How should immune‑checkpoint‑inhibitor–induced colitis be managed?

Management of Immune Checkpoint Inhibitor-Induced Colitis

For immune checkpoint inhibitor-induced colitis, treatment is grade-based: supportive care only for grade 1, high-dose systemic corticosteroids (1-2 mg/kg/day prednisone equivalent) for grade 2 or higher, and infliximab or vedolizumab for steroid-refractory cases within 72 hours. 1

Initial Diagnostic Workup

Before initiating any immunosuppressive therapy, you must systematically exclude infectious causes:

• Obtain stool studies for C. difficile, bacterial pathogens, CMV, and parasites immediately 1, 2
• Measure fecal lactoferrin and calprotectin in all patients with grade ≥2 symptoms (>4 bowel movements above baseline) to stratify risk and determine urgency of endoscopy 1, 2
• Perform colonoscopy with biopsy before initiating high-dose steroids when feasible, as the presence of ulceration on endoscopy predicts steroid-refractory disease requiring early infliximab 1, 2
• Consider CT abdomen/pelvis only if dominant symptoms include severe abdominal pain, fever, or bleeding to rule out perforation, abscess, or typhlitis—not routinely for diarrhea alone 1, 3

A critical pitfall: ICI colitis can progress rapidly within days, particularly with ipilimumab (anti-CTLA-4), so prompt diagnosis and treatment initiation is essential 1, 3.

Grade-Based Treatment Algorithm

Grade 1 (Mild: <4 additional stools/day)

• Continue checkpoint inhibitor therapy or hold temporarily 1, 2
• Provide supportive care only: loperamide if infection excluded, dietary modifications, monitor for dehydration 1
• Monitor closely every 3 days by phone or electronic system until stabilized 1
• Avoid immunosuppressants due to lack of efficacy evidence 2
• Consider gastroenterology consultation for prolonged grade 1 cases with possible endoscopy 1

Grade 2 (Moderate: 4-6 additional stools/day)

• Hold checkpoint inhibitor immediately 1, 2
• Initiate systemic corticosteroids at 1 mg/kg/day prednisone equivalent unless diarrhea is transient 1, 3
• Consult gastroenterology for all grade ≥2 cases 1
• Perform endoscopic evaluation (colonoscopy) to stratify patients for early biologic treatment based on ulceration presence 1, 2
• If no improvement to grade 1 within 72 hours (steroid-refractory), add infliximab (5 mg/kg) or vedolizumab 1, 2
• When symptoms improve to grade ≤1, taper corticosteroids over 4-6 weeks; consider shorter tapers if biologics also used 1, 3

Grade 3-4 (Severe: ≥7 additional stools/day or hospitalization required)

• Admit for inpatient care 1
• Initiate high-dose corticosteroids at 1-2 mg/kg/day prednisone equivalent 1, 3
• Perform urgent colonoscopy and imaging to assess severity and exclude complications 1
• Add infliximab or vedolizumab early if steroid-refractory within 72 hours or if high-risk endoscopic features present 1, 2
• Consider permanently discontinuing CTLA-4 agents; may restart PD-1/PD-L1 agents after recovery to grade ≤1 1

Second-Line Biologic Therapy

When corticosteroids fail (no grade reduction within 72 hours) or for steroid-dependent cases:

• Infliximab (5 mg/kg) and vedolizumab are the established second-line agents with proven efficacy 1, 2
• These target TNF-alpha and gut-selective integrin pathways, mechanisms directly relevant to immune-mediated colitis 3
• Azathioprine or mycophenolate may be considered for steroid-refractory cases, though evidence is limited 2

Critical pitfall to avoid: Do not delay proven therapies (corticosteroids, infliximab, vedolizumab) to trial unproven agents, as this increases complication risk 3. IL-23 inhibitors like risankizumab are not mentioned in any guidelines for checkpoint inhibitor colitis and should not be used 3.

Monitoring Treatment Response and Resuming Immunotherapy

• Target mucosal healing on repeat endoscopy and/or fecal calprotectin ≤116 mg/g before stopping biologic therapy 1, 2
• Consider repeat colonoscopy for grade ≥2 cases to document complete remission before resuming checkpoint inhibitors 1, 2
• Resuming PD-1/PD-L1 agents carries lower flare-up risk than CTLA-4 inhibitors 1
• May resume checkpoint inhibitors when steroid taper completed, symptoms ≤grade 1, and endoscopic/histologic remission achieved 1
• Screen for hepatitis B (surface antigen, core antibody, surface antibody) before any biologic treatment, with annual repeat testing if biologics continued >1 year 1

Additional Considerations

• Review and consider discontinuing medications that alter gut microbiome: proton pump inhibitors, antibiotics, probiotics 1
• Avoid NSAIDs, as they are associated with increased incidence of ICI-induced colitis 2
• Budesonide is ineffective for prophylaxis but may treat ICI-associated microscopic colitis 1
• Patients with pre-existing inflammatory bowel disease may have increased risk of GI adverse events but can still benefit from checkpoint blockade 1