{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:01:37Z","timestamp":1785132097072,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To systematically characterize ocular adverse events (oAEs) associated with immune checkpoint inhibitors (ICIs) and to quantify their disproportionality reporting signals using real-world pharmacovigilance data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective pharmacovigilance study analyzed oAE reports associated with four ICI treatment regimens\u2014anti-CTLA-4 monotherapy, anti-PD-1\/L1 monotherapy, nivolumab plus ipilimumab combination therapy, and the novel nivolumab plus relatlimab combination\u2014using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2011 through the second quarter of 2025. Disproportionality analyses were conducted to detect potential safety signals employing three complementary metrics: reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC). Additional analyses included ophthalmologist-reviewed clinical grouping of uveitis subtypes, stratification by underlying tumor indication, and temporal trend assessment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 5,244 oAE reports associated with ICIs were identified. At the preferred term (PT) level, the strongest overall signals were predominantly inflammatory ocular conditions, including uveitis (ROR 6.04, 95% CI 5.45\u20136.69), scleritis (ROR 4.85, 95% CI 3.20\u20137.36), and optic neuritis (ROR 4.59, 95% CI 3.91\u20135.39). Combination therapy was associated with markedly stronger disproportionality signals; notably, the ROR for uveitis with nivolumab plus ipilimumab reached 15.44 (95% CI 13.24 to 18.00), compared with 4.37 for anti-PD-1\/L1 monotherapy. The nivolumab plus relatlimab regimen showed preliminary signals for keratitis (ROR 13.82, 95% CI 3.44 to 55.61) and diplopia (ROR 9.59, 95% CI 3.07 to 29.91), though based on a very small sample (N = 18). Melanoma was disproportionately represented among uveitis-spectrum cases (53.6%), and temporal analysis revealed a declining uveitis proportion paralleling the expansion of ICI use beyond melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ICIs are strongly associated with disproportionality signals for inflammatory ocular adverse events, with substantially higher signals observed for combination therapies compared with monotherapy. These hypothesis-generating findings highlight the need for prompt ophthalmologic assessment and individualized, multidisciplinary surveillance in patients receiving ICI treatment, particularly combined regimens.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1808874","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:06Z","timestamp":1785130806000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ocular adverse events associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FAERS database"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Beijing Haidian Hospital, Haidian Section of Peking University Third Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Beijing Haidian Hospital, Haidian Section of Peking University Third Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ymeth.2023.11.003","article-title":"T helper (Th) cell profiles and cytokines\/chemokines in characterization, treatment, and monitoring of autoimmune diseases","volume":"220","author":"Ayass","year":"2023","journal-title":"Methods"},{"key":"B2","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/imr.13262","article-title":"Effects of immune\u2010related adverse events (irAEs) and their treatment on antitumor immune responses","volume":"318","author":"Blum","year":"2023","journal-title":"Immunol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1080\/09273948.2020.1773867","article-title":"Ocular adverse events induced by immune checkpoint inhibitors: a comprehensive pharmacovigilance analysis","volume":"30","author":"Bomze","year":"2022","journal-title":"Ocul. Immunol. Inflamm."},{"key":"B4","doi-asserted-by":"publisher","first-page":"109","DOI":"10.2165\/00002018-199920020-00002","article-title":"The medical dictionary for regulatory activities (MedDRA)","volume":"20","author":"Brown","year":"1999","journal-title":"Drug Saf."},{"key":"B5","doi-asserted-by":"publisher","first-page":"122419","DOI":"10.1016\/j.lfs.2024.122419","article-title":"Overview of tumor immunotherapy based on approved drugs","volume":"340","author":"Chen","year":"","journal-title":"Life Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s12967-024-04973-7","article-title":"Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade","volume":"22","author":"Chen","year":"","journal-title":"J. Transl. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.3389\/fphar.2019.01671","article-title":"Organ-specific immune-related adverse events associated with immune checkpoint inhibitor monotherapy versus combination therapy in cancer: a meta-analysis of randomized controlled trials","volume":"10","author":"Da","year":"2020","journal-title":"Front. Pharmacology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.ejca.2020.11.027","article-title":"The association between immune checkpoint or BRAF\/MEK inhibitor therapy and uveitis in patients with advanced cutaneous melanoma","volume":"144","author":"Dimitriou","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.joco.2019.05.002","article-title":"Ocular adverse events with immune checkpoint inhibitors","volume":"31","author":"Fang","year":"2019","journal-title":"J. Curr. Ophthalmol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"156163","DOI":"10.1016\/j.prp.2025.156163","article-title":"Targeting LAG-3: relatlimab, fianlimab, and ieramilimab reshape the landscape of cancer combination immunotherapy","volume":"274","author":"Ghasemi","year":"2025","journal-title":"Pathology - Res. Pract."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1080\/09273948.2021.1890133","article-title":"Risk of ophthalmic adverse events in patients treated with immune checkpoint inhibitor regimens: a systematic review and meta-analysis","volume":"30","author":"Hou","year":"2022","journal-title":"Ocular Immunology Inflammation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/s0923-7534(20)34163-6","article-title":"Ocular adverse effects (OAES) of molecularly targeted agents (MTAS) approved in oncology: a systematic review","volume":"23","author":"Huillard","year":"2012","journal-title":"Ann. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"875974","DOI":"10.3389\/fmed.2022.875974","article-title":"Overview of checkpoint inhibitors mechanism of action: role of immune-related adverse events and their treatment on progression of underlying cancer","volume":"9","author":"Iranzo","year":"2022","journal-title":"Front. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/fimmu.2020.622509","article-title":"Exhausted CD8+T cells in the tumor immune microenvironment: new pathways to therapy","volume":"11","author":"Jiang","year":"2021","journal-title":"Front. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"104808","DOI":"10.1016\/j.critrevonc.2025.104808","article-title":"T cell-mediated mechanisms of immune-related adverse events induced by immune checkpoint inhibitors","volume":"213","author":"Li","year":"2025","journal-title":"Crit. Rev. Oncology\/Hematology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1080\/09273948.2023.2296033","article-title":"Uveitis and scleritis as a risk factor for mortality","volume":"32","author":"Lim","year":"2024","journal-title":"Ocular Immunol. Inflamm."},{"key":"B17","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12943-024-02023-w","article-title":"Regulatory mechanisms of PD-1\/PD-L1 in cancers","volume":"23","author":"Lin","year":"2024","journal-title":"Mol. Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.1016\/j.ophtha.2021.05.008","article-title":"Ocular safety profile of BRAF and MEK inhibitors: data from the world health organization pharmacovigilance database","volume":"128","author":"Mettler","year":"2021","journal-title":"Ophthalmology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1179\/2047480614z.000000000208","article-title":"Adverse event reporting: a brief overview of MedDRA","volume":"23","author":"Morley","year":"2014","journal-title":"Med. Writ."},{"key":"B20","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3389\/fonc.2020.00258","article-title":"Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis","volume":"10","author":"Park","year":"2020","journal-title":"Front. Oncology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/nejmra1703481","article-title":"Immune-related adverse events associated with immune checkpoint blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1002\/cpt.3701","article-title":"FDA adverse Event Reporting System (FAERS) essentials: a guide to understanding, applying, and interpreting adverse event data reported to FAERS","volume":"118","author":"Potter","year":"2025","journal-title":"Clin. Pharmacol. and Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.3390\/cancers13020223","article-title":"Functional T cell reactivity to melanocyte antigens is lost during the progression of malignant melanoma, but is restored by immunization","volume":"13","author":"Przybyla","year":"2021","journal-title":"Cancers"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1007\/s00262-019-02369-x","article-title":"CTLA-4 antibody ipilimumab negatively affects CD4+ T-cell responses in vitro","volume":"68","author":"Rosskopf","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1758835921992989","DOI":"10.1177\/1758835921992989","article-title":"Ocular adverse events associated with immune checkpoint inhibitors: a novel multidisciplinary management algorithm","volume":"13","author":"Shahzad","year":"2021","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"389","DOI":"10.61096\/ijphr.v12.iss4.2024.389-392","article-title":"Meddra coding in Pharmacovigilance: a comprehensive review of its role, challenges, and best practices in adverse event reporting and regulatory compliance","volume":"12","author":"Sriram","year":"2024","journal-title":"Int. J. Pharm. Health Care Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1002\/cac2.12587","article-title":"Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies","volume":"44","author":"Sun","year":"2024","journal-title":"Cancer Commun."},{"key":"B28","unstructured":"2024"},{"key":"B29","doi-asserted-by":"publisher","first-page":"S530","DOI":"10.21037\/tcr.2018.04.04","article-title":"PD-1\/PD-L1 pathway inhibition to restore effector functions in exhausted CD8 + T cells: chances, limitations and potential risks","volume":"7","author":"Veluswamy","year":"2018","journal-title":"Null"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/j.cell.2017.07.024","article-title":"Distinct cellular mechanisms underlie Anti-CTLA-4 and Anti-PD-1 checkpoint blockade","volume":"170","author":"Wei","year":"2017","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.3390\/biomedicines12112547","article-title":"Emerging ocular side effects of immune checkpoint inhibitors: a comprehensive review","volume":"12","author":"Wu","year":"2024","journal-title":"Biomedicines"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.21608\/jbaar.2025.456942","article-title":"IL-6, TNF-\u03b1, IL-1\u03b2, and IFN-\u03b3 cytokines as core inflammatory biomarkers: biological roles, diagnostic utility, and clinical applications","volume":"11","author":"Yameny","year":"2025","journal-title":"J. Biosci. Appl. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13046-021-01987-7","article-title":"Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer","volume":"40","author":"Zhang","year":"2021","journal-title":"J. Of Exp. and Clin. Cancer Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.6004\/jnccn.2020.7640","article-title":"Immune-Related adverse events (irAEs): implications for immune checkpoint inhibitor therapy","volume":"18","author":"Zhou","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1808874\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:08Z","timestamp":1785130808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1808874\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":34,"alternative-id":["10.3389\/fphar.2026.1808874"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1808874","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"1808874"}}