The risk of secondary progressive multiple sclerosis is geographically determined but modifiable
Authors: Sharmin Sifat , Roos Izanne , Simpson-Yap Steve , Malpas Charles , Sánchez Marina M , Ozakbas Serkan , Horakova Dana , Havrdova Eva K , Patti Francesco , Alroughani Raed , Izquierdo Guillermo , Eichau Sara , Boz Cavit , Zakaria Magd , Onofrj Marco , Lugaresi Alessandra , Weinstock-Guttman Bianca , Prat Alexandre , Girard Marc , Duquette Pierre , Terzi Murat , Amato Maria Pia , Karabudak Rana , Grand’Maison Francois , Khoury Samia J , Grammond Pierre , Lechner-Scott Jeannette , Buzzard Katherine , Skibina Olga , van der Walt Anneke , Butzkueven Helmut , Turkoglu Recai , Altintas Ayse , Maimone Davide , Kermode Allan , Shalaby Nevin , Pesch Vincent V , Butler Ernest , Sidhom Youssef , Gouider Riadh , Mrabet Saloua , Gerlach Oliver , Soysal Aysun , Barnett Michael , Kuhle Jens , Hughes Stella , Sa Maria J , Hodgkinson Suzanne , Oreja-Guevara Celia , Ampapa Radek , Petersen Thor , Ramo-Tello Cristina , Spitaleri Daniele , McCombe Pamela , Taylor Bruce , Prevost Julie , Foschi Matteo , Slee Mark , McGuigan Chris , Laureys Guy , Hijfte Liesbeth V , de Gans Koen , Solaro Claudio , Oh Jiwon , Macdonell Richard , Aguera-Morales Eduardo , Singhal Bhim , Gray Orla , Garber Justin , Wijmeersch Bart V , Simu Mihaela , Castillo-Triviño Tamara , Sanchez-Menoyo Jose L , Khurana Dheeraj , Al-Asmi Abdullah , Al-Harbi Talal , Deri Norma , Fragoso Yara , Lalive Patrice H , Sinnige L G F , Shaw Cameron , Shuey Neil , Csepany Tunde , Sempere Angel P , Moore Fraser , Decoo Danny , Willekens Barbara , Gobbi Claudio , Massey Jennifer , Hardy Todd , Parratt John , Kalincik Tomas 
Published: June 2023

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.