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Original Investigation |

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b

Kathryn C. Fitzgerald, ScM1; Kassandra L. Munger, ScD1; Karl Köchert, MD2; Barry G. W. Arnason, MD3; Giancarlo Comi, MD4; Stuart Cook, MD5; Douglas S. Goodin, MD6; Massimo Filippi, MD7; Hans-Peter Hartung, MD, FRCP8; Douglas R. Jeffery, MD, PhD9; Paul O’Connor, MD10; Gustavo Suarez, MD11; Rupert Sandbrink, MD, PhD2,12; Ludwig Kappos, MD13; Christoph Pohl, MD†2,14; Alberto Ascherio, MD, DrPH1,15
[+] Author Affiliations
1Department of Nutrition, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
2Bayer Pharma AG, Berlin, Germany
3Department of Neurology, University of Chicago, Chicago, Illinois
4Department of Neurology, Scientific Institute H. S. Raffaele, Milan, Italy
5Department of Neurology and Neuroscience, Rutgers–New Jersey Medical School, Newark
6Department of Neurology, University of California, San Francisco
7Neuroimaging Research Unit, Scientific Institute and University Vita-Salute, Milan, Italy
8Department of Neurology, University of Dusseldorf, Dusseldorf, Germany
9Department of Neurology, Piedmont Health Care, Mooresville, North Carolina
10Department of Neurology, St Michael’s Hospital, Toronto, Ontario, Canada
11Bayer HealthCare Pharmaceuticals, Whippany, New Jersey
12Bayer Pharma AG, Berlin, Germany
13Department of Neurology, University Hospital Basel, Basel, Switzerland
14Department of Neurology, University Hospital Bonn, Bonn, Germany
15Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
JAMA Neurol. 2015;72(12):1458-1465. doi:10.1001/jamaneurol.2015.2742.
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Importance  Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS.

Objective  To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b.

Design, Setting, and Participants  We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart.

Exposures  Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months.

Main Outcomes and Measures  Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate–enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score.

Results  Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D–binding protein status.

Conclusions and Relevance  Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

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Figure 1.
Relative Rate of Cumulative New Active Lesions (NALs) vs Average of Baseline, 6-Month, and 12-Month 25-Hydroxyvitamin D (25[OH]D) Level Stratified by Geographic Region

The solid lines and shaded regions represent the relative rate ratios of cumulative NALs for changes in 25(OH)D relative to the median level and the corresponding 95% CIs, respectively. Analyses were adjusted for age, sex, randomization status, baseline Expanded Disability Status Scale score, and disease duration (≤1, 2-5, 6-10, and >10 years). Models assume a linear association between the logarithm of the rate of cumulative NALs and serum 25(OH)D. Analyses using cubic splines revealed no significant deviation from linearity. To convert 25(OH)D values to nanograms per milliliter, divide by 2.496.

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Figure 2.
Relative Rate of Cumulative New Active Lesions (NALs) vs Average of Baseline, 6-Month, and 12-Month 25-Hydroxyvitamin D Level Stratified by Baseline Disease Characteristics

From 1482 patients eligible for the analysis, multivariable models excluded patients with missing follow-up information on subsequent magnetic resonance imaging (MRI) (n = 26), patients with missing information for baseline Expanded Disability Status Scale (EDSS) score (n = 2), and patients with missing disease duration (n = 1), leaving 1453 participants in the final models. High disease activity was defined as having at least 2 relapses in the previous 2 years (to study baseline) and at least 1 T1-enhancing lesion on baseline MRI.

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