Differential diagnosis and management of immune checkpoint inhibitor-induced colitis: A comprehensive review

Abstract

Immune checkpoint inhibitors (ICIs) are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4, programmed cell death 1 and programmed death-ligand 1. Checkpoint blockade by ICIs reactivates a tumor-specific T cell response. Immune-related adverse events can occur in various organs including skin, liver, and gastrointestinal tract. Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death. Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome. Unfortunately, its clinical, endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies, such as infection, medication, graft-versus-host disease and inflammatory bowel disease. Thus, a definitive diagnosis can only be rendered after these other possible etiologies are excluded. Sometimes an extensive clinical, laboratory and radiologic workup is required, making it challenging to arrive at a prompt diagnosis. Most patients experience full resolution of symptoms with corticosteroids and/or infliximab. For ICI-induced colitis that is treatment-refractory, small scale studies offer alternative strategies, such as vedolizumab and fecal microbiota transplantation. In this review, we focus on the clinical features, differential diagnosis, and management of ICI-induced colitis with special attention to emerging treatment options for treatment-refractory ICI-induced colitis.

Keywords: Graft-versus-host disease; Immune checkpoint inhibitor; Immune checkpoint inhibitor-induced colitis; Inflammatory bowel disease; Infliximab; Vedolizumab.

Figure 1

Representative images of immune checkpoint inhibitor-induced colitis in a patient with metastatic melanoma treated with nivolumab and ipilimumab for 2 mo (Hematoxylin and eosin). A: Active colitis characterized by mixed inflammatory cell infiltrates in the lamina propria and surface erosion (100 ×); B: High magnification of A. Note the neutrophils, lymphocytes, and plasma cells in the lamina propria (200 ×); C: Active colitis with mild crypt architectural irregularity (100 ×); D: Active colitis with neutrophilic cryptitis (200 ×).

Figure 2

Representative images of infectious colitis (Hematoxylin and eosin). A: Low magnification view of cytomegaloviral (CMV) colitis. Notice the lymphocytes and neutrophils in the lamina propria (100 ×); B: Note an owl-eye inclusion characterized by enlarged nucleus with oval, eosinophilic intranuclear inclusion surrounded by clear halo, consistent with CMV inclusion (400 ×); C: Clostridium difficile colitis. Pseudomembranes composed of fibrin, neutrophils and necrotic epithelial cells are on the surface of the mucosal glands (40 ×). Yellow sign notes a viral inclusiona.

Figure 3

Representative images of medication-induced colitis (Hematoxylin and eosin). A: Ring mitosis caused by docetaxel in duodenum (400 ×); B: Small bowel diaphragm. Fibrotic submucosa protrudes into the intestinal lumen and forms a diaphragm (8 ×); C: Low magnification view of mycophenolate mofetil-induced colitis. (100 ×); D: Higher magnification view of mycophenolate mofetil-induced colitis. There is an inflammatory cell infiltrate consisting of lymphocytes, plasma cells and eosinophils in the lamina propria with neutrophilic cryptitis (400 ×). Yellow sign notes a ring mitosis.

Figure 4

Representative images of inflammatory bowel disease (Hematoxylin and eosin). A: Mucosal inflammation with marked crypt distortion and neutrophilic cryptitis and abscesses in ulcerative colitis (40 ×); B: Higher magnification view shows crypt abscess (100 ×).

Figure 5

Representative images of graft-versus-host disease (Hematoxylin and eosin). A: Colonic graft-versus-host disease characterized by marked crypt architectural distortion and paucity of lamina propria inflammation (40 ×); B: On higher magnification, enterocyte apoptosis (yellow sign) are readily identified (200 ×).