Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist

Because of the sustained T-cell activation, ICIs have been associated with autoimmune-like toxicities known as immune-related adverse events (irAEs).^19,31 Because the PD-1/PD-L1 pathway is more tumor-specific than the CTLA-4 pathway,^21-23 there is a higher incidence of serious irAEs seen with ipilimumab, reported to be around 27%.^18,22 Furthermore, the risk of developing irAEs is dose-dependent and can increase up to 55% when anti-CTLA-4 are used with other ICIs such as nivolumab.^13,32-34

The skin and GI tract are the most commonly involved organs.^14-16 Skin is affected in 50% of patients receiving ipilimumab and 40% of patients on nivolumab or pembrolizumab, often in the form of a rash or pruritus.^12,35-37 The rash is often described as faintly erythematous, reticular, and maculopapular and typically affects the trunk and extremities.³⁸ Importantly, these events usually occur within the first 2 weeks of treatment, and fewer than 5% are severe.^12,36,39 A higher percentage of severe adverse events occurs in the GI tract, with a reported incidence of 12%.^3,14,36,39

Colitis, defined by either the presence of symptoms or radiologic findings suggestive of inflammation, occurs less often than diarrhea alone, with a reported incidence of 2.3%.^37,43 This incidence increases to almost 12% when anti-CTLA-4 and anti-PD-1/PD-L1 are combined.³² Colitis symptoms include abdominal pain (20%), nausea and vomiting (15%), fever (12%), and, less often, bloody diarrhea or rectal bleeding.^19,20 Colitis severity is graded according to the CTCAE (Table 2).⁴² Most patients have mild colitis (grade 1 or 2).¹⁹ The risk for developing severe colitis (grade 3 or higher) is almost 10 times higher with the use of anti-CTLA-4 compared with anti-PD-1/PD-L1 agents.⁴³ Patients with severe disease are at risk of developing life-threatening complications, such as ileus, toxic megacolon, bowel ischemia, necrosis, or even perforation, which has been reported in up to 5% of patients with colitis because of ipilimumab.^13,17

Based on the patient’s symptoms, physical findings, and temporal relationship to ICI therapy, he was believed to have immune-mediated colitis. Stool studies, including those looking for ova and parasites, Clostridium difficile polymerase chain reaction (PCR), and stool cultures were negative.

In a patient undergoing ICI treatment who has diarrhea, the initial assessment should exclude C. difficile and Salmonella by stool culture, PCR, or pathogenic antigens.¹⁹ Cytomegalovirus reactivation should also be considered. Immune-mediated colitis and infection can coexist; thus, a positive infectious etiology does not rule out the presence of immune colitis or vice versa.⁴⁴ Fecal calprotectin, a marker of neutrophil-associated inflammation, is nonspecific for ICI-induced colitis; however, it may help to distinguish inflammatory from noninflammatory diarrhea.^33,45

No clear guideline exists for the use of abdominal imaging. Some experts suggest using computed tomography in patients with severe, persistent, or progressive symptoms in order to exclude bowel obstruction, toxic megacolon, or perforation.^19,46

In patients with typical symptoms, and after infectious etiologies are ruled out, empiric use of corticosteroids can be initiated without an endoscopic evaluation, which is not necessary to establish a diagnosis and rarely changes management.^12,37,47 In patients with atypical presentations or for whom the diagnosis remains in question, endoscopic evaluation with biopsies may be required. Macroscopic findings may be similar to those seen with inflammatory bowel disease (IBD), including erythema, edema, ulceration, granularity, or loss of vascular pattern. Although immune-mediated colitis affects the descending colon more often than IBD, this feature and any macroscopic findings are insufficient to make this distinction.^20,36 Furthermore, the lack of macroscopic abnormalities does not rule out immune-mediated colitis.²⁰

When endoscopic biopsies are obtained, histologic findings for anti-CTLA-4 medications (eg, ipilimumab) usually follow 3 patterns: neutrophilic infiltrate (46%), lymphocytic infiltrate (15%), and mixed infiltrate (38%).⁴¹ Other findings include crypt abscesses and tissue destruction.²⁰ No biopsy-specific pattern has been described with anti-PD-1/PD-L1 medications, such as nivolumab or pembrolizumab.¹⁸ A normal colonic tissue does not exclude the presence of an irAE, as cases of isolated ileitis⁴⁸ or enteritis⁴⁹ without colitis can also occur.