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      Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties

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          Abstract

          Background

          Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-β) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines’ levels.

          Methods

          In a randomized, double blind study of 45 IFNβ-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-γ were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented.

          Results

          25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFNγ were found. Hypercalcemia or other potential major adverse events were not observed.

          Conclusion

          Vitamin D supplementation to IFN−β treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN−β related FLS.

          Trial registration

          ClinicalTrials.gov ID: NCT01005095

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          Most cited references28

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          Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.

          Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor. To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture. A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008. 500,000 IU of cholecalciferol or placebo. Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels. Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures. anzctr.org.au Identifier: ACTRN12605000658617; isrctn.org Identifier: ISRCTN83409867.
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            Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.

            Recent findings in the animal model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis, implicate a novel CD4+ T-cell subset (TH17), characterized by the secretion of interleukin-17 (IL-17), in disease pathogenesis. To elucidate its role in MS, brain tissues from patients with MS were compared to controls. We detected expression of IL-17 mRNA (by in situ hybridization) and protein (by immunohistochemistry) in perivascular lymphocytes as well as in astrocytes and oligodendrocytes located in the active areas of MS lesions. Further, we found a significant increase in the number of IL-17+ T cells in active rather than inactive areas of MS lesions. Specifically, double immunofluorescence showed that IL-17 immunoreactivity was detected in 79% of T cells in acute lesions, 73% in active areas of chronic active lesions, but in only 17% of those in inactive lesions and 7% in lymph node control tissue. CD8+, as well as CD4+, T cells were equally immunostained for IL-17 in MS tissues. Interestingly, and in contrast to lymph node T cells, no perivascular T cells showed FoxP3 expression, a marker of regulatory T cells, at any stage of MS lesions. These observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL-17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.
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              1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A.

              A new class of inflammatory CD4(+) T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], has a direct repressive effect on the expression of IL-17A in both human and mouse T cells. In vivo treatment of mice with ongoing experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) diminishes paralysis and progression of the disease and reduces IL-17A-secreting CD4(+) T cells in the periphery and central nervous system (CNS). The mechanism of 1,25(OH)(2)D(3) repression of IL-17A expression was found to be transcriptional repression, mediated by the vitamin D receptor (VDR). Transcription assays, gel shifting, and chromatin immunoprecipitation (ChIP) assays indicate that the negative effect of 1,25(OH)(2)D(3) on IL-17A involves blocking of nuclear factor for activated T cells (NFAT), recruitment of histone deacetylase (HDAC), sequestration of Runt-related transcription factor 1 (Runx1) by 1,25(OH)(2)D(3)/VDR, and a direct effect of 1,25(OH)(2)D(3) on induction of Foxp3. Our results describe novel mechanisms and new concepts with regard to vitamin D and the immune system and suggest therapeutic targets for the control of autoimmune diseases.
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                Author and article information

                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central
                1471-2377
                2013
                14 June 2013
                : 13
                : 60
                Affiliations
                [1 ]Division of Neuroimmunology & Multiple Sclerosis Center, Carmel Medical Center, 7 Michal Street, Haifa, 34362, Israel
                [2 ]Department of Neurology, Carmel Medical Center, Haifa, Israel
                [3 ]Central Laboratory of Haifa and Western Galilee, Clalit Health Services, Haifa, Israel
                [4 ]Department of Community Medicine & Epidemiology, Carmel Medical Center, Haifa, Israel
                [5 ]Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
                Article
                1471-2377-13-60
                10.1186/1471-2377-13-60
                3691658
                23767916
                2b4a7f6e-ac85-47bf-a9f5-59fc7b1ed19e
                Copyright ©2013 Golan et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 January 2013
                : 31 May 2013
                Categories
                Research Article

                Neurology
                flu-like symptoms,interferon-β,il-17,multiple sclerosis,pth,quality of life,safety,vitamin d
                Neurology
                flu-like symptoms, interferon-β, il-17, multiple sclerosis, pth, quality of life, safety, vitamin d

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