The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Sifat Sharmin^{1

2}, Izanne Roos^{1

2}, Steve Simpson-Yap^{1

3

4}, Charles Malpas^{1

2}, Marina M Sánchez^{1

2

5}, Serkan Ozakbas⁶, Dana Horakova⁷, Eva K Havrdova⁷, Francesco Patti⁸, Raed Alroughani⁹, Guillermo Izquierdo¹⁰, Sara Eichau¹⁰, Cavit Boz¹¹, Magd Zakaria¹², Marco Onofrj¹³, Alessandra Lugaresi¹⁴, Bianca Weinstock-Guttman¹⁵, Alexandre Prat¹⁶, Marc Girard¹⁶, Pierre Duquette¹⁶, Murat Terzi¹⁷, Maria Pia Amato¹⁸, Rana Karabudak¹⁹, Francois Grand'Maison²⁰, Samia J Khoury²¹, Pierre Grammond²², Jeannette Lechner-Scott²³, Katherine Buzzard²⁴, Olga Skibina²⁴, Anneke van der Walt²⁵, Helmut Butzkueven²⁵, Recai Turkoglu²⁶, Ayse Altintas²⁷, Davide Maimone²⁸, Allan Kermode²⁹, Nevin Shalaby³⁰, Vincent V Pesch³¹, Ernest Butler³², Youssef Sidhom³³, Riadh Gouider^{33

34}, Saloua Mrabet^{33

34}, Oliver Gerlach^{35

36}, Aysun Soysal³⁷, Michael Barnett³⁸, Jens Kuhle³⁹, Stella Hughes⁴⁰, Maria J Sa⁴¹, Suzanne Hodgkinson⁴², Celia Oreja-Guevara⁴³, Radek Ampapa⁴⁴, Thor Petersen⁴⁵, Cristina Ramo-Tello⁴⁶, Daniele Spitaleri⁴⁷, Pamela McCombe⁴⁸, Bruce Taylor⁴⁹, Julie Prevost⁵⁰, Matteo Foschi⁵¹, Mark Slee⁵², Chris McGuigan⁵³, Guy Laureys⁵⁴, Liesbeth V Hijfte⁵⁴, Koen de Gans⁵⁵, Claudio Solaro⁵⁶, Jiwon Oh⁵⁷, Richard Macdonell⁵⁸, Eduardo Aguera-Morales⁵⁹, Bhim Singhal⁶⁰, Orla Gray⁶¹, Justin Garber⁶², Bart V Wijmeersch⁶³, Mihaela Simu^{64

65}, Tamara Castillo-Triviño⁶⁶, Jose L Sanchez-Menoyo⁶⁷, Dheeraj Khurana⁶⁸, Abdullah Al-Asmi⁶⁹, Talal Al-Harbi⁷⁰, Norma Deri⁷¹, Yara Fragoso⁷², Patrice H Lalive⁷³, L G F Sinnige⁷⁴, Cameron Shaw⁷⁵, Neil Shuey⁷⁶, Tunde Csepany⁷⁷, Angel P Sempere⁷⁸, Fraser Moore⁷⁹, Danny Decoo⁸⁰, Barbara Willekens^{81

82}, Claudio Gobbi⁸³, Jennifer Massey⁸⁴, Todd Hardy⁸⁵, John Parratt⁸⁶, Tomas Kalincik^{1

2}

Affiliations

¹ CORe, Department of Medicine, University of Melbourne, Melbourne 3050, Australia.
² Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne 3050, Australia.
³ Neuroepidemiology Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne 3050, Australia.
⁴ Menzies Institute for Medical Research, University of Tasmania, Tasmania 7000, Australia.
⁵ Department of Neurology, Hospital Germans Trias i Pujol, Badalona 08916, Spain.
⁶ Faculty of Medicine, Dokuz Eylul University, Konak/Izmir 35220, Turkey.
⁷ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague 12808, Czech Republic.
⁸ Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, Catania 95123, Italy.
⁹ Division of Neurology, Department of Medicine, Amiri Hospital, Sharq 73767, Kuwait.
¹⁰ Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena, Sevilla 41009, Spain.
¹¹ Faculty of Medicine, Karadeniz Technical University, Karadeniz Technical University Farabi Hospital, Trabzon 61080, Turkey.
¹² Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
¹³ Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti 66013, Italy.
¹⁴ Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna 40139, Italy.
¹⁵ Department of Neurology, Jacobs Multiple Sclerosis Center for Treatment and Research, University at Buffalo, Buffalo 14202, USA.
¹⁶ CHUM MS Center, Faculty of Medicine, Universite de Montreal, Montreal H2L 4M1, Canada.
¹⁷ Faculty of Medicine, 19 Mayis University, Samsun 55160, Turkey.
¹⁸ Department NEUROFARBA, University of Florence, Florence 50134, Italy.
¹⁹ Department of Neurology, Hacettepe University, Ankara 6100, Turkey.
²⁰ Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec J4V 2J2, Canada.
²¹ Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.
²² Médecine spécialisée, CISSS Chaudière-Appalaches, Levis G6X 0A1, Canada.
²³ School of Medicine and Public Health, University of Newcastle, Newcastle 2305, Australia.
²⁴ Department of Neurology, Box Hill Hospital, Melbourne 3128, Australia.
²⁵ Department of Neurology, The Alfred Hospital, Melbourne 3000, Australia.
²⁶ Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul 34668, Turkey.
²⁷ Department of Neurology, School of Medicine, Koc University, Koc University Research Center for Translational Medicine (KUTTAM), Istanbul 34450, Turkey.
²⁸ Centro Sclerosi Multipla, UOC Neurologia, ARNAS Garibaldi, Catania 95124, Italy.
²⁹ Perron Institute, University of Western Australia, Nedlands 6009, Australia.
³⁰ Department of Neurology, Kasr Al Ainy MS Research Unit (KAMSU), Cairo 11562, Egypt.
³¹ Service de Neurologie, Cliniques Universitaires Saint-Luc, Brussels 1200 BXL, Belgium.
³² Monash Medical Centre, Melbourne 3168, Australia.
³³ Department of Neurology, Razi Hospital, Manouba 2010, Tunisia.
³⁴ Clinical Investigation Center Neurosciences and Mental Health, Faculty of Medicine, University of Tunis El Manar, Tunis 1068, Tunisia.
³⁵ Academic MS Center Zuyderland, Department of Neurology, Zuyderland Medical Center, Sittard-Geleen 5500, The Netherlands.
³⁶ School for Mental Health and Neuroscience, Department of Neurology, Maastricht University Medical Center, Maastricht 6131 BK, The Netherlands.
³⁷ Department of Neurology, Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul 34147, Turkey.
³⁸ Multiple Sclerosis Clinic, Brain and Mind Centre, Sydney 2050, Australia.
³⁹ Neurologic Clinic and Policlinic, Departments of Medicine and Clinical Research, University Hospital and University of Basel, Basel 4000, Switzerland.
⁴⁰ Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
⁴¹ Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto 4200-319, Portugal.
⁴² Immune tolerance laboratory Ingham Institute and Department of Medicine, University of New South Wales, Sydney 2170, Australia.
⁴³ Department of Neurology, Hospital Clinico San Carlos, Madrid 28050, Spain.
⁴⁴ MS centrum, Nemocnice Jihlava, Jihlava 58633, Czech Republic.
⁴⁵ Department of Neurology, Aarhus University Hospital, Arhus C 8000, Denmark.
⁴⁶ Department of Neurology, Hospital Germans Trias i Pujol, Badalona 8916, Spain.
⁴⁷ Centro Sclerosi Multipla, Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino 83100, Italy.
⁴⁸ Royal Brisbane and Women's Hospital, University of Queensland, Brisbane 4000, Australia.
⁴⁹ Department of Neurology, Royal Hobart Hospital, Hobart 7000, Australia.
⁵⁰ Département de neurologie, CSSS Saint-Jérôme, Saint-Jerome J7Z 5T3, Canada.
⁵¹ Department of Neuroscience, Neurology Unit, S. Maria delle Croci Hospital of Ravenna, Ravenna 48121, Italy.
⁵² College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia.
⁵³ Department of Neurology, St Vincent's University Hospital, Dublin D04 T6F4, Ireland.
⁵⁴ Department of Neurology, Universitary Hospital Ghent, Ghent 9000, Belgium.
⁵⁵ Department of Neurology, Groene Hart Hospital, Gouda 2800 BB, The Netherlands.
⁵⁶ Department of Rehabilitation, CRRF 'Mons. Luigi Novarese', Moncrivello (VC) 16153, Italy.
⁵⁷ Barlo Multiple Sclerosis Centre, St. Michael's Hospital, Toronto M5B1W8, Canada.
⁵⁸ Department of Neurology, Austin Health, Melbourne 3084, Australia.
⁵⁹ Department of Neurology, University Hospital Reina Sofia, Cordoba 14004, Spain.
⁶⁰ Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai 400020, India.
⁶¹ Department of Neurology, South Eastern HSC Trust, Belfast BT16, UK.
⁶² Department of Neurology, Westmead Hospital, Sydney 2145, Australia.
⁶³ Rehabilitation and MS-Centre Overpelt, Hasselt University, Hasselt 3900, Belgium.
⁶⁴ Clinic of Neurology II, Emergency Clinical County Hospital 'Pius Brinzeu', Timisoara 300723, Romania.
⁶⁵ Department of Neurology, Victor Babes University of Medicine and Pharmacy Timisoara, Timisoara 300041, Romania.
⁶⁶ Department of Neurology, Hospital Universitario Donostia, San Sebastián 20014, Spain.
⁶⁷ Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao 48660, Spain.
⁶⁸ Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
⁶⁹ Department of Medicine, Sultan Qaboos University Hospital, Al-Khodh 123, Oman.
⁷⁰ Neurology Department, King Fahad Specialist Hospital-Dammam, Khobar 31952, Saudi Arabia.
⁷¹ Hospital Fernandez, Buenos Aires 1425, Argentina.
⁷² Department of Neurology, Universidade Metropolitana de Santos, Santos 11045-002, Brazil.
⁷³ Department of Clinical Neurosciences, Division of Neurology, Faculty of Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
⁷⁴ Department of Neurology, Medical Center Leeuwarden, Leeuwarden 8934 AD, The Netherlands.
⁷⁵ Neuroscience Department, Barwon Health, University Hospital Geelong, Geelong 3220, Australia.
⁷⁶ Department of Neurology, St Vincents Hospital, Fitzroy, Melbourne 3065, Australia.
⁷⁷ Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
⁷⁸ Department of Neurology, Hospital General Universitario de Alicante, Alicante 3010, Spain.
⁷⁹ Department of Neurology, McGill University, Montreal H3T 1E2, Canada.
⁸⁰ Department of Neurology & Neuro-Rehabilitation, AZ Alma Ziekenhuis, Sijsele-Damme 8340, Belgium.
⁸¹ Department of Neurology, Antwerp University Hospital, Edegem 2650, Belgium.
⁸² Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk 2650, Belgium.
⁸³ Ospedale Civico Lugano, Lugano 6900, Switzerland.
⁸⁴ St Vincent's Hospital Sydney, Sydney 2010, Australia.
⁸⁵ Concord Repatriation General Hospital, Sydney 2139, Australia.
⁸⁶ Royal North Shore Hospital, Sydney 2065, Australia.

PMID: 37369086
PMCID: PMC10629760
DOI: 10.1093/brain/awad218

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Sifat Sharmin et al. Brain. 2023.

. 2023 Nov 2;146(11):4633-4644.

doi: 10.1093/brain/awad218.

Authors

Affiliations

¹ CORe, Department of Medicine, University of Melbourne, Melbourne 3050, Australia.
² Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne 3050, Australia.
³ Neuroepidemiology Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne 3050, Australia.
⁴ Menzies Institute for Medical Research, University of Tasmania, Tasmania 7000, Australia.
⁵ Department of Neurology, Hospital Germans Trias i Pujol, Badalona 08916, Spain.
⁶ Faculty of Medicine, Dokuz Eylul University, Konak/Izmir 35220, Turkey.
⁷ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague 12808, Czech Republic.
⁸ Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, Catania 95123, Italy.
⁹ Division of Neurology, Department of Medicine, Amiri Hospital, Sharq 73767, Kuwait.
¹⁰ Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena, Sevilla 41009, Spain.
¹¹ Faculty of Medicine, Karadeniz Technical University, Karadeniz Technical University Farabi Hospital, Trabzon 61080, Turkey.
¹² Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
¹³ Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio, Chieti 66013, Italy.
¹⁴ Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna 40139, Italy.
¹⁵ Department of Neurology, Jacobs Multiple Sclerosis Center for Treatment and Research, University at Buffalo, Buffalo 14202, USA.
¹⁶ CHUM MS Center, Faculty of Medicine, Universite de Montreal, Montreal H2L 4M1, Canada.
¹⁷ Faculty of Medicine, 19 Mayis University, Samsun 55160, Turkey.
¹⁸ Department NEUROFARBA, University of Florence, Florence 50134, Italy.
¹⁹ Department of Neurology, Hacettepe University, Ankara 6100, Turkey.
²⁰ Neuro Rive-Sud, Hôpital Charles LeMoyne, Quebec J4V 2J2, Canada.
²¹ Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.
²² Médecine spécialisée, CISSS Chaudière-Appalaches, Levis G6X 0A1, Canada.
²³ School of Medicine and Public Health, University of Newcastle, Newcastle 2305, Australia.
²⁴ Department of Neurology, Box Hill Hospital, Melbourne 3128, Australia.
²⁵ Department of Neurology, The Alfred Hospital, Melbourne 3000, Australia.
²⁶ Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul 34668, Turkey.
²⁷ Department of Neurology, School of Medicine, Koc University, Koc University Research Center for Translational Medicine (KUTTAM), Istanbul 34450, Turkey.
²⁸ Centro Sclerosi Multipla, UOC Neurologia, ARNAS Garibaldi, Catania 95124, Italy.
²⁹ Perron Institute, University of Western Australia, Nedlands 6009, Australia.
³⁰ Department of Neurology, Kasr Al Ainy MS Research Unit (KAMSU), Cairo 11562, Egypt.
³¹ Service de Neurologie, Cliniques Universitaires Saint-Luc, Brussels 1200 BXL, Belgium.
³² Monash Medical Centre, Melbourne 3168, Australia.
³³ Department of Neurology, Razi Hospital, Manouba 2010, Tunisia.
³⁴ Clinical Investigation Center Neurosciences and Mental Health, Faculty of Medicine, University of Tunis El Manar, Tunis 1068, Tunisia.
³⁵ Academic MS Center Zuyderland, Department of Neurology, Zuyderland Medical Center, Sittard-Geleen 5500, The Netherlands.
³⁶ School for Mental Health and Neuroscience, Department of Neurology, Maastricht University Medical Center, Maastricht 6131 BK, The Netherlands.
³⁷ Department of Neurology, Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul 34147, Turkey.
³⁸ Multiple Sclerosis Clinic, Brain and Mind Centre, Sydney 2050, Australia.
³⁹ Neurologic Clinic and Policlinic, Departments of Medicine and Clinical Research, University Hospital and University of Basel, Basel 4000, Switzerland.
⁴⁰ Department of Neurology, Royal Victoria Hospital, Belfast BT12 6BA, UK.
⁴¹ Department of Neurology, Centro Hospitalar Universitario de Sao Joao, Porto 4200-319, Portugal.
⁴² Immune tolerance laboratory Ingham Institute and Department of Medicine, University of New South Wales, Sydney 2170, Australia.
⁴³ Department of Neurology, Hospital Clinico San Carlos, Madrid 28050, Spain.
⁴⁴ MS centrum, Nemocnice Jihlava, Jihlava 58633, Czech Republic.
⁴⁵ Department of Neurology, Aarhus University Hospital, Arhus C 8000, Denmark.
⁴⁶ Department of Neurology, Hospital Germans Trias i Pujol, Badalona 8916, Spain.
⁴⁷ Centro Sclerosi Multipla, Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino 83100, Italy.
⁴⁸ Royal Brisbane and Women's Hospital, University of Queensland, Brisbane 4000, Australia.
⁴⁹ Department of Neurology, Royal Hobart Hospital, Hobart 7000, Australia.
⁵⁰ Département de neurologie, CSSS Saint-Jérôme, Saint-Jerome J7Z 5T3, Canada.
⁵¹ Department of Neuroscience, Neurology Unit, S. Maria delle Croci Hospital of Ravenna, Ravenna 48121, Italy.
⁵² College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia.
⁵³ Department of Neurology, St Vincent's University Hospital, Dublin D04 T6F4, Ireland.
⁵⁴ Department of Neurology, Universitary Hospital Ghent, Ghent 9000, Belgium.
⁵⁵ Department of Neurology, Groene Hart Hospital, Gouda 2800 BB, The Netherlands.
⁵⁶ Department of Rehabilitation, CRRF 'Mons. Luigi Novarese', Moncrivello (VC) 16153, Italy.
⁵⁷ Barlo Multiple Sclerosis Centre, St. Michael's Hospital, Toronto M5B1W8, Canada.
⁵⁸ Department of Neurology, Austin Health, Melbourne 3084, Australia.
⁵⁹ Department of Neurology, University Hospital Reina Sofia, Cordoba 14004, Spain.
⁶⁰ Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai 400020, India.
⁶¹ Department of Neurology, South Eastern HSC Trust, Belfast BT16, UK.
⁶² Department of Neurology, Westmead Hospital, Sydney 2145, Australia.
⁶³ Rehabilitation and MS-Centre Overpelt, Hasselt University, Hasselt 3900, Belgium.
⁶⁴ Clinic of Neurology II, Emergency Clinical County Hospital 'Pius Brinzeu', Timisoara 300723, Romania.
⁶⁵ Department of Neurology, Victor Babes University of Medicine and Pharmacy Timisoara, Timisoara 300041, Romania.
⁶⁶ Department of Neurology, Hospital Universitario Donostia, San Sebastián 20014, Spain.
⁶⁷ Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao 48660, Spain.
⁶⁸ Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
⁶⁹ Department of Medicine, Sultan Qaboos University Hospital, Al-Khodh 123, Oman.
⁷⁰ Neurology Department, King Fahad Specialist Hospital-Dammam, Khobar 31952, Saudi Arabia.
⁷¹ Hospital Fernandez, Buenos Aires 1425, Argentina.
⁷² Department of Neurology, Universidade Metropolitana de Santos, Santos 11045-002, Brazil.
⁷³ Department of Clinical Neurosciences, Division of Neurology, Faculty of Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
⁷⁴ Department of Neurology, Medical Center Leeuwarden, Leeuwarden 8934 AD, The Netherlands.
⁷⁵ Neuroscience Department, Barwon Health, University Hospital Geelong, Geelong 3220, Australia.
⁷⁶ Department of Neurology, St Vincents Hospital, Fitzroy, Melbourne 3065, Australia.
⁷⁷ Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
⁷⁸ Department of Neurology, Hospital General Universitario de Alicante, Alicante 3010, Spain.
⁷⁹ Department of Neurology, McGill University, Montreal H3T 1E2, Canada.
⁸⁰ Department of Neurology & Neuro-Rehabilitation, AZ Alma Ziekenhuis, Sijsele-Damme 8340, Belgium.
⁸¹ Department of Neurology, Antwerp University Hospital, Edegem 2650, Belgium.
⁸² Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk 2650, Belgium.
⁸³ Ospedale Civico Lugano, Lugano 6900, Switzerland.
⁸⁴ St Vincent's Hospital Sydney, Sydney 2010, Australia.
⁸⁵ Concord Repatriation General Hospital, Sydney 2139, Australia.
⁸⁶ Royal North Shore Hospital, Sydney 2065, Australia.

PMID: 37369086
PMCID: PMC10629760
DOI: 10.1093/brain/awad218

Abstract

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.

Keywords: disease-modifying therapy; geography; health expenditure; latitude; secondary progressive multiple sclerosis.

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Conflict of interest statement

S.S. has received research support from the MSBase registry. I.R. served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck, and Biogen. C.M. has received conference travel support from Merck, Novartis, and Biogen. He has received research support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. D.H. received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education (project Progres Q27/LF1). E.K.H. received honoraria/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; has been supported by the Czech Ministry of Education research project Progres Q27/LF1. F.P. received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association, and University of Catania. R.A. received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. G.I. received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall, and Teva. S.E. received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. C.B. received conference travel support from Biogen, Novartis, Bayer-Schering, Merck, and Teva; has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. A.L. has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva. Her institutions have received research grants from Novartis (last 4 yrs). B.W.-G. has participated in speaker’s bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen and Horizon. She also has received grant/research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. M.G. received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis, and EMD. He has also received a research grant from Canadian Institutes of Health Research. P.D. served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. M.T. received travel grants from Novartis, Bayer-Schering, Merck, and Teva; has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. M.P.A. received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva, and Sanofi-Aventis; has received research grants by Biogen, Bayer-Schering, Merck, Teva, and Novartis. F.G. received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi, and ONO Pharmaceuticals. S.J.K. received compensation for serving on advisory boards for Merck and Roche. P.G. has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. J.L.-S. travel compensation from Novartis, Biogen, Roche, and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA, and Novartis. K.B. received honoraria and consulting fees from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck, CSL, and Grifols. A.vdW. served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck, and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. H.B. has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd. and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd. and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. A.A. received personal fees and speaker honoraria from Teva, Merck, Biogen—Gen Pharma, Roche, Novartis, Bayer, Sanofi-Genzyme; received travel and registration grants from Merck, Biogen—Gen Pharma, Roche, Sanofi-Genzyme, and Bayer. D.M. received speaker honoraria for Advisory Board and travel grants from Almirall, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. A.K. received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. V.V.P. received travel grants from Merck, Biogen, Sanofi, Celgene, Almirall, and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Celgene, Merck, and Novartis Pharma. M.B. served on scientific advisory boards for Biogen, Novartis, and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck, and Novartis. S.H. has received unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. S.H. received honoraria and consulting fees from Novartis, Bayer Schering, and Sanofi, and travel grants from Novartis, Biogen Idec, and Bayer Schering. C.O.-G. received honoraria as consultant on scientific advisory boards from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA. R.A. received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck and has participated in clinical trials by Biogen, Novartis, Teva, and Actelion. T.P. received funding from Biogen, Merck, Novartis, Sanofi-Aventis, Roche, and Genzyme. C.R.-T. received research funding, compensation for travel or speaker honoraria from Biogen, Novartis, Genzyme, and Almirall. D.S. received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis, and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, and Merck. P.M. received speaker fees and travel grants from Novartis, Biogen, T’évalua, and Sanofi. B.T. received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen, and Novartis, and has served on advisory boards for Biogen, Novartis, Roche, and CSL Australia. J.P. accepted travel compensation from Novartis, Biogen, Genzyme, Teva, and speaking honoraria from Biogen, Novartis, Genzyme, and Teva. M.S. has participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis, and Novartis. G.L. received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. C.S. served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme, and Teva. J.O. has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. B.S. received consultancy honoraria and compensation for travel from Biogen and Merck. O.G. received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche, and Novartis; has received travel grants from Biogen, Merck, Roche, and Novartis; has participated in clinical trials by Biogen and Merck. B.V.W. received research and travel grants, honoraria for MS-Expert advisor and speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. T.C.T. received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. J.L.S.-M. accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva and has participated in clinical trials by Biogen, Merck, and Roche Pamela McCombe received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen, and Bayer Schering. N.D. served on advisory boards for Bayer Argentina, Bayer Latinoamerica, Bayer Global, Merck Serono Argentina, Merck Serono Global, Genzyme Argentina, Genzyme Latinoamerica, Genzyme Global, and Sanofi Global. He received conference travel support from Bayer, Serono, Merck Serono, Novartis, Biogen Idec, Teva-Tuteur, Teva, and Roche. He received honoraria for research or educational event support from Bayer Argentina, Biogen Idec Argentina, Genzyme Argentina, Novartis Argentina, Roche Argentina, Teva Argentina, Sanofi Argentina, and Merck Serono Argentina. Y.F. received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche, and Merck. P.H.L. received honoraria for speaking and or travel expense from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; research support from Biogen, Merck, Novartis. None were related to this work. C.S. received travel assistance from Biogen and Novartis. N.S. received travel compensation from Bayer Schering, Novartis, and Biogen Idec. T.C. received speaker honoraria/conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis, and Teva. F.M. participated in clinical trials sponsored by EMD Serono and Novartis. B.W. received honoraria for acting as a member of Scientific Advisory Boards for Almirall, Biogen, Celgene/BMS, Merck Serono, Novartis, Roche, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme; research and/or patient support grants from Roche, Biogen, Merck-Serono, Sanofi-Genzyme. Honoraria and grants were paid to UZA/UZA Foundation. T.K. served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. The remaining report no competing interests.

Figures

**Figure 1**
**CONSORT chart of patient disposition.** RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.

**Figure 2**
**Map of predicted risk-exceedance probabilities.** Shades of red indicate countries with substantially shorter time to secondary progressive multiple sclerosis (SPMS) conversion than those that are coloured with shades of green. Countries coloured in grey did not contribute to the MSBase registry or were excluded at the data quality assessment.

**Figure 3**
**Posterior median probabilities of remaining SPMS-free.** An example provided for four patients with similar characteristics at study inclusion (asterisk) from four countries. Grey areas represent the respective 95% credible bands. This example illustrates variability in the probability of remaining SPMS-free for patients living in four countries after accounting for patients’ clinical and demographic characteristics.

See this image and copyright information in PMC

References

1. Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: A meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82:1132–1141. - PubMed
1. Simpson S, Wang W, Otahal P, Blizzard L, van der Mei IA, Taylor BV. Latitude continues to be significantly associated with the prevalence of multiple sclerosis: An updated meta-analysis. J Neurol Neurosurg Psychiatry. 2019;90:1193–1200. - PubMed
1. Lucas R, Ponsonby A-L, Dear K, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76:540–548. - PubMed
1. Simpson S Jr, Van der Mei I, Lucas RM, et al. Sun exposure across the life course significantly modulates early multiple sclerosis clinical course. Front Neurol. 2018;9:16. - PMC - PubMed
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The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

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The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

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