Enterocolitis due to immune checkpoint inhibitors: a systematic review

Abstract

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.

Nivolumab‐induced colitis in a patient with malignant melanoma: A case report and immunological analysis

“…All colonic biopsy samples showed the predominance of CD4 immunostaining, while a recent report has shown that colonic mucosal lymphocytes are CD8 + predominant in nivolumabinduced colitis. 3 This result suggested that the immunological response is mostly activated by CD4 + T cells in our case.…”

Immune‐related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies

“…Diarrhoea is the most common clinical presentation for a GI‐irAE, with most patients showing histological evidence of enterocolitis . The incidence of diarrhoea is reported to be up to 13% for anti‐PD‐1/PD‐L1 therapy and 35% for anti‐CTLA‐4 therapy . Severe enterocolitis, which is one of the most frequent severe irAEs, is principally caused by anti‐CTLA‐4, and, in rare cases, leads to perforation and death .…”

“…2 The incidence of diarrhoea is reported to be up to 13% for anti-PD-1/PD-L1 therapy and 35% for anti-CTLA-4 therapy. 2,[5][6][7] Severe enterocolitis, which is one of the most frequent severe irAEs, is principally caused by anti-CTLA-4, and, in rare cases, leads to perforation and death. 2,8 Patients may also experience abdominal pain, nausea, and/or vomiting; haematochezia and fever are less frequent symptoms.…”

Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis

“…The incidence of diarrhea had been reported to be 12.1-13.7% for anti-PD-1 and 30.2-35.4% for anti-CTLA-4, whereas the incidence of colitis had been reported to be 0.7-1.6% for anti-PD-1, 5.7-9.1% for anti-CTLA-4, and 13.6% for the combination of both agents [8]. The endoscopic findings of irColitis closely resemble those of ulcerative colitis and include erythema, loss of vascular pattern, erosions, ulcerations, and luminal bleeding [4].…”

“…Histologically, acute colitis can present as mononuclear cell and neutrophil infiltration of the lamina propria [9]. Blood examination and stool analysis should be carried out to rule out enteropathogens such as CMV and C. difficile [5,8].…”