Abstract
BackgroundIn the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS).MethodsA systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS).ResultsRegression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs.ConclusionsTreatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.
Highlights
In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability
Their analysis was limited to randomized clinical trials (RCTs) directed at relapsing-remitting MS (RRMS) patients, restricting the conclusions that can be drawn regarding the predictive relationship between relapse rates and disability progression in other forms of MS
The following algorithm was used in PubMed and analogous searches were developed for the remaining databases: 1. “Multiple Sclerosis, Relapsing-Remitting”[Mesh] OR “Relapsing-Remitting Multiple Sclerosis” OR “secondary progressive multiple sclerosis” OR (“Multiple Sclerosis”[Mesh] AND “secondary progressive” [TIAB]) OR “clinically isolated syndrome” OR “early MS” OR “early multiple sclerosis” OR “clinically definite MS” OR “clinically definite multiple sclerosis”
Summary
In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability, typically defined by worsening on the Expanded Disability Status Scale (EDSS) [1]. Sormani and colleagues performed a quantitative metaanalysis of the predictive power of annualized relapse rates and new/enlarged T2 lesions on EDSS progression across a wide range of RCTs for RRMS [6]. Inclusion of a non-zero intercept implies that two treatments that do not differ in affecting the predictor (i.e., two treatments that have the same relapse rate) will differ in affecting the outcome (i.e., they will lead to different amounts of EDSS progression) While it is conceptually possible for some pairs of treatments, it would have to hold for all pairs of treatments for the regression to be generalizable. Their analysis was limited to RCTs directed at RRMS patients, restricting the conclusions that can be drawn regarding the predictive relationship between relapse rates and disability progression in other forms of MS
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