Vitamin D and multiple sclerosis hospital admissions in Scotland. Vitamin D-mediated immune regulation in Multiple Sclerosis Therapeutic Effect of Vitamin D3 in Multiple Sclerosis Patients Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis Vitamin D levels in Hispanics with multiple sclerosis A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial Retinyl Palmitate Supplementation Modulates T-bet and Interferon Gamma Gene Expression in Multiple Sclerosis Patients Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Effect of dietary advice and n‐3 supplementation in newly diagnosed MS patients Vitamin D intake and incidence of multiple sclerosis What is needed to keep persons with multiple sclerosis vitamin D-sufficient throughout the year? Safety and T Cell Modulating Effects of High Dose Vitamin D3 Supplementation in Multiple Sclerosis Is serum vitamin D levels associated with disability in patients with newly diagnosed multiple sclerosis? Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis [Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis]. The Effect of Vitamin A Supplementation on Biochemical Parameters in Multiple Sclerosis Patients Preventive effect of vitamin D3 supplementation on conversion of optic neuritis to clinically definite multiple sclerosis: a double blind, randomized, placebo-controlled pilot clinical trial Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A Double-Blind Placebo-Controlled Clinical Trial. Vitamin D as an early predictor of multiple sclerosis activity and progression.
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 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 ) 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 Objective ( s ) : Multiple Sclerosis ( MS ) is known as a progressive inflammatory CNS disease . Cytokines belong to Th1 or Th2 family and inflammatory cells , play significant role in pathophysiology of MS . Thus , any treatment supposed to influence the relation between Th1 to Th2 cytokines expression . Although vitamin D has been prescribed as a therapeutic supplement of MS for a long time , it is not clear how much it may affect the Th1/Th2 ratio . To answer this question the present research was design ed . Material s and Methods : Thirty C57BL/6 adult female mice were used . The animals were r and omly divided into trial and control groups . Experimental Autoimmune Encephalomyelitis ( EAE ) modeling for MS and clinical scoring as cited by others was used . Based on scoring and step of the disease vitamin D3 prescription ( 5 mg/kg ) started and continued for three weeks . Results : By using ELISA and RT-PCR the brain level of TNF-α , IL-10 , IL-4 and IL-12 determined . Significant decrease of clinical symptoms in trial group which received vitamin D was seen comparing to control animals ( P<0.05 ) . The level of TNF-α but not IL-10 significantly decreased  following vitamin D3 administration . By comparing the level of Th1 and Th2 Interleukins and counting the ratio of them we found that in treated animals the ratio was significantly less than non-treated ( P=0.01 ) . Conclusion : According to the results , vitamin D3 may be able to suppress the inflammatory ways that lead to progression of MS . Whether this ability is clinical ly valuable in human subjects is not clear and needs more clinical research 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 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 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 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 : Vitamin A derivatives such as retinoic acid may improve the impaired balance of CD4 + T cells in autoimmune and inflammatory diseases . This study is a double-blind r and omized trial to evaluate the effect of vitamin A ( as form of retinyl palmitate ) supplementation on multiple sclerosis ( MS ) patients . Thirty-nine patients were enrolled and r and omly assigned to two groups . Both groups were followed for 6 months . The experimental group received 25,000 IU of retinyl palmitate daily , while the control group received a placebo . Before and after the study , the expression of interferon gamma ( IFN-γ ) and T-bet genes was evaluated in peripheral blood mononuclear cells of patients by RT-PCR . The results showed that after 6 months of supplementation , expression of IFN-γ and T-bet was significantly decreased . These data suggest that retinyl palmitate supplementation can modulate the impaired balance of Th1 and Th2 cells and vitamin A products that may be involved in the therapeutic mechanism of vitamin A in MS patients . This study provides information regarding the decreased gene expression of IFN-γ and T-bet in MS by retinyl palmitate supplementation In a r and omized , placebo-controlled double-blind trial a combination of lofepramine , phenylalanine and vitamin B(12 ) was found to be effective in relieving the symptoms of multiple sclerosis ( MS ) .  The effect occurred within 2 - 4 weeks , and improved all types of symptoms in all types of MS . The combination was also effective in relieving symptoms in patients with chronic pain and chronic fatigue .  We hypothesize that the action of this combined therapy may relate to activation of the noradrenergic locus coeruleus/lateral tegmentum ( LC/LT ) system which has the potential to influence the functioning of large areas of the brain and spinal cord Objective – To investigate whether supplementation with fish oil given together with dietary advice and vitamin supplementation influenced the clinical outcome in newly diagnosed multiple sclerosis ( MS ) patients . Material and methods – Sixteen consecutive , newly diagnosed patients with multiple sclerosis were recruited to an open intervention study . They were given dietary advice and supplemented with 0.9 g/day of long‐chain marine fatty acids and vitamins . The patients were followed for 2 years with respect to dietary habits , blood parameters and neurological assessment including exacerbation rate . Results – There was a significant reduction in the mean annual exacerbation rate and the mean Exp and ed Disability Status Scale ( EDSS ) as compared to pre‐ study values . The plasma total phospholipid n‐3 fatty acids increased and n‐6 fatty acids decreased significantly . Conclusions – The results suggest that fish oil supplementation given together with vitamins and dietary advice can improve clinical outcome in patients with newly diagnosed MS 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 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 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 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 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 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 Vitamin A has different functions in the body and after being converted to acid form ; it can play many roles in immune system regulation . Therefore , this vitamin can be used as a supplement in the treatment of diseases , such as cancer and autoimmune diseases . Vitamin A is a fat-soluble compound and its long-term consumption in high doses can have some adverse effects . Objective The current study aim ed to investigate the possible complications and find solutions to minimize the adverse effects . Patients and Methods This study was a double blind r and omized clinical trial . In the main study , vitamin A ( as retinyl palmitate ) was given to 35 multiple sclerosis ( MS ) patients in order to regulate their immune system with a dose of 25000 IU/day for a period of six months . To investigate the possible biochemical complications , lipid profiles , fasting blood sugar ( FBS ) , liver enzymes , and C-reactive protein ( CRP ) were tested . Results Vitamin A did not have a significant difference in lipid profiles , FBS and liver enzymes between the two groups receiving vitamin A and the placebo , but CRP increased in patients who were taking vitamin A , 1.65±0.43 ( mg/L ) and 2.88±0.67 , ( Mean±SEM ) , before and after the intervention respectively ( P=0.029 ) , and statistical analysis showed significant differences with the group receiving placebo ( P=0.011 ) and CRP level  in vitamin A group was 1.3 mg/L more than those of the placebo group after intervention ( P=0.011 ) . Conclusions Considering that no significant difference was found in the proven vitamin A side effects , due to the increase in CRP , frequent clinical and biochemical controls are required along with vitamin A supplementation Multiple sclerosis ( MS ) presents with optic neuritis ( ON ) in 20 % of cases and 50 % of ON patients develop MS within 15 years . In this study , we evaluated the preventive effects of vitamin D3 administration on the conversion of ON to MS ( primary outcome ) and on the MRI lesions ( secondary outcome ) of ON patients with low serum 25 ( OH ) D levels . Thirty ON patients ( 15 in each of 2 groups , aged 20–40 years ) with serum 25 ( OH ) D levels of less than 30 ng/ml were enrolled in a double blind , r and omized , parallel-group trial . The treatment group ( cases ) received 50,000 IU of vitamin D3 weekly for 12 months and the control group ( controls ) received a placebo weekly for 12 months . Finally , the subsequent relapse rate and changes in MRI plaques were compared between the two groups . Risk reduction was 68.4 % for the primary outcome in the treatment group ( relative risk = 0.316 , p = 0.007 ) . After 12 months , patients in the treatment group had a significantly lower incidence rate of cortical , juxtacortical , corpus callosal , new T2 , new gadolinium-enhancing lesions and black holes . The mean number of total plaques showed a marginally significant decrease in the group receiving vitamin D3 supplementation as compared with the placebo group ( p = 0.092 ) . Administration of vitamin D3 supplements to ON patients with low serum vitamin 25 ( OH ) D levels may delay the onset of a second clinical attack and the subsequent conversion to MS Decreasing the population and activation of inflammatory T helper cells in multiple sclerosis ( MS ) patients using vitamin A derivatives ( retinoic acids ) has been well documented . The present study determined the effect of vitamin A supplementation on psychiatric signs in MS patients . The subjects were 101 relapsing-remitting MS patients enrolled in a placebo-controlled r and omized clinical trial . The treatment group was administered 25000 IU/d retinyl palmitate ( RP ) for 6 months followed by 10000 IU/d RP for another 6 months . The results for baseline characteristics , modified fatigue impact scale and Beck Depression Inventory-II were recorded at the beginning and end of the one-year study . The non-normal distribution data was compared between groups using a nonparametric test and normal distribution data was analyzed using a parametric test . ( Clinical Trials.gov Identifiers : NCT01417273 ) . The results showed significant improvement in the treatment group for fatigue ( p=0.004 ) and depression ( p=0.01 ) . Vitamin A supplementation helped during interferon therapy in the treatment process and improved psychiatric outcomes for anti-inflammatory mechanisms 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
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 .
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 .