Kathryn C Fitzgerald1, Kassandra L Munger1, Karl Köchert2, Barry G W Arnason3, Giancarlo Comi4, Stuart Cook5, Douglas S Goodin6, Massimo Filippi7, Hans-Peter Hartung8, Douglas R Jeffery9, Paul O'Connor10, Gustavo Suarez11, Rupert Sandbrink12, Ludwig Kappos13, Christoph Pohl14, Alberto Ascherio15. 1. Department of Nutrition, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts. 2. Bayer Pharma AG, Berlin, Germany. 3. Department of Neurology, University of Chicago, Chicago, Illinois. 4. Department of Neurology, Scientific Institute H. S. Raffaele, Milan, Italy. 5. Department of Neurology and Neuroscience, Rutgers-New Jersey Medical School, Newark. 6. Department of Neurology, University of California, San Francisco. 7. Neuroimaging Research Unit, Scientific Institute and University Vita-Salute, Milan, Italy. 8. Department of Neurology, University of Dusseldorf, Dusseldorf, Germany. 9. Department of Neurology, Piedmont Health Care, Mooresville, North Carolina. 10. Department of Neurology, St Michael's Hospital, Toronto, Ontario, Canada. 11. Bayer HealthCare Pharmaceuticals, Whippany, New Jersey. 12. Bayer Pharma AG, Berlin, Germany12Bayer Pharma AG, Berlin, Germany. 13. Department of Neurology, University Hospital Basel, Basel, Switzerland. 14. Bayer Pharma AG, Berlin, Germany14Department of Neurology, University Hospital Bonn, Bonn, Germany. 15. Department of Nutrition, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts15Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Abstract
IMPORTANCE: Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. OBJECTIVE: To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated withinterferon beta-1b. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. EXPOSURES: Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. MAIN OUTCOMES AND MEASURES: Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. RESULTS: Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status. CONCLUSIONS AND RELEVANCE: Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.
RCT Entities:
IMPORTANCE: Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. OBJECTIVE: To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 μg or 500 μg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. EXPOSURES: Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. MAIN OUTCOMES AND MEASURES: Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. RESULTS: Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status. CONCLUSIONS AND RELEVANCE: Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.
Authors: Jennifer S Graves; Lisa F Barcellos; Lauren Krupp; Anita Belman; Xiaorong Shao; Hong Quach; Janace Hart; Tanuja Chitnis; Bianca Weinstock-Guttman; Gregory Aaen; Leslie Benson; Mark Gorman; Benjamin Greenberg; Timothy Lotze; Mar Soe; Jayne Ness; Moses Rodriguez; John Rose; Teri Schreiner; Jan-Mendelt Tillema; Amy Waldman; T Charles Casper; Emmanuelle Waubant Journal: Mult Scler Date: 2019-05-13 Impact factor: 6.312
Authors: L Ferre'; F Clarelli; G Sferruzza; M A Rocca; E Mascia; M Radaelli; F Sangalli; G Dalla Costa; L Moiola; M Aboulwafa; F Martinelli Boneschi; G Comi; M Filippi; V Martinelli; F Esposito Journal: Neurol Sci Date: 2018-05-13 Impact factor: 3.307
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