{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:50:01Z","timestamp":1791273001989,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NHMRC Australia","award":["1129189"],"award-info":[{"award-number":["1129189"]}]},{"name":"NHMRC Australia","award":["1140766"],"award-info":[{"award-number":["1140766"]}]},{"DOI":"10.13039\/100004334","name":"Merck","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004334","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004337","name":"Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006010","name":"Bayer Schering","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006259","name":"Teva Pharmaceutical Industries","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006259","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability.<\/jats:p>\n               <jats:p>We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties.<\/jats:p>\n               <jats:p>We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions.<\/jats:p>\n               <jats:p>Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.<\/jats:p>","DOI":"10.1093\/brain\/awad218","type":"journal-article","created":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T00:36:23Z","timestamp":1687653383000},"page":"4633-4644","source":"Crossref","is-referenced-by-count":27,"title":["The risk of secondary progressive multiple sclerosis is geographically determined but modifiable"],"prefix":"10.1093","volume":"146","author":[{"given":"Sifat","family":"Sharmin","sequence":"first","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne 3050 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izanne","family":"Roos","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne 3050 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Simpson-Yap","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Neuroepidemiology Unit, Melbourne School of Population and Global Health, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Menzies Institute for Medical Research, University of Tasmania , Tasmania 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Malpas","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne 3050 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina M","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"CORe, Department of Medicine, University of Melbourne , Melbourne 3050 , Australia"},{"name":"Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital , Melbourne 3050 , Australia"},{"name":"Department of Neurology, Hospital Germans Trias i Pujol , Badalona 08916 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serkan","family":"Ozakbas","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Dokuz Eylul University , Konak\/Izmir 35220 , Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Horakova","sequence":"additional","affiliation":[{"name":"Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital , Prague 12808 , Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva K","family":"Havrdova","sequence":"additional","affiliation":[{"name":"Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital , Prague 12808 , Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Patti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia , Catania 95123 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed","family":"Alroughani","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Amiri Hospital , Sharq 73767 , Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena , Sevilla 41009 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Eichau","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena , Sevilla 41009 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cavit","family":"Boz","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Karadeniz Technical University , Karadeniz Technical University Farabi Hospital, Trabzon 61080 , Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magd","family":"Zakaria","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Ain Shams University , Cairo 11566 , Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Onofrj","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging, and Clinical Sciences, University G. d\u2019Annunzio , Chieti 66013 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Lugaresi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche e Neuromotorie, Universit\u00e0 di Bologna , Bologna 40139 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Weinstock-Guttman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jacobs Multiple Sclerosis Center for Treatment and Research, University at Buffalo , Buffalo 14202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Prat","sequence":"additional","affiliation":[{"name":"CHUM MS Center, Faculty of Medicine, Universite de Montreal , Montreal H2L 4M1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Girard","sequence":"additional","affiliation":[{"name":"CHUM MS Center, Faculty of Medicine, Universite de Montreal , Montreal H2L 4M1 , 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Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Grand\u2019Maison","sequence":"additional","affiliation":[{"name":"Neuro Rive-Sud, H\u00f4pital Charles LeMoyne , Quebec J4V 2J2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samia J","family":"Khoury","sequence":"additional","affiliation":[{"name":"Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center , Beirut 1107 2020 , Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Grammond","sequence":"additional","affiliation":[{"name":"M\u00e9decine sp\u00e9cialis\u00e9e, CISSS Chaudi\u00e8re-Appalaches , Levis G6X 0A1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Lechner-Scott","sequence":"additional","affiliation":[{"name":"School of Medicine and Public Health, University of Newcastle , Newcastle 2305 , 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Hospital and University of Basel , Basel 4000 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Victoria Hospital , Belfast BT12 6BA , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J","family":"Sa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Centro Hospitalar Universitario de Sao Joao , Porto 4200-319 , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Hodgkinson","sequence":"additional","affiliation":[{"name":"Immune tolerance laboratory Ingham Institute and Department of Medicine , University of New South Wales, Sydney 2170 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Oreja-Guevara","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Clinico San Carlos , Madrid 28050 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radek","family":"Ampapa","sequence":"additional","affiliation":[{"name":"MS centrum, Nemocnice Jihlava , Jihlava 58633, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thor","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Aarhus University Hospital , Arhus C 8000 , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ramo-Tello","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Germans Trias i Pujol , Badalona 8916 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Spitaleri","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla, Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino , Avellino 83100 , 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Maria delle Croci Hospital of Ravenna , Ravenna 48121 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Slee","sequence":"additional","affiliation":[{"name":"College of Medicine and Public Health, Flinders University , Adelaide 5042 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"McGuigan","sequence":"additional","affiliation":[{"name":"Department of Neurology, St Vincent\u2019s University Hospital , Dublin D04 T6F4 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Laureys","sequence":"additional","affiliation":[{"name":"Department of Neurology, Universitary Hospital Ghent , Ghent 9000 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth V","family":"Hijfte","sequence":"additional","affiliation":[{"name":"Department of Neurology, Universitary Hospital Ghent , Ghent 9000 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8600-0460","authenticated-orcid":false,"given":"Koen","family":"de Gans","sequence":"additional","affiliation":[{"name":"Department of Neurology, Groene Hart Hospital , Gouda 2800 BB , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Solaro","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, CRRF \u2018Mons. 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India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Neurology, South Eastern HSC Trust , Belfast BT16 , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Garber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Westmead Hospital , Sydney 2145 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart V","family":"Wijmeersch","sequence":"additional","affiliation":[{"name":"Rehabilitation and MS-Centre Overpelt, Hasselt University , Hasselt 3900 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Simu","sequence":"additional","affiliation":[{"name":"Clinic of Neurology II, Emergency Clinical County Hospital \u2018Pius Brinzeu\u2019 , Timisoara 300723 , Romania"},{"name":"Department of Neurology, Victor Babes University of Medicine and Pharmacy Timisoara , 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Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talal","family":"Al-Harbi","sequence":"additional","affiliation":[{"name":"Neurology Department, King Fahad Specialist Hospital-Dammam , Khobar 31952 , Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma","family":"Deri","sequence":"additional","affiliation":[{"name":"Hospital Fernandez , Buenos Aires 1425 , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Fragoso","sequence":"additional","affiliation":[{"name":"Department of Neurology, Universidade Metropolitana de Santos , Santos 11045-002 , Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice H","family":"Lalive","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Division of Neurology, Faculty of Medicine, Geneva University Hospital , Geneva 1211 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L G F","family":"Sinnige","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Center Leeuwarden , Leeuwarden 8934 AD , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Shaw","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Barwon Health, University Hospital Geelong , Geelong 3220 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Shuey","sequence":"additional","affiliation":[{"name":"Department of Neurology, St Vincents Hospital , Fitzroy, Melbourne 3065 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tunde","family":"Csepany","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, University of Debrecen , Debrecen 4032 , Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-2834","authenticated-orcid":false,"given":"Angel P","family":"Sempere","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital General Universitario de Alicante , Alicante 3010 , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fraser","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Neurology, McGill University , Montreal H3T 1E2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Decoo","sequence":"additional","affiliation":[{"name":"Department of Neurology & Neuro-Rehabilitation, AZ Alma Ziekenhuis , Sijsele-Damme 8340 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Willekens","sequence":"additional","affiliation":[{"name":"Department of Neurology, Antwerp University Hospital , Edegem 2650 , Belgium"},{"name":"Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp , Wilrijk 2650 , 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