Advertisement

Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab

Published:October 25, 2016DOI:https://doi.org/10.1016/j.msard.2016.10.005

      Highlights

      • Recommending vitamin D3 supplements in vitamin D insufficient, relapsing-remitting MS patients is associated with increased 25-hydroxyvitamin D (25(OH)D) levels.
      • Increased 25(OH)D levels in these patients are associated with decreases in the annualized relapse rate (ARR).
      • No association was found between changes in 25(OH)D and changes in gene expression of molecules representing the immune system. This reflects how complex vitamin D research is.

      Abstract

      Background

      Vitamin D insufficiency is common among multiple sclerosis patients, and hypovitaminosis D has been associated with multiple sclerosis (MS) risk and disease activity.

      Objective

      To investigate how recommendations on vitamin D3 supplements affect 25-hydroxyvitamin D (25(OH)D) levels in patients with relapsing-remitting MS (RRMS) and to examine the clinical effects associated with changes in 25(OH)D levels.

      Methods

      In this prospective cohort study, baseline blood samples were collected from 170 natalizumab-treated RRMS patients during winter 2009–2010 and were repeated the following winter. Vitamin D supplements were recommended according to standard clinical practice in our clinic to patients with serum 25(OH)D<50 nmol/l at baseline. Information was obtained on annualized relapse-rate (ARR) the year prior to baseline and the following year.

      Results

      We found that recommending vitamin D supplements in patients with vitamin D insufficiency was associated with a significant increase in serum 25(OH)D concentrations (p=5.1×10−10), which was significantly related with decreases in ARR; for each nmol/l increase in Δ25(OH)D a −0.014 (95% CI −0.026 to −0.003) decrease in ΔARR was observed, p=0.02.

      Conclusion

      Correction of hypovitaminosis D in clinical practice by recommending oral D3 supplements resulted in increases in 25(OH)D levels in serum, which were associated with decreases in ARR in RRMS.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Ascherio, A., Munger, K., White, R., Kochert, K., Simon, K., Polman, C., Freedman, M., Hartung, H., Miller, D., Montalban, X., Edan, G., Barkhof, F., Pleimes, D., Radu, E., Sandbrink, R., Kappos, L., Pohl, C., 2014. Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression. JAMA Neurol.

        • Correale J.
        • Ysrraelit M.C.
        • Gaitan M.I.
        Immunomodulatory effects of Vitamin D in multiple sclerosis.
        Brain. 2009; 132: 1146-1160
        • Dorr J.
        • Ohlraun S.
        • Skarabis H.
        • Paul F.
        Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial.
        Trials. 2012; 13: 15
        • Farias A.S.
        • Spagnol G.S.
        • Bordeaux-Rego P.
        • Oliveira C.O.
        • Fontana A.G.
        • de Paula R.F.
        • Santos M.P.
        • Pradella F.
        • Moraes A.S.
        • Oliveira E.C.
        • Longhini A.L.
        • Rezende A.C.
        • Vaisberg M.W.
        • Santos L.M.
        Vitamin D3 induces IDO(+) tolerogenic DCs and enhances Treg, reducing the severity of EAE.
        CNS Neurosci. Ther. 2013; 19: 269-277
        • Holick M.F.
        Vitamin D: extraskeletal health.
        Endocrinol. Metab. Clin. N. Am. 2010; 39 (table): 381-400
        • Islam T.
        • Gauderman W.J.
        • Cozen W.
        • Mack T.M.
        Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins.
        Neurology. 2007; 69: 381-388
        • James E.
        • Dobson R.
        • Kuhle J.
        • Baker D.
        • Giovannoni G.
        • Ramagopalan S.V.
        The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis.
        Mult. Scler. 2013; 19: 1571-1579
        • Liu Y.
        • Carlsson R.
        • Comabella M.
        • Wang J.
        • Kosicki M.
        • Carrion B.
        • Hasan M.
        • Wu X.
        • Montalban X.
        • Dziegiel M.H.
        • Sellebjerg F.
        • Sorensen P.S.
        • Helin K.
        • Issazadeh-Navikas S.
        FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS.
        Nat. Med. 2014; 20: 272-282
      2. Martinelli, V., Dalla, C., Colombo, B., Dalla, L., Rubinacci, A., Filippi, M., Furlan, R., Comi, G., 2013. Vitamin D Levels and Risk of Multiple Sclerosis in Patients with Clinically Isolated Syndromes. Mult Scler.

        • Mosekilde L.
        Vitamin D requirement and setting recommendation levels: long-term perspectives.
        Nutr. Rev. 2008; 66: S170-S177
        • Mowry E.M.
        • Waubant E.
        • McCulloch C.E.
        • Okuda D.T.
        • Evangelista A.A.
        • Lincoln R.R.
        • Gourraud P.A.
        • Brenneman D.
        • Owen M.C.
        • Qualley P.
        • Bucci M.
        • Hauser S.L.
        • Pelletier D.
        Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis.
        Ann. Neurol. 2012; 72: 234-240
      3. Munger, K., 2013. Molecular Dissection of the Role of Vitamin D in Determining MS Activity.

        • Munger K.L.
        • Levin L.I.
        • Hollis B.W.
        • Howard N.S.
        • Ascherio A.
        Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.
        JAMA. 2006; 296: 2832-2838
        • Munger K.L.
        • Zhang S.M.
        • O'Reilly E.
        • Hernan M.A.
        • Olek M.J.
        • Willett W.C.
        • Ascherio A.
        Vitamin D intake and incidence of multiple sclerosis.
        Neurology. 2004; 62: 60-65
        • Pierrot-Deseilligny C.
        • Rivaud-Pechoux S.
        • Clerson P.
        • de P.R.
        • Souberbielle J.C.
        Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation.
        Therapeutic Adv. Neurol. Disord. 2012; 5: 187-198
        • Platz E.A.
        • Leitzmann M.F.
        • Hollis B.W.
        • Willett W.C.
        • Giovannucci E.
        Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer.
        Cancer Causes Control. 2004; 15: 255-265
        • Polman C.H.
        • Reingold S.C.
        • Edan G.
        • Filippi M.
        • Hartung H.P.
        • Kappos L.
        • Lublin F.D.
        • Metz L.M.
        • McFarland H.F.
        • O'Connor P.W.
        • Sandberg-Wollheim M.
        • Thompson A.J.
        • Weinshenker B.G.
        • Wolinsky J.S.
        Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald criteria".
        Ann. Neurol. 2005; 58: 840-846
        • Powe C.E.
        • Evans M.K.
        • Wenger J.
        • Zonderman A.B.
        • Berg A.H.
        • Nalls M.
        • Tamez H.
        • Zhang D.
        • Bhan I.
        • Karumanchi S.A.
        • Powe N.R.
        • Thadhani R.
        Vitamin D-binding protein and vitamin D status of black Americans and white Americans.
        N. Engl. J. Med. 2013; 369: 1991-2000
        • Pozuelo-Moyano B.
        • Benito-Leon J.
        • Mitchell A.J.
        • Hernandez-Gallego J.
        A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis.
        Neuroepidemiology. 2013; 40: 147-153
        • Prietl B.
        • Treiber G.
        • Pieber T.R.
        • Amrein K.
        Vitamin D and immune function.
        Nutrients. 2013; 5: 2502-2521
        • Runia T.F.
        • Hop W.C.
        • de Rijke Y.B.
        • Buljevac D.
        • Hintzen R.Q.
        Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis.
        Neurology. 2012; 79: 261-266
        • Saltyte B.J.
        • Myhr K.M.
        • Loken-Amsrud K.I.
        • Beiske A.G.
        • Bjerve K.S.
        • Hovdal H.
        • Midgard R.
        • Holmoy T.
        Modelling and prediction of 25-hydroxyvitamin d levels in norwegian relapsing-remitting multiple sclerosis patients.
        Neuroepidemiology. 2012; 39: 84-93
        • Salzer J.
        • Hallmans G.
        • Nystrom M.
        • Stenlund H.
        • Wadell G.
        • Sundstrom P.
        Vitamin D as a protective factor in multiple sclerosis.
        Neurology. 2012; 79: 2140-2145
        • Scott T.F.
        • Hackett C.T.
        • Dworek D.C.
        • Schramke C.J.
        Low vitamin D level is associated with higher relapse rate in natalizumab treated MS patients.
        J. Neurol. Sci. 2013; 330: 27-31
        • Simpson Jr, S.
        • Taylor B.
        • Blizzard L.
        • Ponsonby A.L.
        • Pittas F.
        • Tremlett H.
        • Dwyer T.
        • Gies P.
        Van dM, I: higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis.
        Ann. Neurol. 2010; 68: 193-203
        • Smolders J.
        • Menheere P.
        • Kessels A.
        • Damoiseaux J.
        • Hupperts R.
        Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis.
        Mult. Scler. 2008; 14: 1220-1224
      4. Smolders, J., Hupperts, R., Barkhof, F., Grimaldi, L., Holmoy, T., Killestein, J., Rieckmann, P., Schluep, M., Vieth, R., Hostalek, U., Ghazi-Visser, L., Beelke, M., 2011. Efficacy of vitamin D(3) 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. J. Neurol. Sci.

        • Soilu-Hanninen M.
        • Airas L.
        • Mononen I.
        • Heikkila A.
        • Viljanen M.
        • Hanninen A.
        25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis.
        Mult. Scler. 2005; 11: 266-271
        • Soilu-Hanninen M.
        • Aivo J.
        • Lindstrom B.M.
        • Elovaara I.
        • Sumelahti M.L.
        • Farkkila M.
        • Tienari P.
        • Atula S.
        • Sarasoja T.
        • Herrala L.
        • Keskinarkaus I.
        • Kruger J.
        • Kallio T.
        • Rocca M.A.
        • Filippi M.
        A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2012; 83: 565-571
        • Soilu-Hanninen M.
        • Aivo J.
        • Lindstrom B.M.
        • Elovaara I.
        • Sumelahti M.L.
        • Farkkila M.
        • Tienari P.
        • Atula S.
        • Sarasoja T.
        • Herrala L.
        • Keskinarkaus I.
        • Kruger J.
        • Kallio T.
        • Rocca M.A.
        • Filippi M.
        A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2012; 83: 565-571
        • Sorensen P.S.
        • Koch-Henriksen N.
        • Petersen T.
        • Ravnborg M.
        • Oturai A.
        • Sellebjerg F.
        Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients.
        J. Neurol. 2014;
        • Stewart N.
        • Simpson Jr, S.
        • Van dM I.
        • Ponsonby A.L.
        • Blizzard L.
        • Dwyer T.
        • Pittas F.
        • Eyles D.
        • Ko P.
        • Taylor B.V.
        Interferon-beta and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS.
        Neurology. 2012; 79: 254-260
        • van E.E.
        • Gysemans C.
        • Branisteanu D.D.
        • Verstuyf A.
        • Bouillon R.
        • Overbergh L.
        • Mathieu C.
        Novel insights in the immune function of the vitamin D system: synergism with interferon-beta.
        J. Steroid Biochem. Mol. Biol. 2007; 103: 546-551