Vitamin D and multiple sclerosis: a critical review and recommendations on treatment

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1 Acta Neurol Belg (2012) 112: DOI /s z REVIEW ARTICLE Vitamin D and multiple sclerosis: a critical review and recommendations on treatment Alireza Faridar Ghazaleh Eskandari Mohammad Ali Sahraian Alireza Minagar Amirreza Azimi Received: 18 May 2012 / Accepted: 19 June 2012 / Published online: 6 July 2012 Ó Belgian Neurological Society 2012 Abstract Multiple sclerosis (MS) is an immune-mediated and degenerative disease of nervous system, which affects mostly young adults. Vitamin D deficiency is a well-known environmental risk factor for MS and is considerable in terms of immediate clinical implications. In addition to its classical action on regulation of bone homeostasis, vitamin D may have a potent impact on cytokine profiles and neuro-inflammation. Given the immunomodulatory effects of vitamin D and its high rate of deficiency in MS patients, prescribing vitamin D is a remarkable issue in MS. The results from several experimental and clinical studies indicate that vitamin D supplementation may ameliorate the inflammation during the relapse phase and attenuate disease progression. We present the experimental and clinical studies, which assessed the effects of vitamin D on the pathophysiology, prevalence and management of MS. The authors also discuss current recommendations on prescription of this vitamin to MS patients. A. Faridar, G. Eskandari contributed equally to this work. A. Faridar Department of Neurology, University of California, San Francisco, USA G. Eskandari A. Azimi (&) Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan Abad Square, Tehran, Iran a-azimi@sina.tums.ac.ir M. A. Sahraian SinaMS Research Center, Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran A. Minagar Department of Neurology, LSU Health Sciences Center, Shreveport, LA 71130, USA Keywords Vitamin D Multiple sclerosis Demyelinating Prevention Introduction Multiple sclerosis (MS) is a progressive neuroinflammatory demyelinating disease of central nervous system (CNS), which affects more than two million individuals around the globe worldwide. It is hypothesized that MS mainly affects brain and spinal cord due to activation of basic myelin protein (MBP)-sensitized Th1-proinflamamtory T cells [1, 2]. Although the exact etiology of MS is not well recognized, both genetic and environmental factors have been implicated in developing MS [3, 4]. Clustering of multiple sclerosis within families and risk reduction with increasing genetic distance might be explained by strong genetic component [3]. The human leukocyte antigen (HLA) class II locus is known as a prominent candidate gene [4]. The associations between HLA-DRB1, DQA1 and DQB1alleles and increased risk of MS have been proven to be significant [5, 6]. Outside the MHC, multitude of genes coding for cytokine pathway, signal transduction as well as vitamin D metabolism has been implicated in increased risk of developing MS [7]. In addition, a number of environmental factors are potentially involved in pathogenesis of MS, including vitamin D deficiency, history of infection with Epstein-Barr virus (EBV) and smoking [3, 8]. Presently, vitamin D deficiency is increasingly considered in terms of immediate clinical implications [8]. Vitamin D, as a modulator of calcium and phosphate homeostasis, plays a major role in bone formation and maintenance [9]. In addition to its classic physiologic functions, anti-inflammatory, immunomodulatory and antiproliferative effects of vitamin D have recently become the

2 328 Acta Neurol Belg (2012) 112: focus of intense research [10]. In immune cells, vitamin D plays the role of a potent regulator of gene expression and modifier of various cytokines production [9]. Recent findings suggest that vitamin D modulates the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS [11 13]. However, it should be noted that EAE simulates only certain features of MS and most treatments, which are effective in EAE, are not necessarily safe or effective in MS patients [4]. In this article, the experimental and clinical studies that investigate the effects of vitamin D on the pathophysiology, prevalence, and management of MS are presented and discussed. In addition, current recommendations on administration of this vitamin in MS patients are presented. Vitamin D metabolism and its role in the pathophysiology of MS Previtamin D is synthesized by body through photochemical pathway or it can be provided with certain foods [14]. To convert to the activated form, previtamin D primarily hydroxylates to 25-hydroxycholecalciferol [25(OH)D] by 25-hydroxylase in the liver [15]. 25(OH)D has a long biological half-life and can also be produced from hydroxylation of either vitamin D2 or vitamin D3 [16]. Serum level of 25(OH)D could therefore be an appropriate indicator for evaluating vitamin D level in body [16 20]. In the next activation level, 25(OH)D is transported to the kidneys where it is converted in to 1,25-hydroxycholecalciferol [1,25(OH)2D] by 1-a-hydroxylase [15, 16]. In addition to its much shorter half-life of 4 6 h [21], 1,25(OH)2D has a serum level of 1,000 times lower than that of 25(OH)D. Therefore, 1,25(OH)2D assay is not recommended for the purpose of evaluating total body vitamin D status [22].This activated form of vitamin D binds to the vitamin D receptor (VDR), a member of the nuclear receptor family of transcription factors and modulates expression of nearly one thousand genes [23]. Through this mechanism, vitamin D modulates calcium homeostasis and cytokine profiles. In vitro studies demonstrated that vitamin D inhibits Th1 cell activation [24, 25] and prevents the production of inflammatory cytokines such as IFN-c, IL2 and IL12 [25 27]. Moreover, vitamin D supplementation could alleviate MS symptoms by protecting myelin through activation of oligodendrocytes [28 31]. Recently, the effect of 12-week high-dose vitamin D supplementation on the peripheral B and T cells was evaluated in 15 MS patients. Although, the investigators found no significant shift in B cell differentiation and isotype switching, CD4? T cells have been skewed toward anti-inflammatory state [32, 33]. In the same context, 6 months of vitamin D supplementation in MS patients led to an increase in serum transforming growth factor (TGF)-b1 (an anti-inflammatory cytokine) values and a decline in IL-2 mrna (a proinflammatory cytokine) levels [34]. These findings further add to the notion that vitamin D is a physiological immune modulator in vivo [33]. Role of vitamin D on MS prevalence One of the remarkable features of MS is the significant increase in prevalence as one approaches the poles [35 37] except few discordant findings in Argentine and Canada [38 40]. In addition, strong inverse association between history of sun exposure and subsequent MS development has been reported in the same geographic region [41]. Corroborating these results, a study in Norway demonstrated that increased outdoor summer activities in early life are associated with a decreased risk of MS, even north of the Arctic Circle [42]. Based on the strong correlation between latitude, sun exposure and intrinsic vitamin D production, it can be proposed that Vitamin D might have a substantial effect on MS incidence [30]. However, UV radiation also has some distinct local and systemic immunomodulatory effects; it alters the number of antigen presenting cells in the skin, suppresses cell-mediated immunity systemically and modifies the delayed type of hypersensitivity [43 45]. In a geospatial analysis, Beretich et al. [44] showed strong inverse or negative correlation between MS distribution and UV radiation in North America. However, the main explanation of the role of UV radiation in the development of MS is through an effect of UV on intrinsic vitamin D 2 synthesis [43 45]. In direct evaluation of intrinsic vitamin D levels, it is reported that vitamin D levels even during gestational period have a significant negative impact in developing MS later in the life [1, 46, 47]. In a large prospective case control study in US military personnel, serum 25-hydroxyvitamin D was evaluated in stored serum samples obtained before the start of MS symptoms. The findings demonstrated that in Caucasians, every 50 nmol/l increase in serum 25(OH)D leads to a 41 % decrease in MS risk. The inverse association between the risk of MS and serum vitamin D level was particularly strong for samples taken before the age of 20. Nevertheless, this association between vitamin D and the risk of MS was not found to be significant among other ethnic groups including Hispanics and blacks [1]. It is proposed that insignificant association between serum vitamin D level and the risk of MS in Hispanic and black people might be related to the fact that dark-skinned individuals generally have lower levels of serum vitamin D; a fact which makes it difficult to assess the significance of serum metabolite levels differences

3 Acta Neurol Belg (2012) 112: among different groups in dark-skinned individuals [21]. In addition to intrinsic vitamin D levels, a large prospective cohort also evaluated the role of vitamin D supplementation on MS incidence in women [48]. The outcomes demonstrated that subjects who took supplemental vitamin D had a 40 % lower risk of developing MS than those who did not. In the same population, the association between the risk of MS and oral dietary intake of vitamin D only during adolescence was also evaluated. It was reported that taking more than 400 IU/day of vitamin D supplementation during adolescence led to only a non-significant 27 % reduction in the risk of MS. It is hypothesized that vitamin D consumption throughout an entire lifetime might be more effective in declining the incidence of MS rather than a limited time period [49]. Furthermore, the vitamin D supplementation efficacy is also influenced by the vitamin D metabolism gene polymorphisms in different population. Simon et al. found that intake of C400 IU/d of vitamin D supplementation leads to an 80 % reduction in MS risk only in individuals with specific variant of vitamin D receptor (VDR) [50]. Role of vitamin D in relapse rate and disease progression In 1970, Wuthrich and Rieder [51] reported higher relapse rates in MS patients in Switzerland during winter and early spring. In accord with this outcome, a significant correlation between low levels of prior erythemal ultraviolet radiation and subsequent higher risk of relapses, with peak in winter, was reported in a longitudinal cohort study [52]. Imaging study also reported a compatibility between the curve of seasonal variations in serum 25(OH)D and annual gadolinium-increasing lesion numbers in MS patients [53]. So, it seems that seasonal fluctuation in intrinsic vitamin D levels plays the major role in the cyclic relapse rate oscillation. In the experimental study, vitamin D administration halted EAE progression and maintained disease severity at lower levels [54] by modulating the cytokine profile and also sensitizing the inflammatory cells to apoptotic signals [55]. Thus, theoretically, vitamin D might be an appropriate candidate to alleviate the MS progression. In the clinic, lower serum 25(OH)D levels have been detected during relapse phases in MS patients [24, 50, 56, 57]. However, these studies only demonstrated an association between low serum vitamin D levels and relapse rate, not any causality. Mowry et al. evaluated the impact of vitamin D levels on subsequent relapse rates in pediatric-onset MS. Interestingly, the results showed that each 10 ng/ml increase in the 25(OH)D 3 level during a relapse-free interval is associated with a 34 % reduction in the rate of subsequent relapse [58]. These findings suggest that interventions that lead to increased serum vitamin D reserves might have the potential to reduce the relapse rate in MS. Few clinical trials evaluated the effect of vitamin D supplementation on clinical and radiological aspects of MS patients (Table 1). Goldberg et al. designed a study on 10 MS patients who were treated for 1 2 years with dietary supplements containing calcium, magnesium and vitamin D, without a control group. The number of exacerbations observed during the program was less than one-half the numbers expected based on case histories [59]. A lower rate of relapses was also reported in 15 patients with relapsing remitting MS (RRMS) who received oral calcitriol for 48 weeks [60]. In this pilot study, Expanded Disability Status Scale (EDSS) was also measured to evaluate the disease severity and progression. The mean enrollment EDSS of patients was 1.9, and after 48 weeks of vitamin D supplementation, there was no change in EDSS score. Interestingly, 12 months after discontinuation of calcitriol, the mean EDSS score increased to 3.1. However, it should be considered that this study did not have a control group to compare the outcomes [60]. An open-label 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. After 1 year of high-dose vitamin D 3 (4,000 40,000 IU/day) treatment, a non-significant reduction in the number of relapses was observed in the treated patients (n = 25) in comparison to untreated ones (n = 24). In addition, some trends favoring the high-dose vitamin D3 treatment group were observed in EDSS measures. Since the aim of this study was to evaluate the safety of high-dose vitamin D 3 on MS patients, the trial was not powered or blinded to properly evaluate the clinical outcomes [61]. In 2012, two doubled-blind randomized controlled trails reported the clinical outcomes of 20,000 IU per week cholecalciferol supplementation in MS patients. Kampman et al. [62], in evaluating the Norwegian patients, did not find any significant difference in proportion of relapse-free subjects as well as change in EDSS between the vitamin D3-treated arm and the placebo arm. However, in evaluating the effect of 12-month vitamin D supplementation as an add-on therapy to interferon beta on 66 Finnish MS patients. Individuals in cholecalciferol treated domain showed a significantly lower mean EDSS score and decreased number of T1 gadolinium-enhancing lesions in MRI [63]. The only difference between the methods of these two studies was that all the subjects in Finish study simultaneously received interferon beta. Previously, it has been shown that vitamin D has a synergistic effect to interferon beta, which leads to clear additional immunomodulatory effects [64]. However, it seems that larger multi-center trials with longer follow-up time are necessary to properly address the clinical efficacy of vitamin D supplementation in MS patients.

4 330 Acta Neurol Belg (2012) 112: Table 1 Published studies on the role of supplementary vitamin D on MS Authors Years Case Intervention Duration Outcome 1. Goldberg [59] Vitamin D 5,000 IU/d 1 year Beneficial effect of the supplements on the number of exacerbations 2. Mahon [34] mg calcium plus 6 months Increased TGF-B in case group 1,000 IU/day vitamin D 3. Wingerchuk [60] Oral Calcitriol 2.5 ug/d 48 weeks Lower relapse rate No change in the median of EDSS score 4. Kimball [74] Vitamin D 700 7,000 ug/week plus 1,200 mg Ca/D 28 weeks Decreased gadolinium-enhancing lesions Disease activity were not affected 5. Burton [61] Vitamin D3 4,000 40,000 IU/day 1 year A non-significant reduction in the number of relapses 6. Smolder [33] ,000 IU/d vitamin D3 12 weeks Skewing towards an anti-inflammatory cytokine profile 7. Knippenberg [32] ,000 IU/d vitamin D3 12 weeks Supplementation of high-dose vitamin D[3] does not have substantial effects on phenotypic markers of B cell differentiation in circulating B cells 8. Mosayebi [75] ,000 IU/month vitamin D3 6 months TGF-beta and IL-10 levels in the vitamin D treatment group were significantly higher than the control group. No significant difference in expanded disability status scale scores and number of gadolinium-enhancing lesions 9. Soilu-Hänninen [63] ,000 IU/week Cholecalciferol 1 year Tendency to reduced disability accumulation and significant decrease in T1 enhancing lesion in MRI 10. Kampman [62] ,000 IU/week Cholecalciferol 96 weeks There was no significant difference between case and control group in annualized relapse rate as well as EDSS Vitamin D supplementation in MS Given that vitamin D has an impressive effect on cytokine profiles and neuro-inflammation in MS, supplementary vitamin D might be an appropriate candidate to ameliorate the inflammatory elements in the neuronal damage implicated in MS development [61]. In addition, a relatively high rate of vitamin D deficiency has been reported in MS, reaching 70 % in severely ill patients [65, 66]. It seems that prescribing vitamin D supplementation option can no longer be ignored in MS. In general, the recommended dose of daily supplementary vitamin D in patients with a deficiency in vitamin D is between 200 and 600 IU [67]. However, it appears that the immunoprotective capacity of vitamin D supplementation is not apparent with the above-mentioned dosage [68 71]. Concurrent with this notion, Hiremath et al. did not observe satisfactory immunomodulatory effects with low-dose vitamin D supplementation up to 800 IU/day in MS patients. Thus, a higher dose of vitamin D supplementation is required for optimal immune impact than the maintenance dose for bone health [66]. However, there is a major concern about subsequent side effects in administration of supra-physiologic doses of vitamin D. In clinical trials, it has been shown that receiving vitamin D up to 40,000 IU/d does not lead to any considerable adverse events [61]; only consumption of more than 400,000 IU/day of vitamin D increased the likelihood of severe hypercalcemia [72]. Pierrot-Deseilligny et al. [30] recommended that administration of 2,000 or 3,000 IU/day of vitamin D in MS patients not only impacts the immune system effectively but also leaves a considerable safety margin. However, we opine that, primarily, serum vitamin D level should be assessed in MS patients. If vitamin D deficiency is present, based on the existing guideline [22], the patient should be treated with 50,000 IU of vitamin D3 once a week for 8 weeks, followed by maintenance therapy of 2,000 3,000 IU/d. Nevertheless, if serum levels of 25(OH)D are above 30 ng/ml (75 nmol/ liter), only vitamin D maintenance therapy (2,000 3,000 IU/d) should be initiated. There are several controversies about the preferred form of supplementary vitamin D administration in MS. Because of the presence of vitamin D3 receptor on the surface of immune cells, cholecalciferol [25(OH)D 3 ] or calcitriol [1,25(OH) 2 D 3 ] is more favored than ergocalciferol (vitamin D 2 )[66]. However, several instances of hypercalcemia, kidney stones and atherosclerosis have been reported following calcitriol trials [59 61, 66]. Therefore, to have a

5 Acta Neurol Belg (2012) 112: Table 2 Current clinical trials, evaluating the effect of supplementary vitamin D on MS Current clinical trial Phase Intervention Enrollment 1. Safety and immunologic effect of low-dose versus high-dose vitamin D3 in relapsing remitting multiple sclerosis 2. Safety trial of high-dose oral vitamin D3 with calcium in multiple sclerosis 3. Vitamin D3 Supplementation and the T Cell compartment in multiple sclerosis (MS) 4. The effects of interferon beta combined with vitamin D on relapsing remitting multiple sclerosis patients 5. Vitamin D pilot study in patients with multiple sclerosis 6. A multicentre study of the efficacy and safety of supplementary treatment with cholecalciferol in patients with relapsing multiple sclerosis treated with subcutaneous interferon beta-1a 44 lg 3 times weekly 7. Supplementation of VigantOL Ò oil versus placebo as add-on in patients with relapsing remitting multiple sclerosis receiving Rebif Ò treatment Phase I Phase I, Phase II Cholecalciferol 10,000 IU vs. 1,000 IU Vitamin D3 4,000 40,000 IU vs. up to 4,000 IU Vitamin D3 500 mg/d 15 Phase IV Vitamin D3 800 IU/d? 75,000 IU/3 weeks vs. 800 IU/d? placebo Phase I 19 nor vitamin D Phase II Cholecalciferol 100,000 twice/monthly vs. placebo Phase II Cholecalciferol? interferone beta-1 vs. Placebo plus interferone beta-1 vs. interferone beta-1 alone Data adapted from: direct effect on immune cells as well as to minimize adverse biochemical and clinical events, administration of cholecalciferol [25(OH)D 3 ] would be advisable for MS patients [30, 61, 72]. Recently, new vitamin D analogues have also been presented, which mainly regulate the immune system with marginal effect on calcium metabolism. However, their benefits and side effects are required to be addressed in randomized clinical trials [72, 73]. There are some on-going clinical trials to evaluate the effect of low and/or high dose of different vitamin D analogues on the pathophysiology and clinical outcomes of the MS (Table 2). The outcomes of these good allocation concealment trials can more clarify the role, appropriate dosage and optimum duration of the vitamin D supplementation in MS. In addition to known MS patients, there is an option of supplementary vitamin D administration in high-risk patients who have not diagnosed with MS yet [60]. Pierrot- Deseilligny et al. [68] reported that in the early stages of MS like clinically isolated syndrome there is an inverse correlation between 25(OH)D and future relapse occurrence. To date, no primary prevention trial has been taken to evaluate whether optimizing vitamin D status will reduce the risk of MS [23]. However, until evidence-based data on the protective role of vitamin D supplementation will be published, we suggest assessing the serum vitamin D level in high-risk population such as the first degree relatives of MS patients and also patients with clinically isolated syndrome and managing the likely insufficiency with the recommended supplementary vitamin D dosage. Conclusions Based on experimental and clinical reports, supplementary vitamin D might be an appropriate candidate as add-on therapy to ameliorate the inflammation and attenuate neuronal damage in MS. However, it is necessary to develop a multi-center, large randomized, placebo-controlled, double-blinded clinical trial to evaluate the preventive and therapeutic role of vitamin D in MS and also to determine the ideal form, definitive dosage and the duration of vitamin D supplementation therapy. While awaiting the results of future studies, we suggest the cautious administration of supplementary vitamin D to MS patients to improve the clinical features. Acknowledgments The authors would like to express their gratitude to Professor Abdolmohamad Rostami for constructive comments. We are also so grateful to Ms. Katherine Regan for kindly editing the manuscript. Conflict of interest References None. 1. Munger K, Levin L, Hollis B, Howard N, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23): Giovannoni G (1997) The immunopathogenesis of multiple sclerosis. Baillière s Clin Neurol 6(3): Ascherio A, Munger K (eds) (2008) Epidemiology of multiple sclerosis: from risk factors to prevention. Thieme-Stratton Inc., New York

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