Low levels of vitamin D and exposure to the Epstein-Barr virus (EBV) have been linked to the development of multiple sclerosis (MS), new research shows.
"Changes [in both] vitamin D levels and EBV immunoreactivity even two to three years prior to the first clinical disease manifestation appear to be associated with clinical breakthrough. So we are looking at two factors together several years before the first symptoms and signs of MS," study author Andrew Chan, MD, from St. Josef-Hospital, Ruhr-University, in Bochum, Germany, told Medscape Medical News.
However, investigators could not determine whether one of these risk factors is more important in the development of MS.
"I believe it is safe to say that both factors are associated with clinical disease breakthrough, possibly within a relatively restricted interval," said Dr. Chan. Whether they are independent risk factors that are amenable to intervention remains to be seen, he added.
The study was published online in Journal of Neurology, Neurosurgery & Psychiatry.
Low Vitamin D
The analysis included 56 blood samples donated by 25 patients in Germany (21 female; mean age, 31.5 years at time of donation; 33.4 years when they developed MS).
Researchers obtained serum samples from 18 of the 25 participants after an MS diagnosis was established, and collected 39 serum samples from 25 age- and gender-matched healthy blood donors.
From these samples, researchers investigated both 25-hydroxyvitamin D (25-OH-D) serum levels and immunoglobulin C (IgC) response against the EBV nuclear antigen-1 (EBNA1).
EBNA1 is important for establishing and maintaining the altered state of cells following infection with EBV, according to Masaaki Niino, MD, PhD, director, Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan, who contributed a related editorial. The risk for MS increases more than seven-fold with increasing titers of anti–EBNA1 IgC antibodies, he said.
Cross-sectional analyses revealed a gradual decrease in 25-OH-D levels during the pre–clinically isolated syndrome (CIS) phase. This change was particularly evident during the 24 months before CIS (median, 47.8 mmol/L vs 81.6 mmol/L for healthy controls; P = .004).
Not an Isolated Finding
After an MS diagnosis was established, levels were strongly reduced — median, 24.5 mmol/L (P < .0001) — compared with those of pre-CIS sera (57.1 mmol/L) or healthy controls.
In contrast, IgC response against EBNA1 was increased during the pre-CIS phase compared with that of healthy matched blood donors. The most pronounced alterations were seen in the 36 months before clinical manifestation (median, 185.9 IU/mL vs 63.7 IU/mL for healthy controls; P = .002).
Reverse causality — long-standing disease processes causing changes in 25-OH-D and EBNA1 status — cannot be excluded, according to the authors.
Although the current study did not detect any direct relationship between 25-OH-D levels and EBNA1 immunoreactivity, some previous experimental data did suggest that the two factors may work synergistically, said Dr. Chan.
"For example, vitamin D may influence the immune reaction to EBV."
Dr. Chan hypothesized that the influence of vitamin D on EBV immunoreactivity or on other adaptive immune responses could be especially important during the interval highlighted in the study.
Larger studies are needed to address this issue, he said.
The study included only white patients living in Germany, but its results are compatible with those from other studies from different geographic regions, said Dr. Chan. "I would guess that this is not an isolated finding."
Dr. Chan cited another very large study — conducted with samples from US military staff — that linked lower vitamin D levels with higher risk of developing MS later in life.
"However, in their study, vitamin D levels before the age of 20 [were] important, whereas we saw profound changes a couple of years prior to disease onset," said Dr. Chan.
"Whereas the cohorts can't be directly compared because of selection bias, size, etc., I believe the datasets complement one another, and that our results are hypothesis-generating," he added.
The current study combined results for men (only four) and for women, so it is possible that the results may be gender-specific. However, Dr. Chan and colleagues addressed the issue of sex differences by using gender/age-matched controls.
The study used samples that dated back several years but, according to Dr. Chan, it is unlikely that it would be possible to track the association back any farther.
"While we were able to obtain samples up to seven years prior to disease manifestations, many blood donor centers do not keep samples for very long intervals for logistical reasons. Most of the centers we contacted kept the samples for about five years. Therefore, it is very difficult to track down even earlier time points."
Among the drawbacks of the study were its limited sample size, possible recall bias, and inability to dissect determinants of individual vitamin D levels, including sunlight exposure and diet.
Need for Research in Diverse Populations
In his commentary, Dr. Niino said that the study helps answer the question of whether long-term low vitamin D levels and indication of remote EBV infection are associated with risk factors for developing MS.
"These findings suggest that the two major risk factors of low vitamin D level and remote EBV infection are important, especially during the few years prior to clinical manifestation."
Dr. Niino also noted that vitamin D levels — or at least 25-OH-D levels — are known to differ between races and ethnicities, perhaps because of skin color. Although it is possible that study results would hold true for other ethnicities, to date, few related data have been collected, he said. "We need similar studies with other ethnicities, including Japanese."
Dr. Niino agreed with the authors that although the study did not uncover a direct relationship between the two MS risk factors investigated, "further prospective studies are needed to investigate potential interactions of vitamin D level and remote EBV infection."
Dr. Chan has disclosed that he received personal compensation as a speaker or consultant for Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience, as well as research support from the German Ministry for Education and Research (BMBF, German Competence Network Multiple Sclerosis [KKNMS], CONTROL MS, 01GI0914), Bayer Schering, Biogen Idec, Merck Serono, and Novartis. Dr. Niino has disclosed that he receives research support from Grants-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan, and from the National Hospital Organization of Japan; that he serves on a scientific advisory board for Biogen Idec; and that he has received speaker honoraria from Biogen Idec, Bayer Schering Pharma, Asahi Kasei Kuraray Medical Co Ltd, and Novartis Pharma.
J Neurol Neurosurg Psychiatry. Published online August 11, 2012. Abstract
J Neurol Neurosurg Psychiatry. Published online August 20, 2012. Editorial extract
Pauline Anderson • Medscape Medical News © 2012 WebMD, LLC