From the Department of Medicine, (D.R., A.M., G.S.), University of Toronto, Ontario, Canada; St. Michael's Hospital (D.R., A.M., G.S.), Toronto, Ontario, Canada; Department of Medicine, (J.M.S.), McMaster University, Hamilton, Ontario, Canada; Department of Health Sciences (M.P.S.), Section of Biostatistics, University of Genova, Italy; IRCCS Ospedale Policlinico San Martino (M.P.S.), Genova, Italy; Department of Neurology and Cemcat (X.M.), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona; Department of Pediatrics (X.Y.Y., P.S.), Mount Sinai Hospital, Toronto, Canada; Columbia University Irving Medical Center (D.D.), Department of Neurology, New York City; York Presbyterian Hospital (NYP) (D.D.), New York City; and Institute of Health (P.S.), Policy, Management and Evaluation, University of Toronto, Canada.
Neurol Neuroimmunol Neuroinflamm. 2022 Oct 12;9(6). doi: 10.1212/NXI.0000000000200032. Print 2022 Nov.
No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression.
English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression.
Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses.
In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.
无疾病活动证据（NEDA）-4 已被建议作为缓解复发型多发性硬化症（RRMS）的疾病修正治疗（DMT）的治疗靶点。然而，NEDA-4 区分 MS 长期结局的能力及其与 NEDA-3 的性能比较仍不确定。我们进行了系统评价和荟萃分析，以评估（1）NEDA-4 与 MS 无长期残疾进展之间的关系，以及（2）NEDA-3 和 NEDA-4 在预测无长期残疾进展方面的比较性能。
系统检索了 2006 年 1 月至 2021 年 11 月 MEDLINE、Embase 和 Cochrane 数据库中的英文摘要和手稿，并由 2 名研究者独立进行了审查。我们选择了在 DMT 开始后 1 或 2 年评估 NEDA-4 并进行至少 4 年随访以确定无确认残疾进展的研究。我们使用随机效应模型进行荟萃分析，以确定与 EDA-4 相比，NEDA-4 无残疾进展的汇总优势比（OR）。对于比较分析，我们选择了评估 NEDA-3 和 NEDA-4 并进行至少 4 年随访的研究，并检查了 NEDA-3 和 NEDA-4 与无残疾进展之间关联的差异。
有 5 项关于 1000 名患者（3 项干扰素β和 2 项 fingolimod）的研究符合这两个目标的纳入标准。中位随访时间为 6 年（四分位距：4-6 年）。干扰素β治疗的 NEDA-4 发生率为 4.2%-13.9%，fingolimod 治疗的 NEDA-4 发生率为 24.9%-25.1%。与 EDA-4 相比，NEDA-4 无长期确诊残疾进展的汇总 OR 为 2.14（95%置信区间：1.36-3.37；I = 0）。在比较分析中，我们没有观察到 NEDA-4 与 NEDA-3 之间有任何显著差异。
在 RRMS 患者中，NEDA-4 在 1-2 年内与 6 年内无长期残疾进展的可能性增加 2 倍，与 EDA-4 相比，但与 NEDA-3 相比没有优势。
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