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
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
]. 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.
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.
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
]. 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.