The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis

Abstract

Background: The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS.

Materials and methods: We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed.

Results: Among the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57--0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12).

Conclusions: SLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.

Fig 1. Flow chart of systematic review.

*One study could be included at 12 and 24 months. DMD: Disease Modifying Drug; FLDMD: First-line DMD; SLDMD: Second-line DMD; PCB: Placebo; BPF: Brain Parenchymal Fraction; SIENA: Structural Image Evaluation, using Normalisation, of Atrophy.

Fig 2

Forest plot of comparison between FLDMD and SLDMD at 12 months (A) and 24 months (B). DMD: Disease Modifying Drug; FLDMD: First-line DMD; SLDMD: Second-line DMD; SD: Standard Deviation.

Fig 3

Evolution of the percentage brain volume change up to 48 months (A), from 12 to 48 months (B), from 12 to 48 months using only randomized studies and recommended doses (C) and from 12 to 48 months using only randomized studies, recommended doses and BPF or SIENA techniques (D). *, significant, see p-value in the associated table. DMD: Disease Modifying Drugs; FLDMD: First-line DMD; SLDMD: Second-line DMD; β: Coefficient of monthly PBVC slope; SE: Standard Error; PBVC: Percentage Brain Volume Change; NS: Not significant. Each Circle represents the percentage brain volume change from baseline, in one group of patients treated in the same study by the same treatment. Circle is proportional to the sample size of the studied arms.