Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments.

Ann Marie Weideman,Kory Johnson,Mark Greenwood,Marco Aurelio Tapia-Maltos,Bibiana Bielekova

doi:10.3389/fneur.2017.00577

Abstract

To perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age. We performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs. More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e-09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years. The meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.

Highlights

With the expansion of the multiple sclerosis (MS) drug armamentarium, it is becoming exceedingly difficult to make informed decisions regarding their comparative efficacy
Because interferon-beta preparations were used as active comparators in several clinical trials that lacked a placebo arm, we first performed a linear regression of the efficacy of all interferon-beta treatments against placebo as a function of age
We observed a negative relationship between %percent inhibition of disability progression (IDP) and mean age, and the weighted regression model (I DPWi = 103.04 − 2.03Agei, slope 95% confidence interval (CI) = (−3.22,−0.84)) had strong evidence of a relationship, with age explaining approximately 59% of the variance in %IDP (R2 = 0.5906, two-tailed p = 0.0035; Figure 2, top panel)

Summary

Introduction

With the expansion of the multiple sclerosis (MS) drug armamentarium, it is becoming exceedingly difficult to make informed decisions regarding their comparative efficacy. Experts debate whether first line MS therapy should consist of low- versus high-efficacy drugs and at what age, if any, it is appropriate to withdraw immunomodulatory disease-modifying therapies (DMTs). This debate is confounded by the widely accepted classification of MS patients into relapsing-remitting (RRMS), secondary-progressive (SPMS), and primary-progressive MS (PPMS) subtypes. While these phenotypical categories prove useful in clinical trial designs and conceptual thinking about MS, they de facto dichotomize the continuous process of MS evolution. An analogous uncertainty is frequently encountered in differentiating SPMS from PPMS based on ambiguity in recollecting event(s) in a patient’s history which may or may not represent MS relapses

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Conclusion