Severity of (MS) varies widely among individuals. Understanding of determinants of this heterogeneity will help clinicians optimize the management of MS in individual patients.

This observational study used the global MSBase registry. Disease severity was quantified with MS Severity Score (MSSS, a decile of disability relative to a normative cohort with similar disease duration). The latitude of each study center (stratified by hemisphere) and cumulative annualized UVB dose at study center (calculated from from NASA's Total Ozone Mapping Spectrometer) at ages 6 and 18 and the year of disability assessment were calculated. Quadratic regression was used to model the associations between latitude, UVB and MSSS.

46,128 patients (70% women, mean age 39±12, resident between latitudes 19°35´ and 56°16´, cumulative follow-up 351,196 patient-years) were included. Latitude showed a non-linear association with MS severity. Above 40° of latitude, more severe disease was associated with higher latitudes (β= 0.08, 95%CI: 0.04, 0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β=-0.02, 95%CI: -0.06, 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 (β= - 0.5, 95%CI: -0.6, -0.4) and 18 years (β= - 0.6, 95%CI: -0.7, -0.4) as well as with lower life-time UVB exposure at the time of disability assessment (β=-1.0, 95%CI: -1.1, -0.9).

In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure. Thus, UVB exposure contributes to both MS susceptibility and severity.