What is the management approach for immunotherapy-induced arthralgia?

Management of Immunotherapy-Induced Arthralgia

The management of immunotherapy-induced arthralgia should follow a graded approach based on symptom severity, starting with NSAIDs and acetaminophen for mild cases, progressing to corticosteroids for moderate cases, and considering immunomodulatory agents for severe or refractory cases. 1

Assessment and Grading

Immunotherapy-induced arthralgia should be graded to guide management:

• Grade 1: Mild pain with inflammatory symptoms, erythema, or joint swelling
• Grade 2: Moderate pain with signs of inflammation, limiting instrumental activities of daily living
• Grade 3-4: Severe pain with inflammation, limiting self-care activities 1

Diagnostic workup should include:

• Complete rheumatologic history and examination of all joints
• Laboratory tests: ESR, CRP, ANA, RF, anti-CCP, CK (to rule out myositis)
• Imaging as needed (X-rays, ultrasound, MRI) 1

Management Algorithm

Grade 1 (Mild) Arthralgia:

• Continue immune checkpoint inhibitor (ICPi) therapy
• Initiate analgesia with acetaminophen and/or NSAIDs if no contraindications
• Consider topical treatments for localized pain
• If no improvement in 2-4 weeks, escalate to grade 2 management 1

Grade 2 (Moderate) Arthralgia:

• May hold ICPi therapy and resume upon symptom control
• Initiate prednisone 10-20 mg/day; if symptoms improve, taper over 3-4 weeks
• Consider referral to rheumatology
• If no improvement or need for higher doses after 4 weeks, escalate to grade 3 management
• Consider intra-articular corticosteroid injections if only 1-2 joints affected 1

Grade 3-4 (Severe) Arthralgia:

• Hold ICPi therapy (may resume in consultation with rheumatology if symptoms improve to grade 1 or less)
• Refer to rheumatology
• Initiate prednisone 0.5-1 mg/kg/day
• If no improvement with corticosteroids, consider disease-modifying antirheumatic drugs (DMARDs) such as methotrexate or immunomodulatory biologics
• IL-6 receptor inhibitors (tocilizumab) are preferred, though TNF-α inhibitors may be considered (with caution in patients with colitis or GI metastases) 1

Special Considerations

Clinical Presentations

Immunotherapy-induced arthralgia can present in various patterns:

• Oligoarthritis of large joints (knees, ankles, wrists)
• Symmetrical polyarthritis resembling rheumatoid arthritis
• Polymyalgia-like syndrome with proximal muscle pain 1

Monitoring

• Conduct serial rheumatologic examinations (2 weeks, 4 weeks, then every 4-6 weeks)
• Monitor inflammatory markers to assess treatment response 1

Timing and Incidence

• Arthralgia occurs in up to 40% of patients receiving ICPi therapy
• Median onset is around 100 days but can range from 1 week to several months after treatment initiation 2
• More common with PD-1/PD-L1 inhibitors than with CTLA-4 inhibitors 1

Treatment Efficacy

• Most patients (>70%) respond adequately to NSAIDs and/or low-dose corticosteroids
• Only a small percentage (<10%) require additional immunosuppressive treatment 2
• Interestingly, patients who develop arthralgia may show better overall treatment response to immunotherapy 2

Pitfalls and Caveats

1. Differential diagnosis: Rule out other causes of joint pain including osteoarthritis, crystal arthropathies (gout), and septic arthritis 1

2. Myositis overlap: Always check CK levels to rule out concurrent myositis, which can be life-threatening if cardiac or respiratory muscles are involved 1

3. Treatment duration: Corticosteroid tapers should be slow (over 4-8 weeks) to prevent symptom rebound 1

4. Rechallenge considerations: Cases of toxicity returning upon rechallenge with ICPi have been reported; decisions to resume therapy should be made in consultation with rheumatology 1

5. Monitoring for complications: Long-term corticosteroid use requires monitoring for adverse effects including hyperglycemia, osteoporosis, and increased infection risk 1