Vitamin D and Multiple Sclerosis: A Comprehensive Review

Abstract

Numerous observational studies have suggested that there is a correlation between the level of serum vitamin D and MS risk and disease activity. To explore this hypothesis, a literature search of large, prospective, observation studies, epidemiological studies, and studies using new approaches such as Mendelian randomization was conducted. Available data and ongoing research included in this review suggest that the level of serum vitamin D affects the risk of developing MS and also modifies disease activity in MS patients. Newer Mendelian randomization analyses suggest there is a causal relationship between low vitamin D level and the risk of MS. Post-hoc evaluations from two phase 3 studies, BENEFIT and BEYOND, support the findings of observational trials. Study limitations identified in this review recognize the need for larger controlled clinical trials to establish vitamin D supplementation as the standard of care for MS patients. Though there is increasing evidence indicating that lower vitamin D levels are associated with increased risk of MS and with greater clinical and brain MRI activity in established MS, the impact of vitamin D supplementation on MS activity remains inadequately investigated.

Keywords: Autoimmune disease; Health outcomes; Mendelian randomization; Multiple sclerosis; Optic neuritis; Pregnancy; Relapsing-remitting MS (RRMS); Supplementation; Vitamin D.

Fig. 1

Chemical structures of the physiologically inactive vitamin D2 (a) and vitamin D3 (b); the main circulating vitamin D3 intermediate, 25-hydroxyvitamin D (25[OH]D) (c); and the bioactive vitamin D3 metabolite 1,25-dihydroxyvitamin D (1,25[OH]₂VD) (d), or calcitriol if derived from vitamin D3 [5]

Fig. 2

Sources and metabolism of vitamin D: The main sources of vitamin D are sunlight, diet, and supplementation. The primary forms of vitamin D are biologically inactive and need for their activation two hydroxylation steps in the liver and kidney. The hormonally active final product is 1,25-dihydroxyvitamin D [1,25(OH)₂VDO]. 1,25(OH)₂VD has a half-life of several hours, while the intermediate vitamin D form 25-hydroxyvitamin D [25(OH)D] has a relatively long half-life (20–60 days), and thus more accurately exemplifies the overall vitamin D stores in the body [7]. Reprinted from [7], with permission from Elsevier

Fig. 3

Potential mechanisms of vitamin D immunomodulation: systemic 1,25(OH)2VD3 affects several immune-cell types, including macrophages, dendritic cells (DCs), T and B cells. Macrophages and DCs constantly express vitamin D receptor (VDR), whereas VDR expression in T cells is only upregulated following activation. Reprinted by permission from Macmillan Publishers Ltd: [14]

Fig. 4

Association of vitamin D and relapse risk in MS. The graph shows risk of relapse according to 25(OH)D levels, adjusted for age and month of serum measurement. Size of points is proportional to the inverse of the variance (larger bubbles represent greater precision). Reprinted with permission from Wiley Company [52]

Fig. 5

Magnetic resonance imaging outcomes associated with quintiles of vitamin D in the EPIC study. EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco, USA. Participants (N = 469) had clinical evaluations, brain MRI, and blood draws annually. MRI outcomes were associated with quintiles of vitamin D. In multivariate analyses, each 10 ng/mL (25 nmol/L) higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR],0.85; 95% confidence interval [CI], 0.76–0.95; P = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53–0.87; P + 0.002). Reprinted with permission from Wiley Company [53]

Fig. 6

Multiple sclerosis outcomes according to dichotomous serum 25(OH)D levels. Analyses are based on patients with averaged 6- and 12-month measurements of 25(OH)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 CDMS after 12 months (a); the cumulative number of new active lesions on brain MRI (b); the percentage change in T2 lesion volume from year 1 to year 5 on brain MRI (c); and the percentage change in brain volume from year 1 to year 5 (d). The error bars indicate the standard error of the mean (SEM). Reproduced with permission from [60]. Copyright©2014 American Medical Association. All rights reserved

Fig. 7

Data from the Vitamin D analysis of the BENEFIT trial. Comparison of probability of conversion to CDMS in patients with plasma 25(OH)D < 50 nmol/L versus ≥ 50 nmol/L in all patients and those with early or delayed start of interferon beta-1b. Reproduced with permission from [66]

Fig. 8

The relative rate of cumulative new active lesions (NALs) vs. average of baseline, 6-month, and 12-month 25[OH]D levels 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 EDSS score, and disease duration. 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 ng/mL, divide by 2.496). Reproduced with permission from [61]. Copyright©2015 American Medical Association. All rights reserved

Fig. 9

Change in MRI T2 burden of disease (BOD) from baseline to month 12 in the vitamin D-treated and placebo-treated patients. Data are mean ± standard error of 34 patients in the vitamin D group and 32 patients in the placebo group at baseline and 32 in the vitamin D group and 30 in the placebo group at 12 months. The P value for the difference between vitamin D and placebo is 0.105 (trend). Reproduced from [75], with permission from BMJ Publishing Group Ltd