Vitamin d and multiple sclerosis

And another vitamin D study. This one showing a relationship with multiple sclerosis (see doi:10.1212/WNL.0000000000004489).

Details:
--Prospective, nested-control study of women in the Finnish Maternity Cohort, where there were 1.8 million stored serum samples from over 800,000 pregnant women
--age when 25(OH) D levels were collected: 28; 25(OH) D levels: 55% <30 nmol/L (12 ng/ml), 38% 30-50 nmol/L (12-20 ng/ml), 7% >50 nmol/L.
--age of sample collection: 29; age when multiple sclerosis (MS) diagnosed: 37
--the 25(OH) D levels​ had the expected seasonal variation average baseline: in this case average levels of 20-25 nmol/L in the winter and peaked at 45-50 nmol/L in August
--1092 women developed multiple sclerosis (MS) between 1983 and 2009
--cases were matched to 2123 controls by date of birth and area of residence

Results:
--50 nmol/L (20 ng/ml) increase in 25(OH) D levels was associated with a 39% reduced risk of MS, RR 0.61 (0.44-0.85), p=0.003
--women with 25(OH) D levels​ <30 nmol/L (12 ng/ml) had a 43% higher risk of MS, RR 1.43 (1.02-1.99), p=0.04 vs those with levels >50 nmol/L (20 ng/ml). this was 2-fold higher in those with >= 2 blood samples analyzed, RR 2.02 (1.18-3.45), p=0.01
--those with 25(OH) D levels​ <30 nmol/L (12 ng/ml) had a 27 % higher risk of MS, RR 1.27 (1.07-1.50), p=0.005 vs those with levels 30-50 nmol/L (20 ng/ml).

Commentary:
--Finnish women overall have low 25(OH) D levels and high incidence of MS. This study, however, used patient-specific data to show a higher incidence of MS in those who had lower vitamin D levels. There were not enough women with high levels (>75 nmol/L, or 30 ng/ml) to assess risk in these women
--Several other studies have also found that adequate vitamin D levels are associated with lower risk of MS. For example, a study in Northern Sweden of 192 cases of MS  and a US military study with 148 cases of MS found that higher levels of 25(OH) D levels, >75 nmol/L (30 ng/ml) in the first study or >100 nmol/L (>40 ng/ml) in the second, were associated with about a 60% lower risk of subsequently developing MS, though these studies were from nondiverse populations with pretty high baseline 25(OH) D levels.
--the limitations of this much larger Finnish study include: observational study (so cannot attribute causality: there could be uncontrolled biases, such as those women with higher vitamin D levels had other behaviors that might influence MS, eg getting more exercise outside which may happen more in nonsmokers, and smoking may well be an MS risk factor), the range of vitamin D levels was skewed to lower levels, and this was a largely white population
--a prior study assessed patients with a first event suggestive of multiple sclerosis, with 25(OH) vitamin D levels drawn at baseline and followed prospectively for 5 years, and found that the vitamin D levels in the first 12 months predicted MS activity and progression during the subsequent 4 years. Those with 25(OH) D levels >50 mmol/L (20 ng/ml) had 4-times lower change in T2 lesion volume by MRI, 2-fold lower rate of brain atrophy, and lower disability 4 years later (see doi:10.1001/jamaneurol.2013.5993; or go to http://gmodestmedblogs.blogspot.com/2014/01/vitamin-dmultiple-sclerosis-and-dosing.html for my blog)
--one persistent question re vitamin D testing is: given the seasonal variation, when should we do the test?? an NIH-sponsored study looked at possible clinical events associated with vitamin D deficiency (they included hip fracture, MI, cancer, overall deaths): there was variation ,of vitamin D levels by season (p=0.057, so marginally statistically significant). This data was from the Cardiovascular Health Study, with patients in 4 US communities with pretty different sun intensities, finding overall a 24% higher risk of these clinical endpoints in patients with low vitamin D levels, with season-specific 25(OH) D levels associated with their clinical outcomes to be: 43, 50, 61, 55 nmol/L (17, 20, 24, 22 ng/ml) in the winter, spring, summer and fall (see de Boer. Ann Intern Med 2012; 156: 627)

So, lots of studies finding pretty consistently that lower vitamin D levels are associated with MS, and even that those with first events suggestive of MS have less likely progression/disease activity in the next several years if they have higher vitamin D levels.  Though these studies are not RCTs showing that those randomized to vitamin D supplementation do better, it seems reasonable (to me) to replete those with low vitamin D levels in the community (especially if <50 nmol/L, 20 ng/ml) as both primary prevention against MS (and perhaps other diseases: see http://gmodestmedblogs.blogspot.com/2014/01/vitamin-dmultiple-sclerosis-and-dosing.html as well as if the patient has early signs consistent with MS (likely secondary prevention)