Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management

Abstract

Background: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. Methods: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. Results: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. Conclusion: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis.

Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy

“…6,28,29 Common endoscopy findings include erythema, loss of vascular pattern, granularity, ulcerations, and even normal mucosa. 12,15,30 As endoscopic normal mucosa can show histopathologic features of CPI therapy injury, biopsies are recommended for the diagnosis when CPI therapy injury is clinically suspected. 6 CPI injury is often a pancolitis, but involvement of descending colon only can also be seen.…”

“…The CPI therapy-induced colonic injury can present in a number of histopathologic patterns including active colitis, microscopic colitis (lymphocytic and collagenous), chronic active colitis, increased apoptosis, ischemic colitis, and nonspecific inflammatory reactive changes. 15,30 There can be an overlap between these patterns.…”

Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

“…Gastrointestinal irAEs include colitis, hepatitis, and pancreatitis [125]. The most common is colitis, which usually presents as diarrhea and can affect up to 40% of patients.…”

Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma

“…Dong H et al [33]. As a novel checkpoint, tumorassociated PD-L1 plays important roles in mediating T cell activation and apoptosis, causing immune surveillance attenuated and promote tumor progression [34,35]. Normally, PD-1 pathways and its ligands, PD-L1 and PD-L2, contribute to the balance between activation and inhibitory signals that are needed for physiologic immune system works and for the maintenance of T cell self-tolerance and homeostasis [36].…”