Vitamin D and multiple sclerosis hospital admissions in Scotland. Is serum vitamin D levels associated with disability in patients with newly diagnosed multiple sclerosis? Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial Vitamin D as an early predictor of multiple sclerosis activity and progression. Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis Vitamin D intake and incidence of multiple sclerosis Vitamin D levels in Hispanics with multiple sclerosis What is needed to keep persons with multiple sclerosis vitamin D-sufficient throughout the year? Cytokine profile in patients with multiple sclerosis following vitamin D supplementation Therapeutic Effect of Vitamin D3 in Multiple Sclerosis Patients Vitamin D as a protective factor in multiple sclerosis Vitamin D-mediated immune regulation in Multiple Sclerosis Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis Safety and T Cell Modulating Effects of High Dose Vitamin D3 Supplementation in Multiple Sclerosis Effects of Adjunct Low-Dose Vitamin D on Relapsing-Remitting Multiple Sclerosis Progression: Preliminary Findings of a Randomized Placebo-Controlled Trial
It is now acknowledged that seasonality is a main feature of the complex neurological disorder multiple sclerosis ( MS ) . Having a spring birthday and being exposed to low levels of sunshine significantly increase the risk of MS later in life.1,2 Although global environment is dominated by seasonality , the observation that vitamin D status is inversely associated with risk of MS later in life and that vitamin D regulates the expression of a large number of MS associated genes , strongly indicate that ultra-violet ( UV ) light exposure and consequent effects on vitamin D production are involved in MS etiology.3,4 Intriguingly this essential hormone appears to also play an important role in influencing MS disease course . Studies have shown an inverse association between 25-hydroxyvitamin D ( 25-OH-D ) levels and clinical MS severity and relapse rate.5 Furthermore , in a recent prospect i ve investigation of a large cohort of MS patients , vitamin D status inversely correlated with relapses over the subsequent 6 months.6 Similar Background Although the precise etiology of multiple sclerosis ( MS ) is unknown , it seems that both genetic and environmental factors are important . Recent studies suggest that low serum vitamin D levels are important environmental factor in MS . The aim of this study was to compare the serum levels of vitamin D between MS patients and healthy subjects , and to determine its association with disability  in MS patients . Methods In this cross-sectional study , a total of 52 patients with MS were r and omly recruited and matched for age and sex with 52 healthy subjects .  Demographic characteristics and serum vitamin D levels for both groups , as well as duration of disease Exp and ed Disability Status Scale ( EDSS ) for MS patients were evaluated . Statistical analysis was performed by independent sample s t-test and multiple linear regression analysis . Results The mean serum vitamin D levels were 26.5 ± 16.3 ng/ml in MS patients vs. 37.1 ±19.7 in healthy subjects ( P = 0.003 ) . A linear regression analysis showed no significant association between vitamin D levels and EDSS score of patients with MS ( P = 0.345 ) , after adjusting for the covariates . Conclusion Our findings did not suggest a protective association for serum vitamin D levels against disability in MS patients Background : High vitamin D levels may reduce the risk of relapses and disease progression in multiple sclerosis . Methods : This 96-week r and omised controlled trial was design ed to assess the effect of vitamin D3 supplementation on bone mineral density in persons with multiple sclerosis . Supplementation with 20,000 IU vitamin D3 weekly raised median serum 25-hydroxy vitamin D ( 25[OH]D ) to 121 nmol/L. The modified intention to treat analysis included 35 persons in the vitamin D3 group and 33 in the placebo group . Participants were age 21 to 50 years and fully ambulatory ( median Exp and ed Disability Status Scale ( EDSS ) 2.5 ) . We studied the effect of supplementing vitamin D3 on the exploratory outcomes annualised relapse rate ( ARR ) , EDSS , multiple sclerosis functional composite ( MSFC ) components , grip strength , and fatigue . Results : After 96 weeks , there was no significant difference between groups in ARR ( absolute difference 0.10 , 95 % CI -0.07 to 0.27 ; p = 0.25 ) , EDSS ( absolute difference -0.01 , 95 % CI -0.35 to 0.35 ; p = 0.97 ) , MSFC components , grip strength , or fatigue . Conclusion : Supplementation with 20,000 IU vitamin D3 weekly did not result in beneficial effects on the measured multiple sclerosis-related outcomes . This study was not powered to address clinical outcomes , but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis 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 ( clinical ly isolated syndrome ) . DESIGN , SETTING , AND PARTICIPANTS The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a r and omized trial originally design ed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinical ly 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 r and omized 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 clinical ly 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 ( Exp and ed 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 ( Exp and ed 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 Objective : There is increasing evidence that vitamin D can be protective against the development of multiple sclerosis ( MS ) , but it may also be beneficial for the clinical course of the disease . Our objective was to prospect ively investigate if 25-hydroxy-vitamin D ( 25-OH-D ) levels are associated with exacerbation risk in MS in a study with frequent serum measurements . Methods : This was a prospect i ve longitudinal study in 73 patients with relapsing-remitting MS .  Blood sample s for 25-OH-D measurements were taken every 8 weeks . Associations between 25-OH-D levels and exacerbation rates were assessed using Poisson regression ( generalized estimating equations ) with the individual serum levels as time-dependent variable . Results : During follow-up ( mean 1.7 years ) , 58 patients experienced a total of 139 exacerbations . Monthly moving averages of 25-OH-D levels were categorized into low ( < 50 nmol/L ) , medium ( 50–100 nmol/L ) , and high ( > 100 nmol/L ) levels . Exacerbation risk decreased significantly with higher serum vitamin D levels : respective relative exacerbation rates for the medium and high-level category as compared to the low-level category were 0.7 and 0.5 ( p value for trend : p = 0.007 ) . The association between 25-OH-D concentrations and exacerbation rate was log linear without a threshold . With each doubling of the serum 25-OH-D concentration the exacerbation rate decreased by 27 % ( 95 % confidence interval 8%–42 % , p = 0.008 ) . Conclusions : Our finding that higher vitamin D levels are associated with decreased exacerbation risk in relapsing-remitting MS suggests a beneficial effect of vitamin D on disease course in MS . However , the possibility of reverse causality can not be ruled out completely . R and omized intervention studies are therefore needed to investigate the effect of vitamin D supplementation in MS Objective : Low vitamin D status has been associated with multiple sclerosis ( MS ) prevalence and risk , but the therapeutic potential of vitamin D in established MS has not been explored . Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical , immunologic , and clinical outcomes in patients with MS prospect ively . Methods : An open-label r and omized prospect i ve controlled 52-week trial matched patients with MS for demographic and disease characteristics , with r and omization to treatment or control groups . Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [ 25(OH)D ] rapidly and assess tolerability , followed by 10,000 IU/day ( 12 weeks ) , and further downtitrated to 0 IU/day . Calcium ( 1,200 mg/day ) was given throughout the trial . Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups . Secondary endpoints included 25(OH)D and other biochemical measures , immunologic biomarkers , relapse events , and Exp and ed Disability Status Scale ( EDSS ) score . Results : Forty-nine patients ( 25 treatment , 24 control ) were enrolled [ mean age 40.5 years , EDSS 1.34 , and 25(OH)D 78 nmol/L ] . All calcium-related measures within and between groups were normal . Despite a mean peak 25(OH)D of 413nmol/L , no significant adverse events occurred . Although there may have been confounding variables in clinical outcomes , treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls . Conclusions : High-dose vitamin D ( ∼10,000 IU/day ) in multiple sclerosis is safe , with evidence of immunomodulatory effects . Classification of evidence : This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation . The trial , however , lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures ( relapses and Exp and ed Disability Status Scale scores ) , providing only Class level IV evidence for these outcomes Background : A protective effect of vitamin D on risk of multiple sclerosis ( MS ) has been proposed , but no prospect i ve studies have addressed this hypothesis . Methods : Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women : the Nurses ’ Health Study ( NHS ; 92,253 women followed from 1980 to 2000 ) and Nurses ’ Health Study II ( NHS II ; 95,310 women followed from 1991 to 2001 ) .  Diet was assessed at baseline and up date d every 4 years thereafter . During the follow-up , 173 cases of MS with onset of symptoms after baseline were confirmed . Results : The pooled age-adjusted relative risk ( RR ) comparing women in the highest quintile of  total vitamin D intake at baseline with those in the lowest was 0.67 ( 95 % CI = 0.40 to 1.12 ; p for trend = 0.03 ) . Intake of vitamin D from supplements was also inversely associated with risk of MS ; the RR comparing women with intake of ≥400 IU/day with women with no supplemental vitamin D intake was 0.59 ( 95 % CI = 0.38 to 0.91 ; p for trend = 0.006 ) . No association was found between vitamin D from food and MS incidence . Conclusion : These results support a protective effect of vitamin D intake on risk of developing MS Vitamin D has been associated with multiple sclerosis ( MS ) and several markers of disease state in whites . There are limited reports of vitamin D ’s influence in MS in ethnic groups , such as in Hispanics . In this study , we compared vitamin D levels in  Hispanics and whites with MS and tried to determine whether season or increasing disability influence hypovitaminosis D in Hispanics with MS .  Serum 25-hydroxyvitamin D [ 25(OH)D ] levels and clinical characteristics were compared in a cross-sectional sample of Hispanics ( n = 80 ) and whites ( n = 80 ) with MS recruited from the University of Southern California . Serum 25(OH)D levels were significantly lower in Hispanics than whites with MS ( mean and st and ard deviation 25.1 ± 9.4 and 37.3 ± 19.8 ng/ml , respectively ; p < 0.001 ) . Hispanics were significantly more likely than whites to be  vitamin D insufficient ( ≤30 ng/ml ; 70 vs. 41 % , respectively ; p < 0.001 ) and deficient ( ≤20 ng/ml ; 40 vs. 14 % , respectively , p < 0.001 ) . In Hispanics , serum 25(OH)D levels were not influenced by season ( p = 0.8 ) or higher physical disability ( EDSS ≥6 , p = 0.7 ) . We found that the relationship between vitamin D and MS differs by Hispanic ethnicity . Hypovitaminosis D was significantly more common among Hispanics than among whites with MS , and the majority of Hispanics were vitamin D insufficient . Interestingly , there was no association between vitamin D levels and season or increasing disability in the Hispanics . Our findings imply that factors influencing vitamin D levels and possibly vitamin D  requirements may vary by ethnicity in patients with MS . These results should be confirmed in larger , prospect i ve multi-ethnic cohort studies Vitamin D sufficiency has been associated with lower risk of multiple sclerosis and may also have a favorable effect on the course of the disease . The aim of this work was to identify predictors of serum 25-hydroxy vitamin D ( 25[OH]D ) levels in persons with multiple sclerosis ( MS ) and to assess the effect of high-dose vitamin D3 supplementation on vitamin D status . A 96-week r and omized controlled trial was performed to assess the effect of supplementation with 20,000 IU of vitamin D3 weekly on bone mineral density in 68 patients . We collected  data on vitamin D intake and UV-exposure  and repeatedly measured serum 25(OH)D levels . Half of the participants had sufficient winter vitamin D levels at baseline ( ≥50 nmol/l ) . Vitamin D status was predicted by sun exposure during the last 3 months and by ingested vitamin D from diet and supplements . In the placebo group , the proportion of the participants with sufficient levels increased from 55 % in winter to 92 % during the summer . In the intervention group , all participants had winter 25(OH)D levels above 50 nmol/l at the end of the study . MS patients who have no sun exposure and low dietary vitamin D intake during the winter months should be recommended to take vitamin D supplements to achieve serum 25(OH)D levels of at least 50 nmol/l Multiple sclerosis ( MS ) patients were r and omized , in a double blind design , and placed into either a vitamin D supplemented group or a placebo control group . As expected , serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation ( 17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months ) . Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later . Placebo treatment had no effect on serum TGF-beta 1 levels . Tumor necrosis factor (TNF)-alpha , interferon (IFN)-gamma , and interleukin (IL)-13 were not different following vitamin D supplementation . IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance . Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1 Multiple sclerosis ( MS ) is an inflammatory disease in which the myelin sheaths around the axons of the central nervous system are damaged . The damage leads to demyelination and scarring as well as a broad spectrum of signs and symptoms . The epidemiological data suggest a possible influence of vitamin D as an immunomodulatory agent on multiple sclerosis susceptibility as well as on clinical course of the disease . We investigated the effects of short-term vitamin D3 therapy on Iranian patients with MS . In a prospect i ve r and omized controlled trial study , 62 MS patients received 300,000 IU/month vitamin D3 or placebo as intramuscular injection for 6 months . Our results showed no significant difference between the treatment and the control groups in the exp and ed disability status scale scores and number of gadolinium-enhancing lesions during the 6-month treatment period . After 6 months , the levels of cell proliferation in the vitamin D treatment group were significantly lower than the control group . Also , the levels of transforming growth factor-beta and interleukin-10 in the vitamin D treatment group were significantly higher than the control group . This result suggests that vitamin D therapy may help prevent the development of MS and could be a useful addition to the therapy ABSTRACT Objective : To examine the association between 25-hydroxyvitamin D ( 25[OH]D ) levels and the risk of multiple sclerosis ( MS ) in blood sample s collected prospect ively and during gestation . Methods : In this nested case-control study , 2 population -based biobanks with 291,500 sample s from 164,000 persons collected since 1975 in the northern half of Sweden were used . We identified  prospect ively collected blood sample s from MS cases ( n = 192 , controls matched 2:1 ) and gestational sample s from pregnant mothers where the offspring had later developed MS ( n = 37 , control mothers matched 5:1 ) .  25(OH)D levels were measured using an ELISA , and the risk of MS was analyzed using matched logistic regression . Results : Levels of 25(OH)D ≥75 ( vs < 75 ) nmol/L in prospect ively collected blood sample s were associated with a decreased risk of MS ( odds ratio [ OR ] 0.39 , 95 % confidence interval [ CI ] 0.16–0.98 ) . No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 ( vs < 75 ) nmol/L ( OR 1.8 , 95 % CI 0.53–5.8 ) . The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976–2005 ( p trend = 0.005 ) . Conclusion : This study supports the presence of an association between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS . In the very limited material with sample s drawn in early pregnancy , where month-of-birth effects were controlled for , we found no association between gestational 25(OH)D levels and MS risk in the offspring . Decreasing 25(OH)D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiologic studies Although Vitamin D is best known as a modulator of calcium homeostasis , it also has immune modulating potential . A protective effect of Vitamin D on Multiple Sclerosis ( MS ) is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements . Moreover , high circulating levels of Vitamin D have been associated with lower risk of MS . To gain more insight into putative regulatory mechanisms of Vitamin D in MS pathogenesis , we studied 132 Hispanic patients with clinical ly definite MS , 58 with relapsing remitting MS ( RR MS ) during remission , 34 RR MS patients during relapse , and 40 primary progressive MS cases ( PP MS ) . Sixty healthy individuals matched with respect to place of residence , race/ethnicity , age and gender served as controls  . Levels of 25(OH ) Vitamin D and 1,25(OH)(2 ) Vitamin D  , measured by ELISA were significantly lower in RR MS patients than in controls . In addition , levels in patients suffering relapses were lower than during remissions . By contrast , PP MS patients showed similar values to controls . Proliferation of both freshly isolated CD4 + T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2 ) Vitamin D. Moreover , activated Vitamin D enhanced the development of IL-10 producing cells , and reduced the number of IL-6 and IL-17 secreting cells . Notably , VDR expression was induced by 1,25(OH)(2 ) Vitamin D in both activated and resting cells . Interestingly , T cells were able to metabolize 25(OH ) Vitamin D into biologically active 1,25(OH)(2 ) Vitamin D , since T cells express 1α-hydroxylase constitutively . Finally , 1,25(OH)(2 ) Vitamin D also increased the expression and biological activity of IDO , triggering significant increase in the number of CD4+CD25 + T regulatory cells . Collectively , these findings suggest that 1,25(OH)(2 ) VitaminD plays an important role in T cell homeostasis during the course of MS , suggesting correction of its deficiency may be useful during treatment of the disease Background Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults . Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D , mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse . We here present the protocol of an interventional clinical phase II study to test the hypothesis , that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects . Methods / Design The EVIDIMS trial is a German multi-center , stratified , r and omized , controlled and double-blind clinical phase II pilot study . Eighty patients with the diagnosis of definite multiple sclerosis or clinical ly isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be r and omized to additionally receive either high-dose ( average daily dose 10.200 IU ) or low-dose ( average daily dose 200 IU ) cholecalciferol for a total period of 18 months . The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla . Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration , clinical parameters for disease activity , as well as cognition , fatigue , depression , and quality of life . Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters . Discussion In light of the discrepancy between existing epidemiological and pre clinical data on the one h and and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients . The study design presented here fulfills the criteria of a high- quality clinical phase II trial in MS.Trial Registration Clinical Trials.gov Identifier : Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b ( IFNB ) in patients with multiple sclerosis ( MS ) . Methods 1 year , double blind , placebo controlled , r and omised study in 66 MS patients . The primary outcomes were T2 burden of disease ( BOD ) on MRI scans , proportion of patients with serum levels of 25-hydroxyvitamin D ( 25(OH)D ) ≥85 nmol/l or intact parathyroid hormone ( PTH ) ≤20 ng/l , and number of adverse events . Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions , annual relapse rate , changes in the Exp and ed Disability Status Scale score , timed 25 foot walk test and timed 10 foot t and em walk tests . Results Median change in BOD was 287 mm3 in the placebo group and 83 mm3 in the vitamin D group ( p=0.105 ) . Serum levels of 25(OH)D increased from a mean of 54 ( range 19–82 ) nmol/l to 110 ( range 67–163 ) nmol/l in the vitamin D group . 84 % of patients reached a serum 25(OH)D level > 85 nmol/l in the vitamin D group and 3 % in the placebo group ( p<0.0001 ) . Patients in the vitamin D group showed fewer new T2 lesions ( p=0.286 ) and a significantly lower number of T1 enhancing lesions ( p=0.004 ) , as well as a tendency to reduced disability accumulation ( p=0.071 ) and to improved timed t and em walk ( p=0.076 ) . There were no significant differences in adverse events or in the annual relapse rate . Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS . Trial registration number EudraCT number 2007 - 001958 - 99 and Clinical TrialsGov number NCT01339676 Background A poor vitamin D status has been associated with a high disease activity of multiple sclerosis ( MS ) . Recently , we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS ( RRMS ) patients . In the present study , we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures . Methodology /Principal Findings Fifteen RRMS patients were supplemented with 20 000 IU/d vitamin D3 for 12 weeks . Vitamin D and calcium metabolism were carefully monitored , and T cell characteristics were studied by flowcytometry . All patients finished the protocol without side-effects , hypercalcaemia , or hypercalciuria . The median vitamin D status increased from 50 nmol/L ( 31–175 ) at week 0 to 380 nmol/L ( 151–535 ) at week 12 ( P<0.001 ) . During the study , 1 patient experienced an exacerbation of MS and was censored from the T cell analysis . The proportions of ( naïve and memory ) CD4 + Tregs remained unaffected . Although Treg suppressive function improved in several subjects , this effect was not significant in the total cohort ( P = 0.143 ) . An increased proportion of IL-10 + CD4 + T cells was found after supplementation ( P = 0.021 ) . Additionally , a decrease of the ratio between IFN-γ+ and IL-4 + CD4 + T cells was observed ( P = 0.035 ) . Conclusion / Significance Twelve week supplementation of high  dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism . The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator , and may be used as outcome measure for upcoming r and omized placebo-controlled trials . Trial Registration Clinical trials.gov The aim of this preliminary study was to evaluate the effect of low-dose oral vitamin D in combination with current disease-modifying therapy on the prevention of progression of relapsing-remitting multiple sclerosis ( RRMS ) . A phase II double-blind placebo-controlled r and omized clinical trial conducted between October 2007 and October 2008 included 50 patients with confirmed RRMS aged 25 to 57 years and normal serum 25-hydroxyvitamin D. They were r and omly allocated to receive 12 months of treatment with either escalating calcitriol doses up to 0.5 μg/day or placebo combined with disease-modifying therapy . Response to treatment was assessed at eight-week intervals . In both groups , the mean relapse rate decreased significantly ( P < 0.001 ) . In the 25 patients treated with placebo , the mean ( SD ) Exp and ed Disability Status Scale ( EDSS ) increased from 1.70 ( 1.21 ) at baseline to 1.94 ( 1.41 ) at the end of study period ( P < 0.01 ) . Average EDSS and relapse rate at the end of trial did not differ between groups . Adding low-dose vitamin D to routine disease-modifying therapy had no significant effect on the EDSS score or relapse rate . A larger phase III multicenter study of vitamin D in RRMS is warranted to more assess the efficacy of this intervention
To sum up , low vitamin D  levels are associated with an increased risk of MS
To estimate the associations between vitamin D status and multiple sclerosis ( MS ) .