Immunotherapy-induced cholestasis in cancer: insights from the two real-world pharmacovigilance databases of FAERS and vigiBase

Background: The U.S. Food and Drug Administration (FDA) recently issued a safety alert regarding cholestasis as a potential adverse reaction to immune checkpoint inhibitors (ICIs) therapy. However, the underlying mechanisms of ICIs-induced cholestasis remain poorly elucidated. Methods: This study analyzed adverse event reports of cancer patients treated with ICIs extracted from the FAERS (2013-2023) and VigiBase (1968-2023) databases. The reporting odds ratio (ROR) and information component (IC) methods were employed to evaluate the association between cholestasis and ICIs therapy, while time-to-onset (TTO) analysis was conducted. Clinical data from hospitals and results from mouse experiments were integrated to validate the analysis findings. Results: Both ROR and IC analyses demonstrated a statistically significant elevation in cholestasis risk among ICIs-treated patients compared to those receiving conventional chemotherapy. A heightened risk was observed in the 0-65 age cohort, with no significant gender-specific disparities noted. The TTO analysis revealed a delayed onset of cholestasis in both ICIs-treated patients and female subjects compared to their respective counterparts. Gene expression profiling elucidated multiple cholestasis-associated signaling pathways, encompassing biliary inflammation, bile acid metabolic disorders, and impairment of hepatocellular drug metabolism. Conclusion: ICIs-treated patients exhibit higher cholestasis risk compared to conventional chemotherapy. Long-term liver function monitoring is crucial for patient safety. ICIs-related cholestasis may result from immune-mediated bile duct injury or metabolic disorders, potentially influenced by baseline liver function. This comprehensive article provides crucial evidence for the risk assessment and management of ICIs-related cholestasis, thereby contributing to safe medication use and enhanced patient care in clinical practice.