What is the treatment for a patient with immunotherapy-induced colitis?

Treatment of Immunotherapy-Induced Colitis

For immunotherapy-induced colitis, treatment is grade-dependent: Grade 1 requires supportive care only; Grade 2 requires oral corticosteroids (1 mg/kg/day prednisone) with early escalation to infliximab or vedolizumab if no improvement within 2-3 days; Grade 3-4 requires immediate IV methylprednisolone (1-2 mg/kg/day) with strong consideration for early biologic therapy, particularly if high-risk endoscopic features are present. 1

Grade-Based Treatment Algorithm

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

• Continue checkpoint inhibitor therapy with close monitoring 1
• Provide supportive care with hydration and dietary modifications 1
• Loperamide may be used cautiously after ruling out infection, though some experts prefer to avoid it to prevent masking worsening symptoms 1
• Monitor patients every 3 days by phone or electronic system until stabilized 1
• Obtain gastroenterology consultation for prolonged Grade 1 cases and consider endoscopy with biopsies 1

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

• Hold checkpoint inhibitor immediately 1
• Rule out infectious causes first: obtain stool studies for C. difficile, bacterial pathogens, CMV, and parasites before initiating immunosuppression 1, 2
• Measure fecal lactoferrin and calprotectin to stratify risk and determine urgency of endoscopy 1, 2
• Perform endoscopy with biopsy within 7-14 days of symptom onset—early endoscopy (≤7 days) is associated with shorter symptom duration (19 vs 47 days) and shorter steroid treatment (49 vs 74 days) 1
• Start oral prednisone 1 mg/kg/day (or equivalent) until symptoms improve to Grade 1, then taper over 4-6 weeks 1
• If no improvement within 2-3 days of steroids, add infliximab (5 mg/kg) or vedolizumab rather than continuing steroids alone 1
• Early introduction of selective immunosuppressive therapy (≤10 days from onset) is associated with fewer hospitalizations, less steroid taper failure, and shorter symptom duration compared to delayed introduction 3
• Consider hospitalization if dehydration or electrolyte imbalance present 1

Grade 3-4 (Severe: ≥7 additional stools/day or life-threatening)

• Permanently discontinue CTLA-4 inhibitors (ipilimumab); may consider resuming PD-1/PD-L1 agents after resolution in consultation with gastroenterology 1
• Hospitalize immediately for Grade 4 or Grade 3 with dehydration/electrolyte abnormalities 1
• Start IV methylprednisolone 1-2 mg/kg/day immediately 1
• Strongly consider early infliximab or vedolizumab if high-risk endoscopic features present (ulceration, Mayo Endoscopic Score ≥2) or if no improvement after 3 days of IV steroids 1
• The presence of endoscopic ulceration (Mayo Endoscopic Score 3) is significantly associated with need for infliximab (p=0.008), whereas symptom severity alone does not predict endoscopic findings 4
• Obtain tuberculosis testing (blood test preferred) before first infliximab dose, though treatment should not be delayed for results 1
• Consider repeat colonoscopy if symptoms remain refractory despite treatment 1

Critical Diagnostic Considerations

Endoscopy Timing and Prognostic Value

• Endoscopy should be performed within 2 weeks of symptom onset for all Grade ≥2 cases 1, 2
• Patients with positive fecal lactoferrin should undergo early endoscopy even with Grade 1 symptoms, as lactoferrin has 70% sensitivity for endoscopic inflammation and 90% sensitivity for histologic inflammation 1
• Mayo Endoscopic Score (MES) predicts treatment needs better than symptom severity: MES 3 (ulceration) strongly predicts need for infliximab, while MES 0 rarely requires escalation beyond steroids 4
• Endoscopy performed ≤30 days from onset is associated with significantly shorter steroid duration and reduced symptom recurrence (21.8% vs 50%) 1

Infliximab-Refractory Disease

• Approximately 11% of patients are infliximab-refractory and require additional immunosuppression 5
• Risk factors for infliximab-refractory colitis include: symptom onset within 4 weeks of immunotherapy initiation, underlying autoimmune disease, higher grade colitis, and pancolitis with severe endoscopic features 5
• For infliximab-refractory cases, consider vedolizumab, fecal microbiota transplant, JAK inhibitor tofacitinib, or IL-12 blocking antibody ustekinumab 1

Steroid Tapering and Biologic Duration

Corticosteroid Management

• Taper steroids over 4-6 weeks once symptoms improve to Grade ≤1 1
• Shorter tapers may be appropriate in patients also receiving biologics to minimize infection risk 1
• Long-duration steroids (>30 days) without infliximab are associated with increased infection rates compared to short-duration steroids plus infliximab 1
• Do not resume checkpoint inhibitors until steroid dose is ≤10 mg/day and patient remains symptom-free 1

Biologic Therapy Duration

• Patients receiving 3 or more infusions of selective immunosuppressive therapy achieve histologic remission more frequently and have lower fecal calprotectin levels compared to those receiving 1-2 infusions 3
• Evidence supports up to 3 doses of infliximab, with second dose given 2 weeks after first if needed 1
• Target mucosal healing on repeat endoscopy and/or fecal calprotectin ≤116 mg/g before stopping biologic therapy 1, 2
• Consider maintaining biologic therapy if endoscopic and histologic remission not achieved 1

Resuming Checkpoint Inhibitors

Risk Stratification

• Resuming PD-1/PD-L1 agents is associated with lower risk of flare compared to CTLA-4 inhibitors 1
• Of patients who resume PD-1 monotherapy after colitis resolution, 37% develop recurrent colitis 5
• CTLA-4 inhibitors should be permanently discontinued for Grade ≥2 colitis; continue with PD-1/PD-L1 agent only if combination therapy was used 1

Criteria for Rechallenge

• Resume only after symptoms resolve to Grade ≤1 1
• Steroid taper must be completed or dose ≤10 mg/day 1
• Consider endoscopic and histologic remission before rechallenge 1
• Fecal calprotectin ≤116 mg/g may serve as surrogate for mucosal healing 1

Alternative and Emerging Therapies

Topical Corticosteroids

• Oral beclomethasone dipropionate (5 mg once daily for 28 days) achieved clinical remission in 95% of patients with steroid-dependent or steroid-refractory ICI-induced colitis 6
• Beclomethasone is particularly appealing for patients dependent on systemic corticosteroids (59% of treated patients in one study) as it has fewer systemic side effects 6
• 45% of patients had symptomatic relapse on cessation, but all recaptured response on restarting 6

Combination Therapy Considerations

• Combination ipilimumab/nivolumab causes more frequent (14.5% vs 3.5%), earlier onset (6.3 vs 25.7 weeks), and more severe colitis compared to PD-1 monotherapy 5
• Combination therapy-induced colitis requires higher steroid doses (91% vs 74%) and is more likely to be infliximab-refractory 5

Common Pitfalls to Avoid

• Do not delay endoscopy: waiting >7 days is associated with significantly worse outcomes 1
• Do not rely on symptom severity alone to guide treatment escalation—endoscopic findings are more predictive of treatment needs 4
• Do not continue steroids beyond 3 days without improvement—early escalation to biologics improves outcomes 1, 3
• Avoid NSAIDs, as they are associated with increased incidence of ICI-induced colitis 2
• Do not use infliximab if concomitant hepatitis is present—consider alternative immunosuppressants like mycophenolate that work systemically 1