利妥昔单抗与硫唑嘌呤用于嗜酸性肉芽肿性多血管炎维持治疗的比较：一项随机临床试验

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中文摘要

重要性： 对于嗜酸性肉芽肿性多血管炎（EGPA）患者，指南建议在达到缓解后考虑维持治疗。比较维持治疗选择的数据有限。
目的： 比较利妥昔单抗与硫唑嘌呤维持治疗对近期在标准治疗（包括泼尼松逐渐减量或停药）后达到血管炎缓解的EGPA患者缓解持续时间的影响。
设计、场所和参与者： 2018年3月7日至2022年6月2日，这项双盲、双模拟、研究者发起的优效性随机临床试验从法国36家医院招募了98名EGPA参与者。纳入资格要求为新诊断的EGPA或在标准诱导方案后达到血管炎缓解（伯明翰血管炎活动评分0分[范围0-63，评分越高表示疾病活动越严重]）后30至360天内复发的EGPA。数据分析时间为2025年4月1日至2025年9月17日。额外分析于2026年6月22日结束。
干预： 参与者被随机分配接受预定义标准化的口服泼尼松逐渐减量，并接受每6个月静脉注射500 mg利妥昔单抗共18个月及每日口服硫唑嘌呤安慰剂共24个月（n=49），或每6个月接受利妥昔单抗安慰剂共18个月及每日口服硫唑嘌呤共24个月（n=49）。
主要结局和指标： 主要疗效终点为28个月研究期间在服用泼尼松7.5 mg/d或更少的情况下的总缓解持续时间。14个次要终点包括保持缓解的参与者比例、血管炎复发率以及哮喘或鼻窦炎加重率。
结果： 所有98名随机参与者（平均年龄59.0岁[SD，14.4]；50名女性[51%]）至少接受了1剂试验方案，92名（94%）完成了试验。在泼尼松7.5 mg/d或更少的情况下，利妥昔单抗组和硫唑嘌呤组的平均缓解时间分别为91.1周（95% CI，80.9-101.2）和96.0周（95% CI，85.6-106.5）（P=.38）。在28个月研究期间，在泼尼松7.5 mg/d或更少的情况下保持缓解的参与者比例在利妥昔单抗组和硫唑嘌呤组分别为17/49（34.7%）和11/49（22.4%；相对风险，1.51；95% CI，0.83-2.73；P=.18）。至少发生1次血管炎复发的参与者比例在利妥昔单抗组与硫唑嘌呤组分别为7例（14.3%）和9例（18.4%）；至少发生1次临床显著哮喘加重、鼻窦炎加重或两者兼有的参与者比例分别为16例（32.7%）和19例（38.8%）。硫唑嘌呤组有1名参与者在疫苗研发前死于SARS-CoV-2感染。利妥昔单抗接受者发生严重感染的发生率更高（分别为23例[46.9%]和12例[24.5%]），主要由于严重SARS-CoV-2感染。
结论和相关性： 对于新诊断或复发性EGPA参与者，在28个月期间服用泼尼松7.5 mg/d或更少的情况下，利妥昔单抗在改善总缓解持续时间方面不优于硫唑嘌呤。
试验注册： ClinicalTrials.gov标识符：NCT03164473。

英文摘要

IMPORTANCE: For patients with eosinophilic granulomatosis with polyangiitis (EGPA), guidelines recommend considering maintenance therapy after achieving remission. Data comparing maintenance therapeutic options are limited.
OBJECTIVE: To compare the effects of rituximab and azathioprine maintenance therapies on remission duration for patients with EGPA who recently achieved remission of vasculitis after standard therapy, including prednisone tapering or withdrawal.
DESIGN, SETTING, AND PARTICIPANTS: From March 7, 2018, to June 2, 2022, this double-blind, double-dummy, investigator-initiated, superiority, randomized clinical trial enrolled 98 participants with EGPA from 36 hospitals in France. Inclusion eligibility required a new EGPA diagnosis or relapsing EGPA within 30 to 360 days of achieving vasculitis remission (Birmingham Vasculitis Activity Score of 0 [range, 0-63, with higher scores indicating more severe disease activity]) after a standard induction regimen. Data were analyzed from April 1, 2025, to September 17, 2025. Additional analyses ended June 22, 2026.
INTERVENTIONS: Participants were randomized to receive a predefined standardized tapering of oral prednisone and either 500 mg of intravenous rituximab every 6 months for 18 months and daily oral azathioprine placebo for 24 months (n = 49) or rituximab placebo every 6 months for 18 months and daily oral azathioprine for 24 months (n = 49).
MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the duration of total remission during the 28-month study period while taking 7.5 mg/d or less of prednisone. The 14 secondary end points included proportion of participants remaining in remission, rate of vasculitis relapse, and rate of asthma or rhinosinusitis exacerbations.
RESULTS: All 98 randomized participants (mean age, 59.0 years [SD, 14.4]; 50 women [51%]) received at least 1 dose of the trial regimen and 92 (94%) completed the trial. The mean time in remission with prednisone at 7.5 mg/d or less was 91.1 weeks (95% CI, 80.9-101.2) vs 96.0 weeks (95% CI, 85.6-106.5) in the rituximab and azathioprine groups, respectively (P = .38). The proportion of participants who remained in remission during the 28-month study period with prednisone at 7.5 mg/d or less was 17 of 49 (34.7%) vs 11 of 49 (22.4%; relative risk, 1.51; 95% CI, 0.83-2.73; P = .18) in the rituximab and azathioprine groups, respectively. The proportion of participants with at least 1 vasculitis relapse was 7 (14.3%) vs 9 (18.4%) in the rituximab vs azathioprine groups, respectively, and for those with at least 1 clinically significant asthma exacerbation, rhinosinusitis exacerbation, or both, it was 16 (32.7%) vs 19 (38.8%). One participant in the azathioprine group died of SARS-CoV-2 infection before vaccine development. Rituximab recipients experienced a higher incidence of severe infections (23 [46.9%] vs 12 [24.5%], respectively), primarily due to severe SARS-CoV-2 infections.
CONCLUSIONS AND RELEVANCE: For participants with newly diagnosed or relapsing EGPA, rituximab was not superior to azathioprine for improving the duration of total remission during 28 months while taking prednisone at 7.5 mg/d or less.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03164473.