Effectiveness of Vitamin D Supplementation in the Management of Multiple Sclerosis: A Systematic Review

Objective: to examine the extent of effect vitamin D in Multiple Sclerosis (MS) on pathology and symptoms. Methods: A literature search was performed in November 2018 (CRD42018103615). Eligibility criteria: randomised control trials in English from 2012 to 2018; a clinical diagnosis of MS; interventions containing vitamin D supplementation (vitamin D3 or calcitriol) in disease activity compared to a control/placebo; improvement in: serum 25(OH)D, relapse rates, disability status by Expanded Disability Status Scale (EDSS) scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety and adverse effects. Risk of bias was evaluated. Results: Ten studies were selected. The study size ranged from 40 to 94 people. All studies evaluated the use of vitamin D supplementation (ranging from 10 to 98,000 IU), comparing to a placebo or low dose vitamin D. The duration of the intervention ranged from 12 to 96 weeks. One trial found a significant effect on EDSS score, three demonstrated a significant change in serum cytokines level, one found benefits to current enhancing lesions and three studies evaluating the safety and tolerability of vitamin D reported no serious adverse events. Disease measures improved to a greater extent overall in those with lower baseline serum 25(OH)D levels. Conclusions: As shown in 3 out of 10 studies, improvement in disease measures may be more apparent in those with lower baseline vitamin D levels.


Introduction
There is increasing evidence suggesting that specific environmental factors, such as exposure to infectious agents, smoking, poor diet and inadequate levels of vitamin D can influence the disease course of multiple sclerosis (MS) [1]. Adequate vitamin D status is documented as associated with reduced prevalence, activity and progression of disease in MS, and therefore high intake of vitamin D may be a useful addition to standard treatment [2]. Numerous observational studies investigating variations in sunlight exposure, latitude and diet have supported the correlation between a high serum concentration of vitamin D and reduced severity of the disease course in established MS [3,4].
Epidemiologic and experimental studies investigating the effectiveness of vitamin D supplementation in MS have shown that low serum vitamin D levels may exacerbate MS symptoms and therefore are associated with higher relapse rates, new lesions, and greater degree of disability [5][6][7][8][9]. Although there has been much research performed into the role of vitamin D in MS risk and progression, due to heterogeneity of study designs, there have been conflicting results. For example, baseline serum 25(OH)D levels often differ between studies. Reviews on the topic have thus far been inconclusive and are mainly focused on the role of vitamin D and risk of developing MS, rather than the outcomes after diagnosis [7]. The only two other systematic reviews to date on vitamin D for the clinical efficiency of MS did not use the full range of terms for vitamin D nor was bias assessed [10] and didn't assess cytokine outcomes nor looked at the effects of baseline Vitamin D levels on outcomes [11]. The aim of this review is to assess the evidence from existing randomised controlled trials for the clinical effectiveness of vitamin D supplementation compared to placebo supplementation in the disease and symptom management of people with MS as measured by: improvement in: serum 25(OH)D, relapse rates, disability status by Expanded Disability Status Scale (EDSS) scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety, and adverse effects.

Methods
The systematic review was registered in PROSPERO (CRD42018103615). A literature search was performed in November 2018. Table 1 shows the search terms and number of hits for each database. Reference lists were hand searched for additional papers. Twenty percent of abstracts and papers were checked by a second reviewer. Studies were included if they met each of the following criteria: A clinical diagnosis of MS; Direct relevance of vitamin D supplementation on the management of MS compared to a low dose vitamin D or a placebo supplement; Primary outcome measurements in one or more of: serum 25(OH)D, relapse rates, disability status by EDSS scores, cytokine profile, quality of life, mobility, T2 lesion load and new T2 or T1 Gd enhancing lesions, safety and adverse effects; Randomised control trial (RCT) with a control and intervention group; Published from 2012 and in English; The published data available in full text; Only human randomised controlled clinical trials.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the flow diagram is presented in Figure 1. Bias was assessed using the RoB 2.0 tool at a study level. Data were extracted by one reviewer, and a selection of excluded abstracts and all full papers, and included papers were confirmed by a second reviewer.

Results
Out of 785 studies, ten RCTs were identified as eligible for this review after the application of the inclusion and exclusion criteria. The information from each selected study was extracted, and detailed characteristics are shown in Table 2.

Bias
All studies were considered to have a low risk of bias and therefore systematic error was unlikely and there was no threat to validity.

General Characteristics
The studies reviewed in this report were all double-blind RCTs that focused on the role of vitamin D supplementation in the management of people with MS. Country of origin is shown in Table 2. Inclusion and exclusion criteria, in addition to other demographic information is shown in Table 3.

Results
Out of 785 studies, ten RCTs were identified as eligible for this review after the application of the inclusion and exclusion criteria. The information from each selected study was extracted, and detailed characteristics are shown in Table 2.

Bias
All studies were considered to have a low risk of bias and therefore systematic error was unlikely and there was no threat to validity.

General Characteristics
The studies reviewed in this report were all double-blind RCTs that focused on the role of vitamin D supplementation in the management of people with MS. Country of origin is shown in Table 2. Inclusion and exclusion criteria, in addition to other demographic information is shown in Table 3.

Participants
The studies size ranged from 40 to 94 people with MS. In these ten studies, there was a total of 627 adult participants (463 female and 164 male). Food intake of vitamin D and smoking status were not reported in any of the RCTs.

Interventions
The intervention dose varied across studies. All studies evaluated the use of vitamin D supplements of various doses (ranging from 10 to 98,000 IU), frequency (usually delivered weekly) and formulation (vitamin D3 and calcitriol). Most studies (n = 9) reported concomitant immunomodulatory therapy, often interferon-β as well as different requirements relating to vitamin D and calcium supplementation that were used at baseline. The duration of the vitamin D interventions varied between studies, ranging from 12 to 96 weeks. The included studies (n = 8) compared vitamin D supplementation (321 participants) to placebo (264 participants) or versus low dose of vitamin D (n = 2; 42 participants). A variety of clinical and biochemical outcome measures were assessed at the baseline and the end of the study for intervention and control groups.

Serum 25(OH)D Levels
Nine of ten studies in this review measured the serum 25(OH)D concentration for both intervention and control group (low dose vitamin D) as an outcome parameter (Table 4). Across studies, mean improvements in cytokine profile or EDSS were seen for those with low baseline plasma Vitamin D levels (n = 3). Key findings and significance are shown in Table 5.

Immunologic Markers
Seven of the ten studies in the review used change in serum cytokines level as an outcome parameter with mixed results found and large heterogeneity in markers assessed across studies. Best support was found for Ashtari et al. [16] and Sotirchos et al. [13] in which significant benefits were seen in the high dose Vitamin D groups on IL-10, and on IL-17+CD4+T and CD4+T cells these were also the studies where baseline vitamin D levels were lower than normal.
Golan et al. [12] reported a significant increase in serum IL-17 concentration in people allocated to the low-dose vitamin D from a mean of 4.01 to 9.14 pg/mL at 48 weeks (p = 0.037) and a heterogeneous IL-17 response was observed in the high-dose vitamin D group. Therefore, there was a decrease and thus a beneficial change in 40% of participants and increase and negative change in 45% of participants after 3 months while 15% had IL-17 levels below the detection threshold at both time points. Aivo et al. [14] detected a significant increase in LAP (TGF-β) levels in the vitamin D arm after 48 weeks from a mean of 47 to 55 pg/mL (p = 0.02), while in those receiving placebo, this level increased but these changes were not significant (p = 0.173). Moreover, no significant difference in other cytokines concentration was reported in either group. Ashtari et al. [16] found that serum IL-10 concentration changed significantly in people receiving vitamin D for 12 weeks (p = 0.015) from a median of 12.58 to 13.76 pg/mL. Rosjo et al. [15] indicated no significant differences from baseline values for any of the inflammation markers between those receiving vitamin D or placebo after 96 weeks of treatment. Additionally, people with MS on immunomodulatory treatment (mostly consisting of IFN-b) were observed to have higher mean baseline levels of inflammation markers (IL-1Ra and CXCL16) compared to those not on therapy. However, there was no clear correlation between vitamin D supplementation and immunomodulatory treatment and its influence on the inflammation markers. Toghianifar et al. [18] showed that the proportion of cells including: nTreg, iTreg, Breg, IL4+ Th cells, IL5, and LAP (TGFβ) was not affected by a high-dose vitamin D supplementation. No difference in IL-17 levels between those who received vitamin D, and those who received placebo were observed at 12 weeks. Muris et al. [17] found no beneficial effects of a high-dose vitamin D supplementation on the circulating regulatory immune cell compartment (the fraction of Treg as the proportion of CD4+ T cells, nTregs, IL10+ Th cells) in those with MS. Sotirchos et al. [13] detected a significant change in the proportion of proinflammatory IL-17+CD4+T cells in the high-dose group (p = 0.016) from a mean of 9.32% to 5.62%, while no difference was observed in the low-dose group (p = 0.53). Moreover, a significant difference in IL-17+CD4+T cells in the high-dose group versus low-dose group was reported (p = 0.039). Greater reduction in the proportion of IFN-γ+CD4+ T cells and IFN-γ+IL-17+CD4+ T cells was noted in the high-dose group versus the low-dose group but did not reach statistical significance (p = 0,12; p = 0.14). Also, a decreased proportion of effector memory CD4+T cell was noted after high-dose vitamin D supplementation from a mean of 40.56% to 30.69% (p = 0.021). The proportion of central memory and naive CD4+T cells increased significantly (p = 0.019; p = 0.043) in the high-dose group from a mean of 50.07% to 60.96% and from 38.94% to 42.2%, respectively.

Functional Measures
Only one study assessed functional measures and although there were trends for improvements in the Vitamin D groups, there were no statistically significant changes between the intervention and placebo groups. Soilu-Hänninen et al. [20] demonstrated that 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). However, the difference between vitamin D and placebo groups was not statistically significantly different (p = 0.286). Participants assigned to vitamin D demonstrated lower total number of T1 Gd enhancing lesions (0.6 to 0.1) while in the placebo group no change was reported and a higher decrease in T1 enhancing lesion volume in the vitamin D group (from 57 mm 3 to 3.1 mm 3 ) compared with the placebo group (from 62 mm 3 to 29 mm 3 ) but again the difference between the treatment groups was not statistically significant (p = 0.004, p = 0.320, respectively). There were no statistically significant differences between the treatment groups in timed 10 foot tandem walk (TTW10; p = 0.076) (change from a mean of 11.7 to 9.7 in the vitamin D group and from 9.6 to 11.2 in the placebo group) and T25FW (p = 0.932) at the end of the study (change from a mean of 6.0 to 5.3 in the vitamin D group and from 4.7 to 5.1 in the placebo group).

Relapse Rate
Four of ten studies in this review investigated the effect of supplementation with vitamin D on relapse rates, with no significant differences between the vitamin D and control groups. Kampman et al. [19] demonstrated that vitamin D supplementation resulted in an increase in annualised relapse rate (ARR, calculated as the total number of relapses experienced divided by the sum of participants and duration of follow-up) from 0.11 to 0.14, whereas in placebo group a decrease from 0.15 to 0.8 was reported. The difference between vitamin D and placebo group after 96 weeks was not significant (p = 0.25). Shaygannejad et al. [21] documented that the relapse rate decreased significantly after 48 weeks from a mean of 1.04 to 0.32 in people who received vitamin D (p < 0.001) and from 1.04 to 0.40 in those who received placebo (p < 0.001). The study by Golan et al. [12] found an increase in ARR in patients with MS following the treatment with high-dose per day from 0.28 to 0.51 and decrease in the low-dose from 0.38 to 0.34 at week 48, but this difference was not statistically significant (p = 0.32). The study by Soilu-Hänninen et al. [20] found a decrease in ARR in both treatment arms: in people who received vitamin D from a mean of 0.49 to 0.26 and from 0.51 to 0.28 in those who received placebo, yet with no significant difference between groups.     These differences were significant between groups after 12 weeks (p < 0.001).
[17] Intervention: serum 25(OH)D concentration increased significantly in the vitamin D group from 60 to 231 nmol/L. Placebo: changed to a lesser degree (54 to 60 nmol/L).
The was a significant difference after 48 weeks between the groups (p < 0.001).
[13] High dose: Mean change of 34.9 ng/mL. Low dose: mean change of 6.9 ng/mL A high dose of vitamin D resulted in significantly higher serum 25(OH-D) levels versus low-dose after 24 weeks (p < 0.00001).
[20] Intervention: serum 25(OH)D levels increased from a mean of 54 to 110 nmol/L. Placebo: decreased from a mean of 56 to 50 nmol/L after 48 weeks A significant difference between groups (p < 0.001). No significant differences in the EDSS score or relapse rate between the vitamin D and control groups at the end of the study period; vitamin D supplementation at the doses used seems safe 2. EDSS unchanged in intervention group and increased in control 2. N/A; p < 0.01

Disability
Five of ten studies reported EDSS score as outcome parameter with only one showing a benefit after supplementation with vitamin D. Kampman et al. [19] noted that EDSS score did not differ significantly between the vitamin D and placebo group after 96 weeks (p = 0.97). Shaygannejad et al. [21] found that EDSS score increased significantly (p < 0.01) in a placebo group from a mean of 1.7 to 1.94, whereas it did not change in people receiving vitamin D and therefore there was no significant difference in scores at the end of the trial between intervention and control groups (p > 0.05). Also, Golan et al. [12] demonstrated that high-dose vitamin D supplementation was not associated with reduced disability score with no significant change in EDSS score between two groups (p = 0.26). In contrast, Toghianifar et al. [18] showed a significant difference in EDSS scores between people allocated to vitamin D group (supplemented with 50,000 IU every five days) and placebo group after 12 weeks (p = 0.033) in favour of the vitamin D group, and the baseline vitamin D levels in the participants from this study was below the minimum recommendation. Soilu-Hänninen et al. [20] found no significant change in EDSS score between two groups (p = 0.071).

Safety and Tolerability
Four of the ten studies in this review determined the effect of high-dose vitamin D supplementation among people with MS in terms of safety and tolerability and none of the studies reported significant differences between control/placebo and vitamin D groups nor were any of the adverse events serious in either group. Shaygannejad et al. [21] showed that vitamin D treatment use up to 0.5 µg/day of calcitriol appeared to be safe and well tolerated by those with MS. The adverse events noted were mild in severity. The most frequently reported included constipation (n = 6 and n = 4), dyspepsia (n = 6 and n = 2), fatigue (n = 4 and n = 5), and headache (n = 2 and n = 1) in vitamin D and placebo groups, respectively. There were no significant differences in frequency of events between people who received vitamin D and those who received placebo. Golan et al. [12] indicated that a dose of 4370 IU/day over a 48-week period was safe in people with MS. There were no instances of hypercalcemia and no reports on new adverse events that could be vitamin D supplement related. Sotirchos et al. [13] found that a dose of 10,400 IU of cholecalciferol per day for 24 weeks was safe and tolerable in people with MS, with no serious adverse events. Soilu-Hänninen et al. [20] found no significant differences between the treatment arms in any of the other clinical chemistry parameters studied. No dose adjustments were necessary. Lack of MxA response (MxA < 50 mg/L) was detected in three people in both treatment arms at 12 months. Diarrhoea was a side effect in (n = 5 and n = 2) and fever was noted (n = 2 and n = 5) in the vitamin D group and placebo group, respectively. All other adverse events occurred in a similar number of participants in both groups. There was one serious adverse event in the vitamin D group (erysipelas in the interferon injection site treated with intravenous antibiotics in hospital) and two in the placebo group (elective hip surgery and elbow fracture).

Discussion
This review found some evidence for benefits of vitamin D supplementation, specifically for those with serum levels at the lower normal range in people with RRMS. Therefore, baseline serum vitamin D levels may be a predictor of improvements in disease pathology from vitamin D supplementation, cytokine profile and disability status, but possibly also relapse rate, quality of life, mobility, T2 lesions load and new T2 and T1 Gd enhancing lesions. Five out of ten studies showed improvement in: ARR(x2), EDSS(x2), IFN-gamma, IL-17A, IL-9, IL 10, 17+CD4+ T cells, CD161+CD4+ T cells, and effector memory CD4+ T cells, the proportion of central memory CD4+ T cells and naive CD4+ T, TTW10, T25FW, and MRI brain lesion markers, and these were shown in the intervention group compared with the control/placebo group. Another similar review to date differed in that cytokine outcomes were not assessed and the effects of baseline Vitamin D levels on outcome measures was not explored [11]. McLaughlin et al. [11] found that in higher dose vitamin D arms, there were actually adverse changes in ARR and EDSS and therefore although supplementation may have beneficial effects, there may be specific doses that should be considered. Jagannath et al. [22] looked at outcome measures including fatigue and HRQOL yet found conflicting results in part due to the heterogeneity of the study designs and different doses used. Zheng et al. [23] only looked at changes in ARR and EDSS score, with no beneficial effect of vitamin D as an add-on therapy on either outcome. Whilst further research is needed, this review highlights that all studies on the topic should include baseline vitamin D as part of the assessment. There was also low risk of adverse effects and low risk of bias for all studies and therefore the validity can be considered high. This review not only includes a more extensive search strategy and evaluates bias and although some of the included studies between reviews are similar, the current review is more up to date and encompasses a wider range of symptoms and pathology in MS.
The present consensus on the use of vitamin D supplementation in the management of MS is based on the hypothesis that the serum 25(OH)D is associated with prevalence and severity of the disease course in established MS. Therefore, its measurements are undertaken as part of the clinical management of MS in order to detect vitamin D insufficiency, correct it with supplementation at recommended doses and achieve the beneficial immunological effects [4]. All but one study assessed levels of serum 25(OH) and all reported a significant increase in 25(OH)D levels following vitamin D supplementation. However, the increase in 25(OH)D levels did not appear to affect all MS-related outcomes in the reviewed studies. If participants had 25(OH-D) levels at the lower end of normal at baseline, a high dose vitamin D supplement intervention may contribute to bettering of physiological mechanisms and resulting symptoms, yet if baseline levels are at the higher end of normal (i.e., 50 nmol/L) then further benefits may not be experienced. In the study by Ashtari et al. [16] and Sotirchos et al. [13] participants had levels towards the lower end of normal thereby possibly resulting in the resulting significant benefit in IL-10 and a variety of mechanistic improvements, respectively. Toghianifar et al. [18] found a resulting improvement in EDSS score which wasn't seen in other studies in this review, and again the participants in this study had baseline 25(OH-D) levels at the lower end of normal. All other studies had participants with higher baseline levels and also contained more varied results, with fewer significant changes between groups.
When looking at the immunological outcomes, the reviewed studies reported mixed effects of vitamin D supplementation. Vitamin D plays an important role in immune system function by reducing the production of proinflammatory cytokines and inducing the production of anti-inflammatory cytokines [24]. Only two selected studies detected a significant increase in levels of anti-inflammatory cytokines in the vitamin D group and therefore findings of studies evaluating the effect of the vitamin D supplementation on the reduction of proinflammatory cytokines are conflicting. The heterogeneity of intervention effects on immunologic activity reported in reviewed trials may be explained by considering possible confounding parameters including dosage and duration of administering vitamin D supplementation and supports previous findings demonstrating that a more pronounced immunologic impact of vitamin D supplementation was reported in vitamin D doses up to 40,000 IU per day [24]. Moreover, the fact that almost all participants in above trials were treated by immunomodulatory treatment, which mostly comprised interferon-beta (IFN-β) therapy (Table 6), may have altered the cytokine responses to vitamin D and/ or made it more difficult to determine the isolated effect of vitamin D supplementation and therefore beneficial effects of an increase in 25(OH)D on the outcome markers examined may be undetectable due to the strong immunomodulatory effect of IFN-β [25]. It has been suggested that type of therapy a person receives may influence the observed impact of vitamin D supplementation [26]. Notwithstanding, some studies demonstrated a synergistic immunomodulatory effect of IFN-β and vitamin D that induce favourable alterations in the inflammatory profile in people with MS [12,13]. Also, when considering the study conducted by Golan et al. [12] and Sotirchos et al. [13] including low-dose of vitamin D as a comparator may reduce the ability to notice minor differences compared to the use of a placebo. Although results of studies evaluating changes in immunological profiles in people with MS are not consistent, they suggest that supplementation of vitamin D promotes the immune regulatory cytokines and reduces proinflammatory immune parameters. Only two studies assessed changes in functional measures, and although the relationship between vitamin D and improved outcomes in participants with MS was found by Soilu-Hänninen et al. [20] T1 enhancing lesions and trends in MRI burden of disease (BOD) and EDSS, there is currently not enough clinical data to suggest the effectiveness of the treatment.
The correlation between 25(OH)D and reduced relapse rates have been found in several prospective cohort studies. The study by Laursen et al. [27] reported that the increase in serum 25(OH)D level was associated with decreases in ARR in those with RRMS. Those results were in line with a previously conducted cohort study by Simpson et al. [28] investigating a role of 25(OH)D levels in modulating MS clinical course in 145 participants with RRMS that suggests a benefit of serum 25(OH)D level on relapse rates at levels approximately 100 nmol/L. However, three reviewed studies evaluating vitamin D supplementation in management of MS have demonstrated no effect of 25(OH)D on relapse rate. Although mean serum 25(OH)D level more than doubled in the high-dose intervention groups in the study by Kampman et al. [19], Soilu-Hänninen et al. [20] and Golan et al. [12], they found no significant difference in ARR between groups at the end of the study period (96 and 48 weeks, respectively). Also, Shaygannejad et al. [21] failed to detect significant difference in relapse rate between the intervention and control groups at 48 weeks although the relapse rate decreased significantly in the vitamin D group. One possible explanation for the discrepancies between findings of above trials and previous studies may be related to eligibility criteria for included participants, vitamin D dosage and form, and duration of the intervention. Other explanations for the results in these RCTs may be related to the low ARR at baseline which could contribute to the absence of significant effects. In addition, the study conducted by Kampman et al. [19] enabled participants to continue the use of vitamin D supplements they used prior the study, which contributed to comparatively high 25(OH)D concentration in the placebo group and a difference between groups could not be detected.
High levels of 25(OH)D (>50 nmol/L) have also been shown to be associated with reduced disability measured by EDSS in MS [29]. Based on the evidence contained in this review, the effect of vitamin D supplementation on reducing disability remains unclear. Kampman et al. [19], Soilu-Hänninen et al. [20], Shaygannejad et al. [21] and Golan et al. [12] reported no significant change in EDSS score between the intervention and control groups. Conversely, a trial conducted by Toghianifar et al. [18] demonstrated a significant positive difference in EDSS scores between participants allocated to vitamin D vs placebo groups. Although the inclusion criteria were limited to participants with EDSS < 4 that indicate absence of observations in the higher EDSS range, a dose of 50,000 IU vitamin D every five days after 12 weeks was associated with less neurological disability.
Additionally, four studies looked at the safety and tolerability of high dosing regimens of vitamin D supplementation through the duration of the intervention. Through the studies observed it could be clearly recognised that vitamin D treatments were relatively safe, well-tolerated, and no concerning adverse events such as hypercalcemia and hypercalciuria triggered by high doses of vitamin D were reported. This is consistent with findings from previous studies that demonstrated safety of high-dose vitamin D below the daily limit of 10,000 IU in MS [30]. All other adverse events occurred in a similar number of participants in both groups for all studies. There was one serious adverse event in the vitamin D group (erysipelas in the interferon injection site treated with intravenous antibiotics in hospital) and two in the placebo group (elective hip surgery and elbow fracture). What can be concluded from this systematic review is that it seems participants in all studies adhered to the vitamin D interventions due to a resulting increase in serum levels in all studies (n = 9), and therefore the safety and tolerability of supplementation at high doses can be considered a reliable outcome.  [20] 20,000 IU of vitamin D3 per week IFNβ-1b IFNβ, Interferon-β.

Limitations
As the reviewed studies took place in different geographic locations, sun exposure was different amongst groups and makes the comparison less reliable. Of note, all studies recruited participants with RRMS in order to ensure the homogeneity of the treatment groups in terms of the disease course and mechanisms. However, it has been demonstrated that immunomodulatory strategies employed for RRMS are not considered effective when applied in PPMS, suggesting cause for caution when generalising results to the greater MS population. Disease duration before the commencement of treatment varied between 4 months to 27 years and the time at which vitamin D intervention is implemented may affect the effectiveness of the treatment. Some studies assessed clinical endpoints such as relapse rates, disability scores, and physical changes, while some assessed only biomarker outcomes. As a result, heterogeneity of outcomes may have affected end-line comparisons and made doing a meta-analysis unfeasible.

Conclusions
Vitamin D supplementation may be a promising treatment and represents a reliable background for further exploration of potential benefit for MS regarding clinical improvements. A high dose vitamin D supplement intervention may contribute to bettering of physiological mechanisms if baseline plasma levels are at the lower end of normal. Further research addressing the matters discussed above is required before a causal association between vitamin D supplementation and disease activity in people with MS can be established.

Conflicts of Interest:
There was no conflict of interest.