{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T14:38:52Z","timestamp":1780324732907,"version":"3.54.1"},"reference-count":27,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sphingosine\u20101\u2010phosphate receptor modulators (S1PRM) are used to treat relapsing multiple sclerosis (MS). Each drug has a different S1PR\u2010subtype selectivity. They target the G\u2010protein coupled S1P receptors and exert significant immunomodulatory effects, such as preventing the formation of new CNS lesions and the reactivation of pre\u2010existing lesions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aims to explore the efficacy and safety of S1PRM in treating MS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A systematic literature search of PubMed, Embase, and Cochrane databases was conducted in August 2024. Randomized Controlled Trials that evaluated the efficacy of S1PRM in patients with MS were included. Changes in Annualized Relapse Rate and incidence of adverse effects were chosen as primary outcomes. Standardized mean differences (SMD) and odds ratio (OR) were calculated. Confidence interval was kept at 95%. Individual interventions were compared using the Surface Under Cumulative Ranking Curve (SUCRA). The risk of bias was assessed by the Cochrane risk\u2010of\u2010bias tool for randomized trials (RoB 2).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The search query resulted in a total of 1750 studies. After screening, 17 studies were included in the final analysis, with a population of 16,006. Fingolimod (1.25\u2009mg) was significantly associated with a decreased ARR (SMD\u2009=\u2009\u22120.4422, 95% CI\u2009=\u2009[\u22120.5450 to \u22120.3394], <jats:italic>p<\/jats:italic>\u2010value &lt;\u20090.0001, SUCRA\u2009=\u200992.65%). Whereas, ozanimod (1\u2009mg) was associated with the lowest number of new Gadolinium\u2010enhanced lesions (SMD\u2009=\u2009\u22120.6516, 95% CI\u2009=\u2009[\u22120.8944 to \u22120.4087], <jats:italic>p<\/jats:italic>\u2010value &lt;\u20090.0001, SUCRA\u2009=\u200986.38%). Siponimod (1.25\u2009mg) was associated with the least number of adverse events (OR\u2009=\u20090.4606, 95% CI\u2009=\u2009[0.1893 to 1.1205], <jats:italic>p<\/jats:italic>\u2009=\u20090.0874, SUCRA\u2009=\u200993.20%). Almost all of the studies had a low risk of bias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Fingolimod (1.25\u2009mg) and ozanimod (1\u2009mg) had the best efficacy, and siponimod (1.25\u2009mg and 0.25\u2009mg) had the best safety profile among the S1PRM. Further longitudinal studies should be conducted to assess the long\u2010term effects of these drugs on patient\u2010reported outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70122","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T05:11:26Z","timestamp":1751605886000},"page":"2002-2011","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Comparative Effectiveness and Tolerability of Sphingosine\u20101\u2010Phosphate Receptor Modulators in Patients With Multiple Sclerosis: A Network Meta\u2010Analysis of Randomized Controlled Trials"],"prefix":"10.1002","volume":"12","author":[{"given":"Faizan","family":"Shahzad","sequence":"first","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8721-4795","authenticated-orcid":false,"given":"Taimoon","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momina Riaz","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Hamid","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwah Bintay","family":"Khalid","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haroon","family":"Shabbir","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0685-8991","authenticated-orcid":false,"given":"Besher","family":"Shami","sequence":"additional","affiliation":[{"name":"University of Aleppo  Syrian Arab Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Abdullah","sequence":"additional","affiliation":[{"name":"Rawalpindi Medical University  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Ijlal","family":"Ahmed","sequence":"additional","affiliation":[{"name":"PGY\u20104, SSM Health Saint Louis University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww258"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263\u2010015\u20100261\u2010z"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072\u2010021\u201005049\u2010w"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113341"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.52017"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010019\u201009395\u2010w"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003082"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.0405"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(19)30238\u20108"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000010284"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/13524585211032803"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa0907839"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa052643"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa0909494"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(14)70049\u20103"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458511435984"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(08)60918\u20106"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1104318"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010014\u20107264\u20104"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(13)70102\u20109"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(18)30475\u20106"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(19)30239\u2010x"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1474\u20104422(16)30192\u20102"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp\u20102013\u2010307282"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m311743200"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517728343"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:21:07Z","timestamp":1760404867000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":27,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/acn3.70122"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70122","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]},"assertion":[{"value":"2025-02-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}