While Professor Hutchinson's trial itself may be of interest to some, the background explanation for why Vitamin D may be helpful in CIS is an excellent overview of the subject.
Source URL:
http://www.ncbi.nlm.nih.gov/pubmed/23981773
PMID: 23981773
DOI:
http://dx.doi.org/10.1186/1745-6215-14-272
Journal Title: Trials
Journal Date: 27 Aug 2013
Journal Issue: 1
Journal Volume: 14
Journal First Page: 272
Abstract URL:
http://www.ncbi.nlm.nih.gov/pubmed/2398 ... t=abstract
Article Title: Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial.
Article Authors: Karen O Connell,Siobhan Kelly,Katie Kinsella,Sinead Jordan,Orla Kenny,David Murphy,Eric Heffernan,Risteard O Laoide,Donal O Shea,Carmel McKenna,Lorraine Cassidy,Jean Fletcher,Cathal Walsh,Jennifer Brady,Chris McGuigan,Niall Tubridy,Michael Hutchinson
Background
Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is the most common disabling neurologic disorder of young adults. The causes of MS remain unknown, but it is widely believed that there is interplay between genetic and environmental factors [1]. Evidence for the role of the environment in the development of MS is supported by a strong correlation between MS incidence/prevalence and increased latitude and lower levels of sun exposure, suggesting an association with vitamin D production [2-4]. Individuals who emigrate before the age of 15 years from an area of high MS prevalence to one of low prevalence, acquire the lower risk of MS in their new country of residence.
Migration studies provide perhaps the strongest support for the role of environmental factor(s) in this disease [5,6]. People living at high latitudes are generally deficient in vitamin D, as measured by serum 25- hydroxyvitamin D (25(OH)D) levels [7,8]. In one study, mean winter 25(OH)D levels in healthy control subjects in Ireland were 36.4 nmol/l, and more patients with MS had vitamin D deficiency (serum 25(OH)D levels less than 25 nmol/l) compared with control subjects [9]. Patients have lower serum vitamin D levels during MS relapses, and also have blunted parathyroid hormone responses [10,11]. In 267 Dutch patients with relapsing remitting multiple sclerosis (RRMS), higher vitamin D levels were associated with an increased chance of remaining relapse-free [11]. In 134 North American patients with RRMS or clinically isolated syndrome (CIS) of pediatric onset, the strongest predictor of further relapse was the baseline serum vitamin D level [12]. In a prospective Australian study of 145 patients with RRMS, each increase of 10 nmol/l in baseline serum vitamin D level was associated with a 12% reduction in the risk of a further relapse [13]. Vitamin D deficiency may increase susceptibility to MS even in utero; higher maternal vitamin D intake during pregnancy was associated with a 38% lower risk of MS in offspring [14], and maternal vitamin D levels greater than 75 mmol/l were associated with a 61% reduced risk of MS in children [15]. Month of birth studies showing an increased MS incidence in those with spring versus autumn births also provide evidence of the role of maternal vitamin D [16]. The potential therapeutic effect of vitamin D supplementation was first suggested by Goldberg in 1986 [17]. Dosing studies in healthy volunteers have shown that supplementation with vitamin D 10,000 IU daily results in an increase in serum 25(OH)D levels of 150 nmol/l over a 12 week period [18]. A Canadian phase I/II open-label, placebo=controlled, randomized controlled trial (RCT) of 49 patients with RRMS who were randomized to placebo or escalating doses of vitamin D over a 52 week period showed a trend toward relapse reduction in the actively treated group [19]. This study was primarily aimed at establishing the safety and tolerability of high-dose vitamin D supplementation; the mean vitamin D dose was 14,000 IU per day, and there were no adverse events or hypercalcamia despite maximum mean vitamin D levels of 413 nmol/l being achieved. The results from this phase II trial [19], and from dosing [18] and observational studies [12,13], suggest that pharmacologic doses of vitamin D of up to 10,000 IU/day are safe, and may reduce the risk of relapse by a factor superior to the 30% reduction reported from the pivotal trials of interferons in RRMS [20,21]. Vitamin D modulates both the innate and adaptive immune systems [22]. The active metabolite, 1,25 (OH) vitamin D, primarily mediates its effects through the intracellular vitamin D receptor (VDR) [23], which is present in monocytes, dendritic cells, B-cells, and CD4+ T-cells [11,22]. Activation of VDR alters transcription, proliferation, and differentiation of immune cells [23], and modulates immune response both indirectly, by reducing the activation of pro-inflammatory T-cells by antigen-presenting cells [24], and directly, by inhibiting T-cell and B-cell proliferation [22,25]. This results in a T-helper (Th)2- cell driven anti-inflammatory state [11,22,26].
There is thus accumulating evidence that vitamin D deficiency increases susceptibility to MS, and that vitamin D supplementation reduces disease activity by immunomodulatory mechanisms. It seems probable that serum vitamin D levels of greater than 100 nmol/l are required to produce the immunologic effects of vitamin D and thus, in patients with MS with vitamin D deficiency, doses of 5,000 to 10,000 IU/day are needed to achieve this. Most patients with RRMS, once diagnosed, commence treatment with first-line disease-modifying therapies (DMTs). Several RCTs are underway to examine the effects of vitamin D supplementation in patients with RRMS already receiving first-line DMTs, using clinical and MRI outcomes [27,28]. In the UK and Ireland, patients with CIS are not usually commenced on DMTs until there is clinical or MRI evidence of dissemination in time. These CIS patients, at risk of developing RRMS, may be recruited into trials of potentially therapeutic agents in order to examine the efficacy of specific therapies in preventing the development of clinically definite MS [29]. We have therefore designed this RCT to examine, over a 24 week treatment period the effects on immunologic measures as a primary outcome, both in patients with CIS and in healthy control participants, randomized to either of two doses of vitamin D (5,000 or 10,000 IU) or to placebo. In addition, in the patients with CIS, clinical and MRI efficacy
measures will be assessed as secondary outcomes.