• Mild pain

• Moderate pain; limiting instrumental ADL

• Severe pain; limiting self-care ADL

• Mild pain with inflammation, erythema, or joint swelling

• Moderate pain associated with signs of inflammation, erythema, or joint swelling; limiting instrumental ADL

• Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; disabling; limiting self-care ADL

• No known interventions

• Anticipate immunotherapy to continue
• Encourage physical activity
  • 30 minutes of low-to-moderate–intensity physical activity 5 days per week can improve physical conditioning, sleep, and decreases pain perception
  • For physically inactive patients, advise supervised exercise, resistance training
  • Other: yoga, tai chi, Qigong, Pilates, aquatic exercise, focused dance program
• Anticipate use of analgesia
  • Low-dose NSAIDs
    • Topical: diclofenac (gel or patch). Best for localized, limited, superficial joint inflammation or for use in patients who cannot tolerate oral NSAIDs
    • Oral: ibuprofen, naproxen, celecoxib
      • Anticipatory guidance on proper administration
• Assess patient and family understanding of recommendations and rationale
  • Identify barriers to adherence

If symptoms do not improve in 4–6 weeks, escalate to next level of therapy

• Ipilimumab to be withheld for any Grade 2 event (until Grade 0/1) and discontinued for events persisting ≥6 weeks or inability to reduce steroid dosage to 7.5 mg prednisone or equivalent per day
• Dose of pembrolizumab or nivolumab to be held as to not make symptoms worse
• Pembrolizumab or nivolumab to be discontinued for Grade 2 events persisting ≥12 weeks
• Continue to encourage physical activity
• Anticipate use of analgesia
  • NSAIDs
    • Oral: ibuprofen, naproxen, celecoxib
      • Anticipatory guidance on proper administration
• Anticipate referral to rheumatology for collaborative management and consideration of adjunct treatment
• Anticipate pre-visit assessment: CBC, ESR, CRP, BUN/CR & aminotransferases, ANA, RF
  • Intraarticular steroids to be used for significant symptomatic joint(s)
  • Low-dose corticosteroids (0.5 –1 mg/kg/day) to be used
    • Anticipatory guidance on proper administration
    • Duration of corticosteroid therapy is usually limited, lasting for about 4–6 weeks, with possible resolution of symptoms within weeks to months of treatment
• Assess patient & family understanding of toxicity, rationale for treatment hold (if applicable)
  • Identify barriers to adherence

If symptoms do not improve in 4–6 weeks, escalate to next level of therapy

• Pembrolizumab or nivolumab to be withheld for first-occurrence Grade 3/4 event and discontinued if:
  • Grade 3/4 event recurs
  • Persists ≥12 weeks
• Ipilimumab to be discontinued for any Grade 3/4 event.
• High-dose steroids to be used (1-1.5 mg/kg) daily; [rapid effect within days]
  • Anticipatory guidance on proper administration
  • Onset of action is rapid, typically within days
• Anticipate referral to rheumatology for collaborative management and consideration of adjunct treatment
  • Non-biologic agents (more likely to be recommended)
    • Conventional synthetic DMARDs (csDMARDs), which have a delayed effect and take weeks to work:
      • Methotrexate
      • Sulfasalazine*
      • Hydroxychloroquine
      • Leflunomide
  • Biologic agents (less likely to be recommended)
    • Biologic DMARDs (bDMARDs)
    • TNF inhibitors
      • Infliximab
      • Etanercept
      • Adalimumab
      • Golimumab
      • Certolizumab pegol
    • Anti B-cell agents (CD-20 blocking)
      • Rituximab
  • Agents NOT advised
    • Interleukin (IL)-6 receptor blocking agent (tocilizumab) and JAK inhibitors (tofacitinib) due to risk of colonic perforation
    • T cell co-stimulation inhibitor (abatacept) as it directly opposes the mechanism of checkpoint blockade agents
• Assess patient & family understanding of toxicity and rationale for treatment discontinuation
• Identify barriers to adherence, specifically compliance with medication, physical activity

*Sulfasalazine is associated with rash; do not use in patients with history of or current treatment-related dermatitis