Association between Immune Check Point Inhibitors and Digestive System Inflammatory Adverse Reactions: Evidence from Pharmacovigilance Analysis and Systematic Review

Ya Zou¹Li Qinchuan¹Lu Zhou¹Yun Lu¹Hua Wei¹Yan Zhou¹Shibo Lin¹Xirui Guo¹Shihao Yan¹Hongju Wang¹Fangqing Xie¹Chun Liu¹Li Chen^2*

• ¹Chengdu Second People's Hospital, Chengdu, China
• ²Sichuan University West China Second University Hospital, Chengdu, China

Purpose: Comparative real-world data on the spectrum of digestive inflammatory adverse reactions across ICI classes are limited. Existing evidence on immune-related Sjögren's syndrome/sialadenitis consists largely of case reports and small series. Methods: We performed disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database (2015–2023) to evaluate associations between ICIs and digestive inflammatory adverse reactions. Additionally, we conducted a systematic review up to July 2025 to identify published cases of ICI-associated Sjögren's syndrome/sialadenitis. Results: PD-1 inhibitors (pembrolizumab and nivolumab) showed the strongest associations with immune-mediated oesophagitis and gastritis. Pembrolizumab was also highly associated with hepatobiliary events, including immune-mediated cholangitis (ROR 249.18, 95% CI 169.04-367.32) and hepatitis (ROR 85.51, 95% CI 73.22-99.86). In contrast, the CTLA-4 inhibitor ipilimumab exhibited the strongest signal for immune-mediated enterocolitis. Atezolizumab and ipilimumab were significantly associated with spontaneous bacterial peritonitis. Our systematic review identified 93 cases of ICI-associated Sjögren's syndrome/sialadenitis, predominantly in patients with melanoma or lung cancer receiving PD-1 inhibitors. Conclusion: PD-1 inhibitors are more strongly associated with upper GI and hepatobiliary inflammatory adverse reactions, whereas CTLA-4 inhibitors carry a higher risk of enterocolitis. These findings underscore the need for ICI-specific monitoring protocols. Early recognition and tailored management—including potential treatment interruption or corticosteroid use—are critical to minimizing severe outcomes. Clinicians should maintain a high index of suspicion for rare inflammatory adverse reactions such as sialadenitis, even as incidence remains low. These insights support more personalized risk-benefit assessment and inflammatory adverse reactions management in patients receiving ICIs.