In latitudes lower than 40°, the underlying environmental determinants of MS severity reached saturation and a ceiling effect was observed, with no further systematic shift in the disease severity.
An MSBase registry study of over 75 centers across 26 countries identified a significant nonlinear association between multiple sclerosis (MS) severity, measured by MS Severity Score (MSSS), and latitude. Accrual of disability was faster among those with lower levels of ultraviolet B radiation (UVB) exposure at the ages of 6 and 18 years, as well as with lifetime UVB exposure at the time of the disability assessment.1
All told, latitudes above 40° were associated with more severe disease (ß = 0.08; 95% CI, 0.04-0.12). For example, in these higher latitudes, the magnitude of the association corresponded to a clinically significant difference of 1.3 points of the MSSS between Madrid (40°) and Copenhagen (56°). No such association was observed in latitudes less than 40° (ß = –0.02; 95% CI, –0.06 to 0.03).
Senior author Tomas Kalincik, MD, PhD, head of the Clinical Outcomes Research Unit, University of Melbourne, and colleagues aimed to investigate the association between latitude of residence, UVB exposure, and the severity of MS. The observational study included 46,128 patients who met the 2005 or 2010 McDonald diagnostic criteria for MS and had data on date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and at least 1 Expanded Disability Status Scale (EDSS) score recorded.
The latitude of each study center was derived from www.latitudelongitude.org and satellite-derived UVB data were obtained from NASA’s Total Ozone Mapping Spectrometer. Kalincik and colleagues calculated cumulative UVB dose at the age of 6 and 18 years for each person, after excluding patients whose age at symptom onset was less than 6 or 18 years, respectively.
The cohort consisted of residents located between latitudes 19°35’ and 56°16’, contributing 453,208 total visits with a cumulative follow-up of 351,196 person-years. On multivariable mixed effects model, there was a significant nonlinear relationship between latitude and MSSS, independent from the adjustment variables. Among the covariates, older age at onset, male sex, and progressive MS phenotype were associated with greater MSSS. The model confirmed that the higher prevalence of MS in the country of residence is related to less severe disease (ß = –0.003; 95% CI, –0.005 to 0.001), but this association was of marginal clinical importance (0.03 points of MSSS per 10/100,000 prevalence change).
An analysis of 44,931 eligible patients identified a linear decrease of disease severity with increasing levels of annualized cumulative UVB dose (ß = –1.0; 95% CI, –1.1 to –0.9), which was independent from the association of MSSS with latitude and tended to plateau above the annualized UVB dose of 4 kJ/m2 (corresponding to the mean latitude of 35.38°, median latitude of 37.50°). Notably, the severity of the disease would decrease by 1.0 MSSS point if the annual UVB exposure increased by 1kJ/m2. An association in the same direction but with a smaller magnitude was observed for annualized cumulative UVB exposure at the age of 6 years (ß = –0.5; 95% CI, –0.6 to –0.4) and 18 years (ß = –0.6; 95% CI, –0.7 to –0.4).
"The association of latitude with disease severity observed in our study was partly independent from the estimated UVB exposure. This suggests that factors other than UVB dose could also underpin the latitudinal gradient of MS severity,” Kalincik et al wrote. "Most notably, UVB exposure is modified by behavioral factors, which are in turn determined by a patients’ disability, comorbidities and cultural factors. EBV is another potential candidate determinant. EBV seroprevalence is substantially greater in higher latitudes in both patients with MS and healthy controls."
A subgroup of 31,214 patients who had models adjusted for available data on ethnicity continued to confirm the associations of MSSS with latitude and UVB exposure at the 3 studies time points. In all models, African and Hispanic ethnicity was associated with more severe disease when compared with Caucasian.
To distinguish whether latitude of residence had a different impact on MS severity than latitude of birthplace, investigators conducted an additional analysis. Among nonmigrants (n = 19,929) who had no substantial difference between the latitude of their birthplace and place of residence, the results were consistent between the models that included both factors. On the other hand, while the latitude of residence and the latitude of birth showed similar trends among those who migrated by at least 5° latitude from their birthplace, the models did not find statistical evidence for these associations.