{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:36:48Z","timestamp":1787017008721,"version":"build-2736575974"},"reference-count":32,"publisher":"BMJ","issue":"3","funder":[{"DOI":"10.13039\/100009010","name":"Novartis Pharmaceuticals UK Limited","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2016,12,12]]},"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a chronic, neurodegenerative autoimmune disorder affecting the central nervous system. Relapsing\u2013remitting MS (RRMS) is the most common clinical form of MS and affects \u223c85% of cases at onset. Highly active (HA) and rapidly evolving severe (RES) RRMS are 2 forms of RRMS amenable to disease-modifying therapies (DMT). This study explored the efficacy of fingolimod relative to other DMTs for the treatment of HA and RES RRMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic literature review (SLR) was conducted to identify published randomised controlled trials in HA and RES RRMS. Identified evidence was vetted, and a Bayesian network meta-analysis (NMA) was performed to evaluate the relative efficacy of fingolimod versus dimethyl fumarate (DMF) in HA RRMS and versus natalizumab in RES RRMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>For HA RRMS, the SLR identified 2 studies with relevant patient subgroup data: 1 comparing fingolimod with placebo and the other comparing DMF with placebo. 3 studies were found for RES RRMS: 1 comparing fingolimod with placebo and 2 studies comparing natalizumab with placebo. NMA results in the HA population showed a favourable numerical trend of fingolimod versus DMF assessed for annualised relapse rate (ARR) and 3-month confirmed disability progression. For the RES population, the results identified an increase of ARR and 3-month confirmed disability progression for fingolimod versus natalizumab (not statistically significant). Sparse study data and the consequently high uncertainty around the estimates restricted our ability to demonstrate statistical significance in the studied subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Data limitations are apparent when conducting an informative indirect comparison for the HA and RES RRMS subgroups as the subgroups analyses were retrospective analyses of studies powered to indicate differences across entire study populations. Comparisons across treatments in HA or RES RRMS will be associated with high levels of uncertainty until new data are collected for these subgroups.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2016-013430","type":"journal-article","created":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T20:10:19Z","timestamp":1489176619000},"page":"e013430","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":53,"title":["Systematic literature review and network meta-analysis in highly active relapsing\u2013remitting multiple sclerosis and rapidly evolving severe multiple sclerosis"],"prefix":"10.1136","volume":"7","author":[{"given":"Eline","family":"Huisman","sequence":"first","affiliation":[{"name":"Mapi Group, Houten, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Papadimitropoulou","sequence":"additional","affiliation":[{"name":"Mapi Group, Houten, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Jarrett","sequence":"additional","affiliation":[{"name":"Mapi Group, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Bending","sequence":"additional","affiliation":[{"name":"Mapi Group, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Firth","sequence":"additional","affiliation":[{"name":"Mapi Group, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicity","family":"Allen","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals, Frimley, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Adlard","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals, Frimley, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2017,3,10]]},"reference":[{"key":"2025121422432551000_7.3.e013430.1","unstructured":"National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research, 2015:1\u201336."},{"key":"2025121422432551000_7.3.e013430.2","unstructured":"National Multiple Sclerosis Society. What is Multiple Sclerosis? Brochure updated in 2016. http:\/\/www.nationalmssociety.org\/NationalMSSociety\/media\/MSNationalFiles\/Brochures\/Brochure-What-Is-MS.pdf"},{"key":"2025121422432551000_7.3.e013430.3","doi-asserted-by":"crossref","unstructured":"Havrdova E , Preiningerova JL . Symptoms and diagnosis of multiple sclerosis. Personalized Management of Multiple Sclerosis 2013:36\u201348. http:\/\/www.futuremedicine.com\/doi\/full\/10.2217\/ebo.13.133","DOI":"10.2217\/ebo.13.133"},{"key":"2025121422432551000_7.3.e013430.4","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12883"},{"key":"2025121422432551000_7.3.e013430.5","unstructured":"European Medicines Agency. Gilenya: International non-proprietary name: FINGOLIMOD. Secondary Gilenya: International non-proprietary name: FINGOLIMOD, 2014. http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Assessment_Report_-_Variation\/human\/002202\/WC500169449.pdf"},{"key":"2025121422432551000_7.3.e013430.6","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12090"},{"key":"2025121422432551000_7.3.e013430.7","first-page":"Cd011381","article-title":"Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis","volume":"9","author":"Tramacere","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121422432551000_7.3.e013430.8","doi-asserted-by":"crossref","first-page":"e0144538","DOI":"10.1371\/journal.pone.0144538","article-title":"The effect of disease modifying therapies on disease progression in patients with relapsing-remitting multiple sclerosis: a systematic review and meta-analysis","volume":"10","author":"Tsivgoulis","year":"2015","journal-title":"PLoS ONE"},{"key":"2025121422432551000_7.3.e013430.9","doi-asserted-by":"publisher","DOI":"10.7326\/M14-2385"},{"key":"2025121422432551000_7.3.e013430.10","unstructured":"National Institute for Health and Care Excellence (NICE). Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis, 2007. www.nice.org.uk\/guidance\/ta127 (22 Aug 2007)"},{"key":"2025121422432551000_7.3.e013430.11","unstructured":"National Institute for Health and Care Excellence. Single technology appraisal (STA): user guide for company evidence submission template, 2012. www.nice.org.uk\/process\/pmg24 (8 Jan 2015)"},{"key":"2025121422432551000_7.3.e013430.12","unstructured":"Centre for reviews and dissemination. Systematic reviews: CRD\u2019s guidance for undertaking reviews in health care. York: University of York, 2009."},{"key":"2025121422432551000_7.3.e013430.13","doi-asserted-by":"crossref","first-page":"874","DOI":"10.3111\/13696998.2015.1056794","article-title":"Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England","volume":"18","author":"Maruszczak","year":"2015","journal-title":"J Med Econ"},{"key":"2025121422432551000_7.3.e013430.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jval.2011.04.002"},{"key":"2025121422432551000_7.3.e013430.15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/1741-7015-12-93","article-title":"A process for assessing the feasibility of a network meta-analysis: a case study of everolimus in combination with hormonal therapy versus chemotherapy for advanced breast cancer","volume":"12","author":"Cope","year":"2014","journal-title":"BMC Med"},{"key":"2025121422432551000_7.3.e013430.16","doi-asserted-by":"publisher","DOI":"10.1177\/0272989X12458724"},{"key":"2025121422432551000_7.3.e013430.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2013.11.006"},{"key":"2025121422432551000_7.3.e013430.18","unstructured":"European Medicines Agency. 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