Journal
ANNALS OF NEUROLOGY
Volume 75, Issue 1, Pages 43-49Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.24018
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Funding
- Merck Serono
- Biogen Idec
- Teva
- Actelion
- Synthon
- Allozyne
- EMD Serono Genentech
- GSk
- Novartis
- Roche
- Mitsubishi
- Bayer HealthCare
- Schering
- Biogen-Dompe
- Italian MS Society
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Objective: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS). Methods: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Results: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R-2 = 0.48, p = 0.001) and on active MRI lesions (R-2 = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R-2 = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. Interpretation: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.
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