What is the recommended evaluation and management for a patient receiving immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab, or combination therapy) who develops new abdominal pain, diarrhea, or blood in the stool?

Immunotherapy-Induced Colitis: Evaluation and Management

Immediate Diagnostic Workup

Before initiating any immunosuppressive therapy, you must exclude infectious causes with comprehensive stool studies for Clostridioides difficile, bacterial pathogens, cytomegalovirus (CMV), and parasites. 1, 2, 3

Essential Laboratory Testing

• Obtain fecal lactoferrin and calprotectin immediately in all patients with ≥4 extra stools per day above baseline to stratify severity and determine urgency of endoscopic evaluation 1, 2, 3
• Baseline complete blood count, comprehensive metabolic panel, C-reactive protein, and erythrocyte sedimentation rate 1
• Screen for hepatitis B (surface antigen, core antibody, surface antibody) and tuberculosis before any biologic therapy, particularly if infliximab may be needed 1, 2

Endoscopic Evaluation

Perform colonoscopy with biopsies before initiating high-dose corticosteroids whenever feasible, as endoscopic ulceration predicts steroid-refractory disease and supports early infliximab use. 1, 2, 3

• Colonoscopy is the most accurate method to assess extent and severity 1
• Obtain mucosal biopsies even if endoscopy appears normal, as significant inflammation may only be visible histologically 1
• Immunohistochemical staining is critical to rule out CMV infection 1

Imaging Considerations

Reserve abdominal-pelvic CT for patients with dominant severe abdominal pain, fever, or gastrointestinal bleeding to exclude perforation, abscess, or typhlitis—it is not required for isolated diarrhea. 1, 2, 3

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Grade-Based Treatment Algorithm

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

Continue checkpoint inhibitor therapy with close monitoring only; do not use immunosuppressants including budesonide, as prophylactic corticosteroids are ineffective. 1, 2

• Provide supportive care: loperamide after infection exclusion, bland diet, hydration monitoring 1
• Monitor closely within 24-48 hours for progression 1
• Recognize that rapid progression can occur within days, particularly with ipilimumab (anti-CTLA-4 agents) 1, 2

Grade 2 (Moderate: 4-6 additional stools/day OR abdominal pain/blood in stool)

Immediately hold the checkpoint inhibitor and start systemic corticosteroids at 1 mg/kg/day prednisone-equivalent. 1, 2

• Consult gastroenterology for all grade ≥2 cases 1, 2
• If diarrhea persists without colitis symptoms (pain/bleeding), observe 2-3 days before starting steroids 1
• If diarrhea plus colitis symptoms are present, start prednisone 1 mg/kg/day immediately 1
• If no improvement within 72 hours, escalate to prednisone 2 mg/kg/day or add infliximab 5 mg/kg 1, 2
• When symptoms improve to grade ≤1, taper corticosteroids over 4-6 weeks 1, 2

Resuming immunotherapy after grade 2 colitis:

• Resume only when corticosteroid tapered to ≤10 mg/day and patient remains symptom-free (grade ≤1) 1
• Continue anti-PD-1 or anti-PD-L1 monotherapy 1
• If using combination anti-CTLA-4/anti-PD-1 therapy, permanently discontinue CTLA-4 agent and continue anti-PD-1 agent only 1, 2

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

Admit for inpatient management and administer high-dose intravenous corticosteroids at 1-2 mg/kg/day prednisone-equivalent immediately. 1, 2

• Permanently discontinue checkpoint inhibitor for grade 4; consider permanent discontinuation for grade 3 1
• Obtain urgent colonoscopy and imaging to assess severity and exclude complications 1, 2
• Add infliximab 5 mg/kg or vedolizumab early if steroid-refractory within 72 hours or if high-risk endoscopic features (ulceration) are present 1, 2, 3
• Infliximab can be repeated after 2 weeks if needed; response typically occurs within 1-3 days 1

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Second-Line Biologic Therapy

Infliximab (5 mg/kg) and vedolizumab are the established second-line agents with proven efficacy for steroid-refractory or steroid-dependent checkpoint inhibitor colitis. 1, 2, 3

• Both agents are equally effective 2, 4
• Vedolizumab may be preferred in steroid-dependent cases 1
• Do not delay proven therapies (corticosteroids, infliximab, vedolizumab) to trial unproven agents, as this increases risk of complications 3

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Monitoring Treatment Response and Resuming Immunotherapy

Target mucosal healing on repeat endoscopy and fecal calprotectin ≤116 mg/g before discontinuing biologic therapy. 1, 2

• Repeat colonoscopy for grade ≥2 patients to document complete remission prior to restarting checkpoint inhibitors 1, 2
• Checkpoint inhibitors may be resumed when: (1) corticosteroid taper is complete, (2) symptoms are ≤grade 1, and (3) endoscopic/histologic remission is confirmed 2
• PD-1/PD-L1 inhibitors carry lower flare-up risk than CTLA-4 inhibitors upon rechallenge 1, 2

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Critical Pitfalls to Avoid

Do not assume all diarrhea is checkpoint inhibitor colitis—infectious causes, particularly C. difficile, can complicate or mimic immune-related colitis and require repeated testing if refractory to treatment. 5, 6

• Colitis can develop within days of the first immunotherapy cycle, not just weeks 6
• Combination ipilimumab/nivolumab carries the highest risk (21-37% diarrhea, 4-8% colitis) compared to anti-PD-1 monotherapy (10% diarrhea, 2% colitis) 4
• Review and discontinue medications that alter gut microbiome (proton pump inhibitors, antibiotics, NSAIDs) when managing checkpoint inhibitor colitis 1, 3
• NSAIDs are associated with increased incidence of checkpoint inhibitor-induced colitis and should be avoided 1, 2
• Budesonide is ineffective for prophylaxis but may treat checkpoint inhibitor-associated microscopic colitis 1, 2

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Special Populations

Patients with pre-existing inflammatory bowel disease have increased risk of gastrointestinal adverse events but can still derive cancer treatment benefit from checkpoint blockade. 1, 2