Immune Checkpoint Inhibitor-Associated Uveitis: Insights From Comparative Analyses Across Malignancies and Drug Classes

Victor Bellanda; Matthew J Schulgit; Khaled A Hassan; Lucy B Kennedy; Gabriel Castilho S Barbosa; Yuka Mizuno; Nitesh Mohan; David C Kaelber; Sunil K Srivastava; Sumit Sharma

doi:10.1016/j.ajo.2026.05.046

Immune Checkpoint Inhibitor-Associated Uveitis: Insights From Comparative Analyses Across Malignancies and Drug Classes

Am J Ophthalmol. 2026 Jun 1:289:282-291. doi: 10.1016/j.ajo.2026.05.046. Online ahead of print.

Affiliations

¹ From the Cole Eye Institute (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Uveitis Center of Excellence (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA.
² From the Cole Eye Institute (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Uveitis Center of Excellence (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (M.J.S., N.M., S.S.), Cleveland, Ohio, USA.
³ Cleveland Clinic Taussig Cancer Center (K.A.H. and L.B.K.), Cleveland, Ohio, USA.
⁴ The Center for Clinical Informatics Research and Education (D.C.K.), The MetroHealth System and The Departments of Internal Medicine, Pediatrics, and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁵ From the Cole Eye Institute (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Uveitis Center of Excellence (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Department of Ophthalmology (S.K.S.), MetroHealth, Cleveland, Ohio, USA.
⁶ From the Cole Eye Institute (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Uveitis Center of Excellence (V.B., M.J.S., G.C.S.B., Y.M., N.M., S.K.S., S.S.), Cleveland Clinic, Cleveland, Ohio, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (M.J.S., N.M., S.S.), Cleveland, Ohio, USA. Electronic address: sharmas@ccf.org.

PMID: 42229563
DOI: 10.1016/j.ajo.2026.05.046

Abstract

Purpose: Understanding how the risk of immune checkpoint inhibitor (ICI)-associated noninfectious uveitis (NIU) differs by malignancy and drug class may help understand its pathophysiology and guide targeted ophthalmic surveillance. This study aims to evaluate the comparative risk of ICI-associated NIU across different malignancies and drug classes.

Design: Retrospective, multicenter clinical cohort study.

Subjects: Adults with metastatic melanoma, lung cancer, renal cell carcinoma (RCC), urothelial carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, or nonmelanoma skin cancer. Propensity score matching was performed for demographics, comorbidities, and socioeconomic factors.

Exposures: Prescription of an ICI agent of any class (anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]).

Main outcome measures: The primary outcome was new-onset NIU within 24 months of first ICI prescription. Relative risks (RR) with 95% confidence intervals (CIs) were calculated. Subgroup analyses compared outcomes across malignancies, with and without ipilimumab or nivolumab exposure, and between ICI subclasses when used in monotherapy.

Results: After matching, 16,834 patients with melanoma and 16,834 with lung cancer were included. Melanoma patients had a higher risk of NIU compared with lung cancer (1.10% vs 0.18%; RR, 6.17; 95% CI, 4.20-9.08). Excluding ipilimumab/nivolumab, melanoma remained associated with increased risk (0.53% vs 0.16%; RR, 3.40; 95% CI, 1.68-6.88). Across malignancies, melanoma consistently demonstrated elevated risk relative to other cohorts. Lung cancer showed borderline decreased risk compared to RCC (0.19% vs 0.36%; RR, 0.53; 95% CI, 0.31-0.90), but this effect was not significant after excluding ipilimumab/nivolumab. In drug-class analyses, anti-PD-1 agents did not demonstrate a significantly different risk of NIU compared with anti-PD-L1 agents (0.26% vs 0.20%; RR, 1.33; 95% CI, 0.89-1.99). Anti-cytotoxic T-lymphocyte-associated protein 4 agents could not be compared due to limited use as monotherapy.

Conclusions: Both malignancy type and ICI subclass influence the risk of ICI-associated uveitis. Melanoma carries an intrinsically higher risk independent of ipilimumab/nivolumab exposure, whereas RCC's risk appears largely ipilimumab/nivolumab-driven. These findings underscore the need for careful monitoring of melanoma patients initiating ICIs and suggest that the pathophysiology of ICI-related uveitis is driven by both drug- and disease-specific factors.