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Original Investigation |

Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression

Alberto Ascherio, MD, DrPH1; Kassandra L. Munger, ScD1; Rick White, MSc2; Karl Köchert, PhD3; Kelly Claire Simon, ScD1; Chris H. Polman, MD4; Mark S. Freedman, MD5; Hans-Peter Hartung, MD6; David H. Miller, MD7; Xavier Montalbán, MD8; Gilles Edan, MD9; Frederik Barkhof, MD4; Dirk Pleimes, MD10; Ernst-Wilhelm Radü, MD11; Rupert Sandbrink, MD3,6; Ludwig Kappos, MD11; Christoph Pohl, MD3,12
[+] Author Affiliations
1Harvard School of Public Health, Boston, Massachusetts
2University of British Columbia, Vancouver, Canada
3Bayer HealthCare, Berlin, Germany
4VU University Medical Center, Amsterdam, the Netherlands
5Ottawa Hospital Research Institute, Ottawa, Canada
6Heinrich-Heine Universität, Düsseldorf, Germany
7University College London Institute of Neurology, London, England
8Hospital Universitari Vall d’Hebron, Barcelona, Spain
9CHU-Hôpital Pontchaillou, Rennes, France
10Bayer HealthCare Pharmaceuticals, Montville, New Jersey
11University Hospital Basel, Basel, Switzerland
12Department of Neurology, University Hospital of Bonn, Bonn, Germany
JAMA Neurol. 2014;71(3):306-314. doi:10.1001/jamaneurol.2013.5993.
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Importance  It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes.

Objectives  To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome).

Design, Setting, and Participants  The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging.

Main Outcomes and Measures  New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score).

Results  Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P < .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, −0.17; P = .004) during the subsequent 4 years.

Conclusions and Relevance  Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.

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Figure 1.
Multiple Sclerosis Outcomes According to Dichotomous Serum 25-Hydroxyvitamin D Levels

Analyses are based on patients with month 6 and month 12 measurements of 25-hydroxyvitamin D. Group comparisons are adjusted for age, sex, treatment, time of follow-up, and T2 lesion score at baseline. The graphs show the probability of conversion to clinically definite multiple sclerosis (CDMS) after 12 months (A); the cumulative number of new active lesions on brain magnetic resonance imaging (B); the percentage change in T2 lesion volume from year 1 to year 5 on brain magnetic resonance imaging (C); and percentage change in brain volume from year 1 to year 5 (D). The error bars indicate the standard error of the mean (SEM).

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Figure 2.
Magnetic Resonance Imaging Evidence of Multiple Sclerosis Activity and Progression

A, Rate ratio of new active lesions on brain magnetic resonance imaging up to year 5. B, Change of T2 lesion volume on brain magnetic resonance imaging from year 1 to year 5 by quintiles of serum 25-hydroxyvitamin D (25[OH]D). C, Annualized change in Expanded Disability Status Scale (EDSS) score from 6 months to year 5 by quintiles of serum 25(OH)D. Analyses as in Figure 1. The error bars indicate 95% CIs, with the lowest quintile used as reference.aP = .02.bP = .008.cP = .001.dP = .004.eP = .03.

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