The role of vitamin D in the treatment of multiple sclerosis (MS) took centre stage during the first day of ECTRIMS 2019 in Stockholm, Sweden. In a ‘Hot Topic’ session, Ellen M Mowry, Associate Professor of Neurology and Epidaemiology at Johns Hopkins University (Baltimore, MD, USA) took to the stage to comment on evidence for vitamin D use in clinical practice.
Studies have suggested a 50–60% reduced risk of MS among those with the highest 25-hydroxyvitamin D levels (a prehormone produced by hydroxylation of vitamin D3), indicating that there is an inverse relationship between vitamin D levels and MS.1,2
“But there have been some subsequent studies which have challenged whether this association is truly causal or not,” commented Dr Mowry. Indeed, Lucas et al.3 suggested that it is really increased UV light exposure that appears to be the most relevant driver for lowering MS risk, with a much stronger association than vitamin D itself. Diving deeper, Langer-Gould et al.4 reinforced that higher vitamin D levels in white individuals were inversely linked to MS risk, yet those associations were not true in hispanic or black individuals. Sun exposure was inversely linked with MS risk in all groups.
“Perhaps this relates to differential metabolism of vitamin D,” said Dr Mowry, adding that it has been suggested that vitamin D is more readily increased in those with lighter skin pigment.
“Nonetheless, a lot of MS clinicians took these data, particularly from the mid 2000s, and began extrapolating the data to the MS clinic, where MS patients were routinely supplemented with varying levels of vitamin D.”
At the start of the EPIC study5, initiated in 2004 by the University of California San Francisco, very limited numbers of patients were taking extra vitamin D supplements. Five years later, there was an 8.5-fold higher rate of patients reporting supplementation. “This suggested that clinicians and patients had really taken the risk studies and interpreted them for their own benefit,” said Dr Mowry.
In 2010, and following EPIC, new data on vitamin D levels were found to be inversely associated with relapse risk in MS, with a clearly linear trend in moderate doses.6,7
Dr Mowry et al. then followed up in nearly 500 individuals from EPIC in 2012.8 They sought to determine whether vitamin D status is associated with development of new T2 lesions or contrast-enhancing lesions on brain MRIs in relapsing MS.8 Results indicated an inverse association with vitamin D levels and inflammatory outcomes, with an approximate one-third reduction in gadolinium-enhancing lesions, a 15% reduction in new T2 lesions, and a non-statistical reduction in relapse.
Then, Sotirchos et al. uncovered that high-dose in vivo vitamin D supplementation was associated with favourable changes in immunophenotype (including reduction of interleukin-17 production by CD4(+) T cells and decreased proportion of effector memory CD4(+) T cells).9
“But what about other outcomes?” said Dr Mowry. “We talk a lot about relapses and inflammatory events, but of course also relevant to our MS patient population is long-term disability, and we know that changes in brain volume, in particular grey matter volume, may be prognostic for subsequent clinical changes.”
Importantly, she added that vitamin D has been purported to have associated risk of developing other neurodegenerative diseases, so its possible role in long-term disability needs to be examined.
In the STAyCIS randomised control trial10, higher levels of vitamin D were associated with meaningful preservation of normalised grey matter volume. This year, Nystad et al. found that high doses of vitamin D administered before or during demyelination were associated with less axonal loss.11
On the other hand, Hausler et al. determined that very high doses of vitamin D exacerbate central nervous system autoimmunity by raising T-cell excitatory calcium.12 “Perhaps there is too much of a good thing,” said Dr Mowry.
In the EPIC study, a follow-up publication, Dr Mowry and colleagues did not find any association between vitamin D levels and brain atrophy (whole brain or grey matter).13 Similar results were also seen elsewhere.14
Adding contrasting data once again, this year the randomised CHOLINE trial of high-dose vitamin D – spanning 24 months – revealed no meaningful difference in annualised relapse compared to placebo.15 Other large trials are still ongoing.
Taking on board all of this data, Dr Mowry commented: “I think 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 at what dose and frequency.
“I talk pretty openly with my patients about the holes in evidence … but I still tend – while waiting for additional evidence – to do some modest supplementation for people with low levels of vitamin D.”
She added: “I usually treat to target vitamin D levels, typically 40–60 ng/mL, because I think that those are the levels most supported by observational data. I also think we [will avoid] getting into serum levels that have been associated with toxicities in other studies.”
Also important, she stressed, is regularly re-checking vitamin D levels in MS patients to avoid individual toxicity risk based on metabolic factors.
Offering several conclusions for the audience, Dr Mowry first underlined that vitamin D levels have been demonstrated on several occasions to be inversely associated with MS risk and, in early established MD, inflammatory activity and brain atrophy. However, racial variability and its causal nature (i.e. UV-driven) should be considered.
Second, she stressed that randomised MS trials have failed to meet their primary endpoints, thus larger datasets – and even short-term trials – will need to be built upon to understand more about high-dose effects in the long term.
Finally, she reiterated that, for now, the decision of whether to supplement with vitamin D should be based on individual patient characteristics until more data are collected.
For more coverage from ECTRIMS 2019, please click here.
- Munger et al. JAMA. 2006;296:2832–8.
- Salzer et al. Neurology. 2012;79:2140–5.
- Lucas R, et al. Neurology. 2011.
- Langer-Gould et al. Nutrients. 2018.
- UCSF. EPIC Study.
- Mowry EM, et al. Ann Neurol. 2010.
- Simpson et al. Ann Neurol. 2010.
- Mowry EM, et al. Ann Neurol. 2012.
- Sotirchos E, et al. Neurology. 2016.
- Mowry EM, et al. Journal Neurol. 2016.
- Nystad A, et al. J Neuroimmunol. 2019.
- Hausler et al. Brain. 2019.
- Mowry EM, et al. Neurology, 2018.
- Abbatemarco J, et al. MSARD. 2019.
- Camu et al. N2. 2019.