How is joint pain managed in patients taking Keytruda (pembrolizumab)?

Management of Joint Pain in Patients Taking Keytruda (Pembrolizumab)

Joint pain in patients taking Keytruda should be managed according to a graded approach based on severity, with treatment ranging from NSAIDs for mild cases to corticosteroids and disease-modifying antirheumatic drugs (DMARDs) for more severe cases.

Understanding Immune-Related Arthritis from Keytruda

Pembrolizumab (Keytruda) is an immune checkpoint inhibitor (ICPi) that can cause immune-related adverse events (irAEs), including inflammatory arthritis. This occurs due to the general immunological stimulation from loss of T-cell inhibition 1. Joint pain associated with Keytruda typically presents as:

• Inflammatory arthritis affecting large and/or small joints
• Oligoarthritis of large joints (knees, ankles, wrists)
• Symmetrical polyarthritis resembling rheumatoid arthritis
• Polymyalgia-like syndrome with proximal muscle pain

Joint symptoms can occur at any time during treatment, even many months after starting Keytruda 2.

Assessment and Diagnostic Approach

When a patient on Keytruda reports joint pain, perform:

1. Complete rheumatologic examination of all peripheral joints for:

   • Tenderness
   • Swelling
   • Range of motion limitations
   • Inflammatory symptoms (morning stiffness lasting >30 minutes)

2. Laboratory testing:

   • Inflammatory markers (ESR, CRP) - typically elevated in ICPi-induced arthritis
   • Autoimmune panel (ANA, RF, anti-CCP)
   • If spine symptoms present, consider HLA B27 testing

3. Imaging as clinically indicated:

   • Plain X-rays to exclude metastases and evaluate joint damage
   • Ultrasound or MRI for persistent arthritis or to rule out differential diagnoses 2

Graded Management Algorithm

Grade 1 (Mild pain with inflammation, erythema, or joint swelling)

• Continue Keytruda
• Initiate analgesia with acetaminophen and/or NSAIDs 2
• If NSAIDs ineffective, consider prednisone 10-20 mg daily for 2-4 weeks 2
• Monitor with serial rheumatologic examinations

Grade 2 (Moderate pain with inflammation, limiting instrumental ADL)

• Consider holding Keytruda
• Escalate analgesia with higher doses of NSAIDs
• If inadequately controlled, initiate prednisone 10-20 mg/day for 4-6 weeks
• If improvement, taper prednisone slowly over 4-6 weeks
• If no improvement after initial 4 weeks, treat as Grade 3
• Consider intra-articular corticosteroid injections for large joints
• Refer to rheumatology if symptoms persist >4 weeks 2
• Resume Keytruda upon symptom control and when prednisone ≤10 mg/day

Grade 3-4 (Severe pain with inflammation, irreversible joint damage, limiting self-care ADL)

• Hold Keytruda temporarily
• Initiate oral prednisone 0.5-1 mg/kg
• If no improvement after 2-4 weeks or worsening, consider DMARDs:
  • Synthetic DMARDs: methotrexate, leflunomide, hydroxychloroquine, sulfasalazine
  • Biologic DMARDs: TNF-α or IL-6 receptor inhibitors (caution with IL-6 inhibitors in patients with colitis)
• Mandatory rheumatology referral
• May resume Keytruda in consultation with rheumatology if symptoms improve to Grade 1 2

Special Considerations

1. Early recognition is critical to prevent erosive joint damage 2

2. Polymyalgia-like syndrome:

   • Presents with severe myalgia in proximal muscles
   • Distinguished from myositis by normal CK levels
   • Responds well to corticosteroids 3

3. Corticosteroid-sparing strategies:

   • Start steroid-sparing agents earlier than with other irAEs due to likely prolonged treatment requirements
   • Consider PCP prophylaxis for patients on high-dose corticosteroids for >12 weeks 2

4. Monitoring:

   • Patients with inflammatory arthritis should be monitored with serial rheumatologic examinations including inflammatory markers every 4-6 weeks after treatment initiation 2
   • For patients requiring biologic DMARDs, screen for hepatitis B, C, and tuberculosis before starting treatment 2

Pitfalls to Avoid

1. Delayed diagnosis - inflammatory arthritis can occur at any time during treatment, even months after initiation

2. Inadequate treatment - NSAIDs alone are usually insufficient for controlling symptoms in moderate to severe cases

3. Overlooking differential diagnoses - consider other causes of joint pain including:

   • Degenerative joint disease/osteoarthritis
   • Soft tissue rheumatic disorders
   • Crystal arthropathies (gout, pseudogout)
   • Septic arthritis
   • Metastatic disease 2

4. Failing to recognize life-threatening complications - myositis can occur alongside arthritis and may involve the myocardium, requiring urgent treatment 2

By following this graded approach to managing joint pain in patients on Keytruda, clinicians can effectively control symptoms while potentially allowing continued cancer immunotherapy when appropriate.