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Treatment of Multiple Sclerosis – Relationship between Vitamin D and Interferon β-1b

European Neurological Review, 2015;10(2):124–30 DOI: http://doi.org/10.17925/ENR.2015.10.02.124

Abstract:

There are many reports suggesting an association between vitamin D status and both the development of multiple sclerosis (MS) and its course. This relationship and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of patients are reviewed in the BEtaferon/ Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. In the BENEFIT study the average serum 25-hydroxyvitamin D (25[OH]D) levels strongly predicted MS disease activity and progression. The probability of clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity was lower in these clinically isolated syndrome (CIS) patients with 25(OH)D levels ≥50 nmol/L and in those starting with IFNβ -1b. Furthermore, there was a beneficial effect on relapse rate, occurrence of new active MRI lesions and disease progression for a 50 nmol/L increase in 25(OH)D levels. Similarly, in relapsing-remitting (RR) MS patients from the BEYOND study serum 25(OH)D levels were inversely associated with MRI markers of MS activity. Genetic analysis of patients from these studies indicated that there may be a benefit in monitoring and managing vitamin D levels in early MS patients treated with IFNβ-1b and a cumulative number of risk alleles predict lower 25(OH)D levels in CIS and RRMS patients. Further studies have suggested that some of the IFNβ-1b therapeutic effects on relapse could be mediated through modulation of vitamin D metabolism. Thus, there seems to be a benefit on clinical and MRI measures if patients are treated with both vitamin D and IFNβ-1b. There is a need to further evaluate this effect in clinical trials. The relationship between vitamin D and MS disease activity along with the effects of vitamin D and IFNβ-1b in the treatment of MS patients is reviewed.



Keywords: Vitamin D, 25-hydroxyvitamin D, multiple sclerosis, interferon β-1b
Disclosure: Bruce Taylor receives research support from the National Health and Medical Research Council (NHMRC) Australia, MS Research Australia and the Royal Hobart Hospital Research Foundation. He has served on advisory boards for Novartis Biogen and Genzyme and has received travel assistance from Novartis, Biogen and Teva. Harold Moses has served as a consultant to Biogen, Teva, Serono, Medimmune, Novartis, Genzyme, NIH (Neuronext) and Bayer. Friedemann Paul receives funding from Deutsche Forschungsgemeinschaft (Exc 257), Bundesministerium für Bildung und Forschung (BMBF Competence Network Multiple Sclerosis KKNMS), EU FP7 (combims.eu), Guthy Jackson Charitable Foundation, National Multiple Sclerosis Society of the USA, research support and personal compensation for activities with Alexion, Bayer, Biogen, MerckSerono, Chugai, MedImmune, Novartis, SanofiGenzyme and Teva. Gustavo Suarez is an employee of Bayer HealthCare Pharmaceuticals. Mark Rametta is an employee of Bayer HealthCare Pharmaceuticals.
Acknowledgments: Medical writing support was provided by Ray Ashton, Richmond Medical Communications, which was funded by Bayer HealthCare Pharmaceuticals Inc. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: September 29, 2015 Accepted: October 23, 2015
Correspondence: Bruce Taylor, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. E: bruce.taylor@utas.edu.au.
Support: The publication of this article was supported by Bayer HealthCare Pharmaceuticals Inc. The views and opinions expressed in the article are those of the authors and not necessarily those of Bayer HealthCare Pharmaceuticals Inc.

There is increasing evidence that vitamin D status is associated with both the development of multiple sclerosis (MS) and also the modulation of disease activity and possibly progression. Several publications have reported that the risk of MS is higher in patients with low vitamin D intake or serum 25-hydroxyvitamin D (25[OH]D) levels, for example due to low sun exposure.1,2 However, the findings of studies examining the relationship between vitamin D and MS disease activity are difficult to compare as the patients enrolled often had variable disease duration and it has been problematic to decide if low vitamin D levels were a consequence of MS activity (reverse causality) or if low levels early in the disease can predict long-term progression and disability.3,4

A recent publication analysed systematic reviews and meta-analyses to summarise the risk factors associated with MS.5 Of the 44 meta-analyses (416 primary studies), 11 had high significance (p<0.001). Anti-Epstein- Barr nuclear antigen (anti-EBNA) immunoglobulin (Ig)-G seropositivity, infectious mononucleosis and smoking showed the strongest consistent evidence of an association in these high significance studies. Vitamin D status did not reach significance as a risk factor. However, it is important to note that vitamin D measured at the onset of MS may not necessarily reflect vitamin D levels at other significant times in a person’s life, which may predispose them to later development of MS. Measure of prior sun exposure as potential, although not absolute, proxy for vitamin D levels in a Caucasian population have suggested that lifetime sun exposure, as well as sun exposure in the adolescent period, may be more important factors in MS risk than recent sun exposure.6,7 Effects of vitamin D levels on disease activity may be easier to assess as the exposure (vitamin D) is contemporaneous with the outcome (disease activity).

Here we review the relationship between vitamin D and MS disease activity and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of MS in patients from the BEtaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. Furthermore, the molecular mechanisms underlying the impact of vitamin D on MS disease activity and the possible genetic component associated with vitamin D and MS are considered.

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Keywords: Vitamin D, 25-hydroxyvitamin D, multiple sclerosis, interferon β-1b