The Effect of Disease Modifying Therapies on Disability Progression in Multiple Sclerosis: A Systematic Overview of Meta-Analyses

Abstract

Background: Disease modifying therapy (DMT) efficacy trials make an essential contribution to the development of evidence-based clinical treatments and practices for people with multiple sclerosis (MS). Meta-analysis is a critical part of this process and provides a powerful tool to assess the effects of DMT on MS progression. However, although there have been several meta-analyses on the effect of DMT on MS disease progression, they often do not reach the same conclusions. Objective: Our aim was to better understand and contextualize the results of meta-analyses evaluating DMT, identify differences in methodology that might explain their differing conclusions, and highlight areas for future research that will improve our ability to develop clinical recommendations. Methods: We conducted an overview of systematic reviews with meta-analyses assessing the efficacy of DMT on disability progression in people with MS in PubMed (Medline) and the Cochrane Database of Systematic Reviews. Results: We included 22 meta-analyses in this overview: eight general (on >3 DMT), 11 specific (on ≤3 DMT), 2 that evaluated subsets, and 1 that evaluated long-term effects. We found that there is good evidence that DMT improve short-term (≤2-3 years) disability progression outcomes relative to placebo in people with relapsing-remitting MS. However, results varied substantially between meta-analyses, and there is little evidence of their efficacy in other populations or over longer periods. The relative effects of individual DMT also remain unclear. The variance in results between meta-analyses may be related to the substantial differences in inclusion criteria, which was reflected in the limited overlap in included studies, as well as the year of meta-analysis publication. Of the 123 total unique studies included in the general meta-analyses, 77 (62.6%) were included in only one meta-analysis. This incongruence was also evident in the included DMT. Six of the 16 (37.5%) DMT evaluated in the general meta-analyses were only included in one meta-analysis. Conclusions: Translating DMT efficacy studies into evidence-based clinical practice requires greater methodological consistency in meta-analyses, more data on the relative effects of DMT through head-to-head clinical trials, and better reporting of adverse events.

Keywords: disability progression; disease modifying therapies; meta-analysis; multiple sclerosis; systematic review.

Figure 1

Inclusion flowchart.

Figure 2

The odds of disease progression (measured as accumulated disability) presented here for comparison (odds ratio ± 95%CI after treatment with various DMT compared to placebo, values <1 indicate an effect). For each DMT, each line shows the results of a different meta-analysis/dosage combination. Source citation and dosages (if specified) are given in the data label. These could not be consolidated due to overlap in included studies between meta-analyses). ^* Indicates that the analysis was a traditional meta-analysis, all others were network met-analyses. + Indicates analyses that included all MS phenotypes, all others included only relapsing phenotypes.

Figure 3

Relative risk of disease progression presented here for comparison (RR ± 95% CI after treatment with various DMT compared to placebo, values <1 indicate an effect). For each DMT, each line shows the results of a different meta-analysis/dosage combination. Source citation and dosages (if specified) are listed in the data label. These could not be consolidated due to overlap in included studies between meta-analyses. All meta-analyses included studies of people with relapsing MS. Combined indicates an aggregation of DMT, including dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, peg-interferon beta-1a, and teriflunomide. ^* Indicates that the analysis was a traditional meta-analysis, all others were network met-analyses.

Figure 4

This graph depicts the number of general meta-analyses in which a given study was included. There were 123 unique studies included in meta-analyses evaluating the effect of DMT on disease progression that provided a list of included studies [Zintzaras et al. was excluded]. For example, 77 of the included studies were included by one of the seven general meta-analyses that provided a list of included studies.