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Authors: Myung Soo Chang, Seung Won Lee, Yong Joon Kim
Journal: Ophthalmology (2024)

We appreciate the interest in our research by Hsu et al.1Chang 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 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. We used data from the Korean Health Insurance Review and Assessment, which covers approximately 98% of the South Korean population. During the study period, 5 immune checkpoint inhibitors (ICIs) were approved by the Korean Food and Drug Administration: nivolumab and pembrolizumab (programmed cell death 1 inhibitors); and atezolizumab, durvalumab, and avelumab (programmed cell death ligand 1 inhibitors). These ICIs were reimbursed and prescribed under insurance coverage for lung cancer, melanoma, and bladder cancer in Korea. Because ipilimumab (anticytotoxic T lymphocyte antigen 4 inhibitor) was approved for insurance coverage for renal cell carcinoma in Korea later than other ICIs, ipilimumab was excluded from the study. Given recent reports indicating an increased risk of uveitis associated with the use of ipilimumab, we believe future studies incorporating anticytotoxic T lymphocyte antigen 4 inhibitors are necessary.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 In our study, uveitis of any grade was identified using specific International Classification of Diseases, 10th edition (ICD-10), codes combined with ≥1 prescription of topical, intravitreal/periocular, or systemic steroid treatment for ≥3 consecutive days after the administration of cytotoxic drugs or ICIs. Severe uveitis was defined as that requiring systemic steroid treatment of >20 mg/d of prednisolone or its equivalent. The ICD-10 codes used for noninfectious uveitis are as follows: H20.0, acute and subacute iridocyclitis; H20.1, chronic iridocyclitis; H20.2, lens-induced iridocyclitis; H20.8, other iridocyclitis; H20.9, iridocyclitis, unspecified; H22.1, iridocyclitis in other diseases classified elsewhere; H22.8, other disorders of the iris and ciliary body in diseases classified elsewhere; H30.0, focal chorioretinal inflammation; H30.1, disseminated chorioretinal inflammation; H30.2, posterior cyclitis; H30.8, other chorioretinal inflammations; H30.9, chorioretinal inflammation, unspecified; and H35.05, retinal vasculitis. This code is identical to that used in a previous study using Korean claim data.3Rim T.H. Kim S.S. Ham D.I. et al.Incidence and prevalence of uveitis in South Korea: a nationwide cohort study.Br J Ophthalmol. 2018; 102: 79-83Crossref Scopus (41) Google Scholar,4Chang M.S. Kim H.R. Kim S. et al.Noninfectious uveitis risk after COVID-19 vaccination: a nationwide retrospective cohort study.Am J Ophthalmol. 2024; 258: 22-31Abstract Full Text Full Text PDF Scopus (0) Google Scholar Last, to ascertain the risk factors for incident uveitis following the use of ICIs, we conducted univariate and multivariate analyses based on age group, sex, cancer type, systemic disease, autoimmune disease, Charlson Comorbidity Index, and type of ICI. Autoimmune diseases encompassed sarcoidosis, Reiter's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ankylosing spondylitis, and Behcet's disease, among others, with detailed ICD-10 codes described in our other study.4Chang M.S. Kim H.R. Kim S. et al.Noninfectious uveitis risk after COVID-19 vaccination: a nationwide retrospective cohort study.Am J Ophthalmol. 2024; 258: 22-31Abstract Full Text Full Text PDF Scopus (0) Google Scholar Both univariate and multivariate analyses identified melanoma as the sole risk factor associated with the development of uveitis after ICI treatment, whether acute or delayed in onset. Although the use of programmed cell death 1 inhibitors showed a slightly higher hazard ratio of 1.56 compared with programmed cell death ligand 1 inhibitors in the univariate analysis, it was not statistically significant, with a hazard ratio of 0.99 in the multivariate analysis. One of the significant new findings of our research is that the incidence of uveitis after the use of ICIs in melanoma is higher compared with other types of cancer. The increased incidence of uveitis among the patients with melanoma may be due to an underlying difference in the uveitis risk associated with melanoma itself, distinct from nonmelanoma cancers. The potential cross-reactivity between malignant melanoma cells and normal choroidal melanocytes could trigger posterior uveitis, presenting as the Vogt–Koyanagi–Harada disease. Similarly, vitiligo is another common dermatological manifestation observed in immunotherapy, particularly with the use of nivolumab and pembrolizumab. It is more frequently reported in patients with melanoma than in those with nonmelanoma cancers.5Lo J. Hanania H.L. Keiser M.F. Patel A.B. Immune checkpoint inhibitor-induced vitiligo in cancer patients: characterization and management.Arch Dermatol Res. 2023; 315: 1697-1703Crossref Scopus (2) Google Scholar This result supports that finding that melanoma is a specific risk factor for incident uveitis after ICI treatment. In conclusion, patients with melanoma are at significant risk of developing uveitis and show a higher incidence of the disease after ICI treatment. Vigilant monitoring for uveitis may be particularly crucial in these cases. Our findings underscore the importance of careful ocular monitoring in patients receiving ICI treatment and contribute to a more comprehensive understanding of ICI safety profiles. Future research on the treatment and prognosis of uveitis would help to optimize the use of ICIs in the clinical setting. Re: Chang et al.: Incident noninfectious uveitis risk after immune checkpoint treatment (Ophthalmology. 2024 Mar 22:S0161-6420(24)00198-2. doi: 10.1016/j.ophtha.2024.03.017. Online ahead of print)OphthalmologyPreviewWe thank Chang et al1 for their insight on uveitis risk after immune complex inhibitor (ICI) treatments. However, we believe their current study design warrants further scrutiny. Full-Text PDF