Re: Chang et al.: Incident noninfectious uveitis risk after immune checkpoint treatment (Ophthalmology. 2024;131:867-869)
Authors: Alan Y. Hsu, Chun-Ju Lin, Huan-Sheng Chen, Yi-Yu Tsai
Journal: Ophthalmology (2024)

We thank Chang et al1Chang M.S. Lee S.W. Kim S. et al.Incident non-infectious uveitis risk after immune checkpoint inhibitor treatment.Ophthalmology. 2024 Mar 22; (S0161-6420(24)00198-2) (Online ahead of print)https://doi.org/10.1016/j.ophtha.2024.03.017Abstract Full Text Full Text PDF Scopus (0) Google Scholar for their insight on uveitis risk after immune complex inhibitor (ICI) treatments. However, we believe their current study design warrants further scrutiny. One key aspect pertains to the definition of their exposure of interest, specifically the definition of ICIs. Whereas Chang et al focused on programmed cell death protein 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors, they excluded anticytotoxic T lymphocyte antigen (CTLA-4) inhibitors. We believe this omission is significant; our own multi-institutional study has shown an association between CTLA-4 inhibitors and increased uveitis risk compared with non-ICI comparators.2Kuo H.T. Chen C.Y. Hsu A.Y. et al.Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.Front Immunol. 2023; 141302293Google Scholar By restricting their analysis to PD-1 and PD-L1 inhibitors only, the findings reported by Chang et al may not be generalizable to ICI recipients of CTLA-4 inhibitors. Surprisingly, the authors excluded CTLA-4 inhibitors, as Ipilmumab (belonging to the CTLA-4 inhibitors) has received U.S. Food and Drug Administration approval for treating skin cancer, like metastatic melanoma. Our study, in comparison, showed increased uveitis risk after CTLA-4 use compared with those who did not receive the CTLA-4 class of drugs (hazard ratio [HR], 5.86; 95% confidence interval [CI], 1.99–17.24).2Kuo H.T. Chen C.Y. Hsu A.Y. et al.Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.Front Immunol. 2023; 141302293Google Scholar Furthermore, it is a pity the authors did not include a subgroup analysis according to the 2 types of ICI (PD-1 and PD-L1 inhibitors) in their study, despite conducting many other subgroup analyses. Adding such a subgroup analysis in future investigations could provide further clarity on the role of individual ICI agents in uveitis risk. For example, we previously demonstrated2Kuo H.T. Chen C.Y. Hsu A.Y. et al.Association between immune checkpoint inhibitor medication and uveitis: a population-based cohort study utilizing TriNetX database.Front Immunol. 2023; 141302293Google Scholar a significant increase in uveitis risk among PD-1 recipients alone compared with non-ICI comparators over a 10-year follow-up period (HR, 1.98; 95% CI, 1.65–2.37), whereas PD-L1 recipients alone showed no such association (HR, 1.15; 95% CI, 0.72–1.85). With our larger sample size, including 50 239 PD-1 recipients, 9814 PD-L1 recipients and 1315 recipients of a combination of PD-1 and PD-L1, compared with the cohort of 16 736 PD-1 or PD-L1 recipients reported by Chang et al, our results suggest a more complex relationship among PD-1 and PD-L1 users regarding uveitis risk than what was demonstrated by Chang et al. Another issue concerns the validity of the primary outcome measure noted by Chang et al, which recruited incidences of uveitis after ICI usage based on "non-infectious uveitis [International Classification of Diseases, 10th edition] ICD-10 codes." Although ICD-10 codes are commonly used to classify uveitis, there may be discrepancies in code use across different centers, as highlighted by McKay et al3McKay K.M. Apostolopoulos N. Dahrouj M. et al.Assessing the uniformity of uveitis clinical concepts and associated ICD-10 codes across health care systems sharing the same electronic health records system.JAMA Ophthalmol. 2021; 139: 887-894Crossref PubMed Scopus (0) Google Scholar in a multicenter survey. Chang et al did not specify the exact ICD-10 codes used in their study, which could affect the generalizability of their findings to other studies that may have used different uveitis-related diagnostic codes. In contrast, our study provided detailed information on the ICD-10 codes used to define uveitis risk after ICI treatment. Additionally, Chang et al did not specifically mention which uveitis-related systemic conditions were accounted for as part of their analysis. Chang et al only mentioned adjusting for nonspecific "autoimmune diseases" within their multivariate analysis for uveitis risk, without specifying which ones were excluded. Conditions such as human immunodeficiency virus and rheumatoid arthritis can predispose patients to uveitis. Furthermore, the higher proportion of individuals aged ≥65 years in the ICI-exposed group reported by Chang et al (consisting of 63.10% of their total study population) raises concerns about potential confounding factors secondary to age-related conditions such as chronic kidney disease, systemic lupus erythematosus, or rheumatoid arthritis, which are known to be associated with uveitis occurrence.4Lin C.J. Tien P.T. Lai C.T. et al.Chronic kidney disease as a potential risk factor for uveitis: a 13-year nationwide population-based cohort study in Taiwan.Ocul Immunol Inflamm. Oct-Nov 2022; 30: 1919-1925Crossref Scopus (3) Google Scholar,5Gallagher K. Viswanathan A. Okhravi N. Association of systemic lupus erythematosus with uveitis.JAMA Ophthalmol. 2015; 133: 1190-1193Crossref Scopus (32) Google Scholar In contrast, our study excluded confounding conditions and still demonstrated an increased uveitis risk among ICI recipients compared with controls. The incorporation of such exclusion criteria in retrospective studies analyzing uveitis risk has been validated in previous studies.4Lin C.J. Tien P.T. Lai C.T. et al.Chronic kidney disease as a potential risk factor for uveitis: a 13-year nationwide population-based cohort study in Taiwan.Ocul Immunol Inflamm. Oct-Nov 2022; 30: 1919-1925Crossref Scopus (3) Google Scholar We believe incorporating such exclusion criteria in future research is crucial to enhancing our understanding of the relationship between any exposure of interest and the incidence of uveitis. In conclusion, we commend Chang et al for their efforts in investigating the association between uveitis risk and ICI usage. Our comments aim to offer insights that could aid future researchers in comprehending this complex relationship. Incident Noninfectious Uveitis Risk after Immune Checkpoint Inhibitor TreatmentOphthalmologyPreviewOur findings suggest that although incident uveitis is rare in patients with cancer treated with anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, there is an increased risk in those with skin melanoma, warranting vigilant monitoring for uveitis in this subgroup. Full-Text PDF ReplyOphthalmologyPreviewWe appreciate the interest in our research by Hsu et al.1 First, we would like to clarify that our study was published as a short report rather than a full-length article; as such, there were some omissions in the detailed explanation owing to the word count limit of 1000 words. We kindly ask for your understanding regarding this matter. Full-Text PDF