How should hydroxychloroquine (HCQ)‑induced proximal muscle weakness be managed in a patient with lupus or rheumatoid arthritis?

Hydroxychloroquine-Induced Proximal Muscle Weakness: Management

Immediately discontinue hydroxychloroquine when proximal muscle weakness develops, as this represents drug-induced toxic myopathy that requires prompt cessation to prevent progression to severe disability, respiratory failure, or cardiac involvement. 1, 2

Recognition and Diagnosis

Clinical Presentation:

• Proximal limb weakness is the hallmark feature, often requiring assistance with walking in severe cases 2
• Dysphagia occurs in approximately 70-75% of cases and can be severe enough to cause marked weight loss or aspiration pneumonia 2, 3
• Respiratory muscle involvement occurs in approximately 40-70% of patients, potentially leading to respiratory failure 2, 3
• Severe neck/axial weakness develops in approximately 30% of cases 2
• Symptoms typically develop after minimum 6 months of therapy, but can occur after years to decades of use 2, 4

Diagnostic Workup:

• Creatine kinase may be elevated (up to 1,199 U/L) but can be normal in approximately 25% of cases 2
• EMG shows myopathic motor unit potentials with fibrillation potentials in >90% of cases; myotonic discharges may be present 2, 5
• Muscle biopsy demonstrates vacuolar myopathy with rimmed vacuoles, marked acid phosphatase reactivity, and characteristic curvilinear bodies or multilamellar zebra bodies 1, 2, 3
• Cardiac evaluation is essential, as prolonged QT interval occurs in >80% and cardiomyopathy develops in approximately 30% of cases 2

Immediate Management Algorithm

Step 1: Drug Discontinuation

• Stop hydroxychloroquine immediately upon recognition of myopathy 2, 3, 4
• Do not wait for biopsy confirmation if clinical suspicion is high 3

Step 2: Assess Disease Severity

• Evaluate swallowing function formally; consider modified barium swallow if dysphagia is present 2
• Obtain pulmonary function tests including forced vital capacity and negative inspiratory force to assess respiratory muscle strength 3
• Perform ECG and echocardiogram to evaluate for cardiomyopathy and conduction abnormalities 2
• Document baseline strength using standardized scales (e.g., Medical Research Council grading) 2

Step 3: Supportive Care

• Initiate aspiration precautions and dietary modifications for dysphagia 2
• Consider nasogastric or gastrostomy tube placement if severe dysphagia with weight loss or aspiration risk 2
• Provide respiratory support (non-invasive ventilation or mechanical ventilation) if respiratory failure develops 3
• Monitor cardiac rhythm if QT prolongation or cardiomyopathy is present 2

Step 4: Consider Immunotherapy

• If no improvement occurs 3-6 months after drug discontinuation, consider trial of intravenous immunoglobulin (IVIG), as one case report demonstrated marked improvement with this intervention 6
• Standard IVIG dosing would be 2 g/kg divided over 2-5 days 6

Alternative Disease Management

For Underlying Rheumatologic Disease:

• Substitute with alternative immunosuppressive agents that do not cause myopathy 7
• Consider methotrexate or azathioprine for lupus or rheumatoid arthritis maintenance 1
• Quinacrine may be considered for cutaneous manifestations only, though it carries similar toxicity risks 1, 7
• Intensify other immunosuppressive therapy (azathioprine, mycophenolate, or methotrexate) to maintain disease control without hydroxychloroquine 7

Prognosis and Recovery

Expected Outcomes:

• Approximately 80-85% of patients show marked improvement after drug discontinuation 2, 4
• Recovery typically begins within weeks to months but is often incomplete 2
• Most patients are left with residual weakness despite improvement 2
• Higher cumulative doses and longer exposure duration correlate with more severe disability and less complete recovery 2
• Cardiac and swallowing involvement indicate worse prognosis and higher cumulative exposure 2

Critical Pitfalls to Avoid

Common Errors:

• Delaying diagnosis due to normal creatine kinase levels (occurs in 25% of cases) 2
• Attributing symptoms to underlying rheumatologic disease rather than drug toxicity 3, 4
• Continuing the drug while awaiting biopsy results, which allows progression to irreversible damage 2, 3
• Failing to evaluate cardiac and respiratory involvement, which can be life-threatening 2, 3
• Not recognizing that this is a dose- and duration-dependent toxicity that can occur even at "recommended" doses after prolonged use 2

Monitoring During Recovery

• Serial strength assessments every 4-6 weeks until plateau 2
• Repeat pulmonary function tests if respiratory involvement was present 3
• Follow-up echocardiogram at 3-6 months if cardiomyopathy was identified 2
• Physical therapy and rehabilitation to maximize functional recovery 2