Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis

Objective: To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS). Methods: In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months. Results: Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0–44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0–13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17+CD4+ T cells (p = 0.016), CD161+CD4+ T cells (p = 0.03), and effector memory CD4+ T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4+ T cells (p = 0.018) and naive CD4+ T cells (p = 0.04). These effects were not observed in the low-dose group. Conclusions: Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4+ T cells and decreased proportion of effector memory CD4+ T cells with concomitant increase in central memory CD4+ T cells and naive CD4+ T cells. Classification of evidence: This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

[1]  P. Bhargava,et al.  1,25-Dihydroxyvitamin D3 impairs the differentiation of effector memory T cells in vitro in multiple sclerosis patients and healthy controls , 2015, Journal of Neuroimmunology.

[2]  S. Schwab,et al.  Interferon Beta and Vitamin D Synergize to Induce Immunoregulatory Receptors on Peripheral Blood Monocytes of Multiple Sclerosis Patients , 2014, PloS one.

[3]  P. Bhargava,et al.  The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. , 2014, Contemporary clinical trials.

[4]  Mark S. Sundrud,et al.  Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids , 2014, The Journal of experimental medicine.

[5]  P. Calabresi,et al.  1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization , 2013, Proceedings of the National Academy of Sciences.

[6]  C. McCulloch,et al.  Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis , 2012, Annals of neurology.

[7]  A. Ponsonby,et al.  Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS , 2012, Neurology.

[8]  R. Nussenblatt,et al.  Standardizing immunophenotyping for the Human Immunology Project , 2012, Nature Reviews Immunology.

[9]  F. Paul,et al.  Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial , 2012, Trials.

[10]  F. Barkhof,et al.  Efficacy of vitamin D3 as add-on therapy in patients with relapsing–remitting multiple sclerosis receiving subcutaneous interferon beta-1a: A Phase II, multicenter, double-blind, randomized, placebo-controlled trial , 2011, Journal of the Neurological Sciences.

[11]  J. Damoiseaux,et al.  Effects of vitamin D on the peripheral adaptive immune system: a review. , 2011, Autoimmunity reviews.

[12]  A. Bar-Or,et al.  Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. , 2011, The Journal of clinical endocrinology and metabolism.

[13]  Jeffrey A. Cohen,et al.  Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria , 2011, Annals of neurology.

[14]  P. Menheere,et al.  Safety and T Cell Modulating Effects of High Dose Vitamin D3 Supplementation in Multiple Sclerosis , 2010, PloS one.

[15]  J. Correale,et al.  Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects , 2010, The Journal of Immunology.

[16]  M. López-Botet,et al.  Natural killer receptors distribution in multiple sclerosis: Relation to clinical course and interferon-beta therapy. , 2010, Clinical immunology.

[17]  Maren S Fragala,et al.  Conceptual and methodological issues relevant to cytokine and inflammatory marker measurements in clinical research , 2010, Current opinion in clinical nutrition and metabolic care.

[18]  T. Dwyer,et al.  Higher 25‐hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis , 2010, Annals of neurology.

[19]  E. Mowry,et al.  Vitamin D status is associated with relapse rate in pediatric‐onset multiple sclerosis , 2010, Annals of neurology.

[20]  P. Defechereux,et al.  Optimization and Limitations of Use of Cryopreserved Peripheral Blood Mononuclear Cells for Functional and Phenotypic T-Cell Characterization , 2009, Clinical and Vaccine Immunology.

[21]  L. Cosmi,et al.  Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor , 2008, The Journal of experimental medicine.

[22]  A. Kessels,et al.  Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis , 2008, Multiple sclerosis.

[23]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[24]  A. Ascherio,et al.  Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. , 2006, JAMA.

[25]  S. Nakae,et al.  IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis1 , 2006, The Journal of Immunology.

[26]  K. Spach,et al.  Vitamin D3 Confers Protection from Autoimmune Encephalomyelitis Only in Female Mice1 , 2005, The Journal of Immunology.

[27]  P. Calabresi,et al.  The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Bonneville,et al.  Coordinated Expression of Ig-Like Inhibitory MHC Class I Receptors and Acquisition of Cytotoxic Function in Human CD8+ T Cells1 , 2004, The Journal of Immunology.

[29]  R. Ravid,et al.  Expression of CCR7 in multiple sclerosis: Implications for CNS immunity , 2004, Annals of neurology.

[30]  F. Cosman,et al.  Cytokine profile in patients with multiple sclerosis following vitamin D supplementation , 2003, Journal of Neuroimmunology.

[31]  Peter A. Calabresi,et al.  Chemokine receptor expression on MBP-reactive T cells: CXCR6 is a marker of IFNγ-producing effector cells , 2002, Journal of Neuroimmunology.

[32]  Jorge R. Oksenberg,et al.  Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis , 2002, Nature Medicine.

[33]  P. Kivisäkk,et al.  Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis , 1999, Multiple sclerosis.

[34]  M. Colonna,et al.  A Common Inhibitory Receptor for Major Histocompatibility Complex Class I Molecules on Human Lymphoid and Myelomonocytic Cells , 1997, The Journal of experimental medicine.

[35]  H. DeLuca,et al.  1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Jia Newcombe,et al.  Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. , 2008, The American journal of pathology.

[37]  A. Shao,et al.  Risk assessment for vitamin D. , 2007, The American journal of clinical nutrition.

[38]  B. Steele.  For More Information , 2000, Journal of the National Cancer Institute.