Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, immune-related adverse events (irAEs) in the gastrointestinal (GI) system commonly occur. In this study, data were obtained from the US Food and Drug Administration adverse event reporting system between July 2014 and December 2020. Colitis, hepatobiliary disorders, and pancreatitis were identified as irAEs in our study. Reporting odds ratio (ROR) with information components (IC) was adopted for disproportionate analysis. A total of 70,330 adverse events were reported during the selected period, 4,075 records of which were associated with ICIs. GI toxicities have been reportedly increased with ICI, with ROR025 of 17.2, 6.7, and 2.3 for colitis, hepatobiliary disorders, and pancreatitis, respectively. The risks of colitis, hepatobiliary disorders, and pancreatitis were higher with anti-CTLA-4 treatment than that with anti-PD-1 (ROR025 2.6, 1.3, and 1.1, respectively) or anti-PD-L1 treatment (ROR025 4.8, 1.3, and 1.3, respectively). Logistic analysis indicated that hepatobiliary disorders and pancreatitis more frequently occurred in female patients (adjusted odds ratio, 1.16 and 1.52; both p < 0.05). Consistently, polytherapy was a strong risk factor for colitis (adjusted odds ratio 2.52, p < 0.001), hepatobiliary disorders (adjusted odds ratio 2.50, p < 0.001), and pancreatitis (adjusted odds ratio 2.29, p < 0.001) according to multivariate logistic analysis. This pharmacovigilance analysis demonstrated an increased risk of all three GI irAEs associated with ICI therapies. The comparative analysis offered supportive insights on selecting GI irAEs for patients treated with ICIs.

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis

“…Moreover, patients with pancreatitis induced by anti-PD-L1 were less exposed to concomitant drugs at risk of causing pancreatitis. However, the association between different ICIs and pancreatitis remains controversial, as some other studies have demonstrated that both anti-CTLA4 alone and combination treatments with nivolumab and ipilimumab are associated with a higher incidence of pancreatitis than anti-PD-1/PD-L1 alone (Su et al, 2018;George et al, 2019;Bai et al, 2021). Consequently, prospective studies are warranted to further investigate and ascertain the true association between pancreatitis and different ICIs treatments.…”

“…The findings from a meta-analysis showed that the incidence of ICIPI was 0.9-3% for anti-CTLA-4 monotherapy, 0.5-1.6% for anti-PD-1 monotherapy, and 1.2-2.1% for combination therapy of anti-CTLA-4 and anti-PD-1 (Su et al, 2018). Some pharmacovigilance studies generally describe ICIrelated AEs in the gastrointestinal system, including pancreatitis (Reese et al, 2020;Bai et al, 2021). However, knowledge is still scarce about the detailed safety profile of pancreatic AEs following various ICIs in real-world clinical practice as no pancreatic AEs other than pancreatitis and autoimmune pancreatitis is included in the existing pharmacovigilance studies.…”

“…In addition, the association between different ICIs and pancreatitis is controversial. Some previous studies showed that the risk of pancreatitis was higher with anti-CTLA-4 than that with anti-PD-1 or anti-PD-L1 (Su et al, 2018;Bai et al, 2021), while another study found that anti-PD-L1 versus anti-PD-1 or anti-CTLA-4 was associated with a slightly increased connection of pancreatitis (Reese et al, 2020). Moreover, increased T lymphocytes may attack pancreatic cells such as islet β-cells and acinar cells, which will not only lead to endocrine disorders but also cause damage to exocrine function.…”

Updates of the role of B-cells in ischemic stroke

“…If combined with thrombolytic therapy, immunomodulation can minimize ischemic injury and immune deficiency, thereby preventing systemic infection and improving survival and the long-term prognosis after ischemic cerebral infarction. However, the occurrence of Immune-Related Adverse Events (irAEs) cannot be ignored ( Bai et al, 2021 ; Verheijden et al, 2023 ). Common side effects include non-response of the skin, secondary infection of the nervous system, interstitial pneumonia, enteritis, hepatitis, thyroiditis, etc., which can affect almost all organ systems.…”

Editorial: Cancer therapy: The challenge of handling a double-edged sword

“…ipilimumab). Whilst the incidence of adverse effects may be considered low (1-30%, depending on the agent and organ system), the impact is a rapid deterioration of function and increased risk of mortality (Bai X et al, 2021). Understanding the risk factors with each compound class is necessary to minimize these risks, particularly considering the increasing trend towards polytherapy.…”