Low Vitamin D Predicts Progression in MS

January 24, 2014

More support for the idea that that low vitamin D levels contribute to the progression of multiple sclerosis (MS) has come from a new study reported this week.

The study was led by Alberto Ascherio, MD, Harvard School of Public Health, Boston, Massachusetts, who described the findings in an interview with Medscape Medical News as "some of the strongest evidence yet on the role of vitamin D in MS."

"Our results suggest that identification and correction of vitamin D insufficiency has an important role in the early treatment of MS," the researchers conclude in their report.

"We have previously shown that low levels of vitamin D are associated with a higher risk of developing MS," in a paper published in the JAMA in 2006, Dr. Ascherio told Medscape Medical News. "Now we have shown that patients with MS have a worse prognosis if they have low vitamin D levels.

"Many neurologists are already aware and do screen and supplement their MS patients, but many do not," he added. "I hope this paper will make a difference and persuade more to consider such action."

The study was published online January 20 in JAMA Neurology.

Cause or Consequence?

Dr. Ascherio explained that previous studies looking at the relationship of vitamin D with MS recruited patients at different stages of the disease from right at the beginning to 20 to 30 years after diagnosis. In this situation, it is difficult to determine whether vitamin D is a cause or a consequence.

"But in this study, we used vitamin D levels at the time of the first clinical episode of MS-like symptoms as our benchmark, and we obtained repeated measurements during the first 12 months," he said. "Then we followed the patients for up to 5 years so there was a lag between measuring vitamin D levels and measuring MS disease progression. We also took account of disease activity at baseline."

The researchers measured the difference in disease activity over the study period and looked to see whether that was related to baseline vitamin D level.

"We found that patients with the lowest levels of vitamin D at baseline had a greater progression of MS several years later, as evidenced by a higher rate of new lesion development, a higher total lesion burden, a faster rate of brain atrophy, more relapses and more disability," Dr. Ascherio said.

The current study used data previously collected from the Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial, originally designed to evaluate the effect of early vs delayed interferon β-1b treatment in patients with clinically isolated syndrome.

Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomly assigned had at least one 25(OH)D measurement, and 334 patients had them at both 6 and 12 months. Patients were followed up for 5 years clinically and by MRI.

Results showed that higher 25(OH)D levels at the start of the study predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in mean serum 25(OH)D levels in the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower annual increase in T2 lesion volume (P < .001), and 0.41% lower annual loss in brain volume (P = .07) between months 12 and 60.

Associations were similar between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses that used dichotomous 25(OH)D levels, values of 50 nmol/L (20 ng/mL) or greater at up to 12 months predicted less disability (Expanded Disability Status Scale [EDSS] score, –0.17; P = .004) during the next 4 years.

"Although associations were generally stronger for MRI than for clinical outcomes, the latter were still remarkable considering the overall low rate of relapses…and small EDSS score change…in BENEFIT," the authors write.

They note that these results, along with those from previous epidemiologic studies, imply that serum 25(OH)D levels directly affect the disease process or act as a prognostic marker. Although the marker idea is a possibility, they say the inverse association between vitamin D intake and MS risk, as well as the beneficial effects of vitamin D in animal models of MS, favors a role of vitamin D itself.

Dr. Ascherio pointed out that what constitutes "low levels" of vitamin D is uncertain. "In this population, we had an overall low vitamin D level as the study was conducted mainly in Europe, where levels are generally lower than in the US. We used a level of less than 50 nmol/L to define low levels. That is very conservative, and few would argue that people below 50 nmol/L are not vitamin D deficient."

He said patients with 25(OH)D levels under 50 nmol/L should be treated with vitamin D supplements, but noted that there are no universal recommendations for this. He advises supplementation with 1000 to 2000 IU per day. "This is a conservative intervention, but should take most patients out of danger."

Randomized Trials Underway

The ultimate test of the vitamin D hypothesis would be randomized controlled trials of vitamin D supplementation. Several such trials are now underway, but Dr. Ascherio noted they are looking at raising 25(OH)D levels considerably higher than 50 nmol/L.

One of these, being conducted in the United States, is randomly assigning patients with MS to intervention with 6000 IU of vitamin D daily, which Dr. Ascherio estimates should push levels up to around 100 nmol/L, with the control group receiving a low dose, 600 IU.

Dr. Ascherio pointed out the paradox of this trial: "Half the population in Europe and a quarter of the population of the US are judged to be vitamin D deficient, but in this trial it was decided that patients could not be randomized to placebo and the control group still had to be given a low dose of vitamin D. On this basis, I would expect that there would be general recommendations to screen and treat for vitamin D levels, but these do not exist."

Another study in Europe, known as SOLAR, is testing a very high dose of vitamin D (14,000 IU per day) vs placebo. The dose used in this study is aiming to push vitamin D levels up to 250 nmol/L. Other trials are also underway in Australia and France.

"By putting the results of all the trials together we should be able to identify an optimum level," Dr. Ascherio commented.

This study was supported by the National Institute of Neurological Diseases and Stroke and the National Multiple Sclerosis Society. The BENEFIT study was sponsored by Bayer. Dr. Ascherio reports that he has received honoraria for speaking at scientific symposia by Roche, Sanofi-Aventis, Serono, and Almirall.

JAMA Neurol. Published online January 20, 2014. Abstract

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