IMC is the second most common of all irAEs and often the most severe.42 It is also the most common irAE identified in the emergency department.43 44 Diarrhea is the primary symptom, affecting 13%–37% of patients on immunotherapy.10 11 Up to 9% of patients on ICIs may also develop colitis symptoms, including abdominal pain, fever, blood or mucus in stool, and rectal bleeding. The incidence of lower GI toxicity among ICI recipients is lowest among patients receiving anti-PD-1/L1 therapy and highest among patients receiving combination immunotherapy of CTLA-4 and PD-1/L1. Concurrent tyrosine kinase inhibition may also increase the risk of IMC.45 Infrequently, patients may present with complications of colitis such as bowel obstruction,46 47 perforation,48 toxic megacolon,12 or severe electrolyte derangements.49 Risk factors for the development of colitis include proton pump inhibitor use (hypothesized to be due to modulation of the gut microbiome),50 non-steroidal anti-inflammatory drug use,51 specific intestinal microbiome signals,52 53 obesity,54 and previous inflammatory bowel disease.55 56

The CTCAE grading system is the main severity index used to evaluate IMC symptoms and is based on clinical presentation. Further evaluation including stool infectious workup and fecal lactoferrin and calprotectin is indicated for moderate to severe cases. Infectious workup is necessary to identify possible coinfection with other pathogens such as Clostridioides difficiles,57 Giardia duodenalis,58 Epstein-Barr virus,59 and cytomegalovirus,60 which lead to a more severe disease course.61 It is equally important to exclude infectious causes to avoid empiric antibiotic treatment as these medications have been associated with worse IMC outcomes.62 Lactoferrin and calprotectin are both markers of inflammation and help stratify patients for further assessment: all patients with diarrhea at grade 2 and above and positive stool inflammatory markers or colitis-related symptoms are recommended to undergo endoscopic evaluation as well.

Current guidelines rely on CTCAE gradings to guide IMC evaluation and management.37 63 64 Despite this, multiple studies have shown that the clinical grade of IMC symptoms does not correlate well with the severity of inflammation found on endoscopy or histology,64 highlighting the importance of endoscopic evaluation. High-risk findings on endoscopy and biopsy have been associated with more frequent hospitalization, higher rates of recurrence, and the need for selective immunosuppressive therapy (SIT). Moreover, timely endoscopic evaluation in these patients can lead to earlier SIT introduction, and thus has been associated with shorter durations of symptoms and steroid therapy as well as less recurrence, highlighting the importance of this procedure.65 Flexible sigmoidoscopy has been shown to be a suitable alternative to colonoscopy since as many as 98% of cases have left colon involvement.9 To date, no endoscopic scoring systems have been validated for IMC, but those adopted from inflammatory bowel disease such as the Ulcerative Colitis Endoscopic Index of Severity, Mayo score, and Nancy histological index have shown some prognostic value.66 Other markers such as C reactive protein levels have been shown to be useful for initial severity assessment. That said, they are not specific for IMC and have limited value for disease monitoring after treatment; they are, therefore, largely outdone by the more specific fecal calprotectin.67 68 Finally, the role of CT imaging in the diagnosis is unclear, with studies showing a high positive predictive value69 but a low negative predictive value.70

Grade 1 IMC is managed conservatively with supportive care and antidiarrheal agents such as loperamide and diphenoxylate/atropine. For cases grade 2 and above, corticosteroids are recommended if the diarrhea is not transient, with a taper over 4–6 weeks once symptoms improve to grade 1. Budesonide has been suggested as an effective alternative to systemic steroids in one study.71 Patients with an inadequate response to steroids after 72 hours or with high-risk endoscopic features, such as ulcers >2 mm in depth and >1 cm in size and extensive inflammation, are recommended to start SIT with infliximab or vedolizumab. Both agents have comparable IMC response rates, but vedolizumab is associated with shorter steroid treatment durations and fewer hospitalizations, although with a longer time to clinical response.72 Cases that are refractory to one agent could either be switched to another biologic or considered for fecal microbiota transplantation (FMT), which has shown great promise as both first-line73 and salvage therapy74 for IMC. Alternative agents used include tofacitinib,75 tocilizumab,76 tacrolimus,77 mycophenolate,78 and ustekinumab.79 Extracorporeal photopheresis has been successfully used in one instance.80 Surgical management with a subtotal colectomy is indicated in cases with bowel perforation, and a diverting ileostomy may be considered to control the symptoms of severe colitis in the acute setting.12 Patients with symptoms grade 3 or above should be considered for inpatient management following the above guidelines, and gastroenterology consultation regardless of grade can help reduce symptom duration, hospital readmission, and recurrence rates.81 Earlier GI consultation has been associated with better outcomes.81 82 Factors associated with worse outcomes include findings of colitis on CT imaging,83 non-collagenous or lymphocytic patterns of inflammation on biopsy,84 increased integrin expression,85 and specific endoscopic findings as described above.

Most patients eventually achieve clinical remission of their IMC, with around 90% of steroid-refractory cases improving after administration of infliximab, vedolizumab, or a combination of both.72 86 For those whose symptoms do not respond to treatment with biological agents, FMT has been shown to improve symptoms in roughly 85% of patients with refractory disease.74 Approximately half of patients can resume ICI therapy after resolution of their colitis,10 but this comes with the risk of recurrence in 17%–36% of patients.87 Usually, ICI resumption of anti-CTLA-4 agents is less favored given their higher risk for colitis and its recurrence compared with that of anti-PD-1/L1. Notably, maintenance therapy with infliximab or vedolizumab even after remission of the initial toxicity among these patients on ICI rechallenge is effective at mitigating this risk.88 89 Independent of ICI resumption, IMC is associated with better cancer response and overall survival among these patients.90–92 However, it may also be associated with later development of colonic adenoma.93

Currently, regular endoscopic follow-up can be considered to monitor treatment response and colitis activity.63 64 This can be done after induction doses of SIT64 to confirm endoscopic healing or in case symptoms are refractory to immunosuppression.63 Calprotectin is an excellent and easy-to-obtain marker that can be used in both the initial assessment and long-term follow-up of IMC. Other modalities such as ultrasonography have also been used in a handful of cases for monitoring purposes.94 95 There may be some benefit to continued endoscopic surveillance after disease resolution to monitor for the development of adenomatous polyps.93 A summary of upper and lower GI toxicity features can be found in online supplemental table 1.