{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:59:49Z","timestamp":1790315989947,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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>Sphingosine-1-phosphate (S1P) receptor modulators are used for immune-mediated diseases, and macular oedema is an established ocular adverse effect. However, ocular-focused, class-wide postmarketing reporting across all five approved agents remains incompletely characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) data from 2004 Q1 through 2026 Q1 using report-level deduplication, approval-aligned windows, and primary-suspect exposure. Ocular events were assessed using a curated set of 52 Preferred Term (PT) strings. Sensitivity analyses included report-level macular\/retinal oedema aggregation, same-indication active comparators, temporal and sparse-data analyses, restricted empirical-Bayes assessment, and external validation in Canada Vigilance. Exact-date time to onset was assessed for the aggregated phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The primary cohort included 98,843 primary-suspect reports, of which 8,812 (8.9%) were ocular, representing 12,088 unique ocular report\u2013PT pairs. At the class level, 21 ocular PTs met primary signal criteria; macular oedema showed the strongest anatomically specific signal (n = 947; reporting odds ratio [ROR], 48.18; 95% confidence interval [CI], 44.84\u201351.76). Fingolimod had the broadest signal spectrum; macular oedema was the principal anatomically specific signal for siponimod and ozanimod. No ponesimod PT met primary criteria, and the etrasimod macular oedema estimate was sparse (n = 11). Of 36 primary drug\u2013PT signals, 13 were High, 22 Moderate, and one Low. Report-level aggregation yielded a class-level ROR of 29.47 (95% CI, 27.62\u201331.45). In indication-restricted multiple sclerosis analyses, the association remained elevated versus all non-S1P disease-modifying therapies (ROR, 43.85; 95% CI, 35.75\u201353.78), while ulcerative colitis\/inflammatory bowel disease analyses were sparse and exploratory. For fingolimod, the association persisted after exclusion of the first two post-approval years (ROR, 45.79; 95% CI, 37.26\u201356.26). Median time to onset was 93.0 days for fingolimod and 15.5 days for siponimod. Canada Vigilance showed a concordant class-level association (ROR, 74.00; 95% CI, 59.30\u201392.35).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Macular\/retinal oedema was the most consistent ocular reporting pattern in the S1P receptor modulator class. The association remained evident after phenotype aggregation and indication-restricted analysis and was also observed in Canada Vigilance. Sparse data for newer agents and residual confounding limit comparative interpretation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1908773","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:31:45Z","timestamp":1790314305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ocular safety signals of sphingosine-1-phosphate receptor modulators in postmarketing surveillance"],"prefix":"10.3389","volume":"17","author":[{"given":"Mei","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tangdu Hospital, The Fourth Military Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1136\/bjophthalmol-2021-319115","article-title":"Sphingosine 1-phosphate, a potential target in neovascular retinal disease","volume":"106","author":"Alshaikh","year":"2022","journal-title":"Br. J. Ophthalmol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"158760","DOI":"10.1016\/j.bbalip.2020.158760","article-title":"Post-translational modifications of S1PR1 and endothelial barrier regulation","volume":"1865","author":"Anwar","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1056\/NEJMcp053247","article-title":"Clinical practice. Optic neuritis","volume":"354","author":"Balcer","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"160026","DOI":"10.1038\/sdata.2016.26","article-title":"A curated and standardized adverse drug event resource to accelerate drug safety research","volume":"3","author":"Banda","year":"2016","journal-title":"Sci. Data"},{"key":"B5","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s002280050466","article-title":"A Bayesian neural network method for adverse drug reaction signal generation","volume":"54","author":"Bate","year":"1998","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1097\/WNO.0b013e31829b42e1","article-title":"Fingolimod therapy and macular hemorrhage","volume":"33","author":"Bhatti","year":"2013","journal-title":"J. Neuroophthalmol."},{"key":"B7","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":"B8","doi-asserted-by":"publisher","first-page":"e650","DOI":"10.1016\/j.jcjo.2025.02.022","article-title":"Ozanimod-associated macular edema","volume":"60","author":"Buckley","year":"2025","journal-title":"Can. J. Ophthalmol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s40265-020-01431-8","article-title":"Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects","volume":"81","author":"Chun","year":"2021","journal-title":"Drugs"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/S1474-4422(19)30239-X","article-title":"Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial","volume":"18","author":"Comi","year":"2019","journal-title":"Lancet Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"jjae173","DOI":"10.1093\/ecco-jcc\/jjae173","article-title":"Low incidence of macular edema and other ocular events in the etrasimod development program","volume":"19","author":"Dubinsky","year":"2025","journal-title":"J. Crohns Colitis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1080\/00031305.1999.10474456","article-title":"Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system","volume":"53","author":"Dumouchel","year":"1999","journal-title":"Am. Statistician"},{"key":"B13","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e415","DOI":"10.1097\/WNO.0000000000000991","article-title":"Progressive functional and neuroretinal affectation in patients with multiple sclerosis treated with fingolimod","volume":"41","author":"Garcia-Martin","year":"2021","journal-title":"J. Neuroophthalmol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1093\/brain\/aws098","article-title":"Microcystic macular oedema in multiple sclerosis is associated with disease severity","volume":"135","author":"Gelfand","year":"2012","journal-title":"Brain"},{"key":"B16","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1001\/jama.2023.15389","article-title":"Ulcerative colitis in adults: a review","volume":"330","author":"Gros","year":"2023","journal-title":"Jama"},{"key":"B17","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1212\/WNL.0b013e318248deea","article-title":"Fingolimod-associated macular edema: incidence, detection, and management","volume":"78","author":"Jain","year":"2012","journal-title":"Neurology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1056\/nejmoa0909494","article-title":"A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis","volume":"362","author":"Kappos","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/S0140-6736(18)30475-6","article-title":"Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study","volume":"391","author":"Kappos","year":"2018","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1001\/jamaneurol.2021.0405","article-title":"Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical trial","volume":"78","author":"Kappos","year":"2021","journal-title":"JAMA Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e68938","DOI":"10.1371\/journal.pone.0068938","article-title":"The impact of duration of treatment on reported time-to-onset in spontaneous reporting systems for pharmacovigilance","volume":"8","author":"Karimi","year":"2013","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1007\/s40265-024-02094-5","article-title":"Targeting the Sphingosine-1-Phosphate pathway: new opportunities in inflammatory bowel disease management","volume":"84","author":"Kitsou","year":"2024","journal-title":"Drugs"},{"key":"B23","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1007\/s40264-021-01057-z","article-title":"Safety of S1P modulators in patients with immune-mediated diseases: a systematic review and meta-analysis","volume":"44","author":"Lasa","year":"2021","journal-title":"Drug Saf."},{"key":"B24","doi-asserted-by":"publisher","first-page":"114520","DOI":"10.1016\/j.intimp.2025.114520","article-title":"Identifying cardiovascular toxicity associated with sphingosine 1-phosphate receptor modulators: a case-control study based on the FDA adverse event reporting system","volume":"153","author":"Li","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/eye.2016.258","article-title":"Fingolimod: therapeutic mechanisms and ocular adverse effects","volume":"31","author":"Mandal","year":"2017","journal-title":"Eye (Lond)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1632065","DOI":"10.3389\/fopht.2025.1632065","article-title":"Case report: asymptomatic macular edema in ozanimod","volume":"5","author":"Mauceri","year":"2025","journal-title":"Front. Ophthalmol. (Lausanne)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.1016\/S0140-6736(21)00244-0","article-title":"Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions","volume":"398","author":"McGinley","year":"2021","journal-title":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e107","DOI":"10.1161\/ATVBAHA.111.235408","article-title":"Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier","volume":"31","author":"McGuire","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1186\/s13643-021-01782-7","article-title":"Ocular adverse events from pharmacological treatment in patients with multiple sclerosis-A systematic review of the literature","volume":"10","author":"Mu\u00f1oz-Ortiz","year":"2021","journal-title":"Syst. Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/bcpt.13381","article-title":"Macular oedema and changes in macular thickness in multiple sclerosis patients treated with fingolimod","volume":"126","author":"N\u00f8rgaard","year":"2020","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/s40265-021-01528-8","article-title":"Targeting Sphingosine-1-Phosphate signaling in immune-mediated diseases: beyond multiple sclerosis","volume":"81","author":"P\u00e9rez-Jeldres","year":"2021","journal-title":"Drugs"},{"key":"B32","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. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1053\/j.gastro.2021.07.042","article-title":"Extraintestinal manifestations of inflammatory bowel disease: current concepts, treatment, and implications for disease management","volume":"161","author":"Rogler","year":"2021","journal-title":"Gastroenterology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B35","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1007\/s40263-021-00798-w","article-title":"Sphingosine 1-Phosphate receptor modulators for multiple sclerosis","volume":"35","author":"Roy","year":"2021","journal-title":"CNS Drugs"},{"key":"B36","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1093\/ibd\/izaf319","article-title":"Integrated long-term safety of 10-year Ozanimod treatment: results from clinical trials in patients with moderate-to-severe ulcerative colitis or relapsing multiple sclerosis","volume":"32","author":"Rubin","year":"2026","journal-title":"Inflamm. Bowel Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/S0140-6736(23)00061-2","article-title":"Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies","volume":"401","author":"Sandborn","year":"2023","journal-title":"Lancet"},{"key":"B38","doi-asserted-by":"publisher","first-page":"112197","DOI":"10.1016\/j.biopha.2021.112197","article-title":"Updates on sphingolipids: spotlight on retinopathy","volume":"143","author":"Shiwani","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B39","doi-asserted-by":"publisher","first-page":"100037","DOI":"10.1194\/jlr.TR120000972","article-title":"Sphingolipids as critical players in retinal physiology and pathology","volume":"62","author":"Simon","year":"2021","journal-title":"J. Lipid Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1177\/24741264231215537","article-title":"Ponesimod-associated macular edema: onset and resolution","volume":"8","author":"Singh","year":"2024","journal-title":"J. Vitr. Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"918086","DOI":"10.3389\/fneur.2022.918086","article-title":"Diagnosis and management of fingolimod-associated macular edema","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Neurol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1376494","DOI":"10.3389\/fphar.2024.1376494","article-title":"Potential adverse events associated with sphingosine-1-phosphate (S1P) receptor modulators in patients with multiple sclerosis: an analysis of the FDA adverse event reporting system (FAERS) database","volume":"15","author":"Yang","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1016\/j.ophtha.2012.12.040","article-title":"Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis","volume":"120","author":"Zarbin","year":"2013","journal-title":"Ophthalmology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1908773\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:31:48Z","timestamp":1790314308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1908773\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":43,"alternative-id":["10.3389\/fphar.2026.1908773"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1908773","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"1908773"}}