本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(23)02649-1

摘要内容如下：

背景

具有瓜氨酸蛋白抗原（ACPA）血清抗体、类风湿因子和症状（如炎性关节疼痛）的个体是发展为类风湿性关节炎的高危人群。在类风湿性关节炎临床前阶段使用阿巴西普预防关节炎（APIPPRA）试验中，我们旨在评估使用T细胞共刺激调节剂阿巴西普治疗高危个体的可行性、有效性和可接受性。

方法

APIPPRA研究是一项随机、双盲、多中心、平行、安慰剂对照的2B期临床试验，在英国的28家医院和荷兰的3家医院的早期关节炎诊所进行。参与者（年龄≥18岁）具有ACPA和类风湿因子阳性的类风湿性关节炎风险，并伴有炎性关节疼痛。排除标准包括既往临床滑膜炎发作和既往使用皮质类固醇或缓解病情的抗风湿药物。参与者被随机分配（1:1），使用计算机生成的排列随机区组（区组大小为2和4），按性别、吸烟和国家分层，每周皮下注射125 mg阿巴西普或安慰剂，持续12个月，然后随访12个月。通过每3个月提供四个带有阿巴西普或安慰剂编码标签的预充式注射器的试剂盒（外观和包装相同）来实现掩蔽。主要终点是根据美国风湿病学会（American College of Rheumatology）和欧洲风湿病协会联盟（European Alliance of Associations for Rheumatology）2010年标准，三个或三个以上关节或类风湿性关节炎发生临床滑膜炎的时间，以首先满足的时间为准。超声检查证实滑膜炎。随访于2021年1月13日完成。所有符合意向治疗原则的参与者均纳入分析。该试验已在Eudract注册（2013-003413-18）。

调查结果

在2014年12月22日至2019年1月14日期间，对280人进行了资格评估，在213名参与者中，110人被随机分配到阿巴西普组，103人被随机分配到安慰剂组。在治疗期间，阿巴西普组110名参与者中的7名（6%）和安慰剂组103名参与者中的30名（29%）达到了主要终点。在24个月时，阿巴西普组的110名参与者中有27名（25%）发展为类风湿性关节炎，而安慰剂组的103名参与者中有38名（37%）发展为类风湿性关节炎。在12个月时，阿巴西普组和安慰剂组中保持无关节炎的参与者的估计比例分别为92.8%（SE 2.6）和69.2%（SE 4.7）。24个月的Kaplan-Meier无关节炎生存曲线有利于Abatacept（Log-rank检验P=0.044）。两组间限制性平均生存时间的差异为53天（95%CI 28-78；P<0.0001）（95%CI 38-161；P=0.0016），在24个月时支持Abatacept。在治疗期间，与安慰剂相比，阿巴西普与疼痛评分、功能健康和生活质量测量的改善以及超声检查亚临床滑膜炎的低评分相关。然而，在24个月时，效果并不持续。阿巴西普组发生了7例严重不良事件，安慰剂组发生了11例，其中每组均有1例死亡，被认为与治疗无关。

解释

类风湿性关节炎危险期的治疗干预是可行的，且具有可接受的安全性。用阿巴西普进行12个月的T细胞共刺激调节可减少类风湿性关节炎的进展，有证据表明在治疗期后持续有效，并且没有新的安全性信号。

英文原文如下：

Abstracts

BACKGROUND  Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept.

METHODS  The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18).

FINDINGS  Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment.

INTERPRETATION  Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals.

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