Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti-inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D3 on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D3 supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25-hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 ± 29 to 123 ± 34 nmol/L among patients receiving vitamin D3 supplementation, whereas only a minor increase from 57 ± 22 to 63 ± 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C–X–C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D3 supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D3 supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment.
Multiple sclerosis Vitamin D Systemic inflammation
This is a preview of subscription content, log in to check access.
This work was supported by the Southern and Eastern Norway Regional Health Authority (Grant Number 2013006).
Compliance with ethical standards
The Regional Committee for Medical and Health Research Ethics in Northern Norway approved the study protocol and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was provided before patient enrollment.
Conflicts of interest
E. Røsjø has received honoraria for participation in a clinical trial from Merck Serono. Ø. Torkildsen has served on a scientific advisory board for Biogen Idec, and received speaker honoraria and travel grants from Genzyme, Merck Serono, Novartis and Biogen Idec. T. Holmøy has received speaker honoraria and travel support from Sanofi Aventis, Biogen Idec, Bayer HealthCare Pharmaceuticals, Novartis, Genzyme and Merck Serono. L. H. Steffensen, L. Jørgensen, J. C. Lindstrøm, J. Šaltytė Benth, A. E. Michelsen, P. Aukrust, T. Ueland and M. T. Kampman report no disclosures.
Smolders J, Menheere P, Kessels A et al (2008) Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler 14(9):1220–1224CrossRefPubMedGoogle Scholar
James E, Dobson R, Kuhle J et al (2013) The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis. Mult Scler 19(12):1571–1579CrossRefPubMedGoogle Scholar
Pozuelo-Moyano B, Benito-Leon J, Mitchell AJ et al (2013) A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis. Neuroepidemiology 40(3):147–153PubMedCentralCrossRefPubMedGoogle Scholar
Autier P, Boniol M, Pizot C et al (2014) Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2(1):76–89CrossRefPubMedGoogle Scholar
Belbasis L, Bellou V, Evangelou E et al (2015) Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 14(3):263–273CrossRefPubMedGoogle Scholar
Røsjø E, Myhr KM, Løken-Amsrud KI et al (2014) Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis. J Neuroimmunol 271(1–2):60–65CrossRefPubMedGoogle Scholar
Holmøy T, Løken-Amsrud KI, Bakke SJ et al (2013) Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity. PLoS One 8(9):e75021PubMedCentralCrossRefPubMedGoogle Scholar
Røsjø E, Myhr KM, Løken-Amsrud KI et al (2015) Vitamin D status and effect of interferon-beta1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis. J Neuroimmunol 280:21–28CrossRefPubMedGoogle Scholar
Breuer J, Schwab N, Schneider-Hohendorf T et al (2014) Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol 75(5):739–758CrossRefPubMedGoogle Scholar
Hart PH, Gorman S, Finlay-Jones JJ (2011) Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol 11(9):584–596CrossRefPubMedGoogle Scholar
Milliken SV, Wassall H, Lewis BJ et al (2012) Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function. J Allergy Clin Immunol 129(6):1554–1561CrossRefPubMedGoogle Scholar
Kampman MT, Steffensen LH, Mellgren SI et al (2012) Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler 18(8):1144–1151CrossRefPubMedGoogle Scholar
Steffensen LH, Jørgensen L, Straume B et al (2011) Can vitamin D supplementation prevent bone loss in persons with MS? A placebo-controlled trial. J Neurol 258(9):1624–1631PubMedCentralCrossRefPubMedGoogle Scholar
Grimnes G, Almaas B, Eggen AE et al (2010) Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed. Eur J Endocrinol 163(2):339–348CrossRefPubMedGoogle Scholar
Lucas RM, Ponsby AL, Dear K et al (2011) Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 76(6):540–548CrossRefPubMedGoogle Scholar
Zivadinov R, Treu CN, Weinstock-Guttman B et al (2013) Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry 84(10):1075–1081CrossRefPubMedGoogle Scholar
Stewart N, Simpson S Jr, van der Mei I et al (2012) Interferon-beta and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS. Neurology 79(3):254–260CrossRefPubMedGoogle Scholar
Mahon BD, Gordon SA, Cruz J et al (2003) Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol 134(1–2):128–132CrossRefPubMedGoogle Scholar
Smolders J, Peelen E, Thewissen M et al (2010) Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis. PLoS One 5(12):e15235PubMedCentralCrossRefPubMedGoogle Scholar
Golan D, Halhal B, Glass-Marmor L et al (2013) 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. BMC Neurol 13:60PubMedCentralCrossRefPubMedGoogle Scholar
Mosayebi G, Ghazavi A, Ghasami K et al (2011) Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest 40(6):627–639CrossRefPubMedGoogle Scholar
Åivo J, Hänninen A, Ilonen J et al (2015) Vitamin D3 administration to MS patients leads to increased serum levels of latency activated peptide (LAP) of TGF-beta. J Neuroimmunol 280:12–15CrossRefPubMedGoogle Scholar
Heaney RP, Davies KM, Chen TC et al (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77(1):204–210PubMedGoogle Scholar
Jorde R, Sneve M, Torjesen PA et al (2010) No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects. Cytokine 50(2):175–180CrossRefPubMedGoogle Scholar
Sokol SI, Srinivas V, Crandall JP et al (2012) The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease. Vasc Med 17(6):394–404CrossRefPubMedGoogle Scholar
Yusupov E, Li-Ng M, Pollack S et al (2010) Vitamin d and serum cytokines in a randomized clinical trial. Int J Endocrinol 2010:2010CrossRefGoogle Scholar
Rosito M, Deflorio C, Limatola C et al (2012) CXCL16 orchestrates adenosine A3 receptor and MCP-1/CCL2 activity to protect neurons from excitotoxic cell death in the CNS. J Neurosci 32(9):3154–3163CrossRefPubMedGoogle Scholar
Smolders J, Thewissen M, Peelen E et al (2009) Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One 4(8):e6635PubMedCentralCrossRefPubMedGoogle Scholar