Eschle Daniel

Summary

BACKGROUND

Low serum levels of vitamin D have been implicated as a risk factor for developing multiple sclerosis (MS), and increased disease activity. MS treatment – to avert relapses and long-term disability – is expensive. This is where vitamin D supplementation might fill the gap as an affordable and safe alternative.

METHODS

PubMed was searched with the terms “multiple sclerosis” AND “vitamin D” AND “randomized controlled trial”. Additionally, reviews and meta-analyses were checked for further references. Studies using vitamin D supplementation were relevant if they looked at certain clinical, laboratory and/or brain magnetic resonance imaging parameters of disease activity during a follow-up of at least a year and included a control group.

RESULTS

The final yield was nine relevant trials. Six of these demonstrated outright negative results concerning possible benefits of vitamin D supplementation regarding relapse rate, disability status, changes in brain lesion load and/or serum concentrations of neurofilament light chain. The remaining three studies, although reporting “positive” outcomes, actually did not find any statistically robust improvements when scrutinised more closely because results were skewed by numerous dropouts or other confounders.

CONCLUSIONS

Randomised controlled trials have not been able to provide an evidence base for vitamin D as a disease-modifying treatment in people with MS. This statement comes with the caveat that practically all study patients were already taking established disease-modifying drugs, which could have “diluted” any possible vitamin D effects. But the role of vitamin D in MS could well be just a case of correlation and not causality: Epidemiological studies suggest that sunlight exposure, although correlating with vitamin D levels, is a more decisive factor than vitamin D when it comes to modulating MS risk, in particular in non-white populations.

Keywords: annualised relapse rate, disease modifying drugs, Extended Disability Status Scale, magnetic resonance imaging, sunlight exposure

Introduction and aim

Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system affecting young adults [1]. Mortality (years of lives lost) is only a minor issue according to epidemiological data, more important are the potential years lived with disability if left untreated [2]. Disease-modifying drugs (DMDs) – to avert relapses and long-term disability – are expensive. This is where vitamin D supplementation might fill the gap as an affordable and save alternative because “numerous observational studies have suggested that there is a correlation between the level of serum vitamin D and MS risk and disease activity” [3] or, for example, “among patients with MS treated with interferon beta-1b, higher (vitamin D) levels were associated with lower rates of MS activity observed on (magnetic resonance imaging)” [4].

This review looked at randomised controlled trials (RCTs) that might provide an evidence base for using vitamin D as a DMD in people with MS, and how to implement these findings in clinical practice, because inappropriate prescribing or self-medication can sometimes make vitamin D supplementation downright dangerous [5]. So far, vitamin D supplementation trials for health outcomes other than MS have been disappointing; for example, there were no benefits in treating diabetic neuropathy, and preventing cancer, cardiovascular events or Parkinson’s disease [6–8]. Is the situation any different regarding MS?

Some vitamin D facts

When skin is exposed to sunlight this leads to the endogenous production of biologically inert vitamin D3 (cholecalciferol). Hydroxylation in the liver converts vitamin D3 to 25-hydroxyvitamin D3 (25-OH-D3 or calcidiol), which undergoes a further transformation to the active compound called 1,25-dihydroxyvitamin D3 (calcitriol) [3]. The generic term “vitamin D” is used in several ways. In the context of food and in particular supplements, “vitamin D” refers to vitamin D3 (cholecalciferol). Additionally, certain foods can also contain vitamin D2 (which behaves in an equivalent manner to vitamin D3). Serum concentrations of “vitamin D” on the other hand refer to 25-hydroxyvitamin D3 and D2. Because of its much longer half-life, the 25-hydroxy form is the preferred measure to reflect the body’s vitamin D stores. Vitamin D serum concentrations are expressed in ng/ml or nmol/l: 1 ng/ml is equal to 2.5 nmol/l. Typically, the following cut-offs are in use: vitamin D concentrations above 30 ng/ml (75 nmol/l) are sufficient, levels between 20 und 30 ng/ml (50-75 nmol/l) are insufficient and less than 20 ng/ml (50 nmol/l) is called deficient. But reference values and terminology vary according to different professional bodies [9]. The German Nutrition Society determined that a daily vitamin D supply of 800 units is adequate for children and adults. Dietary intake will usually not suffice to meet this need. In the absence of relevant exposure to sunlight, a vitamin D supplement is needed [10]. The tolerable upper intake level for adults is considered to be 4000 units/day, and serum levels above 125–150 nmol/l should be avoided to prevent hypercalcaemia. At the other end of the spectrum, concentrations below 12 ng/ml (30 nmol/l) are particularly worrisome because of the association with rickets in children, and osteomalacia in adults [11]. The scientific literature is rife with statements that supplementing vitamin D will have a beneficial effect on a whole variety of other health issues, but subsequently this did not stand up to scrutiny in large RCTs [7].

Search strategy and results

PubMed was searched with the terms “multiple sclerosis” AND “vitamin D” AND “randomized controlled trial” on 04 August 2020 (with a total of 41 hits). Additionally, reviews and meta-analyses were checked for further references [12–14].

Studies using vitamin D supplementation were relevant if they looked at certain clinical, laboratory and/or brain magnetic resonance imaging (MRI) parameters of disease activity during a follow-up of at least a year and included a control group. Results were grouped into the following themes. (1) Analysis of the effect of vitamin D supplementation on the serum levels of neurofilament light chain (NfL), which is considered a promising in-vitro parameter with regards to disease activity and therapeutic efficiency [15]. Papers examining other biochemical parameters were excluded. (2) Studies looking at vitamin D supplementation and clinical or MRI indicators of disease activity. Criteria in clinical trials of new DMDs typically include the following: annualised relapse rate, Extended Disability Status Scale (EDSS) [16] and/or lesion load seen in MRI (new T2 and enhancing plaques in a follow-up MRI of the brain). Patient-reported outcome measures were not included. Because indicators of disease activity such as the annualised relapse rate are meaningful only after a longer period of observation, studies with a follow-up of significantly less than a year were excluded (the shortest follow-up was 48 weeks).

The final yield was nine publications pertinent to the aim of this review [17–25]. Additionally, Holmøy [26] reported the serum NfL results of the patients already presented by Kampman a few years earlier [18]. These two publications were counted as one and evaluated together as a single trial.

Results were deemed significant at a level of chance <5%, and wherever possible they refer to the intention-to-treat population. Drop-out rates of ≥20% were considered as problematic for robust conclusions. Pooling individual trial data and meta-analysis did not seem pragmatic owing to the heterogeneity of study designs.

All results are summarised in table 1.

Table 1

Results of the randomised controlled trials of vitamin D supplementation in multiple sclerosis.

First author and year	Vitamin D (n)	Control (n)	DMD (%)	Units/day	Duration in weeks	ARR	EDSS	MRI	NfL
Burton, 2010 [17]	24	23	56/58	14000	52	Ø	Ø	–	–
Kampman, 2012 [18]	35	33	49/52	2860	96	Ø	Ø	–	Ø
Shaygannejad, 2012 [19]	25	25	92/88	a	52	Ø	Ø	–	---
Soilu-Hänninen, 2012 [20]	32	30	100/100	2860	52	Ø	Ø	(+)	–
Golan, 2013 [21]	15	15	100/100	4370/800	52	Ø	Ø	–	–
Camu, 2019 [22]	45	45	100/100	7140	96	(+)	(+)	Ø	–
Hupperts, 2019 [23]	113	116	100/100	13400	48	Ø	Ø	(+)	–
Dörr, 2020 [24]	28	25	100/100	10200/200	78	Ø	Ø	Ø	–
Smolders, 2020 [25]	24	16	100/100	13415	48	–	–	–	Ø

a = the treatment group received “active” vitamin D, i.e., 0.5 µg/day calcitriol; ARR = annualised relapse rate; DMD = disease modifying drugs (used in % of intervention/control group); EDSS = Expanded Disability Status Scale; MRI = brain magnetic resonance imaging (new enhancing and new T2 lesions); n = number of patients in the intervention (vitamin D supplementation) and control group evaluated (mostly intention-to-treat population); NfL = neurofilament light chain (serum concentration)
+ statistically significant improvement in the vitamin D in comparison to the control group at end of follow-up with significance level set at <5%; (+) result is not robust, e.g. far too many dropouts or other confounders (see main text for details); Ø no statistically significant improvement between vitamin D and control group at end of follow-up
Kampman [18]: Additional vitamin D supplements taken by some patients (also in control group)! Patients without disease modifying drugs (about 50%) not evaluated separately except for NfL. The serum NfL results are also included here, although they were reported in a separate paper [26]: Holmøy et al. Acta Neurol Scand. 2019;139(2):172-76.
Soilu-Hänninen [20]: A subgroup analysis found similarly low levels of NfL in both groups, see Hänninen et al. Brain Behav. 2020;e01772.
Golan [21]: intervention group 4370 units vitamin D per day and 800 units/day for controls with per-protocol analysis of only 15/21 in intervention and 15/24 in control group
Camu [22]: per-protocol analysis
Dörr [24]: 20,400 units vitamin D every other day in the treatment group and 400 units every other day for controls

As practically every study used a different vitamin D supplementation regimen, all doses were converted to units/day in table 1. Range of vitamin D doses was from 2860 to 14000 units/day. One treatment group received “active” vitamin D instead, namely, 0.5 µg/day calcitriol [19]. In two studies, the control group was not a placebo arm as such, but also received a form of low dose vitamin D supplementation.

Some studies also prescribed calcium supplements for all participants. Sunlight exposure was not assessed in any of the RCTs (see “Discussion” for relevance).

In only two out of the nine studies a relevant number of participants did not use DMDs: in the study by Burton [17] a little over 40% did not use DMD and in the Kampman trial around 50% were DMD naïve [18]. Both reported outcome data irrespective of DMD use for annualised relapse rate and EDSS. NfL data for the patients studied by Kampman were published separately at a later date [26], and no differences between those with and without DMDs were found.

Six of the nine trials demonstrated outright negative results concerning possible benefits of vitamin D supplementation regarding relapse rate, EDSS, changes in brain MRI lesion load and/or serum concentrations of NfL [17–19, 21, 24, 25]. The remaining three studies, although reporting “positive” outcomes, actually did not find any statistically robust improvements when scrutinised more closely, for the following reasons:

• Soilu-Hänninen et al. [20]: number of enhancing lesions were significantly lower in vitamin D group, but not the number of new/enlarging T2 lesions, thus, there was no strict indication that there was less disease progression in the vitamin D group.
• Camu et al. [22]: over 28% dropouts from original cohort in the vitamin D group and nearly 32% in the placebo group.
• Hupperts et al. [23]: Only 98/115 (85%) in the vitamin D and 88/117 (75%) in the placebo group finished the study, but data were not shown separately for these, so data are for all patients, i.e., intention-to-treat population.

Adverse events were mostly mild and similar to the perceived side effects reported by the control/placebo groups. Both Camu [22] and Hupperts [23] reported all serious health issues during the study period as adverse events, including a case of appendicitis in the vitamin D group and a malignant lung neoplasm in the placebo group (which does not truly reflect possible vitamin D side effects). One trial made no mention of possible adverse events [25].

Discussion

Because food is only a minor source of vitamin D, humans need exposure to sunlight, which in the end determines vitamin D synthesis. A lack of sunlight and (by consequence) vitamin D have been implicated as risk factors for developing MS and increased disease activity. Disease modifying treatment – to avert relapses and long-term disability – is expensive. This is where vitamin D supplementation might fill the gap as an affordable and safe alternative. Previous meta-analyses and reviews of this topic found no or at best unclear benefits for vitamin D supplementation in MS. For instance, the 2018 Cochrane Review categorically states: “Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions” [12].

This update looked once again at the RCTs that examined the effect of vitamin D supplementation on relapse rate, EDSS, changes in brain MRI lesion load and/or serum concentrations of NfL, and provided an adequate follow-up of at least a year. There were nine RCTs in patients with MS, all with a follow-up of ≥48 weeks [17–26]. Six out of nine studies were outright negative; that is, supplementing vitamin D did not improve any of the various outcome measures in MS. In the remaining three studies, one or more positive outcomes were attributed to vitamin D supplementation by the authors (see table 1). But these positive results have to be viewed critically. None of them is robust, because either the results were skewed by numerous dropouts or other confounders.

Apart from these methodological considerations, it should be kept in mind that practically all study patients already used established DMDs, which could have “diluted” any possible vitamin D effects. Strictly speaking, the lack of convincing evidence that vitamin D supplementation acts as a DMD in MS only applies when vitamin D is used as an “add-on” measure. Unfortunately, no RCT has actually studied vitamin D supplementation as a stand-alone alternative for other DMDs (despite the numerous speculations on this topic).

Furthermore, if there were any benefit from vitamin D, we cannot automatically assume that “more is better”. In two (negative) trials the controls also received vitamin D supplements (at a much lower dose), which theoretically still might have been effective [21, 24]. In the Kampman study, just over a quarter of the placebo group made continued use of previous vitamin D supplements (not seen as a protocol violation), which might have had a confounding effect [18]. Although “a protective effect of vitamin D intake on risk of developing MS” has been shown in large cohort studies [27], this association does not automatically imply that supplementation at a later date will reverse or attenuate the underlying pathophysiology in established disease.

Hedström et al. studied the hypothesis that vitamin D, although dependent on sunlight, might actually be just an innocent bystander. They calculated that the influence of vitamin D deficiency (on developing MS) is only 30%; i.e., there are effects mediated by sunlight but independent from vitamin D [28].

A similar conclusion has previously been published by an Australian group (again in predominantly white participants): “Sun exposure and vitamin D status may have independent roles in the risk of (central nervous system) demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention” [29].

In a multi-ethnic case/control study, Langer-Gould found evidence of an association between higher 25-hydroxyvitamin D levels and reduced MS risk among whites, “but no evidence of any protective effect in Hispanics and blacks” and they concluded that “the protective association of sun exposure is not explained by current serum (25-hydroxyvitamin D) levels in blacks, Hispanics or even fully in whites. This indicates that the protective effect of sun exposure is most likely mediated through immunomodulatory mechanisms independent of vitamin D” [30].

Previous studies have also indicated that vitamin D deficiency is not relevant for MS risk in blacks or Hispanics (only in whites) [31]. It seems that a person’s genetic make-up (which differs by race/ethnicity) is more relevant to individual MS risk than the actual vitamin D status.

The available evidence presently gives sunlight a bigger role than vitamin D – at least when it comes to the development of MS. Sunlight is a confounding factor in this scenario because it influences vitamin D levels and also the risk of developing MS, or potentially modifies the course of MS in persons with a certain genetic make-up (the association of low vitamin D levels and MS risk would be erroneously construed as causality).

How sunlight can be harnessed is unclear: On the one hand, because the crucial period regarding protective effects of sunlight exposure seems to be during childhood and early adolescence, before MS becomes symptomatic in the majority of cases [32]. And on the other hand, excessive sunlight exposure is generally discouraged by health authorities because of the risk of inducing skin cancer [33]. Clinical applications are still in their infancy (one underpowered RCT without a statistically significant effect regarding phototherapy) [34].

Apart from MS, vitamin D supplementation trials for other health outcomes have also been disappointing [35]. And inappropriate prescribing or self-medication can sometimes make vitamin D supplementation downright dangerous [5]. Does this mean that we can forget about vitamin D in MS entirely? To prove that vitamin D might be an alternative DMD we would have to conduct studies in a very large number of DMD-naïve patients for at least a year or more to reliably assess relapse rate, disability, brain MRI lesion load and/or NfL over time, and also assess sunlight exposure as a possible confounder. Given the enthusiastic publicity “vitamin D and MS” have generated so far, it might be hard (and some may consider it downright unethical) to recruit patients, because nobody wants to run the risk of being randomised into the placebo arm (or the results could be “contaminated” by participants using additional over-the-counter vitamin D supplements). The effort and expense for such a trial could be used to give all MS patients a vitamin D supplement at a reasonable and safe dose from the start, see “some vitamin D facts”. Even if we postulate that vitamin D is neutral with regards to MS, it is still a vital substance for the prevention of osteomalacia [11]. This would benefit in particular those MS patients with mobility issues who spend less time outdoors (in the sun), and those that do not tolerate heat/sun very well. Furthermore, when discussing affordable treatment options, bear in mind that giving up smoking is always worthwhile for people with MS [36, 37].

The appeal of vitamin D as a potential DMD in MS is its low cost. But presently we lack the evidence to recommend it for this purpose. The challenge now is to either conduct an appropriate trial or find other affordable DMDs for MS patients worldwide, for example by “resurrecting” a generic compound that has some data to back it up [38]. One might add that the World Health Organization list of essential medicines does not mention any DMD for MS (with the possible exception of rituximab) [39]. This is an area where further research and resources are needed in the future.

Disclosure statement

The author declares that there are no conflicts of interest, in particular none with a manufacturer of pharmaceutical products or nutritional supplements. This manuscript is not under review by another journal. This paper is based on previously published work, so no new studies in humans or animals were necessary.

Correspondence

Daniel Eschle, MD, MSc, Consultant Neurologist, Kantonsspital Uri, CH-6460 Altdorf, daniel.eschle[at]ksuri.ch

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