BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, 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 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

From the CORe Geelong Australia

Neurology. 2022 Jun 14;98(24):997-998. doi: 10.1212/WNL.0000000000200105. PubMed

See more in PubMed

Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017;13(1):25-36. PubMed

Simpson S Jr., 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

Ramagopalan SV, Handel AE, Giovannoni G, Rutherford Siegel S, Ebers GC, Chaplin G. Relationship of UV exposure to prevalence of multiple sclerosis in England. Neurology. 2011;76(16):1410-1414. PubMed PMC

Colotta F, Jansson B, Bonelli F. Modulation of inflammatory and immune responses by vitamin D. J Autoimmun. 2017;85:78-97. PubMed

Becklund BR, Severson KS, Vang SV, DeLuca HF. UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proc Natl Acad Sci USA. 2010;107(14):6418-6423. PubMed PMC

Alla S, Pearson JF, Taylor BV, et al. . An investigation of the relationship between latitude and multiple sclerosis severity in New Zealand. Mult Scler. 2016;22:705-707. PubMed

Jelinek GA, Marck CH, Weiland TJ, Pereira N, van der Meer DM, Hadgkiss EJ. Latitude, sun exposure and vitamin D supplementation: associations with quality of life and disease outcomes in a large international cohort of people with multiple sclerosis. BMC Neurol. 2015;15:132. PubMed PMC

Nakamura Y, Matsushita T, Sato S, et al. . Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study. J Neuroinflamm. 2016;13:239. PubMed PMC

Ostkamp P, Salmen A, Pignolet B, et al. . Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity. Proc Natl Acad Sci USA. 2021;118(1):118. PubMed PMC

Butzkueven H, Chapman J, Cristiano E, et al. . MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler. 2006;12:769-774. PubMed

Kalincik T, Kuhle J, Pucci E, et al. . Data quality evaluation for observational multiple sclerosis registries. Mult Scler. 2017;23(5):647-655. PubMed

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33(11):1444-1452. PubMed

Neurostatus training. Accessed May 1, 2019. neurostatus.net/index.php?file=about&content=2

Roxburgh RH, Seaman SR, Masterman T, et al. . Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005;64(7):1144-1151. PubMed

Zhou Y, Claflin SB, Stankovich J, et al. . Redefining the Multiple Sclerosis Severity Score (MSSS): the effect of sex and onset phenotype. Mult Scler. 2020;26(13):1765-1774. PubMed

Latitude and Longitude. Accessed May 1, 2019. latitudelongitude.org

NASA. Accessed November 10, 2019. iridl.ldeo.columbia.edu/SOURCES/.NASA/.GSFC/.TOMS/

Herman JR. Global increase in UV irradiance during the past 30 years (1979-2008) estimated from satellite data. J Geophys Res Atmospheres 2010:115.

Atlas of MS 2013: Mapping Multiple Sclerosis Around the World. Multiple Sclerosis International Federation; 2013.

MSBase. Accessed April 1, 2019. https://msbase.org/about-us/how-is-data-collected

Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol. 2003;2(2):117-127. PubMed

Sundstrom P, Nystrom M, Ruuth K, Lundgren E. Antibodies to specific EBNA-1 domains and HLA DRB1*1501 interact as risk factors for multiple sclerosis. J Neuroimmunol. 2009;215:102-107. PubMed

Levin LI, Munger KL, O'Reilly EJ, Falk KI, Ascherio A. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010;67(6):824-830. PubMed PMC

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. PubMed PMC

Sandberg L, Biström M, Salzer J, Vågberg M, Svenningsson A, Sundström P. Vitamin D and axonal injury in multiple sclerosis. Mult Scler. 2016;22:1027-1031. PubMed

Jacobs BM, Noyce AJ, Giovannoni G, Dobson R. BMI and low vitamin D are causal factors for multiple sclerosis: a mendelian randomization study. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e662. PubMed PMC

Mokry LE, Ross S, Ahmad OS, et al. . Vitamin D and risk of multiple sclerosis: a mendelian randomization study. PLoS Med. 2015;12(8):e1001866. PubMed PMC

Ostkamp P, Goerlich D, Andlauer T, et al. . Influence of ultraviolet radiation and diminished-function melanocortin 1 receptor variants on multiple sclerosis disease severity in two large multicenter cohort studies. Paper presented at ECTRIMS; September 2019; Stockholm.

Hart PH, Lucas RM, Booth DR, et al. . Narrowband UVB phototherapy for clinically isolated syndrome: a trial to deliver the benefits of vitamin D and other UVB-induced molecules. Front Immunol. 2017;8:3. PubMed PMC

ANZCTR. PrevANZ. Accessed May 1, 2019. Panzctr.org.au/Trial/Registration/TrialReview.aspx?id=363026

Disanto G, Pakpoor J, Morahan JM, et al. . Epstein-Barr virus, latitude and multiple sclerosis. Mult Scler. 2013;19:362-365. PubMed

Wandinger K, Jabs W, Siekhaus A, et al. . Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology. 2000;55(2):178-184. PubMed

Horakova D, Zivadinov R, Weinstock-Guttman B, et al. . Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study. PLoS One. 2013;8(1):e53996. PubMed PMC

Farrell RA, Antony D, Wall GR, et al. . Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009;73(1):32-38. PubMed PMC

Munk Nielsen N, Corn G, Frisch M, et al. . Multiple sclerosis among first- and second-generation immigrants in Denmark: a population-based cohort study. Brain. 2019;142:1587-1597. PubMed

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