Association of No Evidence of Disease Activity With No Long-term Disability Progression in Multiple Sclerosis: A Systematic Review and Meta-analysis

Objective: We conducted a systematic review and meta-analysis to evaluate the relationship between No Evidence of Disease Activity (NEDA) and no long-term disability progression on low and high efficacy therapy in relapsing-remitting multiple sclerosis (RRMS). Methods: MEDLINE, Embase, and the Cochrane Database were searched from January 1, 2006 to January 26, 2021. We selected studies which evaluated NEDA-3 (no relapse, new MRI lesion, or confirmed disability progression) at one or two years and had a minimum of four years' follow-up for determination of disability progression. Data were extracted by two independent reviewers and were meta-analyzed using a random effects model. Primary outcome of no disability progression was defined as no confirmed progression on the Expanded Disability Status Scale (EDSS) during follow-up. We assessed the odds ratio for no disability progression with NEDA vs. Evidence of Disease Activity (EDA). Positive predictive value of NEDA for no disability progression was summarized for studies with prevalence of no progression >80% vs. <80% separately. Results: We included 29 studies in our qualitative synthesis of which 27 (16 low efficacy, 11 high efficacy) were included in the meta-analysis (n=10,935 participants). Median follow-up was 5.6 years (IQR: 4.3, 8.0 years). The pooled odds ratios for no progression with NEDA-3 vs. EDA were 2.32 (95% CI: 1.58-3.42; I2=73%) for low efficacy therapy and 3.19 (1.86-5.47; I2=86%) for high efficacy therapy. Among studies with prevalence of no progression at follow-up >80%, the pooled positive predictive value for low efficacy therapy was 91% (95% CI: 89-93%) and for high efficacy therapy was 92% (95% CI: 88-94%). Among studies with prevalence of no progression <80%, the pooled positive predictive value for low efficacy therapy was 81% (95% CI: 75-86%) and for high efficacy therapy was 86% (95% CI: 80-90%). Conclusions: NEDA-3 is associated with no long-term disability progression in RRMS on both low and high efficacy therapies. Further studies of early composite outcome measures incorporating easily measurable biomarkers, and longer follow-up, may help to improve on prognostic value of NEDA-3 in RRMS.