How to manage joint pains caused by Nivolumab (nivolumab) therapy?

Management of Joint Pain Caused by Nivolumab

For patients experiencing joint pain from nivolumab therapy, first-line treatment includes NSAIDs and low-dose corticosteroids (10-20 mg/day prednisone), with escalation to higher doses (0.5-1 mg/kg) for severe cases, followed by disease-modifying antirheumatic drugs (DMARDs) if symptoms persist.

Clinical Presentation and Evaluation

Nivolumab-induced joint pain typically presents as:

• Oligoarthritis affecting large joints (knees, ankles, wrists)
• Symmetrical polyarthritis resembling rheumatoid arthritis
• Polymyalgia-like syndrome with proximal muscle pain
• Reactive arthritis with accompanying conjunctivitis or urethritis

Initial evaluation should include:

• Complete rheumatologic examination of all peripheral joints
• Laboratory tests:
  • Inflammatory markers (ESR, CRP) - typically elevated in immune-related arthritis
  • Autoimmune panel (ANA, RF, anti-CCP) - often negative or low titer
  • Creatine kinase (CK) - to differentiate from myositis
• Imaging as needed (X-ray, ultrasound, or MRI) to exclude metastases and evaluate joint damage

Treatment Algorithm Based on Severity

Grade 1 (Mild Pain with Inflammation)

• Continue nivolumab therapy
• Initiate acetaminophen and/or NSAIDs
• Monitor symptoms closely

Grade 2 (Moderate Pain Limiting Instrumental ADLs)

• Consider temporarily holding nivolumab 1
• Increase NSAID dosage as needed
• If inadequate control, start prednisone 10-20 mg/day 1
• Consider intra-articular steroid injections for large joints
• If no improvement after 4 weeks, treat as Grade 3
• Refer to rheumatology

Grade 3-4 (Severe Pain Limiting Self-Care ADLs)

• Hold nivolumab temporarily 1
• Initiate oral prednisone 0.5-1 mg/kg 1
• If no improvement after 2 weeks, consider DMARDs:
  • Synthetic DMARDs: methotrexate, leflunomide, hydroxychloroquine, sulfasalazine
  • Biologic DMARDs: TNF-α or IL-6 antagonists for refractory cases 1, 2
• Urgent rheumatology referral

Important Considerations

• Joint pain is common with immune checkpoint inhibitors, affecting up to 40% of patients 1
• Symptoms can occur at any time during treatment, even months after initiation 1
• Inflammatory markers are usually significantly elevated in immune-related arthritis 1
• NSAIDs alone are often insufficient for symptom control 1
• Early recognition is critical to avoid erosive joint damage 1
• Consider steroid-sparing agents earlier than with other immune-related adverse events 1

Duration and Prognosis

• Joint symptoms may persist for an average of 9.2 months after the last dose of immunotherapy 3
• Most cases can be managed with low to moderate doses of corticosteroids (≤20 mg/day prednisone) 3
• In some cases, nivolumab may be continued with appropriate management of joint symptoms 4
• For refractory cases, IL-6 inhibitors like sarilumab have shown rapid improvement in symptoms 2

Pitfalls to Avoid

• Don't assume all joint pain is immune-related; consider other causes such as:

  • Degenerative joint disease or osteoarthritis
  • Crystal arthropathies (gout, pseudogout)
  • Septic arthritis
  • Soft tissue rheumatic disorders

• Don't delay treatment of moderate to severe symptoms, as early intervention prevents joint damage

• Don't forget to screen for other concurrent immune-related adverse events, as they can occur simultaneously

• For patients requiring biologic DMARDs, test for viral hepatitis B, C, and tuberculosis before initiating treatment 1