那他珠单抗停药后富马酸二甲酯、芬戈莫德和奥瑞珠单抗的比较。
Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation.
机构信息
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Clinical Outcomes Research Unit (CORe), Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
出版信息
JAMA Neurol. 2023 Jul 1;80(7):739-748. doi: 10.1001/jamaneurol.2023.1542.
IMPORTANCE
Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses.
OBJECTIVES
To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab.
DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023.
EXPOSURES
Dimethyl fumarate, fingolimod, and ocrelizumab.
MAIN OUTCOMES AND MEASURES
Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method.
RESULTS
Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab.
CONCLUSION AND RELEVANCE
Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.
重要性：纳武利尤单抗停药与疾病活动反弹的风险相关。确定纳武利尤单抗停药后最佳的转换疾病修饰治疗策略对于限制严重复发至关重要。
目的：比较多发性硬化症（RRMS）患者停用那他珠单抗后使用二甲基富马酸、芬戈莫德和奥瑞珠单抗的有效性和持久性。
设计、地点和参与者：在这项观察性队列研究中，从 2010 年 6 月 15 日至 2021 年 7 月 6 日，从 MSBase 注册处收集患者数据。中位随访时间为 2.7 年。这是一项多中心研究，包括使用那他珠单抗治疗 6 个月或更长时间且在那他珠单抗停药后 3 个月内转换为二甲基富马酸、芬戈莫德或奥瑞珠单抗的 RRMS 患者。未纳入基线数据的患者从分析中排除。数据分析时间为 2022 年 5 月 24 日至 2023 年 1 月 9 日。
暴露因素：二甲基富马酸、芬戈莫德和奥瑞珠单抗。
主要结局和测量指标：主要结局是年化复发率（ARR）和首次复发时间。次要结局是确认残疾进展、残疾改善和随后的治疗停药，由于服用二甲基富马酸的患者数量较少，前 2 项的比较仅限于芬戈莫德和奥瑞珠单抗。使用逆概率治疗加权法平衡协变量后分析关联。
结果：在 66840 例 RRMS 患者中，1744 例患者使用那他珠单抗治疗 6 个月或更长时间，并在那他珠单抗停药后 3 个月内转换为二甲基富马酸、芬戈莫德或奥瑞珠单抗。排除 358 例无基线数据的患者后，共有 1386 例患者（平均年龄 41.3[10.6]岁；990 例女性[71%]）转换为二甲基富马酸（138[9.9%]）、芬戈莫德（823[59.4%]）或奥瑞珠单抗（425[30.7%]）。每种药物的 ARR 如下：奥瑞珠单抗为 0.06（95%CI，0.04-0.08）；芬戈莫德为 0.26（95%CI，0.12-0.48）；二甲基富马酸为 0.27（95%CI，0.12-0.56）。芬戈莫德与奥瑞珠单抗的 ARR 比值为 4.33（95%CI，3.12-6.01），二甲基富马酸与奥瑞珠单抗的 ARR 比值为 4.50（95%CI，2.89-7.03）。与奥瑞珠单抗相比，芬戈莫德的首次复发时间风险比（HR）为 4.02（95%CI，2.83-5.70），二甲基富马酸的 HR 为 3.70（95%CI，2.35-5.84）。芬戈莫德和二甲基富马酸的停药 HR 分别为 2.57（95%CI，1.74-3.80）和 4.26（95%CI，2.65-6.84）。与奥瑞珠单抗相比，使用芬戈莫德与残疾进展风险增加 49%相关。芬戈莫德和奥瑞珠单抗在残疾改善率方面没有显著差异。
结论和相关性：研究结果表明，在从那他珠单抗转换为二甲基富马酸、芬戈莫德或奥瑞珠单抗的 RRMS 患者中，奥瑞珠单抗的使用与最低的 ARR 和停药率以及首次复发时间最长相关。
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