  • SARS-CoV-2 (emerging reports) 4
• Other infectious agents causing direct muscle damage

Other Causes

• Graft-versus-host disease 4
• Toxic exposures 5
• Hypothyroidism (can present with necrotizing features) 4

Pathophysiological Features

IMNM Characteristics

• Severe myopathy with minimal inflammatory infiltrate on muscle biopsy
• Macrophages surrounding necrotic muscle fibers
• Atrophic and regenerating fibers present
• T lymphocytes (CD3) and macrophages (CD68) around necrotic and regenerating muscle fibers 1
• Variable deposition of membrane attack complex on capillaries and muscle fibers 5

Non-Immune Mediated Necrotizing Myopathy

• Similar histological pattern of necrosis
• Absence of immunohistochemical abnormalities typically seen in IMNM 5
• Resolves with removal of the toxic exposure

Clinical Implications

The distinction between immune-mediated and non-immune mediated necrotizing myopathy is crucial for treatment decisions. IMNM often requires multiple immunosuppressive agents, with approximately 90% of patients needing two or more immunotherapeutic medications to prevent irreversible muscle damage and mortality 2. Non-immune mediated forms typically improve with removal of the causative agent.

Early diagnosis through muscle biopsy and autoantibody testing is essential, as delayed therapy can lead to permanent muscle damage, significantly affecting quality of life and increasing mortality risk 2, 6.

1, 2

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