Statin-related Muscular Disease

❓What❓

• Refers to spectrum of statin-related muscular disease ranging from amyopathic myalgias → toxic myopathy → necrotizing myopathy

• Pathophysiology involves mitochondrial dysfunction in amyopathic myalgias, toxic myonecrosis, or antibody-mediated myofiber damage

❓Epidemiology❓

• Drug-related risk factors include route of metabolization (CYP3A4 → atorvastatin, simvastatin, & lovastatin) & dose

• Other risk factors include pre-existing genetic myopathy (may provoke 1st presentation), hypothyroidism, & other drugs (steroids, cyclosporine, daptomycin, colchicine)

• Symptom onset is usually w/i weeks-months but can occur at any time, & symptoms usually resolve w/i days-weeks (unless IMNM)

• Amyopathic myalgia & toxic myopathy occur with a frequency of ~2-11%

• If IMNM is diagnosed in a patient without statin ingestion, take dietary history for oyster mushrooms, red yeast rice, & Puerh tea, which contain statin molecules

❓Presentation❓

• Symptoms of muscle discomfort (e.g. aches, soreness, stiffness, tenderness, cramps) without CK elevation

• Muscular weakness ⊕/⊖ CK elevation

• Muscular weakness ⊕ CK > 5,000 that fails to resolve vs. worsens weeks after statin discontinuation → Rhabdomyolysis-mediated pigment nephropathy

• Graves’ opthalmopathy mimicker (i.e. extra-ocular muscle weakness)

• Mononeuritis multiplex (i.e. antibody-mediated neuromyopathy)

❓Diagnosis❓

• Amyopathic myalgia & Toxic myopathy: careful history for temporal association between statin/symptoms as well as symptom cessation with statin withdrawal. Importantly, CK trend should improve

• IMNM: anti-HMGCR & anti-SRP antibodies are diagnostic, but if antibodies are ⊖ & there is high clinical suspicion, muscle biopsy required to assess for seronegative disease. Pathology is non-specific with findings compatible with both toxic myopathies as well as early muscular dystrophies. When inflammatory infiltrate is present, there is no CD8+ T-cell invasion & macrophages are the predominant finding, more so being involved in the tissue repair process of necrotic fibers

❓Treatment❓

• Amyopathic myalgia & Toxic myopathy: statin withdrawal ⊕/⊖ hydration if rhabdomyolysis at risk for pigment nephropathy

• IMNM: always requires immunosuppression (steroids, methotrexate, IVIG, rituximab)

📚 References 📚

• https://www.nytimes.com/2022/05/26/magazine/statin-immune-mediated-necrotizing-myopathy-imnm-diagnsosis.html

• https://www.uptodate.com/contents/statin-muscle-related-adverse-events?search=statin myopathy&source=search_result&selectedTitle=1~32&usage_type=default&display_rank=1

• https://www.mayoclinicproceedings.org/article/S0025-6196(17)30076-9/fulltext

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