Serum Vitamin D Levels Predict Severity of MS
A 5-year prospective study suggests that low levels of vitamin D are a robust predictor of worse disease outcomes. But is vitamin D just a highly predictive marker or is it also a potential treatment?
Results from a 5-year prospective study demonstrate that people with low levels of vitamin D and early signs of MS get worse faster than people with higher vitamin D levels. In a study published online January 20, 2014, in JAMA Neurology (Ascherio et al., 2014), researchers at the Harvard School of Public Health confirmed a robust association between depressed vitamin D levels and the development of more severe measures of multiple sclerosis (MS)—including time to diagnosis, new lesions, volume of lesions, and brain volume.
The study, led by Alberto Ascherio, M.D., of the Harvard School of Public Health, confirms the association between depressed vitamin D levels and MS progression. The authors reported that MS patients with high blood levels of vitamin D had a 57% lower rate of new brain lesions, a 57% lower relapse rate, and a 25% lower yearly increase in lesion volume compared to those with the lowest levels of vitamin D.
Yet the study leaves unanswered the question of whether insufficient vitamin D itself causes a more aggressive disease course or if low levels of vitamin D are only a biomarker, not the cause. Of central importance, it’s still unclear whether treating MS with vitamin D could be therapeutic.
“It’s a very good study,” said Philippe Autier, M.D., director of the International Prevention Research Institute in Lyon, France, and author of a recent vitamin D review paper (Autier et al., 2013). “The data is really good. If I received this paper for review I would accept it without any problem.” But, he told MSDF, “The real problem is one of interpretation.”
The path connecting serum vitamin D levels and MS is a long and winding one. Depressed levels of serum vitamin D are associated with a number of diseases, including MS. But the reason for that connection is not so obvious.
In the case of MS, a series of logical steps makes the link. We know that people who grow up at high latitudes (north or south) have an increased risk of MS. The most obvious effect of latitude is exposure to sunlight, since people who live at higher latitudes see less sunshine than those who live closer to the equator. And the most obvious connection between sunlight exposure and health is vitamin D. Research on the bone disease rickets established long ago that the ultraviolet light in sunlight stimulates the synthesis of vitamin D in human skin and prevents rickets.
A series of studies have demonstrated that vitamin D levels in the blood are inversely correlated with the progression of MS. That is, people with high levels of vitamin D tend to have a milder form of the disease and people with low levels of vitamin D experience a more aggressive form of the disease.
Cause or effect?
What is not clear is what causes what. In other words, does MS cause vitamin D levels to fall, or do low levels of vitamin D cause an increased risk of MS? A third possibility is that neither vitamin D nor MS directly influences the other. Instead, an independent factor may be causing both depressed vitamin D and MS progression. And the fourth possibility is that low levels of vitamin D in utero, childhood and adolescence, or even in early adulthood could cause physiological changes that increase the risk of MS later in life.
The current study was meant to distinguish between the first two alternatives. The study’s authors reasoned that by looking at vitamin D levels very early in disease progression, they could minimize the likelihood that depressed vitamin D levels resulted from the disease itself. Using data from 465 patients from Bayer Health Care’s BENEFIT test of interferon β-1b treatment, the authors measured disease outcomes starting 12 months after the start of the original study. “We are removing any outcomes that may have happened in that first 12 months,” Kassandra Munger, M.Sc., one of the study’s authors, explained to MSDF. “So patients’ vitamin D levels become predictive of what’s going to happen 12 months out.”
Says Munger, “There are some critics of the etiology of our work [who say] ‘You don’t really know when MS starts.’ ’Maybe the vitamin D levels you are measuring aren’t truly before onset.’ Those are issues we try to get around by putting as much time as we can between when we measure vitamin D and when MS starts.”
Autier is one of those critics. He says he’s convinced the causality works the other way, arguing that the illness and inflammation associated with MS cause depressed vitamin D levels. While he didn’t exclude the possibility that vitamin D levels early in life might influence MS risk in adults, he says there’s no evidence for that so far. “There’s no reason to treat people with high doses of vitamin D. At this moment we see no advantage of doing so,” he said.
But Munger and Ascherio think it makes sense to provide supplemental vitamin D to MS patients, most of whom have depressed vitamin D levels. In their paper, they conclude, “… our results suggest that identification and correction of vitamin D insufficiency has an important role in the early treatment of MS.” And in a Harvard University press release, Ascherio went a step further, arguing, “The findings of our study indicate that identifying and correcting vitamin D insufficiency should become part of the standard of care for newly diagnosed MS patients.” The authors concluded that “low vitamin D was not a consequence of the disease process itself but rather its predictor” and that “the inverse association between vitamin D intake and MS risk and the beneficial effect of vitamin D in animal models of MS favor a role of vitamin D itself.”
MSDF asked Nicholas Jewell, Ph.D., of the University of California, Berkeley, to read Ascherio’s paper and give his opinion. Jewell is a biostatistician with no intellectual stake in either MS or vitamin D research. He agreed that the data were interesting and good, but described the conclusion that vitamin D supplements were a likely treatment as “a leap of faith.” After reading the paper on a cross-country flight and drawing some causal diagrams, he concluded, “That’s not supported at all by this data. I remain to be convinced.” The study also doesn’t rule out the possibility of a third factor, he says, a factor that causes both low vitamin D levels and rapid MS progression. But “just because you see an association naturally in your system does not mean that taking a vitamin supplement will have any impact whatsoever.” Nevertheless, he’s not siding with Autier.
“This is a very tricky thing to do until you do randomized trials,” Jewell said. A currently running clinical trial called SOLAR does just that, assigning patients randomly to receive high doses of a patented vitamin D supplement from Merck. But the results will not be out until March of 2015. Autier, for one, is betting against the supplement working. “Why not?” he laughs. “We’ll see. They use a very high dose. I would bet 1 against 10 they will get nothing.”
Key open questions
- Why is low serum vitamin D associated with worse MS outcomes?
- Do ill health and inflammatory processes generally lower vitamin D levels in the blood?
- To what extent do low levels of vitamin D in utero and early life influence the risk of MS later in life?
- Is early (or concurrent) exposure to sunshine the primary mediator for setting serum vitamin D status and MS risk, or is UVB exposure an independent factor?
- What is the mechanism by which treatment with vitamin D might be expected to slow progression of MS?
The various authors of the JAMA Neurology study reported relationships with the following commercial entities: Acorda, Actelion, Allozyne, Almirall, BaroFold, Basilea, Bayer HealthCare, Bayer Schering Pharma, Bayhill, Biogen-Dompé, Biogen Idec, Boehringer Ingelheim, Eisai, Elan, EMD, Genentech, Genmab, Genzyme, GlaxoSmithKline, MediciNova, Merck Serono, Neurotec, Novartis, Roche, Sanofi-Aventis, Santhera, Shire, Teva, UCB, and Wyeth. Dr. Autier and Dr. Jewell declared no relevant conflicts of interest.
Over at his Mulitple Sclerosis Research Blog, Dr. Gavin Giovannoni has written some interesting commentary on this study. An excerpt: