High Vitamin D Levels Linked to Lower MS Disease Activity

Pauline Anderson

October 15, 2015

There's more evidence of the positive effect of vitamin D in people with multiple sclerosis (MS). A new study shows that patients with relapsing-remitting MS (RRMS) treated with interferon β-1b who had the highest serum 25-hydroxyvitamin D (25[OH]D) levels had the lowest disease burden.

Along with other recent research, the study provides "crucial complementary evidence" of the importance of correcting vitamin D deficiency in patients with MS and in helping to identify the optimal level of this vitamin, said lead author Kathryn Fitzgerald, PhD, postdoctoral research fellow, Department of Nutrition, School of Public Health, Harvard University, Boston, Massachusetts.

The study was published online October 12 in JAMA Neurology.

Geographic Variation

The study included patients with RRMS from the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial. BEYOND was a large, phase 3 prospective blinded randomized trial with two interferon β-1b (Betaferon, Bayer) groups (250 and 500 μg administered every other day) and a group receiving daily glatiramer acetate (Copaxone, Teva).

The analysis included 1456 patients receiving Betaferon who had at least two 25(OH)D measurements performed 6 months apart and follow-up information on MRI measurements. The included patients had a median disease duration of 3 years.

Researchers performed seasonal adjustments of vitamin D levels within four broad regions: Eastern Europe (including Russia), Western Europe (including Israel), North America, and the Southern hemisphere (including Australia, Argentina, and Brazil).

They separated average vitamin D levels into the following categories: less than 37.5, 37.5 to 49.9, 50.0 to 74.9, 75.0 to 99.9 and 100.0 nmol/L or higher. Levels were assessed both overall and stratified by region.

Investigators found that the average 25(OH)D levels in study patients varied markedly by region, with the lowest levels in Russia and the highest in Australia. There were also clinical differences, the most important being higher-volume, T2-hyperintense lesions; younger age at onset; and longer disease duration among patients from Eastern Europe and Russia compared with those from other areas.

Best-Case Scenario

In cross-sectional analyses adjusted for age, sex, randomization treatment group (interferon β-1b, 250 or 500 μg) baseline Expanded Disability Status Scale (EDSS) score, disease duration, and region of residence, baseline vitamin D levels were inversely associated with T2-hyperintense lesion volume. A 50-nmol/L higher level corresponded to a difference of –0.11 cm3 in log[T2 lesion volume] (95% confidence interval [CI], –0.20 to –0.02 cm3; P = .02).

Vitamin D levels were also inversely associated with the cumulative number of new active lesions (defined as the sum of new T2- and T3-enhancing lesions) between baseline and 12 months (0.76; 95% CI, 0.60 - 0.98; P =.03).

In longitudinal analyses, vitamin D was significantly inversely correlated with the cumulative number of active lesions from baseline to the last MRI (average follow-up, 2 years). A 50-nmol/L higher serum 25(OH)D level was associated with a 31% lower rate of new lesions (relative risk [RR], 0.69).

This inverse association was also strong and significant in analyses restricted to patents with 25(OH)D levels greater than 50.0 nmol/L (RR, 0.62) and was consistently observed in each region.

These results seem to suggest that 50.0 nmol/L may be too low a target in patients with MS.

"Our conclusion was that there is evidence to suggest that maybe having a higher level would be the best-case scenario for MS patients, although we can't draw a causal inference since this is observational data," said Dr Fitzgerald.

No Link to Brain Volume

Patients with a vitamin D level greater than 100.0 nmol/L had a 47% lower rate of new active lesions compared with patients who had serum levels of 50.0 to 74.9 nmol/L (RR, 0.53).

In an analysis that also adjusted for HLA-DRB1*15, results were slightly stronger (RR per 50.0 nmol/L, 0.65; P = .02), as they also were after adjustment for vitamin D–binding protein status (RR per 50.0 nmol/L, 0.63; P = .01).

The association between serum 25(OH)D and MS activity was slightly altered after adjustment for race/ethnicity and baseline T2 lesion volume but remained statistically significant.

Researchers found no significant association between baseline vitamin D status and the number of relapses in the previous 2 years or the number of relapses from baseline to the last visit. This may be because clinical assessments of relapses using scales such as the EDSS are less sensitive to disease activity than are MRI measures, said Dr Fitzgerald.

No association was seen between vitamin D levels and brain volume at baseline or at 12 months. There are several possible reasons for this, said Dr Fitzgerald.

"It could be that vitamin D is related to the inflammatory processes in MS. It could also be that our study had a relatively short follow-up period of 2 years and that might not have been enough time for neurodegeneration," he said.

She pointed out that a similar study with a longer follow-up (5 years) did find an association between lower vitamin D levels and brain atrophy (JAMA Neurol. 2014;71:306-314).

Higher Vitamin D Better?

Although the evidence suggests higher levels are better, the optimal level is "not completely hammered out," said Dr Fitzgerald.

The authors maintain that no convincing evidence shows increasing 25(OH)D levels above the physiologic limit of about 150.0 nmol/L is beneficial and that such levels could be detrimental.

"There is not really much known physiologically about the consequences of having such high levels," said Dr Fitzgerald, adding that there is a "tolerable upper limit" for vitamin D.

Many experts are waiting for the results of the Vitamin D to Ameliorate MS (VIDAMS) trial for a more definitive word on whether to recommend high-dose vitamin D supplements to patients with MS.

"So far, it's mostly been observational studies and some smaller randomized trials," said Dr Fitzgerald.

This VIDAMS trial has enrolled 172 patients with RRMS at 16 sites in the United States and will compare relapse rates in groups receiving high doses of vitamin D (5000 IU daily) with those in patients getting lower doses (600 IU daily). Follow-up will continue through 2016.

Commenting on the findings for Medscape Medical News, Anthony Reder, MD, professor, neurology, University of Chicago in Illinois, said that although it was a correlation and not a placebo-controlled study, "everything was perfectly matched" and its results amount to "a powerful suggestion" that vitamin D and MS disease activity are related.

It appears that there may be additive effects of vitamin D, which is safe and inexpensive, with interferon, said Dr Reder. "If it adds to the effect of interferon, this changes our in-office calculations of the relative effectiveness of all MS drugs."

It's not clear from the study, however, what the optimum level of the combination of interferon and vitamin D might be, he said.

The study was supported by the National Multiple Sclerosis Society. The BEYOND study was sponsored by Bayer. Dr Fitzgerald has disclosed no relevant financial relationships.

JAMA Neurol. Published online October 12, 2015. Abstract

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