{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:49:19Z","timestamp":1791640159183,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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":["Euro J of Neurology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Reference\u2010arm annualized relapse rates (ARRs) in relapsing multiple sclerosis trials have declined. We examined whether baseline disease activity and the treatment environment during recruitment changed alongside this trend.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 15 treated\u2010reference arms from nine Phase 3 programs. ARR was related to recruitment era, prior\u2010year relapse activity, MRI markers, and an Operational Selection Pressure Index (OSPI) combining recruitment geography with time since ocrelizumab approval. Associations were descriptive; disability outcomes were audited separately.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Reference\u2010arm ARR declined from 0.370 in TEMSO and 0.320 in TOWER to 0.109\u20130.140 in BTK inhibitor\u2010era programs (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u22120.906; 95% CI, \u22120.985 to \u22120.279;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915). Prior\u2010year relapse activity correlated with ARR (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.739; 95% CI, 0.158 to 0.928;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200913) and declined over time (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u22120.725; 95% CI, \u22120.965 to \u22120.157;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200913). MRI findings were inconsistent. OSPI clustered at 0\u20137.3 in six programs and 65.2\u201380.5 in BTK inhibitor\u2010era programs and correlated inversely with ARR (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u22120.892; 95% CI, \u22121.000 to \u22120.569;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20099). The association persisted across sensitivities but was negligible after adjustment for recruitment midpoint (partial\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u22120.020). Disability trends depended on reporting metric and effective follow\u2010up.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Lower baseline relapse activity accompanied declining event yield. OSPI made a treatment\u2010ecosystem transition measurable but could not be separated from calendar era or establish mechanism. Trials require conservative event assumptions, harmonized reporting, and validation using screening and country\u2010 or period\u2010specific outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70781","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T12:54:43Z","timestamp":1791636883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparator Event Rates, Baseline Activity, and Operational Selection Pressure in Relapsing Multiple Sclerosis Trials: A Meta\u2010Epidemiological Analysis"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5171-4845","authenticated-orcid":false,"given":"Steffen","family":"Pfeuffer","sequence":"first","affiliation":[{"name":"Department of Neurology Justus Liebig University Giessen  Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2496-1415","authenticated-orcid":false,"given":"Lars","family":"Masanneck","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-2277","authenticated-orcid":false,"given":"Marc","family":"Pawlitzki","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0614-6989","authenticated-orcid":false,"given":"Hans\u2010Peter","family":"Hartung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"},{"name":"Brain and Mind Centre University of Sydney  Sydney Australia"},{"name":"Department of Neurology Palack\u00fd University Olomouc  Olomouc Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458510379246"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458511406309"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458511435715"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458513481009"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137052"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050347"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010025\u201004603\u2010z"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(20)30067\u20103"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.2738"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.4011"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458510391837"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(13)70103\u20100"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(24)00328\u20104"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2415985"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","unstructured":"J.Oh A.Bar\u2010Or G.Giovannoni et\u00a0al. \u201cEfficacy and Safety of Fenebrutinib vs Teriflunomide in Relapsing Multiple Sclerosis: Results of the FENhance 1 and 2 Studies. 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