What is the treatment for checkpoint (immune checkpoint) colitis?

Treatment of Checkpoint Inhibitor-Induced Colitis

Treatment is grade-dependent and centers on corticosteroids as first-line therapy, with early escalation to biologics (infliximab or vedolizumab) for steroid-refractory cases, while holding or permanently discontinuing the checkpoint inhibitor based on severity. 1

Grade 1 (≤4 stools/day above baseline)

• Continue checkpoint inhibitor therapy with close monitoring every 24-48 hours for symptom progression 1
• Rule out infectious causes with stool studies if symptoms persist 1
• Supportive care with dietary modifications (bland diet during acute diarrhea) 1
• Loperamide may be used cautiously only after infection is excluded and only for diarrhea without colitis symptoms 1

Grade 2 (4-6 stools/day above baseline, abdominal pain, or blood/mucus in stool)

Hold checkpoint inhibitor immediately 1

Initial Management:

• Start prednisone 1 mg/kg/day (or equivalent methylprednisolone) immediately if colitis symptoms present (abdominal pain ± blood in stool) 1
• If diarrhea only without colitis symptoms, observe 2-3 days before starting steroids 1
• Obtain stool studies (culture, C. difficile, parasites, CMV), inflammatory markers (CRP, ESR, fecal calprotectin), and consider imaging 1
• Colonoscopy is highly recommended for grade ≥2 to identify high-risk endoscopic features (ulcerations) that predict steroid-refractory disease 1

Escalation Strategy:

• If no improvement within 48-72 hours, increase to prednisone 2 mg/kg/day 1
• Consider early infliximab 5 mg/kg or vedolizumab for steroid-refractory cases (no grade reduction in 72 hours), steroid-dependent cases, or high-risk endoscopic features 1
• Recent evidence shows infliximab achieves complete remission in 52% after one dose and 73% after two or more doses, with symptom improvement typically within 3 days 2

Steroid Tapering:

• When symptoms improve to grade ≤1, taper corticosteroids over 4-6 weeks 1
• Shorter tapers may be considered if biologics are used concurrently 1
• Resume checkpoint inhibitor only when steroids tapered to ≤10 mg/day and patient remains symptom-free 1
• Continue PD-1/PD-L1 monotherapy; if using combination therapy, continue PD-1 agent only and permanently discontinue CTLA-4 inhibitor 1

Critical pitfall: High-dose prednisolone at start of tapering (≥75 mg/day) is associated with increased mortality (HR 1.67), so optimize infliximab use before escalating steroid doses 2

Grade 3 (≥7 stools/day, severe abdominal pain, peritoneal signs)

Withhold checkpoint inhibitor and consider hospitalization 1

Immediate Actions:

• Start IV methylprednisolone 1-2 mg/kg/day immediately 1
• Complete infectious workup, inflammatory markers, imaging, and GI consultation 1
• Perform colonoscopy to assess disease severity and guide therapy 1

Biologic Therapy:

• Consider early infliximab 5 mg/kg or vedolizumab if inadequate response to steroids after 3 days or high-risk endoscopic features 1
• Infliximab can be repeated after 2 weeks if needed; response typically occurs within 1-3 days 1
• If refractory to infliximab (10% of cases), vedolizumab is an alternative 1, 2

Checkpoint Inhibitor Resumption:

• May consider resuming when steroids tapered to ≤10 mg/day and patient remains symptom-free 1
• Should permanently discontinue CTLA-4 agents 1
• PD-1/PD-L1 agents may be resumed with caution after endoscopic/histologic remission or fecal calprotectin ≤116 mg/g 1

Grade 4 (Life-threatening consequences)

Permanently discontinue checkpoint inhibitor and provide inpatient care 1

• IV methylprednisolone 1-2 mg/kg/day until improvement to grade 1, then taper over 4-6 weeks 1
• Early biologics (infliximab or vedolizumab) if inadequate response after 3 days 1
• Consider repeat colonoscopy if refractory to treatment 1
• For refractory cases, consider fecal microbiota transplant, tofacitinib (JAK inhibitor), or ustekinumab (IL-12 blocker) 1

Important Safety Considerations

Infection Risk:

• 24% of patients require hospitalization for infection during treatment, with median duration of 7 days 2
• 16% develop secondary GI infections, most commonly C. difficile (64% of infections) 2
• 10% experience thromboembolic events within 90 days of infliximab treatment 2
• Screen for HIV, hepatitis A/B, and tuberculosis before starting biologics if prolonged use anticipated 1

Steroid Exposure:

• Patients receive a median accumulated corticosteroid dose of 3978 mg (IQR 2552-6414 mg) 2
• Prolonged steroid courses increase infection risk and mortality 2
• Mycophenolate mofetil alongside high-dose corticosteroids may reduce steroid exposure and colitis flare rates (36% flare rate vs. higher historical rates) 3

Monitoring:

• Fecal calprotectin ≤116 mg/g can serve as surrogate for endoscopic/histologic remission before resuming checkpoint inhibitors 1
• Consider repeat colonoscopy to document mucosal healing before restarting therapy 1

Key principle: Infliximab should be optimized early rather than escalating steroid doses, given the association between high steroid doses and increased mortality, plus the high burden of infections in this population 2