CORe, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
Health and Biosecurity Unit, Commonwealth Scientific and Industrial Research Organisation, Melbourne, Victoria, Australia.
J Neurol Neurosurg Psychiatry. 2023 Dec;94(12):1004-1011. doi: 10.1136/jnnp-2023-331499. Epub 2023 Jul 6.
Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years.
Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement.
23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability.
The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
在延长的随访中，缺乏对复发缓解型多发性硬化症（RRMS）多种疾病修饰疗法的同时比较。在此，我们通过模拟随机试验，同时比较了 5 年内 6 种常用疗法的疗效。
从 35 个国家的 74 个中心的 MSBase 中获取数据。对每位患者的首次合格干预进行分析，以治疗改变/停药为截尾点。比较的干预措施包括那他珠单抗、芬戈利莫德、富马酸二甲酯、特立氟胺、干扰素-β、聚乙二醇干扰素和无治疗。使用边缘结构 Cox 模型（MSMs）来估计平均治疗效果（ATE）和治疗人群中的平均治疗效果（ATT），每隔 6 个月重新平衡比较组的年龄、性别、出生年份、妊娠状态、治疗、复发、疾病持续时间、残疾和疾病过程。分析的结果是复发的发生率、12 个月确认的残疾恶化和改善。
23236 名符合条件的患者被诊断为 RRMS 或临床孤立综合征。与聚乙二醇干扰素（参照）相比，几种疗法在减少复发方面显示出更高的 ATE：那他珠单抗（HR=0.44，95%CI=0.40 至 0.50）、芬戈利莫德（HR=0.60，95%CI=0.54 至 0.66）和富马酸二甲酯（HR=0.78，95%CI=0.66 至 0.92）。此外，那他珠单抗（HR=0.43，95%CI=0.32 至 0.56）在减少残疾恶化和残疾改善方面显示出更高的 ATE（HR=1.32，95%CI=1.08 至 1.60）。成对的 ATT 比较也显示那他珠单抗随后是芬戈利莫德在复发和残疾方面的效果更好。
那他珠单抗和芬戈利莫德在活跃的 RRMS 中的有效性优于富马酸二甲酯、特立氟胺、聚乙二醇干扰素和干扰素-β。本研究证明了 MSM 在模拟试验中同时比较多种干预措施的临床效果的实用性。
