title: The case for vitamin D supplementation in multiple sclerosis.
abstract: BACKGROUND
  Given that vitamin D has a role in immunomodulation, and its levels appear to correlate with the development of Multiple Sclerosis (MS), it is conceivable that vitamin D may also influence disease activity in MS patients. In this regard, we conducted a systematic review investigating the evidence for: (1) the role of vitamin D in disease activity in MS, and (2) the therapeutic supplementation of vitamin D in MS.
  
  
  METHODS
  A comprehensive search of Medline, Embase, Pubmed, clinical trials registries, and conference proceedings, followed by screening and application of inclusion and exclusion criteria, yielded 57 studies for detailed appraisal. Following careful data extraction, studies addressing the role of vitamin D in disease activity were appraised on the basis of common epidemiological principles, while those involving vitamin D supplementation were assessed for potential bias using Cochrane guidelines. The overall evidence was interpreted in the context of the Bradford-Hill criteria of causation, and the number needed to treat (NNT) to prevent one patient from relapsing over a year was calculated for each supplementation study examining relapse rate.
  
  
  CONCLUSIONS
  Both cross-sectional and longitudinal studies have fairly consistently demonstrated a strong positive correlation between vitamin D deficiency and subsequent relapse and/or disability in patients with MS. As well, there appears to be a negative correlation between vitamin D levels and inflammatory markers in MS patients, suggesting that vitamin D modifies serum cytokines to a more anti-inflammatory profile. Therefore, vitamin D fulfills the Bradford-Hill criteria for strong and consistent association, biological plausibility, and coherence. However, the criteria of temporality, dose-response, and experimental evidence are yet to be adequately met, although there is preliminary evidence from longitudinal studies and randomized clinical trials (RCTs) of supplementation that vitamin D can attenuate the autoimmune response in patients, and potentially reduce relapse rates and burden of disease. Currently published data on relapse prevention with vitamin D indicates the possibility of small NNTs in the range of 1.36-25.00, but they arise from very heterogeneously designed studies.
  
  
  CONCLUSIONS
  Ultimately, the current evidence does not permit inference of a causal relationship between vitamin D deficiency and disease activity in MS. Vitamin D supplementation appears to be a promising treatment worthy of further exploration, but owing to the paucity of RCTs with placebo or comparator arms, the evidence is not definitive and appropriate dosing remains uncertain.
authors: Resident, Clinical Neurosciences, University of Calgary, 1403 29 Street NW Calgary, Alberta, Canada T2N 2T9. Electronic address: aravindganeshy@yahoo.ca.
authors: Aravind
authors: A
authors: Ganesh
authors: Undergraduate Medical Education, University of Calgary, 33 Discovery Rise SW Calgary, Alberta, Canada T3H 4N6. Electronic address: sapel@ucalgary.ca.
authors: Sabrina
authors: S
authors: Apel
authors: Clinical Neurosciences, University of Calgary, 1403 29 Street NW Calgary, Alberta, Canada T2N 2T9. Electronic address: Luanne.Metz@albertahealthservices.ca.
authors: Luanne
authors: L
authors: Metz
authors: Psychiatry and Community Health, University of Calgary, 3330 Hospital Drive NW Calgary, Alberta, Canada T2N 4N1. Electronic address: patten@ucalgary.ca.
authors: Scott
authors: S
authors: Patten
keywords: Causation; Dietary Supplements; Immunomodulation; Multiple Sclerosis; Relapse prevention; Vitamin D