Grade 3 immune-mediated colitis on combination immunotherapy
A 62-year-old man with BRAF V600E-mutant metastatic melanoma begins nivolumab plus ipilimumab. On day 18 he reports six to eight watery stools daily for three days, crampy abdominal pain, and one episode of vomiting. He is febrile at 38.2°C, blood pressure 104/66 mmHg, and looks volume-depleted. Creatinine has risen from 0.9 to 1.7 mg/dL; ALT is 165 U/L (grade 2) and bilirubin is normal. He took two doses of loperamide without improvement. He is on no other new medicines and has no recent antibiotics. He asks whether he can take oral steroids at home and continue treatment next week because his scan is scheduled.
1. What is your immediate assessment and management, including whether home oral steroids are appropriate?
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This is not a routine side-effect to manage at home. The combination of grade 3 diarrhoea, fever, hypotension, rising creatinine and transaminitis suggests immune-mediated colitis with possible sepsis or hypovolaemia. I would admit, start IV fluids, obtain blood cultures, stool testing for Clostridioides difficile, bacterial pathogens and CMV, and check CBC, electrolytes, renal and liver function, CRP and lactate. I would hold nivolumab and ipilimumab and start IV methylprednisolone 1–2 mg/kg/day once cultures are taken, with empirical antibiotics if sepsis is suspected. Oral steroids and outpatient monitoring are unsafe with hypotension and renal impairment. Loperamide should stop. I would involve gastroenterology early and monitor stool frequency, abdominal examination, urine output and creatinine. The hepatitis is grade 2, so it does not by itself change the colitis plan, but it requires close monitoring and ruling out other causes.
2. If symptoms persist after 48 hours of high-dose steroids, what agent would you choose and what must you exclude first? How does the presence of hepatitis change your choice?
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After 48–72 hours without improvement, I would give infliximab 5 mg/kg for steroid-refractory immune colitis. Before dosing I would exclude perforation, abscess, bowel obstruction and active infection, including C. difficile, CMV and bacterial sepsis; infliximab is contraindicated in perforation or uncontrolled sepsis. I would screen for hepatitis B and tuberculosis according to local policy. The grade 2 hepatitis matters: infliximab is not the treatment for immune-mediated hepatitis and can itself cause hepatotoxicity. If hepatitis progressed to grade 3 or 4, I would use corticosteroids and consider mycophenolate for steroid-refractory hepatitis, with hepatology input. Vedolizumab could be considered if infliximab is contraindicated, but it is not a substitute for excluding infection. I would also review all medicines for alternative causes of diarrhoea and liver injury.
3. How would you counsel him about continuation of immunotherapy and the evidence for rechallenge?
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I would explain that he cannot simply continue treatment next week. Grade 3 colitis on ipilimumab plus nivolumab is a serious toxicity; ipilimumab should be permanently discontinued, and the combination should not be restarted. After full resolution, rechallenge with nivolumab alone could be discussed only as a shared decision, because evidence is limited and colitis can recur; it would not be routine. The scan is less urgent than treating the colitis and excluding infection. I would document the grade, treatment, response and follow-up plan. I would also explain warning symptoms-fever, increasing diarrhoea, abdominal pain, black stools, reduced urine output-and give a direct contact. If he has steroid-refractory disease or recurrent colitis, I would favour stopping immunotherapy and focusing on alternative cancer treatment.