{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:00:45Z","timestamp":1793041245149,"version":"4.5.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T00:00:00Z","timestamp":1754697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Comparative assessments of all available disease-modifying therapies (DMTs) in patients with highly active relapsing-remitting multiple sclerosis (RRMS) are lacking, even though some of these DMTs are restricted to this MS subpopulation. We therefore aimed to compare DMTs in patients with highly active RRMS using re-analyses of individual patient data (IPD) provided by study sponsors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We searched for randomised controlled trials (RCTs) that included adult patients with RRMS and directly compared alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, ofatumumab, ozanimod, ponesimod and teriflunomide, or compared these DMTs with other drugs or placebo. Re-analyses of IPD for subpopulations of patients with high disease activity despite previous DMT were included in network meta-analyses (NMAs). As there is no widely accepted definition of high disease activity in RRMS, criteria were chosen to cover as wide a range of definitions as possible, while being sufficiently similar across studies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We identified 14 relevant RCTs, including only 3 head-to-head comparisons of DMTs, and no relevant studies on natalizumab. All studies were pivotal studies for approval. The available re-analyses of IPD did not allow comprehensive NMAs. The main reasons for this were the overall paucity of RCTs, especially head-to-head comparisons, and a high risk of bias. In addition, data on patient-relevant outcomes and long-term follow-up (&gt;\u20092 years) were lacking.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Based on the largest possible evidence base, including previously unpublished data, our systematic review shows substantial evidence gaps for DMTs in highly active RRMS. This indicates a need for further research beyond regulatory requirements.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>Clinical trial number: not applicable.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12883-025-04338-7","type":"journal-article","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T11:52:43Z","timestamp":1754740363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Comparative effectiveness of disease-modifying therapies for highly active relapsing-remitting multiple sclerosis despite previous treatment \u2013 a systematic review and network meta-analysis"],"prefix":"10.1186","volume":"25","author":[{"given":"Michael","family":"K\u00f6hler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedemann","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Janke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Sturtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Preukschat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Ostlender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela Florina","family":"Kerekes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,9]]},"reference":[{"issue":"1","key":"4338_CR1","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","volume":"4","author":"M Filippi","year":"2018","unstructured":"Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. 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FP declares the following competing interests: research support (recipient: Charit\u00e9) from the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, and Roche; personal honoraria for lectures, presentations, and speakers bureaus from Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Merck, Sanofi Genzyme, Novartis, Viela Bio, UCB, Mitsubishi Tanabe, Celgene, Guthy Jackson Foundation, Serono, and Roche; support for attending meetings and\/or travel by Merck, Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene. FP has participated in advisory boards for Celgene, Roche, UCB, and Merck. He is also an Academic Editor of the journal PLOS ONE and Associate Editor of the journal Neurology\u00ae Neuroimmunology & Neuroinflammation.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"328"}}