What is the incidence and clinical significance of dry eye disease in patients treated with immune checkpoint inhibitors? A systematic review and meta-analysis of ocular immune-related adverse events.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may cause immune-related adverse events (irAEs), including dry eye disease (DED). This study aimed to quantify the incidence of ICI-associated DED and to evaluate factors contributing to variability across studies.

METHODS: A systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251091266). PubMed, the Cochrane Library, and Web of Science were searched from inception through September 13, 2025. Eligible studies included adults (≥18 years) treated with ICIs (anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)) reporting DED outcomes with extractable ICI-exposed denominators. Two independent reviewers screened studies, extracted data, and assessed risk of bias using the Newcastle-Ottawa Scale (observational studies), ROBINS-I (non-randomized interventional studies), and Cochrane RoB 2 (randomized controlled trials). Pooled incidence and 95% confidence interval (CI) estimates were calculated using random-effects models on the logit-transformed scale and back-transformed to proportions. Subgroup analyses evaluated ICI class, combination therapy, and tumour type.

RESULTS: Thirteen studies were included. The pooled incidence of DED among ICI-treated patients was 2% (95% CI: 1%-3%), with marked heterogeneity across studies (0.2%-65%), likely reflecting variation in surveillance intensity, diagnostic criteria, and ascertainment approaches. Combination ICI therapy (CTLA-4 plus PD-1) demonstrated a numerically higher pooled incidence (25%) than monotherapies (CTLA-4: 5%; PD-1: 13%; PD-L1: 15%), although subgroup differences were not statistically significant (p = 0.18); these regimen-stratified estimates were derived from a limited subset of studies with extractable regimen-specific denominators and heterogeneous surveillance intensity and therefore are not directly comparable to the overall pooled incidence. Lung cancer cohorts showed higher observed rates (41%) compared with melanoma (4%) and renal cancer cohorts (32%) (p = 0.05); however, these apparent subgroup differences may reflect not only tumour- or regimen-specific biology, but also systematic differences in surveillance intensity, access to ophthalmic assessment, and referral enrichment across cohorts, which may materially influence observed event rates. Mechanistic findings were consistent with immune-mediated lacrimal dysfunction, with abnormal Schirmer's test results reported in 62% of symptomatic cases. Most DED events were mild and managed with topical therapy, while a minority required escalation to systemic immunomodulation.

CONCLUSION: DED occurs in approximately 1 in 50 ICI-treated patients in pooled estimates from heterogeneous study designs, although reported incidence varies substantially across study designs and ascertainment approaches. Combination therapy and ICI-treated lung cancer cohorts demonstrated numerically higher DED rates, but these subgroup estimates should be interpreted cautiously given potential differences in referral patterns and diagnostic intensity. Incidence variability highlights the need for standardized ocular assessment. High-risk patients should be proactively monitored to maintain quality of life and treatment adherence.