Management of Immune Checkpoint Inhibitor-Induced Colitis
For grade ≥2 immune checkpoint inhibitor-induced colitis, immediately hold the checkpoint inhibitor and start systemic corticosteroids at 1 mg/kg/day prednisone-equivalent after ruling out infection; escalate to infliximab 5 mg/kg within 72 hours if no improvement occurs. 1, 2
Initial Diagnostic Workup
Before initiating any immunosuppressive therapy, exclude infectious etiologies with comprehensive stool testing including C. difficile, bacterial culture, CMV PCR, and ova/parasites. 3, 1 This is critical because immunosuppression in the setting of undiagnosed infection can lead to fulminant sepsis.
Measure fecal lactoferrin and calprotectin in any patient with ≥4 stools above baseline per day to stratify severity and determine urgency of endoscopic evaluation. 1, 2 These inflammatory markers help distinguish true colitis from functional diarrhea and guide treatment intensity.
Obtain baseline laboratory studies including CBC, comprehensive metabolic panel, CRP, and ESR to assess systemic inflammation and organ function. 1
Screen for hepatitis B (surface antigen, core antibody, surface antibody) and latent tuberculosis before initiating biologic agents such as infliximab, as reactivation can be fatal. 1
Perform colonoscopy with biopsies before starting high-dose corticosteroids whenever feasible, as endoscopic ulceration predicts steroid-refractory disease and supports early infliximab use. 3, 1, 2 Even when the mucosa appears normal endoscopically, obtain biopsies because significant inflammation may be present only histologically. 3, 1 Use immunohistochemical staining to exclude CMV infection. 3, 1
Reserve abdominal-pelvic CT for patients with severe abdominal pain, fever, or gastrointestinal bleeding to rule out perforation, abscess, or typhlitis; CT is not required for isolated diarrhea. 1
Grade-Based Treatment Algorithm
Grade 1 (Mild: <4 additional stools/day)
Continue checkpoint inhibitor therapy with close monitoring; do not use prophylactic corticosteroids as they are ineffective. 1 Provide supportive care with loperamide (after infection exclusion), bland diet, and hydration monitoring. 1
Reassess within 24-48 hours for progression, as rapid deterioration can occur within days, especially with anti-CTLA-4 agents like ipilimumab. 1
Grade 2 (Moderate: 4-6 additional stools/day or abdominal pain/blood)
Hold the checkpoint inhibitor immediately and start systemic corticosteroids at 1 mg/kg/day prednisone-equivalent. 1, 2 Do not delay steroid initiation if colitis symptoms are present.
Obtain gastroenterology consultation for all grade ≥2 cases. 1
Escalate to prednisone 2 mg/kg/day or add infliximab 5 mg/kg if no improvement within 72 hours. 1, 2 This 72-hour window is critical—waiting longer increases risk of complications including perforation. 4
When symptoms improve to grade ≤1, taper corticosteroids over 4-6 weeks. 1, 2 Shorter tapers (even 2-3 weeks) are acceptable if biologic therapy is also used. 1
Resume immunotherapy only after corticosteroids are tapered to ≤10 mg/day and the patient remains symptom-free (grade ≤1). 1 Continue anti-PD-1/PD-L1 monotherapy, but if the patient was on combination anti-CTLA-4/anti-PD-1 therapy, permanently discontinue the CTLA-4 agent and continue the PD-1/PD-L1 agent alone. 1
Grade 3-4 (Severe: ≥7 additional stools/day or hospitalization)
Admit for inpatient management and start high-dose intravenous corticosteroids (1-2 mg/kg/day prednisone-equivalent) immediately. 1, 2
Permanently discontinue the checkpoint inhibitor for grade 4; consider permanent discontinuation for grade 3. 1
Obtain urgent colonoscopy and imaging to assess severity and exclude complications such as perforation, abscess, or typhlitis. 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 Infliximab may be repeated after 2 weeks if needed; clinical response typically occurs within 1-3 days. 1
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 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 including perforation and death. 2 IL-23 inhibitors like risankizumab have no established role in checkpoint inhibitor colitis despite efficacy in inflammatory bowel disease. 2
Monitoring Treatment Response and Resuming Immunotherapy
Target mucosal healing on repeat endoscopy and fecal calprotectin ≤116 mg/g before discontinuing biologic therapy. 1, 2
Perform repeat colonoscopy for grade ≥2 patients to document complete remission prior to restarting checkpoint inhibitors. 1, 2
PD-1/PD-L1 inhibitors carry a lower risk of flare-up upon rechallenge compared with CTLA-4 inhibitors. 1
Critical Pitfalls to Avoid
Recognize that rapid progression can occur within days, not just weeks—fulminant colitis has been reported as early as 3 days after the first dose of dual checkpoint blockade. 4 Maintain high clinical suspicion even when timing is atypical.
Review and discontinue medications that alter the gut microbiome including proton-pump inhibitors, antibiotics, and NSAIDs when managing checkpoint inhibitor colitis. 1 NSAIDs are specifically associated with increased incidence of checkpoint inhibitor-induced colitis and should be avoided. 1, 5
Do not confuse checkpoint inhibitor colitis with inflammatory bowel disease despite clinical similarities—the treatment algorithms differ, and checkpoint inhibitor colitis typically lacks features of chronicity on histology. 3, 2
Budesonide is ineffective for prophylaxis but may be useful for treating checkpoint inhibitor-associated microscopic colitis. 1