Editor’s note: This is the second story in a three-part report examining experts’ answers to the question “Should vitamin D supplements be recommended for MS patients?”, which was a topic discussed at this year’s Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Here, we take an in-depth look at the arguments presented in favor of vitamin D supplementation.
‘Yes’ to Vitamin D Supplements
In his presentation, “MS patients should be advised to take vitamin D for MS,” Ascherio highlighted two landmark studies in which researchers showed there is an inverse link between vitamin D and MS risk.
Pooled data from the two large studies, Nurses’ Health Study (NHS) and Nurses’ Health Study II, (involving more than 187,000 women at the time) were the only prospective studies looking at the link between taking vitamin D and MS risk. The results showed that women with the largest overall intake of vitamin D (approximately 700 IU/day, both from diet and supplements) were about 33% less likely to develop MS, compared with those with a lower intake (approximately 60 IU/day).
Ascherio showed that, in contrast to vitamin D coming from diet (which had no significant association), women who used vitamin D supplements (400 IU/day or more) had a 41% reduced risk of developing MS compared with non-users.
In another key study, researchers did repeated measures over time of serum vitamin D levels in more than 7 million men and women from the U.S. military. Again, individuals with higher vitamin D levels (measured as 25(OH)D, or 25-hydroxyvitamin D) were less prone to develop MS years later, even after controlling the data for age, sex, and race/ethnicity. Those results also were confirmed in large studies done in Sweden and Finland, Ascherio noted.
“This brought in the question of what happens in individuals who already have MS?” the researcher said.
Randomized controlled trials to address this question face “numerous obstacles” that have resulted in limitations and uncertainties, Ascherio said.
“That’s because individuals with MS, because of their symptoms, may change their behavior. Individuals with more severe disease are less likely to go to the beach or expose themselves to UV light; they can change their diet, and in particular, they can take vitamin D supplements,” he noted.
Furthermore, MS patients can change treatment, which could make major symptoms disappear or be associated with side effects.
“So, how to deal with all that? I think it’s a major, major challenge,” Ascherio said.
Data supporting benefits of supplement
“We had the unique opportunity to look at vitamin D levels very early in the course of the disease, at the time of the first demyelination symptoms,” he said.
In the study, serum concentrations of 25[OH]D (what is typically measured in a blood test) were assessed over the first two years in people who had their first neurological attack, or clinically isolated syndrome (CIS). Researchers then looked at what happened in the long-term disease course in intervals of three, five, and 11 years.
The first results, released in 2014, showed that within the first year of CIS, individuals with high vitamin D levels “had a markedly lower risk of new active lesions, lower EDSS [disability level] increase, lower brain volume loss,” Ascherio said, suggesting that vitamin D levels also are “important in individuals with MS.”
According to him, a rise in vitamin D serum levels from less than 50 nmol/L to 100 nmol/L (or above) provides a clinically significant benefit.
But how can a clinical trial properly test this hypothesis?
A small, randomized, double-blind, placebo-controlled trial done in Finland, in which patients received 20,000 IU/week (about 3,000 IU/day) of oral vitamin D3 as add-on treatment to interferon beta-1b (their median vitamin D concentration was 50 nmol/L), showed a significant reduction in the number of active brain lesions and trends favoring the vitamin D group.
But statistically significant associations were hard to obtain, Ascherio noted, because the study was too “underpowered,” given the few patients enrolled (about 65 patients). Nonetheless, in his opinion, there was “a clear benefit in terms of the magnitude of the effect,” which was consistent with prior studies.
Of note, 3,000 IU of oral vitamin D3 per day, is “what I formally recommend when people ask me how much vitamin D should people with MS take,” Ascherio said, because with that amount, serum levels go from 50 nmol/L to a minimum of 100.
Current trials do not address ‘key question’
None of the recent or ongoing trials are addressing the key question, “which is what should we do with our patients when half of them are below 50 nmol/L” of vitamin D. “So, we are left in a situation in which we need to make a decision based on incomplete evidence, [based on] our best judgment,” Ascherio said.
Regarding safety, high levels of vitamin D supplements can be toxic, but according to the researcher, at a dose of 3,000 IU per day, “it’s completely safe, there is no evidence of significant side effects, and the probability of giving a benefit I would put it at 80% if you don’t know the vitamin D level of your patient, and probably higher if you do.”
Yes, but in moderate doses
At ECTRIMS, Mowry provided insights to the pros and cons of the routine use of vitamin D supplements in clinical practice, and explained why she advises her patients to take it in low doses.
She first focused on the association between MS risk and vitamin D and UV light exposure.
Mowry emphasized data from a 2011 Australian study showing that “it’s really UV light measures, indications of sun exposure, that appear to be most relevant for MS risk, with a much stronger association between higher cumulative UV light doses and lower odds of subsequent MS, than the effect estimates for vitamin D levels.”
Another important factor to take into account is race, as vitamin D levels “may not have the same meaning across races,” Mowry said.
In a 2018 study, researchers found that vitamin D levels in white people were associated with MS risk — with higher vitamin D levels being associated with lower odds of MS — but such association was not true in Hispanics or blacks.
In contrast, “in all three groups, sun exposure was linked with MS risk — with higher amounts of UV exposure in the past, being associated with a lower odd of MS,” Mowry said.
She suggested this could be justified by a differential metabolism of vitamin D, as genetic findings suggest that blacks “may be more efficient users of vitamin D, so perhaps the levels are not as relevant.”
“Or perhaps it is just because vitamin D is a better marker for sun exposure in white individuals [who have less pigment on their skin], and the risk is mediated through a different mechanism,” she added.
According to Mowry, particularly from the mid-2000s, “vitamin D supplementation became trendy in MS,” as many “began extrapolating the data to the MS clinic, where MS patients were routinely supplemented with varying degrees of vitamin D.”
To shed more light on this question, Mowry led a study, called EPIC, in which a group of relapsing MS patients were followed for five years to determine whether vitamin D status is associated with inflammatory lesions on brain MRI scans.
At the beginning of the study (2004–2005), very few MS patients reported taking vitamin D supplements, whereas five years later “there was a 8.5 higher odds of people reporting vitamin D supplementation.” For Mowry, this suggests that clinicians and patients “had really taken these risk studies, and interpreted them for their own benefit.”
Data supporting or refuting supplementation in MS
Mowry’s and another research group in Australia published studies suggesting that higher vitamin D levels are associated with a lower relapse risk both in children and adults, and importantly “this association was linear.”
Furthermore, a five-year follow-up of the EPIC study showed an inverse association between vitamin D levels and inflammatory MRI outcomes, with higher levels lined with “about a 15% reduction in the risk of new T2 lesions, [and] about a one-third reduction in the risk of gadolinium-enhancing lesions.”
A small pilot study testing the immunological effects of low- versus high-doses of vitamin D supplements, also showed that supplementation was associated with favorable changes in the pattern of immune cells, with a reduction in IL-17-producing T-cells and memory T-cells, which are involved in inflammation.
Regarding other clinical outcomes, “also relevant to our MS patient population is long-term disability, and we know that changes in brain volume — particularly in gray matter volume — may be prognostic for subsequent clinical changes over a long period of time,” Mowry said.
In the STAyCIS trial, which evaluated the effect of atorvastatin (a cholesterol-lowering medication) in a small group of individuals with CIS, higher levels of vitamin D “were associated with a meaningful preservation of normalized gray matter volume,” she added.
In animal models, vitamin D supplementation also was associated with less nerve fiber loss.
In contrast, evidence from a recent animal study suggests there is a “sweet spot” for vitamin D doses, as a high dose exacerbates central nervous system autoimmunity. Mice receiving a standard dose of vitamin D had lower clinical disease scores, but those receiving very high doses (associated with excess calcium levels) actually had worse clinical outcomes.
“In our EPIC study … we also did not find that vitamin D levels were associated with brain volume changes over the 5-year study, so perhaps what we have seen in the CIS group had different implications,” Mowry said.
Similar results were seen in patients enrolled in the SPRINT-MS trial (NCT01982942), which evaluated ibudilast‘s effectiveness for treating progressive MS; the data showed that “vitamin D levels did not appear to be associated with meaningful disability and imaging clinical outcomes.”
Current knowledge and future ahead
“There are a few ongoing trials, but we have to yet await their results,” Mowry said. In the meantime “we are still left with an unanswered question, but as clinicians we are still forced to make a decision when we are talking to a newly diagnosed patient about whether or not we should advocate for vitamin D supplementation, and also what dose to take and what frequency.
“I talk pretty frankly with my patients about the holes in the evidence, what we don’t know and what we do,” Mowry said. While waiting for additional evidence, she said, she tends to “do some modest supplementation of people with low levels of vitamin D; and instead of giving a generic advice of a certain dose for an individual, I usually treat to a target of vitamin D levels, typically between 40 to 60 ng/mL.”
According to Mowry, 40–60 ng/mL are the levels most supported by observational data. “For my patients, that means they typically need anywhere between 2,000 IU and 5,000 IU per day, and as long as they don’t have changes in their dosing per weight, I would just recheck it in three months, and if they’ve hit their target they should be good to go.”
This recheck is important, because MS patients don’t seem to metabolize vitamin D as efficiently as healthy people, Mowry emphasized.
On the safety topic, the neurologist said there is no evidence that higher doses are helpful, and they actually can be considered potentially harmful.
“Mega-doses of vitamin D are probably not safe, based on what we know from the general population, and we don’t know about long-term effects,” Mowry said. “So, I typically don’t recommend very high and intermittent doses of vitamin D, but tend to stick to a more low dose daily recommendation.”
“I always say to patients, if you’re gonna choose between vitamin D supplements and getting a good night’s sleep, eating healthy food and exercising, perhaps focus on your broader lifestyle … but for now, we do continue to recommend modest doses of supplementation,” she concluded.