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免疫调节剂联合治疗用于预防已接受皮质类固醇治疗的严重 Behçet 病患者葡萄膜炎复发:一项随机、开放标签、头对头试验。

Combinations of immunomodulatory agents for prevention of uveitis relapse in patients with severe Behçet's disease already on corticosteroid therapy: a randomised, open-label, head-to-head trial.

机构信息

The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, China.

School of Public Health, Chongqing Medical University, Chongqing, China.

出版信息

Lancet Rheumatol. 2024 Nov;6(11):e780-e790. doi: 10.1016/S2665-9913(24)00194-2. Epub 2024 Sep 2.

Abstract

BACKGROUND

Data from head-to-head trials of immunomodulatory therapies for Behçet's disease are scarce. We aimed to compare the efficacy and safety of ciclosporin, interferon alfa-2a, and adalimumab, each combined with corticosteroids, in preventing uveitis relapse in patients with severe Behçet's disease.

METHODS

We did a randomised, open-label, assessor-masked, head-to-head trial at a large, specialised uveitis centre in Chongqing, China. Patients aged 18 years or older with severe Behçet's disease uveitis on corticosteroids and naive to anti-TNF therapy were eligible. Patients were randomly assigned in a 1:1:1 ratio to ciclosporin (2-5 mg/kg per day orally), interferon alfa-2a (3 million IU per day subcutaneously), or adalimumab (40 mg every 2 weeks subcutaneously), each combined with a tapering dose of corticosteroids with subsequent dose adjustments. The primary outcome was the annualised relapse rate of uveitis, assessed in the full analysis set (all randomly assigned patients with at least one post-baseline assessment). The non-inferiority margin of difference between the interferon alfa-2a and adalimumab groups was set to 1·0 for the primary outcome. Safety was assessed in all patients who received at least one dose of trial drugs. Individuals with lived experience of Behçet's disease uveitis were involved in the trial design and implementation. This study is registered with Chinese Clinical Trial Registry, ChiCTR2000031637. The trial is ongoing, but is closed to new participants.

FINDINGS

Between May 12, 2020, and Feb 22, 2022, a total of 270 patients (mean age 38·1 years [SD 9·8]; 213 [79%] men, 57 [21%] women; 270 [100%] east Asian ethnicity) were randomly assigned to ciclosporin, interferon alfa-2a, or adalimumab (n=90 in each group); 261 patients were included in the full analysis set. For the primary outcome, the least-squares mean was 1·84 (95% CI 1·40 to 2·44) with ciclosporin, 1·44 (1·10 to 1·89) with interferon alfa-2a, and 0·95 (0·64 to 1·40) with adalimumab. The annualised relapse rate was significantly higher in patients receiving ciclosporin than in those receiving adalimumab (least-squares mean difference 0·90 [95% CI 0·27 to 1·53]; p=0·0054 for superiority). The least-squares mean difference between interferon alfa-2a and adalimumab was 0·50 (-0·04 to 1·04), which did not meet non-inferiority criteria (p=0·034 for non-inferiority). The primary outcome did not differ substantially between interferon alfa-2a and ciclosporin (least-squares mean difference -0·40 [-1·05 to 0·25]; p=0·23 for superiority). Serious adverse events were reported in 12 (13%) of 90 patients on ciclosporin plus corticosteroids, eight (9%) of 90 patients on interferon alfa-2a plus corticosteroids, and seven (8%) of 90 patients on adalimumab plus corticosteroids. There were no treatment-related deaths.

INTERPRETATION

Adalimumab plus corticosteroids was superior to ciclosporin plus corticosteroids with respect to uveitis relapse rate in patients with severe Behçet's disease naive to anti-TNF therapy, and interferon alfa-2a plus corticosteroids was not found to be non-inferior to adalimumab plus corticosteroids or superior to ciclosporin plus corticosteroids.

FUNDING

National Natural Science Foundation of China Key Program, Major Program of Medical Science and Technology Project of Health Commission of Henan Province, Chongqing Key Laboratory of Ophthalmology, and China National Postdoctoral Program for Innovative Talents.

摘要

背景

用于治疗 Behçet 病的免疫调节疗法的头对头试验数据很少。我们旨在比较环孢素、干扰素 alfa-2a 和阿达木单抗联合皮质类固醇预防重度 Behçet 病患者葡萄膜炎复发的疗效和安全性。

方法

我们在中国重庆的一家大型专门的葡萄膜炎中心进行了一项随机、开放标签、评估者盲法、头对头试验。符合条件的患者为正在接受皮质类固醇治疗且对 TNF 拮抗剂治疗无经验的重度 Behçet 病葡萄膜炎患者,年龄 18 岁或以上。患者以 1:1:1 的比例随机分配至环孢素(2-5mg/kg/天口服)、干扰素 alfa-2a(300 万 IU/天皮下注射)或阿达木单抗(40mg 每 2 周皮下注射)组,联合皮质类固醇逐渐减量,随后进行剂量调整。主要结局是葡萄膜炎的年复发率,在全分析集(至少有一次基线后评估的所有随机分配患者)中进行评估。干扰素 alfa-2a 和阿达木单抗组之间差异的非劣效性边界设定为 1.0。在接受至少一剂试验药物的所有患者中评估安全性。有 Behçet 病葡萄膜炎个人经历的个体参与了试验设计和实施。该研究在中国临床试验注册中心(ChiCTR2000031637)注册,试验正在进行中,但已停止招募新患者。

结果

2020 年 5 月 12 日至 2022 年 2 月 22 日,共有 270 名患者(平均年龄 38.1 岁[标准差 9.8];213 名[79%]男性,57 名[21%]女性;270 名[100%]东亚人种)被随机分配至环孢素、干扰素 alfa-2a 或阿达木单抗组(每组 90 名);261 名患者被纳入全分析集。主要结局的最小二乘均数分别为环孢素组 1.84(95%CI 1.40-2.44)、干扰素 alfa-2a 组 1.44(1.10-1.89)和阿达木单抗组 0.95(0.64-1.40)。接受环孢素治疗的患者年复发率明显高于接受阿达木单抗治疗的患者(最小二乘均数差值 0.90[95%CI 0.27-1.53];p=0.0054 表示优效性)。干扰素 alfa-2a 与阿达木单抗之间的最小二乘均数差值为 0.50(-0.04-1.04),不符合非劣效性标准(p=0.034 表示非劣效性)。干扰素 alfa-2a 与环孢素之间的主要结局差异不显著(最小二乘均数差值-0.40[-1.05-0.25];p=0.23 表示优效性)。环孢素加皮质类固醇组 90 名患者中有 12 名(13%)、干扰素 alfa-2a 加皮质类固醇组 90 名患者中有 8 名(9%)和阿达木单抗加皮质类固醇组 90 名患者中有 7 名(8%)报告了严重不良事件。没有与治疗相关的死亡。

解释

对于抗 TNF 治疗无经验的重度 Behçet 病患者,阿达木单抗联合皮质类固醇治疗在葡萄膜炎复发率方面优于环孢素联合皮质类固醇治疗,干扰素 alfa-2a 联合皮质类固醇治疗与阿达木单抗联合皮质类固醇治疗相比不具有非劣效性或优于环孢素联合皮质类固醇治疗。

资金

国家自然科学基金重点项目、河南省医学科技重大项目、重庆市眼科重点实验室和中国国家博士后创新人才支持计划。

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