What are the causes of proximal myopathy?

Causes of Proximal Myopathy

Proximal myopathy has a broad differential diagnosis spanning toxic/drug-induced, endocrine/metabolic, inflammatory, hereditary, infectious, and neoplastic etiologies, with the most critical immediate considerations being drug-induced (especially statins), thyroid disease, vitamin D deficiency, and idiopathic inflammatory myopathies. 1

Drug-Induced and Toxic Causes

Statins are the most common drug cause of proximal myopathy and can produce two distinct patterns:

• Statin-associated myopathy presents with proximal muscle weakness, elevated creatine kinase (CK), and muscle pain, typically resolving after drug discontinuation 2
• Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal muscle weakness and elevated CK that persist despite statin discontinuation, positive anti-HMG CoA reductase antibody, necrotizing changes on muscle biopsy, and requires aggressive immunosuppression with high-dose corticosteroids, IVIG, and methotrexate 3, 2

Other drug and toxic causes include: 1, 4

• Corticosteroids (chronic use)
• Alcohol (chronic use)
• SGLT2 inhibitors
• Antimalarials
• Colchicine (especially when combined with statins) 2

Endocrine and Metabolic Disorders

The most common reversible causes that must be screened initially: 1, 4

• Hypothyroidism - can cause proximal weakness and may unmask underlying hereditary myopathies like proximal myotonic myopathy (PROMM) 5
• Hyperthyroidism - also causes proximal muscle weakness 4
• Cushing's syndrome (glucocorticoid excess) 4
• Adrenal insufficiency 4
• Osteomalacia/Vitamin D deficiency - should be tested with 25(OH) vitamin D levels 1
• Hyperparathyroidism and hypoparathyroidism 4

Idiopathic Inflammatory Myopathies (IIM)

These represent critical diagnoses requiring urgent immunosuppression: 3

• Polymyositis (PM) - symmetric proximal weakness with CD8+ T cell invasion of muscle fibers on biopsy 6
• Dermatomyositis (DM) - proximal weakness with pathognomonic skin findings (heliotrope rash, Gottron's sign/papules), elevated CK, and requires immediate cancer screening in adults due to substantial malignancy risk 6, 3
• Immune-mediated necrotizing myopathy (IMNM) - severe myopathy with minimal inflammatory infiltrate, triggered by statins, viral infections, or malignancy 6, 3
• Inclusion body myositis (IBM) - most prevalent acquired myopathy above age 50, with vacuolization and abnormal protein accumulation 6, 4
• Juvenile dermatomyositis (JDM) - in children <18 years with calcinosis cutis, cutaneous vasculitis, and potential gastrointestinal vasculopathy 6

Immune checkpoint inhibitor (ICI)-induced myositis is rare but potentially fatal, more common with anti-PD-1/PD-L1 agents, presenting with proximal weakness, markedly elevated CK, and can involve the myocardium with high mortality when combined with myocarditis or myasthenia gravis 6

Hereditary/Congenital Myopathies

These typically present earlier in life but can manifest in adulthood: 4

• Limb girdle muscular dystrophies
• Facioscapulohumeral muscular dystrophy
• Duchenne and Becker muscular dystrophy
• Proximal myotonic myopathy (PROMM) - autosomal dominant with proximal leg weakness, myotonia on EMG (may be subclinical), cataracts, and normal CTG repeat size (distinguishing it from myotonic dystrophy) 7, 8, 5
• Glycogen storage diseases (e.g., McArdle disease)
• Lipid deposition myopathies

Infectious Causes

Viral infections associated with proximal myopathy: 4

• HIV
• SARS-CoV-2 (COVID-19 and post-vaccination)
• Influenza virus
• Hepatitis B and C viruses
• Dengue virus

Other Systemic Conditions

• Sarcoidosis - can manifest as muscle weakness and myalgia 1, 4
• Systemic lupus erythematosus (SLE) 4
• Sjögren's syndrome 4
• Malignancy - paraneoplastic syndromes or direct muscle involvement 1

Critical Diagnostic Approach

Initial laboratory evaluation must include: 1

• Creatine kinase (CK) levels
• Thyroid function tests (TSH, free T4)
• 25(OH) vitamin D levels
• Inflammatory markers (ESR, CRP) if inflammatory myopathy suspected

For patients without identified toxic, metabolic, or endocrine cause, or with features suggesting inflammatory/hereditary myopathy, proceed with: 1

• Myositis-specific antibody panels (anti-Jo-1, anti-SRP) 3
• Electromyography (EMG) - essential for detecting myotonic discharges even when clinical myotonia is absent 7, 8
• Muscle MRI - identifies inflammation and guides biopsy site 6, 3
• Muscle biopsy - necessary to distinguish IIM subtypes and confirm diagnosis 3

Red flag features requiring urgent evaluation: 3

• Respiratory muscle weakness (medical emergency requiring potential ICU admission)
• Cardiac involvement (myocarditis)
• Adult dermatomyositis (mandates comprehensive cancer screening)
• Rapidly progressive weakness with very high CK (consider necrotizing myopathy)