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January 26, 2016; 86 (4) Article

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

Elias S. Sotirchos, Pavan Bhargava, Christopher Eckstein, Keith Van Haren, Moira Baynes, Achilles Ntranos, Anne Gocke, Lawrence Steinman, Ellen M. Mowry, Peter A. Calabresi
First published December 30, 2015, DOI: https://doi.org/10.1212/WNL.0000000000002316
Elias S. Sotirchos
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Pavan Bhargava
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Christopher Eckstein
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Keith Van Haren
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Moira Baynes
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Achilles Ntranos
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Anne Gocke
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Lawrence Steinman
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Ellen M. Mowry
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Peter A. Calabresi
From the Department of Neurology (E.S.S., P.B., M.B., A.N., A.G., E.M.M., P.A.C.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (C.E.), Duke University School of Medicine, Durham, NC; and Department of Neurology (K.V.H., L.S.), Stanford University School of Medicine, Palo Alto, CA.
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Citation
Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis
Elias S. Sotirchos, Pavan Bhargava, Christopher Eckstein, Keith Van Haren, Moira Baynes, Achilles Ntranos, Anne Gocke, Lawrence Steinman, Ellen M. Mowry, Peter A. Calabresi
Neurology Jan 2016, 86 (4) 382-390; DOI: 10.1212/WNL.0000000000002316

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Abstract

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.

GLOSSARY

25(OH)D=
25-hydroxyvitamin D;
CI=
confidence interval;
EAE=
experimental autoimmune encephalitis;
IFN=
interferon;
IL=
interleukin;
IND=
investigational new drug application;
LOWESS=
locally weighted scatterplot smoothing;
MHC=
major histocompatibility complex;
MS=
multiple sclerosis;
PBMC=
peripheral blood mononuclear cells

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received May 25, 2015.
  • Accepted in final form October 5, 2015.
  • © 2015 American Academy of Neurology
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Letters: Rapid online correspondence

  • Author response to Drs. Golan & Miller
    • Elias S. Sotirchos, Johns Hopkins University School of Medicineess@jhmi.edu
    • P Bhargava, Baltimore, MD; PA Calabresi, Baltimore, MD
    Submitted May 11, 2016
  • Re:Vitamin-D supplementation: Is the MS community studying too high a dose?
    • Elias S. Sotirchos, Johns Hopkins University School of Medicineess@jhmi.edu
    • Peter A. Calabresi, Baltimore, MD
    Submitted April 26, 2016
  • Vitamin-D supplementation: Is the MS community studying too high a dose?
    • Daniel Kantor, President, Kantor Neurologyinfo@KantorNeurology.com
    Submitted April 12, 2016
  • The influence of Vitamin D supplementation on Th-17 cell activity in patients with Multiple Sclerosis
    • Daniel Golan, 1.Division of Neuroimmunology & Multiple Sclerosis Center, Lady Davis Carmel Medical Center, Haifa,golan.daniel@gmail.com
    • Ariel Miller, Haifa, Israel
    Submitted February 25, 2016
  • Re: Vitamin D and MS: Not all is hunky dory
    • Elias S. Sotirchos, Johns Hopkins University School of Medicine, Baltimore, MDess@jhmi.edu
    • Pavan Bhargava, Baltimore, MD; Peter A. Calabresi, Baltimore, MD;
    Submitted February 22, 2016
  • Vitamin D and MS: Not all is hunky dory
    • Jagannadha Avasarala, Associate Professor of Neurology, Greenville Health Systemjavasarala@ghs.org
    Submitted February 04, 2016
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