Myopathies - drug-induced
Description
- *The commonest cause of myopathy in hospital practice* - and the only one where the cure is a prescription change
- Five mechanisms, and they behave differently:
| Mechanism | Example | CK | Course after stopping |
|---|---|---|---|
| Atrophic/metabolic | Glucocorticoids | NORMAL | Reverses over weeks-months |
| Necrotising (direct toxic) | Statins, fibrates, alcohol | inc | Reverses |
| IMMUNE-mediated necrotising | Statin -> anti-HMGCR IMNM | >10x ULN | *PERSISTS or WORSENS - needs immunosuppression* |
| Inflammatory/autoimmune | Checkpoint inhibitors, D-penicillamine, interferon | inc | Needs immunosuppression |
| Amphiphilic / autophagic | Hydroxychloroquine, amiodarone, colchicine | inc or normal | Slow (months) |
| Mitochondrial | Zidovudine, statins (coenzyme Q10 depletion) | inc | Slow |
Epidemiology
- Statin myalgia reported by 5-10% in observational studies
- *But only ~1% in blinded RCTs (SAMSON, StatinWISE) - most is nocebo*
- Statin myopathy with CK >10x ULN: ~1 in 10,000 patient-years; rhabdomyolysis ~1-3 per 100,000 patient-years
- Anti-HMGCR IMNM: ~2-3 per 100,000 statin users - rare but serious
- Steroid myopathy in up to 60% on prolonged high-dose glucocorticoid
Aetiopathogenesis
Glucocorticoid myopathy
- inc Protein catabolism (ubiquitin-proteasome), dec synthesis (dec IGF-1), dec glucose uptake
- *Selective TYPE II (fast, glycolytic) fibre atrophy - hence no necrosis, no inflammation, normal CK*
- Fluorinated steroids (dexamethasone, betamethasone, triamcinolone) are worse than prednisolone
- Dose- and duration-dependent; rarely below prednisolone 10 mg/day
Statin myotoxicity
- dec Mevalonate pathway -> dec coenzyme Q10, dec prenylated proteins, dec cholesterol in the myocyte membrane -> mitochondrial dysfunction, apoptosis
- Risk rises with: high dose, lipophilic statins (simvastatin, atorvastatin), hypothyroidism, renal or hepatic impairment, age, low body mass, vitamin D deficiency, SLCO1B1 variants, alcohol, strenuous exercise
- *CYP3A4 interactions - the commonest avoidable cause: clarithromycin/erythromycin, azole antifungals, protease inhibitors, ciclosporin, verapamil/diltiazem, amiodarone, grapefruit*
- Gemfibrozil + statin (glucuronidation) - use fenofibrate instead
Anti-HMGCR immune-mediated necrotising myopathy
- Statin upregulates HMG-CoA reductase -> in a genetically susceptible host, tolerance is lost -> autoantibody against the statin's own pharmacological target
- *HLA-DRB111:01 association**
- *Can begin, and does continue, after the statin is stopped* - the defining feature
- Occurs in statin-naive patients too (paraneoplastic, or idiopathic)
Diagnosis
The two discriminations that matter
A. Steroid myopathy vs a myositis flare
| Steroid myopathy | Inflammatory myositis | |
|---|---|---|
| Onset | Insidious, weeks-months | Subacute, weeks |
| Pain | *Painless* | Variable, often painless too |
| Distribution | Proximal - hip girdle first, then shoulder | Proximal, symmetrical |
| CK | *NORMAL* | Raised |
| ESR/CRP | Unchanged | Variable |
| EMG | Normal, or non-irritative myopathic | Irritative - fibrillations, sharp waves |
| MRI | No oedema; fatty atrophy | STIR oedema |
| Urinary creatine | Raised | Raised |
| Response | *Improves on dose REDUCTION* | Worsens on reduction |
- *The bedside test: reduce the steroid. If the patient improves, it was the steroid*
B. Simple statin myopathy vs anti-HMGCR IMNM
| Statin myopathy | Anti-HMGCR IMNM | |
|---|---|---|
| CK | Mildly-moderately raised | *>10x ULN* |
| After stopping the statin | Resolves in weeks | *Persists or PROGRESSES* |
| Antibody | Negative | *Anti-HMGCR - highly specific* |
| Biopsy | Minimal change / mild necrosis | Necrosis + regeneration, MHC-I upregulation, scant inflammation |
| Treatment | Stop the statin | Stop the statin AND immunosuppress |
Work-up of any suspected drug myopathy
- CK, UEC, LFT, TSH, vitamin D, calcium, magnesium, phosphate
- Urine myoglobin/dipstick blood without red cells -> rhabdomyolysis
- Full medication and supplement history, including recent additions (the new macrolide is usually the culprit)
- Anti-HMGCR and myositis antibody panel if CK >10x ULN or weakness persists after cessation
- EMG, MRI, biopsy if the diagnosis is unclear or does not resolve
- Exclude: hypothyroidism, hypokalaemia, hypocalcaemia, vitamin D deficiency, alcohol, hereditary metabolic myopathy (McArdle, CPT2)
Management
1. Stop or change the drug
- Statin myalgia with CK <4x ULN: continue and monitor, or stop and rechallenge
- Washout 2-6 weeks, then rechallenge with a different statin - rosuvastatin or pravastatin (hydrophilic, less CYP3A4), low dose, or alternate-day rosuvastatin
- N-of-1 blinded rechallenge where nocebo is likely
- If truly intolerant: ezetimibe, then a PCSK9 inhibitor (evolocumab, alirocumab), bempedoic acid (a prodrug not activated in muscle), inclisiran
- *Do NOT abandon lipid lowering* - the cardiovascular risk is real and the myalgia usually is not
- CK >10x ULN, or any weakness, or rhabdomyolysis -> STOP immediately
- Steroid myopathy: reduce to the lowest effective dose, switch a fluorinated steroid to prednisolone, add a steroid-sparing agent, resistance exercise and physiotherapy
2. Anti-HMGCR IMNM - treat as autoimmune disease
- Permanently stop the statin (and record the allergy)
- Prednisolone 1 mg/kg/day plus methotrexate, with IVIG added early (within 6 months) or instead where methotrexate is unsuitable
- IVIG has particular efficacy in anti-HMGCR IMNM and can be used as monotherapy
- Rituximab if refractory
- Continue for at least 2 years before attempting withdrawal; relapse on tapering is common
3. Rhabdomyolysis
- Aggressive IV crystalloid to maintain urine output 200-300 mL/h
- Monitor potassium, phosphate, calcium, creatinine and CK; treat hyperkalaemia
- Urinary alkalinisation and mannitol remain unproven
4. Checkpoint inhibitor myositis
- *Always screen for CONCURRENT MYOCARDITIS (troponin, ECG) and MYASTHENIA* - the triad is frequently fatal
- Withhold the immunotherapy; high-dose steroids; escalate early to IVIG, plasma exchange or abatacept
5. Prevention
- Check TSH, vitamin D, renal function before starting a statin
- *Review interacting drugs at every prescription - hold the statin during a short course of clarithromycin*
- Use the lowest effective steroid dose and the shortest duration; exercise throughout
Associations
- Statins, fibrates (esp. gemfibrozil combinations), ezetimibe (rare)
- Glucocorticoids - especially fluorinated
- Checkpoint inhibitors - myositis + myocarditis + myasthenia
- Colchicine (with renal impairment, or with a CYP3A4/P-gp inhibitor - clarithromycin, ciclosporin) - vacuolar myopathy + neuropathy
- Hydroxychloroquine, amiodarone - amphiphilic vacuolar myopathy (plus neuropathy)
- Zidovudine - mitochondrial, ragged red fibres
- Alcohol - acute necrotising and chronic myopathy
- D-penicillamine, interferon, imatinib, hydroxyurea - inflammatory myositis
- Corticosteroid + non-depolarising neuromuscular blocker in ICU - critical illness myopathy
- Drugs causing hypokalaemia (diuretics, liquorice) or hypophosphataemia - metabolic weakness
- Vitamin D deficiency, hypothyroidism - amplify statin myotoxicity
Natural history & complications
- Most drug myopathies resolve completely within weeks to months of stopping - the reason a full drug history is worth more than an EMG
- Steroid myopathy: weeks to months, faster with exercise
- Statin myopathy: 2-6 weeks
- Hydroxychloroquine/amiodarone: months (slow tissue clearance)
- *Anti-HMGCR IMNM does not remit spontaneously* - relapses on tapering, often requires years of therapy, and residual weakness is common
- Rhabdomyolysis -> AKI in ~10-50%, compartment syndrome, hyperkalaemic arrest
- Failure to recognise a drug cause leads to unnecessary immunosuppression, or to stopping a statin that was never the problem and losing cardiovascular protection
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