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REVIEW ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 149-154

The effect of Vitamin D in multiple sclerosis: An updated review


Department of Medicine, Umm AlQura University, College of Medicine, Umm Al-Qura University, Makkah, Kingdom of Saudi Arabia

Date of Submission11-May-2021
Date of Decision11-Oct-2021
Date of Acceptance27-Oct-2021
Date of Web Publication6-Dec-2021

Correspondence Address:
Mawddah Hassan Faqeeh
College of Medicine, Umm Al-Qura University, Makkah 24372
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_70_21

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  Abstract 


Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. The pathophysiology of MS has been correlated with low serum Vitamin D levels as one of the risk factors. However, limited evidence of the specific role of Vitamin D in managing MS cases has been reported. A literature search was performed in October 22, 2019, on PubMed database using search terms: “multiple sclerosis,” “Vitamin D,” “deficiency,” “therapeutic use,” “administration and dosage,” and “adverse effects.” Eligibility criteria: All study designs written in English language, applied on human, in the previous 0 years, related to the research question, a clinical diagnosis of MS and interventions containing Vitamin D supplementation (Vitamin D3 or calcitriol). Fourteen articles matched the criteria and were included in this review article. In this review article, we are discussing the effectiveness of Vitamin D supplementation in MS patients, the ideal dose, the duration of treatment, and to highlight the main adverse effects of the supplements.

Keywords: Dose, duration, multiple sclerosis, side effects, supplement, Vitamin D


How to cite this article:
Alkhotani AM, Faqeeh MH, Aldoobi RS, Sheikh GE, Halabi RH, Alsharif WK. The effect of Vitamin D in multiple sclerosis: An updated review. Saudi J Health Sci 2021;10:149-54

How to cite this URL:
Alkhotani AM, Faqeeh MH, Aldoobi RS, Sheikh GE, Halabi RH, Alsharif WK. The effect of Vitamin D in multiple sclerosis: An updated review. Saudi J Health Sci [serial online] 2021 [cited 2022 May 23];10:149-54. Available from: https://www.saudijhealthsci.org/text.asp?2021/10/3/149/331780




  Introduction Top


Multiple sclerosis (MS) is an immune disorder of the central nervous system (CNS), in which T-cells and other immune effectors demyelinate CNS cells.[1] Most of biological activities of 1,25-dihydroxyvitamin D3 are mediated by Vitamin D receptor. Thus, Vitamin D3 by binding to its receptor inhibits production of interleukins, interferon γ, and tumor necrosis factors α and β. In addition, Vitamin D supplementation has positive effects on MS activity that is augmented during low ultraviolet-B seasons.[2]

Furthermore, it has been noted that the gene codes for the enzymes 25(OH)D1-hydroxylase(CYP27B1) lies within a genomic reign of an association identified in genome-wide association studies of multiple sclerosis. another gene found to be involved in the pathogenesis of multiple sclerosis (CYP24A1). Which encodes the enzyme that degrades the Vitamin D. And these genes contribute in the multiple sclerosis risk by decreasing the level of active Vitamin D.[3.4]

This review article aims to discuss the role and effect of Vitamin D supplementation in MS, the ideal dose, duration of treatment, and possible adverse effects of the supplements.


  Methods Top


A literature search was performed in October 22, 2019, on PubMed database using search terms: “multiple sclerosis,” “Vitamin D,” “deficiency,” “therapeutic use,” “administration and dosage,” and “adverse effects.” Eligibility criteria: all study designs written in English language, applied on human, in the previous 10 years, related to the research question, a clinical diagnosis of MS and interventions containing Vitamin D supplementation (Vitamin D3 or calcitriol). Fourteen articles matched the criteria and were included in this review article.


  Discussion Top


Role of Vitamin D

Timing of Vitamin D supplementation

Studies showed that the timing of Vitamin D insufficiency affects the risk of MS development. High levels of Vitamin D supplementation early in life (during prenatal and childhood phase) can prevent the development of many autoimmune disorders including MS.[5],[6] Furthermore, women whose mothers had higher predicted 25(OH) D during pregnancy tend to have lower MS risk according to the Nurses' Health Study II cohort results.[7] In addition, MS risk reduction might be highly modified during the adolescence period when supplemented with the commonly used doses of Vitamin D contained in cod liver oil.[6]

Levels of serum Vitamin D

A normal serum level of Vitamin D is between 30 and 100 ng/ml; a level between 11 and 30 ng/ml is considered as insufficiency, and a level below 11 ng/ml is considered as deficiency. Giving a dose of 40 ng/ml (100 ml) is suggested to be sufficient for MS protection.[8] The role of Vitamin D in MS is dependent on the serum baseline levels of Vitamin D, studies suggested that patients with lower initial Vitamin D levels could benefit from the supplements and it may improve their condition.[9] Surprisingly, MS patients have a lower increase in serum Vitamin D in comparison to healthy individuals; this could be due to their altered gut motility or alteration of gut microbiota that leads to decrease absorption of Vitamin D.[10] In addition, many cross-sectional and prospective association studies suggested that low Vitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, strengthened by a dose-response relationship, although several meta-analyses of clinical trials have shown conflicting results.[5] In addition, it was concluded that levels lower than 10 ng/ml may aggravate autoimmune disorders such as MS.[7]

Immunological response of Vitamin D supplements

CD4 interlukin-17 (IL-17), T-cells, and T-helper 17 (Th17) have been implicated as a major contributor to the immunopathogenesis of MS. IL-17 gene expression is increased in MS lesions and during MS exacerbation phases in the peripheral blood and the cerebrospinal fluid. In addition, CD161 (KLRB1) as a surface marker of IL-17-producing cells has been associated with an increased risk of MS. Therefore, literature suggested that decreased proportion of CD4 IL-17 T-cells in the peripheral blood of MS patients might be a major mechanism of the possible therapeutic role of Vitamin D.[11]

Patients may experience the benefits of Vitamin D by enhancing their physiological process and its important role in regulating the immune system. It is reported that Vitamin D acts by reducing the pro-inflammatory cytokines and inducing the anti-inflammatory cytokines.[2],[9],[10],[12]

Furthermore, it enhances T-regulatory cells, blocks Th17 differentiation, down-regulate Th1, and effector memory CD4 T cells with an increase in the central memory and naive CD4 T-cells.[7],[11] However, evidence showed that higher doses of Vitamin D could lead to these immunological responses in contrast to the lower doses.[5],[11]

While one study reported that when reaching a level of 45 nmol/l in patients with relapsing remitting MS, each 12.5 nmol increase will lead to 1.4% absolute decrease in IL-17-producing CD4 t cells.[10] Another study has indicated that every 5 ng/ml increase of serum Vitamin D above 18 ng/ml will lead to 1.0% absolute decrease of IL-17 percentage.[11] On the contrary, one study mentioned that there were no sustained changes in the immunological markers after the supplementation of Vitamin D.[13]

Effect of Vitamin D on the metabolism

In the longitudinal metabolomics study, it was found that the effect of Vitamin D supplementation on the metabolism on MS group is debilitated when compared to the healthy control group, in addition to minimal lowering of oxidative stress markers in MS patients. This suggests the probability for the MS patients to be resisting the metabolic effects of Vitamin D, therefore altering Vitamin D metabolism or signaling.[10]

Prevention of new T2 lesions

Regarding the role of Vitamin D in the prevention of future new T2 lesions, evidence has shown that there is no effective role of Vitamin D as compared to placebo.[9],[13] Other trials of Vitamin D supplementation for MS patients have shown improvement in magnetic resonance imaging (MRI) parameters, but with little convincing evidence of clinical benefits.[14] On a systematic review of ten randomized clinical trials, five have showed improvement in brain MRI lesion markers. One of them found benefits to current enhancing lesions where Vitamin D3 as add on treatment to interferon-beta (IFN-B) significantly decreased total number of T1 MRI gadolinium-enhancing lesions in the intervention group (0.6–0.1), while in the placebo group, no change was reported (P = .004). In addition, Vitamin D supplementation resulted in fewer new T2 lesions (a mean of 0.5 compared to a mean of 1.1 in the placebo group) and decreased T1 enhancing lesion volume in the Vitamin D group (from 57 mm3 to 3.1 mm3) compared with the placebo group (from 62 mm3 to 29 mm3). However, the difference between intervention and placebo groups was not statistically significant (P = .286 and P = .320, respectively).[10] Another systematic review concluded that Vitamin D supplements have no effect on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% confidence interval [CI]-0.45–0.48; I2 = 12%; two trials; 256 participants; very low-quality evidence according to GRADE).[13]

Effect of Vitamin D on the disability

Many of the studies reported nonsignificant results associated with the effect of high 25(OH) D serum level on reducing the Expanded Disability Status Scale (EDSS).[9] In addition, a meta-analysis of eight studies that assessed the change in the EDSS score, it found no differences between the groups when re-evaluated at a different durations. The mean difference at 52 weeks was (MD-0.25, 95% CI-0.61–0.10), at 26 weeks (MD-0.10, 95% CI-0.37–0.17), and (MD 0.35, 95% CI-0.21–0.91) after 96 weeks.[13] However, the evidence concerning this topic remains unclear. However, one study reported a significant difference in (EDSS) score (P = .033) in the Vitamin D group when compared to the placebo, and it has been recognized only in patients who had Vitamin D baseline level below the minimum recommendation. Although the included participants' EDSS score was <4, the higher range group was not observed.[9]

Effect of Vitamin D on relapse rate

Effect of Vitamin D on the relapse rate is still debatable; multiple studies have reported no satisfying effect of Vitamin D on the relapse rate, expect for one study which documented that the relapse rate has decreased significantly from a mean of 1.04–0.32 (P ≤ 0.001), after receiving 0.25 μg/d of calcitriol for 2 weeks and then 0.5 μg/d for 46 weeks.[7],[9],[14] While two studies reported that higher doses of the supplementation can decrease the relapse rate.[14],[2] Moreover, approximately 50% reduction of the absolute relapse rate (ARR) was observed during the Vitamin D supplementation phase.[2]

Effect of Vitamin D on the quality of life

Concerning cognition and the mental state, there was a role of improvement by the supplements reported by different studies.[13],[15] Memory was positively affected in patients who took a short course of Vitamin D supplementation, as it was found that giving participants a high dose of 10,000 IU daily for 3 months was correlated with improvement in the memory as measured by BVAT–DR (Brief Visuospatial Memory Test-Delayed Recall) and MoCA (Montreal Cognitive Assessment).[15] Moreover, a better cognitive performance on the BVAT–DR and MoCA was predicted by sufficient serum levels (≥35 ng/ml) at the baseline (P ≤ 0.008) and after 3 months of the trail (P ≤ 0.1).[15] However, there was no role of the Vitamin D over the clinical symptoms.[13] As for additional therapy, one of the reviewed article reported that higher doses of Vitamin D in association with IFN beta1-b could improve the mental quality of life when compared to placebo.[5]

Ideal dose of Vitamin D and duration of treatment

Evidence favoring the high doses of Vitamin D supplements

It was found that high doses of Vitamin D supplementation (below 10,000 IU daily) are safe and tolerable in most cases of MS. Furthermore, in MS patients whom serum baseline level at the lower end (i.e. 50 nmol/L) and receiving the supplements, they have an improvement in their physiological mechanisms and symptoms. Even though it was reported that different doses can affect the immunological markers in variable degrees, this could be explained by the confounding inconsistent duration of treatment and the use of immunomodulatory therapy (IFN-B).[9]

It was recommended to establish Vitamin D supplementation in patients with serum level below 40 ng/ml with a large replacing dose (50,000 IU capsules per week for 8–12 week), then if serum levels continued to be low, another replacing dose is advised. Maintenance is achieved by 1500–2000 IU daily or intermittently (twice a week or every month). In addition, patients with limited physical activity a dose of 1000 IU daily or intermittently are considered adequate.[13]

While other studies suggested that high doses of the supplements may prevent the development of MS from optic neuritis, in addition to decrease the disease progression and disability state. In contrast to lower doses of Vitamin D, which it was associated with the increased risk for the development of clinically definite MS from clinically isolated syndrome.[14]

Another evidence mentioned that giving daily dose of 5000 IU, 125 ug to MS patient and lead to lower increase in the serum Vitamin D level.[10]

As for the clinical symptoms, a dose of 50,000 IU Vitamin D every 5 days after 12 weeks was associated with less neurological disability and a significant decrease in EDSS score. Furthermore, another study found an association between reduced disability measured by EDSS in MS and high levels of 25(OH) D (>50 nmol/L).[9]

Decreased in ARR was found by approximately 50% during Vitamin D supplementation of 18,950 IU per week.[5] While in the Darwish study, patients who took high dose Vitamin D supplements (10,000 IU daily for 3 months) reaching a serum level >25 ng/ml were found to have less anxiety score as compared to those who have serum baseline <25 ng/ml and continued their usual treatment which may contain the supplements at variable doses. Furthermore, Vitamin D levels >35 ng/ml are associated with improved cognitive performance.[15]

In addition, it was mentioned that high dose of Vitamin D (50,000 every 4 days for 3 months) in accompany with the use if IFN-B improves the mental quality of life in patient with MS. However, generally, large randomized trials are needed to determine the sufficient doses of Vitamin D.[5]

Two studies suggested that a dose of 10,400 IU daily could produce immunological effects on MS patients and reduce the serum cytokines. Moreover, it is safe and tolerable for several months without adverse effects.[7],[11] In contrast to the low dose of 800 IU, these favorable outcomes were not observed.[11]

Finally, Vitamin D supplementation in doses up to 40,000 IU per day lead beneficially affects the immunological response. However, these benefits may not be observed if the baseline levels of Vitamin D were high or normal (i.e. 50 nmol/L).[9]

Evidence favoring the low doses of Vitamin D supplements

Physiologic doses of Vitamin D supplements were recommended, to reach a serum level between 40 and 100 ng/ml (100-159 nmol/L), with the necessity to recheck the serum levels every 3 months. In comparison, the use of supra-physiological doses of Vitamin D either as monotherapy or as an add-on therapy leading to a serum level >100 ng/mg is not recommended due to higher risk of toxicity.[12] The supplementation of Vitamin D with a dose of 600–800 IU/D during adolescence led to the largest protection from MS, and there is a positive relationship between the duration of supplementation and the risk reduction of MS disease.[6]

Nevertheless, one study has shown that Vitamin D, regardless to its dose and form, has no beneficial effect neither on the clinical symptoms or the MRI lesions, despite generally being safe when used in MS patients.[13] while other studies showed vitamin D had no effect on the bone mass density of patients with MS.[16]

Adverse effects

Serious adverse effects

The signs of toxicity were mostly observed when very large single dose was used. A randomized controlled trial was performed, reporting adverse outcomes with one annual dose of 500,000 IU. While doses (>300,000 IU Vitamin D2) were associated with high risk of wrist, hip and femur fractures, and falls in elderly women [Table 1].[7] Therefore, a daily, weekly, biweekly, or monthly (or at even longer intervals) doses strategies were preferred and safe because of the long half-life of Vitamin D.[5],[7]
Table 1: Ideal dose, duration of treatment, outcomes, and adverse effects of using Vitamin D in multiple sclerosis

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In addition, another evidence showed that there were no serious adverse events with Vitamin D3 supplements of 5,000 IU/day for 90 days, with normal serum, calcium levels at mid-and final study visits.[10],[17] As for hyperkalcemia or hypercalciuria, it was not recognized to be triggered by high doses of Vitamin D or causing nephrolithiasis alone or with calcium combination.[9],[10],[13]

The Cochrane review recommended discontinuing Vitamin D supplements when serum level has reached >100 ng/ml and reverse should be rechecked after 6 months of discontinuation and urine analysis needs to be done to exclude the risk of hypercalciuria and renal stones.[13]

Minor adverse effects

In Bereziwksa study, Vitamin D compared to placebo was found to be safe and tolerable by most of the patients. While the majority of the adverse effects were reported to be minor in nature [Table 1], including constipation, dyspepsia, fatigue, and headache, although high doses of Vitamin D supplements can cause hyperkalcemia and hypercalciuria; hence, daily doses below 10,000 IU are recommended.[9]

In the Cochrane review, there was evidence of low certainty that denies serious adverse events (SAEs) in eight studies with 621 participants and neither the combination of Vitamin D with calcium can increase the risk of nephrolithiasis nor caused serious adverse effects (SAEs) or minor adverse effects, although one case of hyperkalcemia (>10 mg/dL) who had to discontinue treatment and one case of hypercalciuria were reported.[13]

In the Soturchos randomized trial, treatment was discontinued due to the development of adverse events most likely related to the supplements. When three patients (one using low dose and two using high dose supplements) complained of nausea that improved after the discontinuation of therapy, one patient in the high dose group had a mid-study calcium level of 10.6 mg/dl while having a baseline of 10 mg/dl (reference range 8.4–10.5 ng/dl) and having normal urine calcium: creatinine ratio, after 6 months' follow-up, calcium levels were reversed. In addition, by the end of the study, urine calcium: creatinine ratio was increased in the high dose group as compared to the low dose. Furthermore, there is evidence that Vitamin D supplements within a range of 26–52 weeks' follow-up did not increase the risk of serious adverse effects, while minor adverse effects were within a range of 26–96 weeks' follow-up.[13] Therefore, if urine calcium: Creatinine ratio (0.21 mg/mL) is elevated, a 24-h urine calcium needs to be performed and if it appeared to be elevated (≥300 mg/24 h), the everyday dosing frequency is decreased.[11]


  Conclusion Top


Vitamin D supplementation is safe and tolerable by MS patients. Its benefits are observed mainly in reducing the immunological markers and improving mental status of the patients, with little evidence favoring its efficacy in managing the clinical symptoms and controlling the disease activity. Most of the articles suggest that high doses of Vitamin D are more effective as compared to lower doses, with average duration (3–6 months) and its beneficial effect is profoundly observed in those who have lower serum baseline. Future trails assessing the efficacy of Vitamin D as a monotherapy without the confounding factors including having another co-therapy, different demographic patients' characteristics, serum baseline and initial disease status or therapy, in addition to specifying the duration of Vitamin D supplementation that will aid in the assessment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Harandi AA, Harandi AA, Pakdaman H, Sahraian MA. Vitamin D and multiple sclerosis. Iran J Neurol 2014;13:1-6.  Back to cited text no. 1
    
2.
Miclea A, Miclea M, Pistor M, Hoepner A, Chan A, Hoepner R. Vitamin D supplementation differentially affects seasonal multiple sclerosis disease activity. Brain Behav 2017;7:e00761.  Back to cited text no. 2
    
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McLaughlin L, Clarke L, Khalilidehkordi E, Butzkueven H, Taylor B, Broadley SA. Vitamin D for the treatment of multiple sclerosis: A meta-analysis. J Neurol 2018;265:2893-905.  Back to cited text no. 3
    
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Alharbi FM. Update in Vitamin D and multiple sclerosis. Neurosciences (Riyadh) 2015;20:329-35.  Back to cited text no. 4
    
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Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, Bruyere O, Cooper C, Cutolo M, et al. Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: Research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO). Endocrine 2017;56:245-61.  Back to cited text no. 5
    
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Cortese M, Riise T, Bjørnevik K, Holmøy T, Kampman MT, Magalhaes S, et al. Timing of use of cod liver oil, a Vitamin D source, and multiple sclerosis risk: The EnvIMS study. Mult Scler 2015;21:1856-64.  Back to cited text no. 6
    
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Jahromi SR, Sahraian MA, Togha M, Sedighi B, Shayegannejad V, Nickseresht A, et al. Iranian consensus on use of Vitamin D in patients with multiple sclerosis. BMC Neurol 2016;16:76.  Back to cited text no. 7
    
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GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:269-85.  Back to cited text no. 8
    
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Berezowska M, Coe S, Dawes H. Effectiveness of Vitamin D supplementation in the management of multiple sclerosis: A systematic review. Int J Mol Sci 2019;20:E1301.  Back to cited text no. 9
    
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Bhargava P, Steele SU, Waubant E, Revirajan NR, Marcus J, Dembele M, et al. Multiple sclerosis patients have a diminished serologic response to Vitamin D supplementation compared to healthy controls. Mult Scler 2016;22:753-60.  Back to cited text no. 10
    
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Sotirchos ES, Bhargava P, Eckstein C, Van Haren K, Baynes M, Ntranos A, et al. Safety and immunologic effects of high- vs. low-dose cholecalciferol in multiple sclerosis. Neurology 2016;86:382-90.  Back to cited text no. 11
    
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Marques VD, Passos GR, Mendes MF, Callegaro D, Lana-Peixoto MA, Comini-Frota ER, et al. Brazilian consensus for the treatment of multiple sclerosis: Brazilian Academy of Neurology and Brazilian Committee on treatment and research in multiple sclerosis. Arq Neuropsiquiatr 2018;76:539-54.  Back to cited text no. 12
    
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Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev 2018;9:CD008422.  Back to cited text no. 13
    
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Lucas RM, Byrne SN, Correale J, Ilschner S, Hart PH. Ultraviolet radiation, Vitamin D and multiple sclerosis. Neurodegener Dis Manag 2015;5:413-24.  Back to cited text no. 14
    
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Darwish H, Haddad R, Osman S, Ghassan S, Yamout B, Tamim H, et al. Effect of Vitamin D replacement on cognition in multiple sclerosis patients. Sci Rep 2017;7:45926.  Back to cited text no. 15
    
16.
Holmøy T, Lindstrøm JC, Eriksen EF, Steffensen LH, Kampman MT. High dose vitamin D supplementation does not affect biochemical bone markers in multiple sclerosis-A randomized controlled trial. BMC Neurol 2017;17:67.  Back to cited text no. 16
    
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Bhargava P, Fitzgerald KC, Calabresi PA, Mowry EM. Metabolic alterations in multiple sclerosis and the impact of Vitamin D supplementation. JCI Insight 2017;2:95302.  Back to cited text no. 17
    



 
 
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