Window of opportunity in MS treatmentThursday, October 03, 2013, 11:25 - 11:37
Vitamin D as a predictor of multiple sclerosis activity and progressionA. Ascherio, K. Munger, R. White, K. Kochert, C. Simon, C. Polman, M.S. Freedman, H.-P. Hartung, D.H. Miller, X. Montalban, G. Edan, F. Barkhof, D. Pleimes, R. Sandbrink, L. Kappos, C. Pohl (Boston, US; Vancouver, CA; Berlin, DE; Amsterdam, NL; Ottawa, CA; Düsseldorf, DE; London, GB; Barcelona, ES; Rennes, FR; Montville, US; Basel, CH)
Objective: To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis after a clinically isolated syndrome.
Methods: BENEFIT was a randomized trial originally designed to evaluate the impact of early- versus delayed-interferon beta-1b (IFNB-1b) treatment in patients with a first event suggestive of MS. Serum 25(OH)D concentrations were measured at baseline, 6, 12, and 24 months. At least one 25(OH)D measurement was conducted for 465 of the 468 patients randomized in BENEFIT, and 334 patients had 25(OH)D measurements at both 6 and 12 months (ie, in opposing season). Clinical and MRI follow-up lasted for 5 years. Analyses used Cox proportional hazard models or generalized mixed effects models adjusted for age, sex, initial treatment, number of T2 lesions at baseline, and type of onset (monofocal vs multifocal) to relate season-adjusted serum 25(OH)D concentrations to MS outcomes.
Results: Higher 25(OH)D levels predicted slower conversion to MS, reduced MS activity, and slower rate of progression. These associations were stronger when seasonally asynchronous blood samples were used to assess long-term average 25(OH)D levels. Between 6 and 60 months, the hazard ratios (HRs) for a 50-nmol/L increment in 25(OH)D were 0.44 for McDonald MS (p=0.003) and 0.48 (p=0.025) for clinically-definite MS. A 50-nmol/L increment in average serum 25(OH)D levels at 12 months predicted a 57% lower rate of new active lesions (p=0.0009), 57% lower relapse rate (p=0.03), 25% lower increase in T2 lesion volume (p=0.00004), and 0.41% lower yearly loss in brain volume (p=0.07) from 12 to 60 months. Similar associations were found between 25(OH)D measured at 12 months and MS activity or progression from 24 to 60 months. In analyses using dichotomous 25(OH)D levels, >= 50 nmol/L at 12 months predicted fewer active lesions at MRI (HR=0.73; p=0.002), a lower increase in T2 lesion volume (difference = - 9%/year; p=0.008), a lower rate of brain loss (0.32% vs 0.66% per year; p=0.005), and lower disability (EDSS = - 0.17; p=0.004) during the subsequent 4 years.
Conclusions: Among patients with MS treated with IFNB-1b, low 25(OH)D levels early in the disease course were a strong risk factor for long-term MS activity and severity. These results suggest that vitamin D supplementation may have a role as a key additional component in the early treatment of many patients with MS.
A Ascherio has received honoraria for speaking at scientific symposia by Roche, Sanofi Aventis, and Serono
KL Munger has no disclosures
R White has served as a consultant for and received financial compensation from Bayer Schering Pharma
K Köchert is a statistical consultant paid by Bayer Pharma AG
C Simon has no conflicts of interest to disclose
CH Polman has received personal compensation from Biogen Idec, Bayer Schering Pharma AG, Teva Pharmaceutical Industries, Merck Serono, Novartis Pharmaceutical Corporation, GlaxoSmithKline, Actelion Pharmaceuticals Ltd, UCB, and Roche for consulting services. The VU University Medical Center received financial support for research activities from Bayer Schering, Biogen Idec, Merck Serono, Teva, Novartis, GSK, and Roche
MS Freedman has received personal compensation and research support from Teva Pharmaceutical Industries, Merck Serono, Bayer Schering Pharma AG, Biogen-Dompé, and Genmab
H-P Hartung has received honoraria for consulting and speaking at symposia from Bayer-Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Sanofi Aventis, with approval by the rector of Heinrich-Heine University
DH Miller has received honoraria and compensation through payments to University College London (UCL) Institute of Neurology for advisory committee and/or consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, and Bayer Schering, and for work as editor of Journal of Neurology. DM has received research grant support through UCL Institute of Neurology for performing central MRI analysis of MS trials from GlaxoSmithKline, Biogen Idec, and Novartis
X Montalbán has received compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Serono, Genentech, Inc., Genzyme, Novartis, Sanofi Aventis, Teva Neuroscience, and Almirall
G Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sanofi Aventis, received personal compensation for serving on the BENEFIT scientific advisory board, and for speaking from Bayer Schering Pharma AG. GE has also received research support from Serono: grant to University Hospital to support a research program on MRI in MS and from Teva: grant to support a research program on anti-IBF neutralizing antibodies
F Barkhof has received compensation for consultancy from Bayer-Schering Pharma, Biogen-Idec, Merck Serono, Novartis, Sanofi Aventis, Genzyme, Roche, Teva and has received research support from the Dutch Foundation for MS Research (an NGO)
D Pleimes is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. DP owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals
R Sandbrink is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. RS owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals
L Kappos has lectured at medical conferences or in public and received honoraria that have been exclusively used for funding research for his department. Research and the clinical operations (nursing and patient care services) of the MS Center in Basel have been supported by nonrestricted grants from Acorda Therapeutics, Inc., Actelion Pharmaceuticals Ltd, Allozyne, BaroFold, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, Boehringer Ingelheim, Eisai, Inc., Elan, Genmab, GlaxoSmithKline, Merck Serono, MediciNova, Novartis, Roche, Sanofi Aventis, Santhera Pharmaceuticals, Shire plc, Teva, UCB, and Wyeth, and by grants from Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis, and Roche Research Foundations
C Pohl is a salaried employee of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals. CP owns stock in Bayer AG, the owner of Bayer Pharma AG/Bayer HealthCare Pharmaceuticals