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. 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. 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. 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.

Academic MS Center Zuyderland Department of Neurology Zuyderland Medical Center Sittard Geleen 5500 The Netherlands

Barlo Multiple Sclerosis Centre St Michael's Hospital Toronto M5B1W8 Canada

Centro Sclerosi Multipla Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino 83100 Italy

Centro Sclerosi Multipla UOC Neurologia ARNAS Garibaldi Catania 95124 Italy

CHUM MS Center Faculty of Medicine Universite de Montreal Montreal H2L 4M1 Canada

Clinic of Neurology 2 Emergency Clinical County Hospital 'Pius Brinzeu' Timisoara 300723 Romania

Clinical Investigation Center Neurosciences and Mental Health Faculty of Medicine University of Tunis El Manar Tunis 1068 Tunisia

College of Medicine and Public Health Flinders University Adelaide 5042 Australia

Concord Repatriation General Hospital Sydney 2139 Australia

CORe Department of Medicine University of Melbourne Melbourne 3050 Australia

Département de neurologie CSSS Saint Jérôme Saint Jerome J7Z 5T3 Canada

Department NEUROFARBA University of Florence Florence 50134 Italy

Department of Clinical Neurosciences Division of Neurology Faculty of Medicine Geneva University Hospital Geneva 1211 Switzerland

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania 95123 Italy

Department of Medicine Sultan Qaboos University Hospital Al Khodh 123 Oman

Department of Neurology Aarhus University Hospital Arhus C 8000 Denmark

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague 12808 Czech Republic

Department of Neurology and Neuro Rehabilitation AZ Alma Ziekenhuis Sijsele Damme 8340 Belgium

Department of Neurology Antwerp University Hospital Edegem 2650 Belgium

Department of Neurology Austin Health Melbourne 3084 Australia

Department of Neurology Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases Istanbul 34147 Turkey

Department of Neurology Bombay Hospital Institute of Medical Sciences Mumbai 400020 India

Department of Neurology Box Hill Hospital Melbourne 3128 Australia

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto 4200 319 Portugal

Department of Neurology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary

Department of Neurology Groene Hart Hospital Gouda 2800 BB The Netherlands

Department of Neurology Hacettepe University Ankara 6100 Turkey

Department of Neurology Haydarpasa Numune Training and Research Hospital Istanbul 34668 Turkey

Department of Neurology Hospital Clinico San Carlos Madrid 28050 Spain

Department of Neurology Hospital de Galdakao Usansolo Galdakao 48660 Spain

Department of Neurology Hospital General Universitario de Alicante Alicante 3010 Spain

Department of Neurology Hospital Germans Trias i Pujol Badalona 08916 Spain

Department of Neurology Hospital Germans Trias i Pujol Badalona 8916 Spain

Department of Neurology Hospital Universitario Donostia San Sebastián 20014 Spain

Department of Neurology Jacobs Multiple Sclerosis Center for Treatment and Research University at Buffalo Buffalo 14202 USA

Department of Neurology Kasr Al Ainy MS Research Unit Cairo 11562 Egypt

Department of Neurology McGill University Montreal H3T 1E2 Canada

Department of Neurology Medical Center Leeuwarden Leeuwarden 8934 AD The Netherlands

Department of Neurology Postgraduate Institute of Medical Education and Research Chandigarh 160012 India

Department of Neurology Razi Hospital Manouba 2010 Tunisia

Department of Neurology Royal Hobart Hospital Hobart 7000 Australia

Department of Neurology Royal Victoria Hospital Belfast BT12 6BA UK

Department of Neurology School of Medicine Koc University Koc University Research Center for Translational Medicine Istanbul 34450 Turkey

Department of Neurology South Eastern HSC Trust Belfast BT16 UK

Department of Neurology St Vincent's University Hospital Dublin D04 T6F4 Ireland

Department of Neurology St Vincents Hospital Fitzroy Melbourne 3065 Australia

Department of Neurology The Alfred Hospital Melbourne 3000 Australia

Department of Neurology Universidade Metropolitana de Santos Santos 11045 002 Brazil

Department of Neurology Universitary Hospital Ghent Ghent 9000 Belgium

Department of Neurology University Hospital Reina Sofia Cordoba 14004 Spain

Department of Neurology Victor Babes University of Medicine and Pharmacy Timisoara Timisoara 300041 Romania

Department of Neurology Westmead Hospital Sydney 2145 Australia

Department of Neuroscience Imaging and Clinical Sciences University G d'Annunzio Chieti 66013 Italy

Department of Neuroscience Neurology Unit S Maria delle Croci Hospital of Ravenna Ravenna 48121 Italy

Department of Rehabilitation CRRF 'Mons Luigi Novarese' Moncrivello 16153 Italy

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna 40139 Italy

Division of Neurology Department of Medicine Amiri Hospital Sharq 73767 Kuwait

Faculty of Medicine 19 Mayis University Samsun 55160 Turkey

Faculty of Medicine Ain Shams University Cairo 11566 Egypt

Faculty of Medicine Dokuz Eylul University Konak Izmir 35220 Turkey

Faculty of Medicine Karadeniz Technical University Karadeniz Technical University Farabi Hospital Trabzon 61080 Turkey

Hospital Fernandez Buenos Aires 1425 Argentina

Immune tolerance laboratory Ingham Institute and Department of Medicine University of New South Wales Sydney 2170 Australia

Médecine spécialisée CISSS Chaudière Appalaches Levis G6X 0A1 Canada

Menzies Institute for Medical Research University of Tasmania Tasmania 7000 Australia

Monash Medical Centre Melbourne 3168 Australia

MS centrum Nemocnice Jihlava Jihlava 58633 Czech Republic

Multiple Sclerosis Clinic Brain and Mind Centre Sydney 2050 Australia

Multiple Sclerosis Unit Hospital Universitario Virgen Macarena Sevilla 41009 Spain

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut 1107 2020 Lebanon

Neuro Rive Sud Hôpital Charles LeMoyne Quebec J4V 2J2 Canada

Neuroepidemiology Unit Melbourne School of Population and Global Health University of Melbourne Melbourne 3050 Australia

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne 3050 Australia

Neurologic Clinic and Policlinic Departments of Medicine and Clinical Research University Hospital and University of Basel Basel 4000 Switzerland

Neurology Department King Fahad Specialist Hospital Dammam Khobar 31952 Saudi Arabia

Neuroscience Department Barwon Health University Hospital Geelong Geelong 3220 Australia

Ospedale Civico Lugano Lugano 6900 Switzerland

Perron Institute University of Western Australia Nedlands 6009 Australia

Rehabilitation and MS Centre Overpelt Hasselt University Hasselt 3900 Belgium

Royal Brisbane and Women's Hospital University of Queensland Brisbane 4000 Australia

Royal North Shore Hospital Sydney 2065 Australia

School for Mental Health and Neuroscience Department of Neurology Maastricht University Medical Center Maastricht 6131 BK The Netherlands

School of Medicine and Public Health University of Newcastle Newcastle 2305 Australia

Service de Neurologie Cliniques Universitaires Saint Luc Brussels 1200 BXL Belgium

St Vincent's Hospital Sydney Sydney 2010 Australia

Translational Neurosciences Research Group Faculty of Medicine and Health Sciences University of Antwerp Wilrijk 2650 Belgium

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