Low vitamin D: a consequence rather than a cause of MS

In last week's BMJ there was a short article that suggested that low vitamin D levels could be a consequence rather then the cause of disease. The investigators' showed that when someone is admitted to hospital and have a surgical procedure their vitamin D levels drop in parallel with changes in other markers of inflammation. These results are consistent with other results in the literature. 

Gama et al. Hypovitaminosis D and disease: consequence rather than cause? BMJ. 2012 Aug 24;345:e5706. doi: 10.1136/bmj.e5706. 

This would imply that vD levels may be low in MS as a result of disease MS disease activity, i.e. the inflammation itself lowers the levels, possibly by consuming vD as part of the inflammatory reaction. This would mean that we may to re-look at studies suggesting causal links:

Mowry et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012 Aug;72(2):234-40. doi: 10.1002/ana.23591.

OBJECTIVE: This study sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain MRI in RRMS.

METHODS: EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated MSers with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (EDSS).

RESULTS: A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor.

INTERPRETATION: Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation. 

Løken-Amsrud et al. Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment. Neurology. 2012 Jul 17;79(3):267-73. 

OBJECTIVE: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in MS, and high doses are suggested as add-on treatment to interferon-β (IFN-β). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each MSer.

METHODS: This was a cohort study comprising 88 MSers with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN-β, and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-β treatment.

RESULTS: Prior to IFN-β treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. MSers with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-β. HLA-DRB1*15 status did not affect the results.

CONCLUSION: In untreated MSers with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.

Association vs. Causation
"Both these studies hint at a causal pathway, but that may be incorrect. This is why we need prospective double-blind placebo-controlled studies to assess whether or not vD supplementation decreases MS disease activity."

"I have previously highlighted causation theory on this blog. If you are interested in it you may want to read these old posts."

21 Mar 2012
Did you know that there is a whole science behind causation? It started way back in the later 1800's when Robert Koch formulated his postulates to persuade his contemporaries that the he had found the cause of tuberculosis.
07 May 2012
An example is causation theory; causation theory is a well-established field in science and it requires several criteria to be met to prove causation. Despite reblogging the post on causation theory repeatedly a lot of readers ...

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