Each 20 ng/mL increment in serum levels of 25-hydroxyvitamin D (25-OH-D), the active metabolite of vitamin D, averaged during the first 12 months of participation in a clinical trial of interferon-beta (Betaseron) was associated with nearly 60% lower rates of new MRI lesions and clinical relapses (both P<0.05) during subsequent follow-up relative to those with smaller or no increases in 25-OH-D levels, according to Alberto Ascherio, MD, DrPH, of Harvard School of Public Health, and colleagues.
Higher 25-OH-D levels shortly after the initial clinical attack were also associated with significantly smaller T2 lesion volumes later on, and there was a trend toward less brain atrophy as well, the researchers reported online in JAMA Neurology. Disability as measured by the Expanded Disability Status Score (EDSS) was lower in those with high 25-OH-D levels at the trial's 5-year mark as well (mean difference 0.17 points, P=0.004).
Ascherio and colleagues noted that treatment assignments in the randomized immediate-versus-delayed therapy trial were not associated with 25-OH-D levels -- in other words, 25-OH-D was not simply a marker of interferon-beta response.
Some of the results had been presented last year at the European Committee for Treatment and Research in Multiple Sclerosis meeting.
Lawrence Steinman, MD, of Stanford University in Palo Alto, Calif., who was not involved in the study, told MedPage Today that it was of "great importance" and that it supported a causal relation between higher vitamin D levels and reduced MS disease activity.
"Epidemiologists are notoriously reluctant to give a 'cause and effect' conclusion, but a reasonable experimentalist could attribute a cause and effect relationship," Steinman said in an email.
"Simply stated, I am willing to support that if your vitamin D levels are high, early on in MS, your disease activity will be reduced. The cause and effect association is based on the known immune suppressive properties of vitamin D on the major pro-inflammatory pathways."
In particular, he said, vitamin D regulates expression of interleukin-17, "one of the key mediators of MS."
The double-blind trial, called BENEFIT, was conducted in the early 2000s to test the effects of interferon-beta on patients' progression from clinically isolated syndrome to clinically definite MS. Participants who had had a single MS-like attack were randomized 5:3 to either interferon-beta or placebo 2 years, followed by open-label treatment with interferon-beta for all participants choosing to continue.
As part of the study, blood samples were collected at baseline and at 6, 12, and 24 months into the study. Patients were followed for 5 years after study entry with brain MRI scans and clinical exams.
A total of 465 patients (out of 468 enrolled) had at least one measurement of 25-OH-D, including 417 with two or more and 303 with analyzable samples from all four collections. Ascherio and colleagues restricted some analyses to participants with 25-OH-D measurements at the 6-month as well as baseline time points, which would provide a check on seasonal variations in vitamin D levels (which are affected by sun exposure).
During the 5 years of follow-up, about 80% of patients converted to definite MS by the relatively expansive 2001 McDonald criteria, and 47% converted according to more rigorous standards set by Poser et al.
Just over half of patients had "low" 25-OH-D levels, defined as an average of the three first-year measurements below 20 ng/mL. Patients with average first-year levels of 20 ng/mL or higher were classed as "high."
By year five, the following were seen in the "low" versus "high" groups, after adjusting for age, sex, treatment assignment, follow-up duration, and baseline T2 lesion volume:
Mean cumulative new active MRI lesions: 12.5 low versus 8.5 high (P=0.002)
Mean percent increase in T2 lesion volume: 93% low versus 22% high (P=0.008)
Mean percent decrease in brain volume: 2.4% low versus 1.8% high (P=0.005)
For each 20-ng/mL increment in first-year 25-OH-D levels, adjusted relative risks from study month 12 to the 5-year evaluation were as follows:
New active lesions: 0.43 (95% CI 0.26-0.70)
Clinical relapse: 0.43 (95% CI 0.20-0.92)
Ascherio and colleagues also found that each 20 ng/mL increment in the first-year average of 25-OH-D predicted a 25% smaller T2 lesion volume (95% CI 14%-34%).
There was a trend toward lower EDSS score with each 20-ng/mL increment in 25-OH-D (-0.18 points per increment, P=0.19), but first-year averages classed as "high" were significantly associated with lower scores relative to the group classed as "low," the researchers found.
They stopped short of concluding that vitamin D levels were directly causative of the clinical and MRI results, or that patients would benefit from vitamin D supplements. They did, however, venture to say that "low vitamin D was not a consequence of the disease process but rather its predictor."
Steinman told MedPage Today that "there are always alternative explanations" in studies of this type. Still, he suggested that the results probably do indicate some type of causation and perhaps even a result of vitamin D supplementation.
"I might wonder if these data might explain the progressive decrease in relapse rate in the placebo arm of clinical trials of MS over the past decade. Maybe more and more individuals are aware of vitamin D, and that they are taking vitamin D supplements, thus lowering the relapse rate in placebo arms of trials."
Small randomized trials of supplements have been conducted in MS patients with mostly negative results. Nevertheless, Steinman said he recommends them to his patients and to healthy people as well.