What are the likely causes and recommended evaluation and management for new onset myalgia and gait instability occurring shortly after a rituximab (Rituxan) infusion?

Myalgia and Gait Changes After Rituximab Infusion

New-onset myalgia and gait instability following rituximab infusion most likely represent either an infusion-related reaction (if occurring within hours) or, more concerning, immune-mediated myositis (if developing days later), and require immediate evaluation with creatine kinase, autoimmune myositis panel, and urgent neurology or rheumatology consultation if CK is elevated or weakness is present. 1

Timing and Differential Diagnosis

The temporal relationship to rituximab infusion is critical for determining the cause:

Immediate to 2-Hour Window (Infusion-Related Reaction)

• Myalgia occurring during or within 1-2 hours of infusion represents a typical infusion-related reaction, which occurs in up to 77% of patients during first infusion and includes flu-like symptoms such as myalgia, fever, rigors, and chills. 2, 3
• These reactions are usually mild to moderate and decrease markedly with subsequent infusions. 4
• Gait instability in this timeframe would more likely reflect hypotension, dizziness, or constitutional symptoms rather than true neuromuscular pathology. 3

Days to Weeks Post-Infusion (Immune-Mediated Myositis)

• Myalgia and gait changes developing days after infusion raise concern for immune-mediated myositis, a serious adverse effect that requires urgent evaluation. 1
• The mean lag time for clinical responses in autoimmune conditions can be 8-66 weeks, but paradoxical immune activation can occur earlier. 5
• Gait instability combined with myalgia suggests proximal muscle weakness, a hallmark of inflammatory myopathy. 1

Immediate Diagnostic Workup

For any patient presenting with myalgia and gait changes after rituximab, obtain the following immediately:

• Creatine kinase (CK) level – elevation ≥3 times upper limit of normal indicates muscle injury and necessitates corticosteroid therapy. 1
• Complete rheumatologic history examining temporal pattern, distribution of muscle pain, presence of weakness (not just pain), difficulty with stairs or rising from chair, and any dysphagia or respiratory symptoms. 1
• Autoimmune myositis panel including anti-Jo-1, anti-Mi-2, anti-SRP, anti-HMGCR, and other myositis-specific antibodies. 1
• Inflammatory markers (ESR, CRP) to assess systemic inflammation. 1
• EMG and MRI of affected proximal limbs if diagnosis is uncertain or if weakness is present on examination. 1
• Consider muscle biopsy if the diagnosis remains uncertain after initial workup. 1

Critical Red Flags Requiring Urgent Intervention

Immediately refer to neurology or rheumatology if any of the following are present:

• Elevated CK with objective muscle weakness on examination. 1
• Severe weakness limiting mobility. 1
• Dysphagia, respiratory difficulty, or any cardiac symptoms (chest pain, palpitations, dyspnea). 1, 6
• Myocardial involvement must be ruled out, as this mandates permanent rituximab discontinuation. 1, 6

Management Algorithm

If CK is Normal and No Weakness Present (Grade 1)

• Offer analgesia with acetaminophen or NSAIDs if no contraindications. 1
• Continue monitoring and may continue rituximab therapy. 1
• Symptoms likely represent benign infusion-related myalgia. 4

If CK is Elevated (≥3× ULN) or Muscle Weakness Present (Grade 2)

• Hold rituximab and do not resume until symptoms resolve, CK normalizes, and prednisone dose is <10 mg daily. 1
• Initiate prednisone 0.5-1 mg/kg daily immediately. 1
• Urgent referral to rheumatology or neurology for co-management. 1
• May require permanent discontinuation if objective findings persist (elevated enzymes, abnormal EMG, abnormal muscle MRI or biopsy). 1

If Severe Weakness, Respiratory Compromise, or Cardiac Involvement (Grade 3-4)

• Permanently discontinue rituximab if any evidence of myocardial involvement. 1, 6
• Consider hospitalization for severe weakness limiting mobility. 1
• Initiate prednisone 1 mg/kg or methylprednisolone 1-2 mg/kg IV (or higher-dose bolus if severe compromise with cardiac, respiratory, or dysphagia symptoms). 1
• May offer plasmapheresis or IVIG therapy for refractory cases. 1
• May offer additional immunosuppression (methotrexate, azathioprine, mycophenolate) if no improvement after 4-6 weeks. 1

Important Caveats and Pitfalls

Common pitfall: Attributing all post-rituximab myalgia to benign infusion reactions without checking CK or assessing for weakness. Immune-mediated myositis is a serious, potentially life-threatening complication that requires early recognition and aggressive treatment. 1

Cardiac monitoring is mandatory: Rituximab can cause myocardial infarction, ventricular fibrillation, and cardiogenic shock. 3, 6 Any patient with chest pain, dyspnea, or cardiac symptoms requires immediate ECG, troponin, and cardiology consultation. 6

Do not confuse timing: Infusion reactions occur during or within 1-2 hours of infusion, not days later. 2, 3 Symptoms developing days to weeks after infusion suggest a different mechanism (immune-mediated or infectious). 1

Infection must be excluded: Rituximab causes B-cell depletion and increases risk of serious bacterial, fungal, and viral infections. 6, 7 If fever, systemic symptoms, or elevated inflammatory markers are present, obtain blood cultures and consider empiric antibiotics while awaiting workup. 6

Progressive multifocal leukoencephalopathy (PML): Although rare, PML can present with new neurologic manifestations including gait changes. 6 If gait instability is accompanied by cognitive changes, focal neurologic deficits, or other CNS symptoms, obtain brain MRI and lumbar puncture to evaluate for PML. 6