Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist
Since their introduction for melanoma treatment, the use of immune checkpoint inhibitors (ICIs) has rapidly expanded. Though their impact on survival is irrefutable, these medications have been associated with autoimmune-like adverse events related to their ability to induce the immune system. One of the most commonly affected organ systems is the gastrointestinal (GI) tract, in which manifestations range from mild diarrhea to severe colitis with intestinal perforation. Because of the increased use of ICIs, hospitalists are caring for an increasing number of patients experiencing their adverse events. We present a case-oriented review of the GI adverse events associated with the use of ICIs to familiarize the hospitalist with their mechanism of action and potential complications and to emphasize the importance of early diagnosis and treatment to decrease morbidity and mortality.
© 2018 Society of Hospital Medicine
CASE MANAGEMENT STRATEGY
The patient was started on intravenous (IV) methylprednisolone 2 mg/kg twice a day. After 48 hours, he still had more than 7 episodes of diarrhea per day, so he was treated with 1 dose of infliximab 5 mg/kg without stopping corticosteroids. Within 72 hours, the patient’s abdominal pain improved and his diarrhea stopped. He was discharged on an 8-week taper of prednisone starting at 1 mg/kg/day, pneumocystis pneumonia (PCP) prophylaxis was started, and ICI therapy was discontinued indefinitely.
MANAGEMENT OF COLITIS
Management of grade 1 and 2 colitis is mainly supportive, consisting of fluid and electrolyte replacement, the American Dietetic Association colitis diet, and antimotility agents, such as loperamide, oral diphenoxylate hydrochloride, or atropine sulfate.36,37 Persistent grade 2 symptoms (lasting >3 days), should prompt initiation of 0.5 to 1 mg/kg/day of oral prednisone or an equivalent.19 If symptoms do not improve with oral corticosteroids, patient hospitalization for IV corticosteroids should be considered.37 Importantly, opioids and antidiarrheals may mask the pain and severity of symptoms and, therefore, should be used cautiously.19
Patients with grade 3 and 4 colitis (≥7 stools per day, severe abdominal pain, or complications) require the use of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or an equivalent.15 Patients who fail to respond to prednisone alone may benefit from the addition of oral budesonide at a dose of 9 to 12 mg/day.50 In severe cases of colitis, hospitalization may be necessary for IV hydration, electrolyte replacement, and IV methylprednisolone at a starting dose of 2 mg/kg twice a day for 1 to 2 days before transitioning to oral corticosteroids.12,15 Though improvement is usually noted within the first 2 weeks of treatment, prednisone should be slowly tapered over a period of 4 to 8 weeks to ensure complete healing and prevent relapse.20,36 Patients who receive an equivalent dose of prednisone 20 mg daily during a period of 4 weeks or more should receive PCP prophylaxis.51 Some patients fail to respond to IV corticosteroids despite adequate dosing. Many of these patients have severe disease, possibly because of delayed recognition and initiation of treatment.19 As with IBD, the addition of infliximab to corticosteroids at 5 mg/kg as a single dose is usually successful for this population subset.52-54 Although a response is seen within 1 to 3 days,41 some patients benefit from an additional dose of infliximab 2 weeks after the initial dose.19 If sepsis or perforation is suspected at any point, corticosteroids or infliximab should be avoided and antibiotics should be started immediately.15,19 Patients with a medically unresponsive disease may require partial or complete colectomy.20 The use of prophylactic budesonide to prevent diarrhea or colitis has not been proven effective and should not be used.55 Despite complications, mortality from colitis has markedly decreased given the increased awareness of this adverse event, reduction in the time to recognition and treatment, and increased adherence to corticosteroids.12
Treating physicians may be delayed in starting appropriate therapy because patients are concerned that using corticosteroids will negatively impact immunotherapy efficacy. Current evidence shows that the use of temporary immunosuppression to treat irAEs does not affect overall survival, efficacy, or time to treatment failure of the ICI.12,56 Restarting ICI therapy is a complex decision and should always be individualized. In grade 1 and 2 colitis, ICI therapy is typically restarted after symptoms have improved.5 In grade 3 and 4 colitis, ICI therapy is often permanently discontinued.20
CONCLUSION
ICIs have not only increased our understanding of the biology of cancer, but they have also improved survival in advanced stages of malignancies like melanoma, NSCLC, and renal cell carcinoma. The expanding use of these medications increases the likelihood that healthcare providers will encounter patients experiencing their adverse events.
Immune-mediated GI adverse events include a wide range of symptoms, from mild diarrhea to severe colitis complicated by perforation and death. Diagnosis requires exclusion of an infectious process. Early recognition and treatment with corticosteroids or another immunosuppressant such as infliximab hastens recovery and decreases complications and mortality. Treatment should be started within 5 days of symptom onset. Corticosteroids should be slowly tapered for no less than 4 weeks to prevent relapse and PCP prophylaxis administered in appropriate patients. Restarting ICI therapy may be considered in cases of mild colitis, but in severe cases, ICI therapy is usually discontinued.
