Immune Checkpoint Inhibitor-induced Uveitis: Disproportionality and Timing Analyses of the Japanese Pharmacovigilance Database

Abstract

Background/aim: Immune checkpoint inhibitors (ICIs) are widely used anticancer drugs, but they can trigger immune-related adverse events (irAEs), including rare but potentially blinding uveitis. In this study, the associations between ICIs and uveitis, and the time to uveitis onset, were evaluated using data from the Japanese Adverse Drug Event Report (JADER) database.

Patients and methods: We performed disproportionality analysis using data from the JADER database (April 2004-June 2024). Positive signals were identified using reporting odds ratios (RORs) with 95% confidence intervals (CIs). Time-to-onset analyses were performed with the Weibull distribution model, and sex-based differences were assessed with Kaplan-Meier curves and the log-rank test.

Results: Among 914,713 cases in the JADER database, 346 were suspected ICI-induced uveitis. Positive signals were detected for nivolumab [ROR, 9.05 (95%CI=7.81-10.50)], ipilimumab [9.82 (8.20-11.76)], and pembrolizumab [4.94 (4.05-6.01)] but not for other ICIs. The median onset time was approximately 2 months (65 days for nivolumab, 61 days for ipilimumab, and 70 days for pembrolizumab). Pembrolizumab-induced uveitis occurred significantly earlier in female patients than in male patients (29.5 vs. 91 days, p=0.015). Onset patterns were classified as early failure for nivolumab and random failure for ipilimumab and pembrolizumab. The outcomes were mostly good, and severe cases of uveitis were rare.

Conclusion: ICI-induced uveitis typically occurs within two months of treatment initiation, with pembrolizumab-induced uveitis occurring earlier in females than in males. Because causation cannot be established on the basis of this analysis, large-scale prospective clinical studies are needed.

Keywords: Adverse reactions; Japanese Adverse Drug Event Report database; immune checkpoint inhibitors; time-to-onset; uveitis.