Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.
Department of Neuroscience, Central Clinical School, Alfred Campus, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Box Hill Hospital, Monash University, Box Hill, Victoria, Australia.
Mult Scler Relat Disord. 2018 Aug;24:11-19. doi: 10.1016/j.msard.2018.04.020. Epub 2018 May 2.
Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months.
TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment.
Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0-2.0 to ≥3.0, 2.0-3.0 to ≥4.0, and 4.0-5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively).
In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0-9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0-5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.
虽然扩展残疾状况量表（EDSS）常用于评估复发缓解型多发性硬化症（RRMS）患者的残疾程度，但用于定义残疾进展的标准适用于基线残疾程度广泛的患者在相对短期的试验中。因此，并非所有 EDSS 变化在未来残疾方面都具有相同的重要性，并且治疗益处（如降低达到特定残疾里程碑的风险）可能无法可靠地捕捉到。本分析的目的是评估在 Tysabri 观察性计划（TOP）中，288 周时 EDSS 特定里程碑（即 EDSS 评分≥3.0、≥4.0 或≥6.0）确认的残疾恶化的概率，并检查在接受≥24 个月纳替珠单抗治疗的 TOP 患者中发生的复发对纳替珠单抗治疗的影响。
TOP 是一项正在进行的、开放性、前瞻性、观察性研究，涉及临床实践中的 RRMS 患者。入组患者在开始治疗时对纳替珠单抗初次治疗或在入组时接受了≤3 剂。静脉注射纳替珠单抗（300mg）每 4 周一次，在治疗期间每 24 周评估一次 EDSS。
在至少随访 24 个月的 4161 名 TOP 患者中，3253 名患者基线 EDSS 评分可继续接受纳替珠单抗治疗，908 名患者（因报告缺乏疗效而停药的患者占 5.4%，因其他原因停药的患者占 16.4%）在 24 个月时停药。因缺乏疗效而停药的患者基线 EDSS 评分较高（中位数为 4.5 比 3.5），治疗期间复发率较高（0.82 比 0.23），24 个月时 EDSS 恶化的累积概率较高（16%比 9%）。在 24 个月的完成治疗者中，在接受纳替珠单抗治疗约 5.5 年后，24 周确认的 EDSS 恶化累积概率分别为 18.5%和 7.9%（24 周确认），分别为 13.5%和 5.3%（48 周确认）。与无治疗相关复发的患者相比，治疗期间有复发的患者发生 24 周和 48 周确认 EDSS 恶化的风险显著更高。对特定 EDSS 里程碑的时间分析表明，在 TOP 中，从 EDSS 评分 0.0-2.0 到≥3.0、2.0-3.0 到≥4.0 以及 4.0-5.0 到≥6.0 的 48 周确认转移的概率分别为 11.1%、11.8%和 9.5%，无治疗相关复发的患者的概率分别为 8.1%、8.4%和 5.7%。
在基线 EDSS 评分中位数（范围）为 3.5（0.0-9.5）、完成 24 个月纳替珠单抗治疗的 TOP 患者中，48 周确认残疾恶化事件的发生率低于 15%；在接受纳替珠单抗治疗约 5.5 年后，86.5%和 94.7%的患者 EDSS 评分分别没有增加≥1.0 或≥2.0 点。存在复发与更高的整体残疾恶化率相关。通过评估向 EDSS 里程碑的转变，得到了这一结果的确认。在没有复发的情况下，整体 48 周确认 EDSS 恶化率和从 EDSS 评分 4.0-5.0 到≥6.0 的转化率较低，表明复发仍然是残疾恶化的重要驱动因素，纳替珠单抗治疗患者的治疗期间复发具有预后意义。
