Does a Vitamin D Deficiency Elevate the Risk of Multiple Sclerosis?

Check out this answer from Consensus:

The evidence suggests that vitamin D deficiency is a significant risk factor for the development of MS. While vitamin D supplementation shows promise in modulating immune responses and potentially impacting disease activity, further research is needed to establish optimal dosing regimens and long-term safety. Given the high prevalence of vitamin D insufficiency, especially in temperate regions, addressing this deficiency could have important public health implications for reducing the risk of MS.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) characterized by demyelination and axonal damage. The etiology of MS is multifactorial, involving genetic predisposition and environmental factors. Among these, vitamin D deficiency has garnered significant attention as a potential risk factor for the development and progression of MS. This article explores the relationship between vitamin D deficiency and the risk of MS, drawing on findings from recent research studies.

Vitamin D and MS Risk

Epidemiological Evidence

Several epidemiological studies have suggested a strong association between low levels of vitamin D and an increased risk of developing MS. For instance, a study conducted on the Finnish Maternity Cohort found that maternal vitamin D deficiency during early pregnancy was associated with a nearly two-fold increased risk of MS in offspring4. Similarly, research using the Danish Newborn Screening Biobank indicated that low neonatal vitamin D levels were linked to a higher risk of MS later in life7.

Genetic Factors

Genetic studies have also highlighted the role of vitamin D in MS. A low-frequency synonymous coding variant in the CYP2R1 gene, which significantly affects vitamin D levels, was found to increase the risk of MS5. This genetic predisposition underscores the importance of adequate vitamin D levels in potentially mitigating the risk of MS.

Vitamin D and Disease Progression

Clinical Trials and Meta-Analyses

Clinical trials and meta-analyses have investigated the therapeutic potential of vitamin D supplementation in MS patients. A meta-analysis of randomized, double-blind, placebo-controlled clinical trials revealed that vitamin D supplementation had no significant therapeutic effect on disability or relapse rates in MS patients1 2 3. However, some studies suggested non-significant trends favoring vitamin D for various outcome measures, indicating a need for further research to determine optimal dosing and duration2.

Immunoregulatory Effects

Vitamin D is known to have immunomodulatory effects, which may be relevant to the pathophysiology of MS. It influences various immune cells, including T and B lymphocytes, and has been shown to exert beneficial immunomodulatory effects in MS patients7 8. These effects may help reduce inflammation and modulate the immune response, potentially impacting disease activity and progression.

Potential Mechanisms

Molecular and Cellular Pathways

Vitamin D deficiency has been linked to several molecular and cellular pathways that may contribute to MS. For example, developmental vitamin D deficiency in animal models has been shown to dysregulate brain proteins involved in oxidative phosphorylation, redox balance, and synaptic plasticity, which are critical for maintaining CNS health10. These findings suggest that vitamin D plays a crucial role in maintaining neuronal function and integrity.

Interaction with Other Risk Factors

Vitamin D insufficiency may interact with other genetic and environmental risk factors for MS, such as HLA-DRB1*1501 allele, Epstein-Barr virus infection, obesity, smoking, and hormonal factors9. These interactions may modulate the overall risk of developing MS, highlighting the complex interplay between various factors in the disease’s etiology.

 

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Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Dimitry Krementsov has answered Likely

An expert from University of Vermont in Immunogenetics, Cell Biology, Microbiology

The previous answers sum it up nicely – the evidence for low vitamin D as a predictor of MS risk is strong. The more recent Mendelian randomization studies also lend support to it having a causative role. Unfortunately, as mentioned above, clinical trials have not shown a consistent benefit to supplementation (e.g. this recent metanalysis: PMID: 29778041), and there are many potential reasons for this, some of which are described in the other posts. 

Nonetheless, allow me to add two caveats:

Genetics matter

The association between low vitamin D and increased MS risk only holds up in white populations, but not in black and Hispanic populations, as already seen in the original landmark paper by Ascherio and Munger (PMID: 17179460), and subsequently in a number of other studies (e.g., PMID: 21606454, 2258825, 24620971, 28975580, 29495467, 29414925). We also have experimental evidence supporting this notion (Krementsov, et al, under review). Hence, the genetic background may modify the influence of vitamin D status on MS risk.

Sunlight is important

As alluded to by Dr. Smolders above, exposure to UV-B radiation (in the form of sunlight) is well-documented to have vitamin D-independent effects on the immune system that could theoretically prevent MS, and vitamin D levels are of course highly related to sun exposure habits. A review by Prue Hart and colleagues sums this up nicely here (PMID: 26477548). Hence, increasing vitamin D levels through increasing sunlight or UV-B exposure, rather than vitamin D supplementation, would be a theoretically more beneficial approach. There are in fact trials underway to test this (PMID: 29780610).

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Prue Hart has answered Likely

An expert from University of Western Australia in Immunopathology

If one considers blood 25-OH vitamin D levels (not vitamin D per se), one could state that a deficiency is a risk factor for multiple sclerosis. However, this does not support a causal role for vitamin D metabolites in MS pathogenesis, and trials of vitamin D supplementation to MS patients have generally been disappointing. One must reflect that low 25-OH vitamin D levels merely reflect in most individuals a lack of sun (and UV radiation (UVR)) exposure over the past 2 months. In addition, 25-OH vitamin D has yet to be metabolised into the metabolite, 1,25 dihydroxy vitamin D, for activity. Genetic polymorphisms coding the enzyme for conversion of 25-OH vitamin D to 1,25 dihydroxy vitamin D have been identified as a risk factor for MS and similarly, polymorphisms for the enzyme breaking down 25-OH vitamin D and 1,25 dihydroxy vitamin D.

If UVR-induced vitamin D, and its metabolites, are of little benefit to MS patients, it is the properties of other UVR-induced molecules that may explain the inverse associations between serum 25-OH vitamin D levels and MS risk. Why would evolution have allowed only one molecule to be made in our skin? A review in Nat Rev Immunol in 2011 discusses several UVR-induced immunomodulatory molecules (Hart et al). An interesting article has been published by Simpson and colleagues in Feb 2018 in Front Neurol 9(16), Sun Exposure across the life course significantly modulates early MS clinical course. Interestingly, this was in contrast to no significant links with pre-MS 25(OH)D levels. Another article worth reading is by Langer-Gould et al, Nutrients 2018, 10:184 titled Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis. The contents of both articles challenge any role for vitamin D in MS pathogenesis.

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Robyn Lucas has answered Likely

An expert from Australian National University in Epidemiology

There are now many studies that show that a low level of vitamin D (or really 25-hydroxyvitamin D since that is what we use to measure vitamin D status) in the blood is associated with an increased risk of MS.

Many people believe that low blood 25OHD should now be considered to be an established risk factor for MS. But what we also know is that several vitamin D supplementation studies have shown very little benefit (at least clinically) for people with MS. Now this could be because onset of MS has different risk factors to progression of MS, or it could be that the vitamin D supplementation studies have been done in people who already have sufficient 25OHD levels and supplementing doesn’t then make any difference.

I would argue that we need to also consider what 25OHD level is measuring. For most people, in most of the studies that have provided this evidence, the 25OHD comes from sun exposure. There have been a couple of studies that have tried to show that higher intake of oral vitamin D is also associated with reduced risk of MS, but they have been unconvincing. For example, one nested case-control study showed that total vitamin D intake (supplements + diet) was associated with lower risk of MS, but the supplement data assumed that multivitamins (the main supplement) all contained 400 IU of cholecalciferol. Dietary intake alone was not associated with reduced MS risk, and it is not clear, at the time the data were collected, that supplements did contain this amount of vitamin D. So it could be that something else in the supplements was driving this effect – it is very weak evidence of a vitamin D effect per se.

Exposure to sunlight – especially exposure of the skin to UV radiation – is the main source of vitamin D (and the main determinant of higher 25OHD levels). But when skin is exposed to UV radiation, the UV photons are absorbed by a wide range of molecules in the skin – DNA, trans-urocanic acid, tryptophan, and others – with sequelae, including DNA damage (that may eventually lead to skin cancer), but importantly changes in immune function. These changes tend to drive a more regulatory immune milieu – that would plausibly ‘control’ the aberrant immune response that is core to the development of MS. The question has thus become – is it vitamin D or sun exposure that is protective for MS. But really that is the wrong question – it is more – how much of the protective effect of sun exposure for MS is mediated by vitamin D (higher 25OHD is a marker of recent sun exposure). That question is important because it tells us how much of the sun exposure effect could be achieved through vitamin D supplementation, rather than advising people to expose their skin to the sun.

We have recently published that, not only does higher sun exposure over the lifecourse reduce the risk of MS (but this could just be a vitamin D effect), but also that higher sun exposure over the lifecourse reduces the risk of progressing from CIS to MS, and higher sun exposure (but not 25OHD) after a diagnosis of CIS is associated with reduced risk of progression to MS and lower relapse rate post-MS diagnosis. Our recently published PhoCIS study ( Hart et al, Mult Scler J 2018) reported the results of a very small trial of UVB phototherapy in people with CIS, in relation to conversion to MS. 100% of the people who did not receive phototherapy had developed MS by 12 months from diagnosis of CIS, but only 70% of those in the phototherapy arm did. The result was not statistically significant, very possibly because of the small sample size. However, we believe this is a promising result that needs further evaluation in a larger study.

So yes, I do believe that vitamin D deficiency (as in 25OHD <50nmol/L) increases the risk of MS. But I do not believe that vitamin D supplementation to achieve high 25OHD levels will reduce the risk of MS – but regular sun exposure to achieve vitamin D sufficiency may reduce the risk of MS (and this may be particularly important during pregnancy and childhood).

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Marianna  Cortese has answered Likely

An expert from Harvard University in Nutrition

The evidence on the role of vitamin D in determining the risk for MS is convincing.

There are major prospective studies conducted in different populations (e.g. in the US, Sweden, Finland) indicating that vitamin D deficiency increases the risk of developing MS. Furthermore, recently two well-designed Mendelian randomization studies suggested that genetically determined vitamin D levels predict MS risk, providing so far the most causally interpretable evidence. Considering that a primary prevention trial on the effect of vitamin D against MS is unlikely to ever be conducted, as such a trial would neither be ethical nor feasible, recommendations for public health intervention like universal vitamin D supplementation will need to rely on well-designed observational investigations like these, and more prospective studies are needed to investigate ideal timing of the supplementation and potential group differences, for example by sex or by ethnicity.

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Joost Smolders has answered Likely

An expert from Netherlands Institute for Neuroscience in Neurology, Immunology, Phytopathology

A low vitamin D status likely increases MS risk, but to which extent is uncertain. 

In a landmark study, people who developed MS in later life had lower 25-hydroxyvitamin D (25(OH)D) levels in their circulation prior to disease onset (Munger et al., JAMA 2006). The question is why these levels are lower. This may be due to a limited sunlight exposure, the most important source of vitamin D which has immune-suppressive effects by itself. Alternatively, an already more active immune system or subclinical-disease activity may lower 25(OH)D-levels in an inflammatory reaction. The strongest message that vitamin D affects MS risk comes from the genetic studies: genetic variations which are associated with low 25(OH)D levels are also (cumulative) risk-alleles for MS (Rhead et al., Neurol Genet 2016; Manousaki et al., Am J Hum Genet 2017). Since all explanations are possible and likely interact, it is difficult to dissect to which extent vitamin D influences the risk of MS. 

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Aravind Ganesh has answered Likely

An expert from University of Calgary in Neurology, Epidemiology

Both cross-sectional and longitudinal studies have fairly consistently demonstrated a strong positive correlation between vitamin D deficiency and subsequent relapse and/or disability in patients with MS. As well, there appears to be a negative correlation between vitamin D levels and inflammatory markers in MS patients, suggesting that vitamin D modifies serum cytokines (blood markers of inflammation) to a more anti-inflammatory profile. There is preliminary evidence from longitudinal studies and randomized clinical trials (RCTs) of supplementation that vitamin D can attenuate the autoimmune response in patients who already have MS, and potentially reduce relapse rates and burden of disease (Ganesh et al, MSARD 2013).

Ultimately, however, as Dr Smolders (a far, FAR greater expert on this topic than me) pointed out, current evidence does not permit us to definitively infer a causal relationship between vitamin D deficiency and disease onset or activity in MS. That being said, vitamin D supplementation appears to be a promising treatment, but owing to the paucity of RCTs with placebo or comparator arms, the evidence is not definitive and appropriate dosing remains uncertain. Despite the absence of definitive evidence, many of my colleagues and I routinely recommend it to patients with MS or those with single episodes at risk of developing MS given the low risk of the treatment itself.

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Brent Richards has answered Near Certain

An expert from McGill University in Genetics

The short answer is that the best available evidence suggests strongly that lowered vitamin D elevates the risk of multiple sclerosis (MS). Below, I’ve tried to explain the long answer.

Before I explain the evidence to support this statement, I’d like to point out that this does not necessarily mean that treating people who already have MS with vitamin D will improve their disease.

Some of the evidence that supports the role of lowered vitamin D levels in increasing the risk of MS is summarized briefly:

1. Nurses who had higher levels of vitamin D were protected against the onset of MS (PMID: 14718698)
2. Lower vitamin D levels in US military personnel were associated with an increased risk of MS (PMID 17179460)
3. And most interestingly, even lower levels of vitamin D in newly born babies was associated with an increased risk of MS later in life. (PMID 27903815)

However, the above studies do not allow us to conclude that lower vitamin D levels cause MS since they can test associations only, which may be influenced by confounding, where the vitamin D levels may actual act as a proxy for another causal factor, which is unmeasured, or improperly measured in the study.

Modern genetic methods can allow us to test if these associations are more likely to be causal by asking if the genetic variants that lead to lowered vitamin D levels are associated with MS. This study type overcomes confounding because genetic variants are randomly assigned at conception, much like treatment is randomly assigned in a randomized controlled trial. Such studies are called Mendelian randomization studies.

Mendelian randomization studies have consistently shown that genetically lower vitamin D levels are strongly associated with a higher risk of MS:

1. Taken together, the genetic variants that lower vitamin D levels strongly increased the risk of MS in a cohort of 14,498 cases and 24,091 controls (PMID 26305103)
2. Further, a recent study identifying an additional vitamin D lowering genetic agent, with large effects on vitamin D levels was associated with large effects on risk of MS (PMID: 28757204).

Last, I’ll point out that the best way to test whether vitamin D can protect against MS is to do a randomized controlled trial of giving vitamin D and finding out if the people who were assigned to vitamin D tablets were protected against MS. However, such a trial will likely never be done. This is due in part for the following reasons:

1. MS is (thankfully) a rare disease, this means that a very, very large sample of people would have to be enrolled in such a trial.
2. It is possible that the vitamin D may need to be given at a very early age, and people would have to be followed until at least the mean age of onset of MS, which would be several decades.
3. Vitamin D is not patentable. Therefore, such a trial would be reliant upon the limited means of government/charities to organize a trial. Because the trial would be large and long, it would be very expensive.

In summary, the best available evidence suggests that lower vitamin D levels do increase the risk of MS. This does not mean that even most people with lowered vitamin D levels will get MS. But it does suggest to me that those with a strong risk of MS (such as having a first-degree family member with MS) should make sure that their vitamin D levels are adequate.

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Bruce  Hollis has answered Near Certain

An expert from Medical University of South Carolina in Biochemistry

First let me say that everyone wants evidence based medicine to answer this question. That being said, we will never have a randomized clinical trial, RCT, to prove that vitamin D can prevent MS. I know this because several years ago MS experts were called to a meeting by The National MS Society to try to design such an RCT. In the end such a trial was estimated to cost 10’s of millions of dollars and would have consumed The MS Society’s entire budget for at least 5 years. Needless to say it did not and will not happen. Thus we are left to look at retrospective observational trials, meta analysis and genetics looked at by Mendelian randomization studies. ALL of these study types have concluded that vitamin D deficiency is a major risk factor for developing MS. If one wants to read about these things in detail you can access the PubMed web site and search it for information. My belief is that MS could be prevented later in the infants life if pregnant women have a 25(OH)D blood level of at least 40 ng/ml. To attain this level would generally require mothers to take 4000 IU/day vitamin D preferably prior to conception. Once MS is established vitamin D will not cure it but it will likely help in alleviating some of its symptoms.

 

Does a vitamin D deficiency elevate the risk of multiple sclerosis?

Kassandra Munger has answered Likely

An expert from Harvard University in Epidemiology, Nutrition

It is important to distinguish between vitamin D sufficiency as reducing the risk of MS and vitamin D deficiency increasing risk of MS. In two of the three prospective studies conducted, vitamin D deficiency per se was not reported either due to lack of deficiency in the population (Munger JAMA 2006) or results not included in the publication (Salzer Neurology 2012). The conclusion from these studies is that high vitamin D levels (>=75 to >100 nmol/L) are associated with a reduced risk of MS. In the one study where there was a large portion of the sample with deficient vitamin D levels (<=30 nmol/L) (Munger Neurology 2017), there was an increased (~2-fold) risk of MS. Further studies in generally vitamin D deficient populations are needed. As noted by others here, these studies certainly do not mean this association is causal. The Mendelian Randomization studies do lend support to a causal role of vitamin D in determining MS risk. However, considering the vast literature on vitamin D, sun exposure, and related genetics and MS, it does appear quite likely that vitamin D has a role in MS etiology.