Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis

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 in 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: 13 trials including more than 13500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated both with treatment effects on brain atrophy (R2=0.48, p=0.001) and on active MRI lesions (R2=0.61, p<0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R2=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 two MRI measures predict the treatment effect on disability more closely when used in combination.