title: Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Safety and T Cell Modulating Effects of High Dose Vitamin D3 Supplementation in Multiple Sclerosis Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. Vitamin D, pregnancy, breastfeeding, and postpartum multiple sclerosis relapses. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis The Hawthorne Effect: a randomised, controlled trial Vitamin D and multiple sclerosis hospital admissions in Scotland. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis Effects of Adjunct Low-Dose Vitamin D on Relapsing-Remitting Multiple Sclerosis Progression: Preliminary Findings of a Randomized Placebo-Controlled Trial Vitamin D levels in Hispanics with multiple sclerosis Vitamin D-mediated immune regulation in Multiple Sclerosis Cytokine profile in patients with multiple sclerosis following vitamin D supplementation The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. Survey of 71 "negative" trials. [Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis]. Vitamin D intake and incidence of 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 Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis.
abstract: A group of young patients having multiple sclerosis was treated with dietary supplements containing calcium , magnesium and vitamin D for a period of one to two years . The experimental design employed self-pairing : the response of each patient was compared with his/her own case history as control . The number of exacerbations observed during the program was less than one half the number expected from case histories . No side effects were apparent . The dietary regimen may offer a new means of controlling the exacerbation rate in MS , at least for younger patients . The results tend to support a theory of MS which states that calcium and magnesium are important in the development , structure and stability of myelin 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 Objective : To determine whether interferon-β ( IFN-β ) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk . Methods : In a prospect i ve cohort of 178 persons with clinical ly definite multiple sclerosis ( MS ) living in southern Tasmania in 2002–2005 ,  serum 25-hydroxyvitamin D [ 25(OH)D ] was measured biannually , with assessment by question naire for relevant factors , including IFN-β treatment . Results : Subjects reporting IFN-β use had significantly higher mean 25(OH)D than persons who did not ( p < 0.001 ) . This was mediated by an interaction between personal sun exposure and IFN-β , with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy . The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-β therapy ( p = 0.82 ) . 25(OH)D was associated with a reduced relapse risk only among persons on IFN-β ( p < 0.001 ) . Importantly , IFN-β was only protective against relapse among persons with higher 25(OH)D ( hazard ratio [ HR ] 0.58 [ 95 % confidence interval ( CI ) 0.35–0.98 ] ) , while among 25(OH)D-insufficient persons , IFN-β  increased relapse risk ( HR 2.01 [ 95 % CI 1.22–3.32 ] ) . Conclusion : In this study , we found that IFN-β therapy is associated with greater production of vitamin D from sun exposure , suggesting part of the therapeutic effects of IFN-β on relapse in MS may be through modulation of vitamin D metabolism . These findings suggest persons being treated with IFN-β should have vitamin D status monitored and maintained in the sufficiency range . Classification of evidence : This study provided Class III evidence that IFN-β is associated with reduced risk of relapse , and this effect may be modified by a positive effect of IFN-β on serum 25(OH)D levels 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 : CONTEXT Epidemiological and experimental evidence suggests that high levels of vitamin D , a potent immunomodulator , may decrease the risk of  multiple sclerosis .  There are no prospect i ve studies addressing this hypothesis . OBJECTIVE To examine whether levels of 25-hydroxyvitamin D  are associated with risk of multiple sclerosis . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study among more than 7 million US military personnel who have serum sample s stored in the Department of Defense Serum Repository . Multiple sclerosis cases were identified through Army and Navy physical disability data bases for 1992 through 2004 , and diagnoses were confirmed by medical record review . Each case ( n = 257 ) was matched to 2 controls by age , sex , race/ethnicity , and date s of blood collection . Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum sample s collected before the date of initial multiple sclerosis symptoms . MAIN OUTCOME MEASURES Odds ratios of multiple sclerosis associated with continuous or categorical levels ( quantiles or a priori-defined categories ) of serum 25-hydroxyvitamin D within each racial/ethnic group . RESULTS Among whites ( 148 cases , 296 controls ) , the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D ( odds ratio [ OR ] for a 50-nmol/L increase in 25-hydroxyvitamin D , 0.59 ; 95 % confidence interval , 0.36 - 0.97 ) . In categorical analyses using the lowest quintile ( < 63.3 nmol/L ) as the reference , the ORs for each subsequent quintile were 0.57 , 0.57 , 0.74 , and 0.38 ( P = .02 for trend across quintiles ) . Only the OR for the highest quintile , corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L , was significantly different from 1.00 ( OR , 0.38 ; 95 % confidence interval , 0.19 - 0.75 ; P = .006 ) . The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years . Among blacks and Hispanics ( 109 cases , 218 controls ) , who had lower 25-hydroxyvitamin D levels than whites , no significant associations between vitamin D and multiple sclerosis risk were found . CONCLUSION The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis OBJECTIVE To determine whether low levels of 25-hydroxyvitamin D ( 25[OH]D ) contribute to the increased risk of postpartum multiple sclerosis ( MS ) relapses . DESIGN Prospect i ve cohort study . SETTING Out patients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics . PATIENTS Twenty-eight pregnant women with MS . INTERVENTIONS We prospect ively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews .  Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2 , 4 , and 6 months after giving birth . The data were analyzed using longitudinal multivariable methods . MAIN OUTCOME MEASURES Levels of 25(OH)D and relapse rate . RESULTS Fourteen ( 50 % ) women breastfed exclusively , and 12 women ( 43 % ) relapsed within 6 months after giving birth . During pregnancy , the average 25(OH)D levels were 25.4 ng/mL ( range , 13.7 - 42.6 ) and were affected only by season ( P=.009 ) . In contrast , in the postpartum period , 25(OH)D levels were significantly affected by breastfeeding and relapse status . Levels of 25(OH)D remained low in the exclusive breastfeeding group , yet rose significantly in the nonexclusive breastfeeding group regardless of season ( P=.007 , unadjusted ; P=.02 , adjusted for season ) . By 4 and 6 months after childbirth , 25(OH)D levels were , on average , 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group ( P=.001 ) . CONCLUSIONS Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels  in women with MS . However , these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses . These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Vitamin D is important for bone health and immune regulation , and has been shown to be low in multiple sclerosis ( MS ) . We sought to determine the effect of over the counter low dose cholecalciferol ( LDC ) and high dose ergocalciferol ( HDE ) on the vitamin D levels in MS patients . Methods We retrospectively evaluated serum 25-hydroxy-vitamin D [ 25(OH)D ] levels of 199 patients ( CIS , n = 32 ; RRMS , n = 115 ; PPMS , n = 10 ; SPMS , n = 16 ; Transverse Myelitis ( TM ) , n = 9 ; other neurological diseases , n = 16 ) attending our clinic between 2004 and 2008 . We examined the change in  25(OH)D levels in 40 MS patients who took either LDC ( ≤800 IU/day ) or HDE ( 50,000 IU/day for 7 - 10 days , followed by 50,000 IU weekly or biweekly ) . Results The average 25(OH)D level was 71 ± 39 nmol/L ( Mean ± SD ) , and 167(84 % ) patients had insufficient levels ( ≤100 nmol/L ) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels . However , 25(OH)D levels increased by 42 nmol/L ( P = 0.01 ) in the patients originally taking LDC and then prescribed HDE . Optimal levels ( ≥100 nmol/L ) were only achieved in less than 40 % of patients . Conclusions We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC . Prospect i ve studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety , immunological response , and ultimately the clinical efficacy of vitamin D replacement therapy 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 Background The ' Hawthorne Effect ' may be an important factor affecting the generalisability of clinical research to routine practice , but has been little studied . Hawthorne Effects have been reported in previous clinical trials in dementia but to our knowledge , no attempt has been made to quantify them . Our aim was to compare minimal follow-up to intensive follow-up in participants in a placebo controlled trial of Ginkgo biloba for treating mild-moderate dementia . Methods Participants in a dementia trial were r and omised to intensive follow-up ( with comprehensive assessment visits at baseline and two , four and six months post r and omisation ) or minimal follow-up ( with an abbreviated assessment at baseline and a full assessment at six months ) . Our primary outcomes were cognitive functioning ( ADAS-Cog ) and participant and carer-rated quality of life ( QOL-AD ) . Results We recruited 176 participants , mainly through general practice s. The main analysis was based on Intention to treat ( ITT ) , with available data . In the ANCOVA model with baseline score as a co-variate , follow-up group had a significant effect on outcome at six months on the ADAS-Cog score ( n = 140 ; mean difference = -2.018 ; 95%CI -3.914 , -0.121 ; p = 0.037 favouring the intensive follow-up group ) , and on participant-rated quality of life score ( n = 142 ; mean difference = -1.382 ; 95%CI -2.642 , -0.122 ; p = 0.032 favouring minimal follow-up group ) . There was no significant difference on carer quality of life . Conclusion We found that more intensive follow-up of individuals in a placebo-controlled clinical trial of Ginkgo biloba for treating mild-moderate dementia result ed in a better outcome than minimal follow-up , as measured by their cognitive functioning . Trial registration Current controlled trials : IS RCT 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 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 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 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 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 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 Seventy-one " negative " r and omized control trials were re-examined to determine if the investigators had studied large enough sample s to give a high probability ( greater than 0.90 ) of detecting a 25 per cent and 50 per cent therapeutic improvement in the response . Sixty-seven of the trials had a greater than 10 per cent risk of missing a true 25 per cent therapeutic improvement , and with the same risk , 50 of the trials could have missed a 50 per cent improvement . Estimates of 90 per cent confidence intervals for the true improvement in each trial showed that in 57 of these " negative " trials , a potential 25 per cent improvement was possible , and 34 of the trials showed a potential 50 per cent improvement . Many of the therapies labeled as " no different from control " in trials using inadequate sample s have not received a fair test . Concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials Multiple sclerosis ( MS ) is a consequence of genetic and environmental factors . Geographic , genetic , and biological evidence suggests that an important immunopathogenic factor might be the insufficiency of vitamin D. The aim of our study was to investigate the immunomodulatory effect of alfacalcidol , a vitamin D analogue , on cytokine levels in RRMS patients in relapse . We investigated 15 patients suffering from RRMS relapse ( an RRMS group ) and two control groups : one control group of healthy subjects ( n=10 ) and a NIND group , consisting of patients with non-inflammatory neurological diseases ( n=10 ) . All of the MS patients were treated with 5 microgr/day of oral alfacalcidol for a period of five days . The serum cytokine levels of TNF-alpha , IL-10 , IL-4 , and IL-12 were measured in all the MS patients one day prior to and one day after therapy , and in all the control subjects ( ELISA , Quantikine human immunoassay , R&D Systems , UK ) . Our results showed significantly lower IL-4 and IL-12 levels in the RRMS patients group compared to the N group and the NIND group ( p<0.001 Mann-Whitney U-test ) . No significant differences in TNF-alpha and IL-10 levels were found between the groups , and there was no influence of alfacalcidol on these cytokines in RRMS patients . High doses of oral alfacalcidol induced significant increases in IL-4 and IL-12 levels in RRMS patients ( p<0.001 , Wilcoxon rank signed test ) . Therefore , there were no differences in IL-4 and IL-12 levels compared to the N group and the NIND group . Alfacalcidol therapy in RRMS patients did not provoke any side effects .  Vitamin D and its analogues , such as alfacalcidol , act as immunomodulatory agents , with potential therapeutic effects for patients with multiple sclerosis 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 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 CONTEXT The active metabolite of vitamin D , 1,25-dihydroxyvitamin D [ 1,25(OH)(2)D ] , is a potent modulator of immune cells in vitro . OBJECTIVE Our objective was to determine whether the sun-dependent nutrient , cholecalciferol , can alter disease-associated cellular immune abnormalities in patients with multiple sclerosis ( MS ) . DESIGN This was an open-label , 12-month , r and omized controlled trial . SETTING Patients with MS were recruited from the MS Clinic at St. Michael 's Hospital , Toronto . PATIENTS Forty-nine patients were matched ( for age , sex , disease duration , disease-modifying drug , and disability ) and enrolled ( treated n = 25 ; control n = 24 ) . Four patients were lost to follow-up ( n = 2 from each group ) . INTERVENTION Treated patients received increasing doses of cholecalciferol ( 4,000 - 40,000 IU/d ) plus calcium ( 1200 mg/d ) , followed by equilibration to a moderate , physiological intake ( 10,000 IU/d ) . Control patients did not receive supplements . MAIN OUTCOME MEASURES At enrollment and at 12 months , peripheral blood mononuclear cell ( P BMC ) proliferative responses to disease-associated , MS-relevant , and control antigens were measured , along with selected serum biochemical markers . RESULTS At 12 months , mean serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations were 83 ± 35 nmol/liter and 179 ± 76 nmol/liter in control and treated participants , respectively ( paired t , P < 0.001 ) . Serum 1,25(OH)(2)D did not differ between baseline and 1 yr . In treated patients , 12-month P BMC proliferative responses to neuron antigens myelin basic protein and exon-2 were suppressed ( P = 0.002 ) . In controls , there were no significant changes in disease-associated P BMC responsiveness . There were no significant differences between groups in levels of selected biomarkers . INTERPRETATION MS-associated , abnormal T cell reactivities were suppressed in vivo by cholecalciferol at serum 25(OH)D concentrations higher than 100 nmol/liter
target: RESULTS / DISCUSSION Both cross-sectional and longitudinal studies have fairly consistently demonstrated a strong positive correlation between  vitamin D deficiency and subsequent relapse and /or disability in patients with MS .
  As well , there appears to be a negative correlation between vitamin D levels and inflammatory markers in MS patients , suggesting that vitamin D modifies serum cytokines to a more anti-inflammatory profile .
  However , the criteria of temporality , dose-response , and experimental evidence are yet to be adequately met , although there is preliminary evidence from longitudinal studies and r and omized clinical trials ( RCTs ) of supplementation that vitamin D can attenuate the autoimmune response in patients , and potentially reduce relapse rates and burden of disease .
  Ultimately , the current evidence does not permit inference of a causal relationship between vitamin D deficiency and disease activity in MS .
background: INTRODUCTION Given that vitamin D has a role in immunomodulation , and its levels appear to correlate with the development of Multiple Sclerosis ( MS ) , it is conceivable that vitamin D may also influence disease activity in MS patients .
  In this regard , we conducted a systematic review investigating the evidence for : ( 1 ) the role of vitamin D in disease activity in MS , and ( 2 ) the therapeutic supplementation of vitamin D in MS .