Effect of Vitamin D supplements on relapse rate and Expanded Disability Status Scale (EDSS) in multiple sclerosis (MS): A systematic review and meta-analysis

Sara Hanaei, Mohammad Ali Sahraian, Mehdi Mohammadifar, Sreeram V Ramagopalan, Mahsa Ghajarzadeh

Abstract


Background: Multiple sclerosis (MS) is an inflammatory disease while there are controversies regarding the role of vitamin D supplements in controlling relapse and disability improvement during treatment. Objective: The goal of this systematic review and meta-analysis was to evaluate the effect of vitamin D supplements on MS-related relapse and the Expanded Disability Status Scale (EDSS). Methods: We searched databases to include randomized clinical trials (RCTs) which were published up to October 2018. We included RCTs, being single-blinded or double-blinded or open-label trials in which one of the main outcomes was EDSS and/or relapse after vitamin D supplementation. All statistical analyses were performed using RevMan 5.3. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for relapse between treatment arms. The mean difference was calculated for EDSS comparisons. Results: Nine articles were included for analysis. Of these nine studies, five compared vitamin D supplement groups with placebo (group 1 studies), and four compared high- and low-dose vitamin D groups. A total of 561 patients were analyzed. Being treated with vitamin D instead of placebo showed no effect on relapse rate (OR = 0.66, 95% CI = 0.28–1.54) as well as EDSS (mean difference = 0.06, 95%CI [-0.31, 0.42]). The results of studies comparing high- vs. low-dose vitamin D interventions showed no significant effect on relapse rate (OR = 1.08, 95%CI [0.29–4.08] as well as final EDSS (mean difference = 0.17, 95% CI = -0.73, 1.07). Conclusions: Our findings show that vitamin D supplements (high or low dose) have no significant effect on relapse rate and disability during treatment in MS patients.

Keywords


Disability; multiple sclerosis; relapse; systematic review; vitamin D

Full Text:

PDF

References


Ghajarzadeh M, Jalilian R, Eskandari G, Sahraian MA,

Azimi A and Mohammadifar M. Fatigue in multiple sclerosis:

Relationship with disease duration, physical disability, disease

pattern, age and sex. Acta Neurol Belg 2013;113:411‑4.

Ghajarzadeh M, Owji M, Sauraian MA, Naser Moghadasi A,

Azimi A.Emotional Intelligence (EI) of Patients with Multiple

Sclerosis (MS).Iran J Public Health. 2014;43:1550-6.

Eskandari G, Ghajarzadeh M, Yekaninejad MS, Sahraian MA,

Gorji R, Rajaei F, et al. Comparison of serum vitamin D level

in multiple sclerosis patients, their siblings, and healthy controls.

Iran J Neurol 2015;14:81‑5.

van der Mei IA, Ponsonby A‑L, Blizzard L, Dwyer T. Regional

variation in multiple sclerosis prevalence in Australia and its

association with ambient ultraviolet radiation. Neuroepidemiology

;20:168‑74.

Bäärnhielm M, Hedström A, Kockum I, Sundqvist E,

Gustafsson SA, Hillert J, et al. Sunlight is associated with

decreased multiple sclerosis risk: No interaction with human

leukocyte antigen‑DRB1* 15. Eur J Neurol 2012;19:955‑62.

Bivona G, Gambino CM, Iacolino G, Ciaccio M. Vitamin D and

the nervous system. Neurol Res 2019;41:827‑35.

Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin

D as an immune modulator in multiple sclerosis, a review.

J Neuroimmunol 2008;194:7‑17.

Bivona G, Agnello L, Bellia C, Iacolino G, Scazzone C, Lo

Sasso B, et al. Non‑skeletal activities of vitamin D: From

physiology to brain pathology. Medicina (Kaunas) 2019;55:341.

Bivona G, Lo Sasso B, Iacolino G, Gambino CM, Scazzone C,

Agnello L, et al. Standardized measurement of circulating

vitamin D [25(OH) D] and its putative role as a serum biomarker

in Alzheimer’s disease and Parkinson’s disease. Clin Chim Acta

;497:82‑7.

Bivona G, Agnello L, Ciaccio M. The immunological implication

of the new vitamin D metabolism. Cent‑Eur J Immunol

;43:331‑4.

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A.

Serum 25‑hydroxyvitamin D levels and risk of multiple sclerosis.

JAMA 2006;296:2832‑8.

Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB,

Belman AL, et al. Vitamin D status is associated with relapse rate

in pediatric‑onset multiple sclerosis. Ann Neurol 2010;67:618‑24.

Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R.

Association of vitamin D metabolite levels with relapse rate and

disability in multiple sclerosis. Mul Scler 2008;14:1220‑4.

Runia TF, Hop WC, de Rijke YB, Buljevac D, Hintzen RQ.

Lower serum vitamin D levels are associated with a higher

relapse risk in multiple sclerosis. Neurology 2012;79:261‑6.

Burton J, Kimball S, Vieth R, Bar‑Or A, Dosch HM, Cheung R,

et al. A phase I/II dose‑escalation trial of vitamin D3 and calcium

in multiple sclerosis. Neurology 2010;74:1852‑9.

Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. 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 2012;18:1144‑51.

Laursen JH, Søndergaard HB, Sørensen PS, Sellebjerg F,

Oturai AB. Vitamin D supplementation reduces relapse rate

in relapsing‑remitting multiple sclerosis patients treated with

natalizumab. Multi Scler Relat Disord 2016;10:169‑73.

Soilu‑Hänninen M, Åivo J, Lindström B‑M, Elovaara I,

Sumelahti ML, Färkkilä M, et al. A randomised, double blind,

placebo controlled trial with vitamin D3 as an add on treatment

to interferon β‑1b in patients with multiple sclerosis. J Neurol

Neurosurg Psychiatry 2012;83:565‑71.

James E, Dobson R, Kuhle J, Baker D, Giovannoni G and

Ramagopalan SV. The effect of vitamin D‑related interventions

on multiple sclerosis relapses: A meta‑analysis. Mult Scler

;19:1571‑9.

Ghajarzadeh M, Keshtkar AA, Azimi A, Sahraian MA,

Mohammadifar M, Ramagopalan SV. The effect of vitamin D

supplements on clinical and para‑clinical outcomes in patients

with multiple sclerosis: Protocol for a systematic review. JMIR

Res Protoc 2019;8:e12045.

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D,

Oxman AD, et al. The cochrane collaboration’s tool for assessing

risk of bias in randomised trials. Bmj 2011;343:d5928.

Achiron A, Givon U, Magalashvili D, Dolev M, Liraz

Zaltzman S, Kalron A, et al. Effect of alfacalcidol on

multiple sclerosis‑related fatigue: A randomized, double‑blind

placebo‑controlled study. Mult Scler 2015;21:767‑75.

Sotirchos ES, Bhargava P, Eckstein C, Van Haren K, Baynes M,

Ntranos A, et al. Safety and immunologic effects of high‑ vs

low‑dose cholecalciferol in multiple sclerosis. Neurology

;86:382‑90.

Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P.

Therapeutic effect of vitamin D3 in multiple sclerosis patients.

Immunol Invest 2011;40:627‑39.

Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects

of adjunct low‑dose vitamin d on relapsing‑remitting multiple

sclerosis progression: Preliminary findings of a randomized

placebo‑controlled trial. Mult Scler Int 2012;2012:452541.

Golan D, Halhal B, Glass‑Marmor L, Staun‑Ram E,

Rozenberg O, Lavi I, et al. 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

;13:60.

Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR,

et al. A randomized trial of high‑dose vitamin D2 in

relapsing‑remitting multiple sclerosis. Neurology 2011;77:1611‑8.

Zheng C, He L, Liu L, Zhu J, Jin T. The efficacy of vitamin D

in multiple sclerosis: A meta‑analysis. Mult Scler Relat Disord

;23:56‑61.

Pierrot‑Deseilligny C, Rivaud‑Péchoux S, Clerson P, de Paz R,

Souberbielle J‑C. Relationship between 25‑OH‑D serum

level and relapse rate in multiple sclerosis patients before and

after vitamin D supplementation. Ther Adv Neurol Disord

;5:187‑98.

Embry AF, Snowdon LR, Vieth R. Vitamin D and seasonal

fluctuations of gadolinium‑enhancing magnetic resonance

imaging lesions in multiple sclerosis. Ann Neurol 2000;48:271‑2.

Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less

effective than vitamin D3 in humans. J Clin Endocrinol Metab

;89:5387‑91.