{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:21:27Z","timestamp":1791498087547,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Ophthalmologica"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may cause immune\u2010related adverse events (irAEs), including dry eye disease (DED). This study aimed to quantify the incidence of ICI\u2010associated DED and to evaluate factors contributing to variability across studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic review and meta\u2010analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta\u2010Analyses (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 (\u226518 years) treated with ICIs (anti\u2010programmed cell death protein 1 (PD\u20101), anti\u2010programmed death\u2010ligand 1 (PD\u2010L1), anti\u2010cytotoxic T\u2010lymphocyte\u2013associated protein 4 (CTLA\u20104)) reporting DED outcomes with extractable ICI\u2010exposed denominators. Two independent reviewers screened studies, extracted data, and assessed risk of bias using the Newcastle\u2013Ottawa Scale (observational studies), ROBINS\u2010I (non\u2010randomized interventional studies), and Cochrane RoB 2 (randomized controlled trials). Pooled incidence and 95% confidence interval (CI) estimates were calculated using random\u2010effects models on the logit\u2010transformed scale and back\u2010transformed to proportions. Subgroup analyses evaluated ICI class, combination therapy, and tumour type.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Thirteen studies were included. The pooled incidence of DED among ICI\u2010treated patients was 2% (95% CI: 1%\u20133%), with marked heterogeneity across studies (0.2%\u201365%), likely reflecting variation in surveillance intensity, diagnostic criteria, and ascertainment approaches. Combination ICI therapy (CTLA\u20104 plus PD\u20101) demonstrated a numerically higher pooled incidence (25%) than monotherapies (CTLA\u20104: 5%; PD\u20101: 13%; PD\u2010L1: 15%), although subgroup differences were not statistically significant (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.18); these regimen\u2010stratified estimates were derived from a limited subset of studies with extractable regimen\u2010specific 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%) (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.05); however, these apparent subgroup differences may reflect not only tumour\u2010 or regimen\u2010specific 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\u2010mediated lacrimal dysfunction, with abnormal Schirmer\u2019s 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DED occurs in approximately 1 in 50 ICI\u2010treated patients in pooled estimates from heterogeneous study designs, although reported incidence varies substantially across study designs and ascertainment approaches. Combination therapy and ICI\u2010treated 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\u2010risk patients should be proactively monitored to maintain quality of life and treatment adherence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aos.70058","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:05:20Z","timestamp":1773050720000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["What is the incidence and clinical significance of dry eye disease in patients treated with immune checkpoint inhibitors? A systematic review and meta\u2010analysis of ocular immune\u2010related adverse events"],"prefix":"10.1111","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0540-1079","authenticated-orcid":false,"given":"Kai\u2010Yang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of General Medicine Chang Gung Memorial Hospital (Linkou Branch)  Taoyuan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi\u2010Chun","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Pharmacy China Medical University  Taichung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi\u2010Ming","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Cardinal Tien Hospital  New Taipei City Taiwan"},{"name":"School of Medicine Fu Jen Catholic University  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.4103\/sjopt.sjopt_296_23"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000296"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40123\u2010025\u201001161\u20108"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/09273948.2020.1773867"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200694"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12886\u2010024\u201003575\u20107"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102016\u2010209595"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102024\u2010011049"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0000000000002181"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joco.2019.05.002"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/01676830.2024.2385010"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol\u20102020\u2010316970"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/RHU.0000000000001777"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1305133"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246\u2010020\u201000301\u20104"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326\u20106066.CIR\u201014\u20100053"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000224"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2011.26.7.938"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2025.101956"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000040669"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.36401\/JIPO\u201022\u201014"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0323546"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3238\/arztebl.2015.0071"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13317\u2010019\u20100124\u20106"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amolm.2025.100090"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/09273948.2019.1583347"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18470"},{"issue":"118","key":"e_1_2_12_29_1","first-page":"114","article-title":"Sicca\/Sj\u00f6gren's syndrome triggered by PD\u20101\/PD\u2010L1 checkpoint inhibitors. 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