Certain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA. In this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48. Forty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified. In MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients. NIH US National Library of Medicine, NCT02557100 . Registered on September 23, 2015.

中文翻译：

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RA 的 HLA-DRB1 风险等位基因与对阿巴西普和阿达木单抗的不同临床反应性相关：来自自身抗体阳性早期 RA 的头对头、随机、单盲研究的数据

与自身抗体阳性类风湿性关节炎 (RA) 相关的某些风险等位基因与较差的预后有关。在自身抗体阳性 RA 患者中，阿巴西普显示出与肿瘤坏死因子抑制剂不同的疗效。我们的目的是研究对阿巴西普和阿达木单抗的临床反应与 RA 中编码人白细胞抗原 (HLA)-DRB1 共享表位 (SE) 的风险等位基因的存在之间的关系。在这项头对头研究中，对早期（≤ 12 个月）、中度至重度 RA 且对甲氨蝶呤 (MTX-IR) 反应不足、抗环瓜氨酸肽 2 和类风湿因子，以 1:1 随机接受每周一次皮下阿巴西普 125 mg 或每 2 周一次皮下注射阿达木单抗 40 mg，持续 24 周，每周一次口服稳定的 MTX。随后是 48 周的开放标签期，在此期间，接受阿达木单抗治疗的患者改用阿巴西普。针对 HLA-DRB1 等位基因对患者进行基因分型，并分类为 SE 阳性（≥ 1 个 SE 等位基因）或 SE 阴性（无 SE 等位基因）。在第 24 周和第 48 周评估疗效。 40 名患者各接受阿巴西普（9 名 SE 阴性，30 名 SE 阳性，1 名未知）或阿达木单抗（9 名 SE 阴性，31 名 SE 阳性）。平均年龄和病程分别为 46.0 岁和 5.5 个月。在第 24 周时，与阿达木单抗患者（分别为 73% 和 45%）和差异估计值（95% 置信区间 [CI]）相比，更多百分比的阿巴西普患者在 ACR 标准 (ACR50) 方面实现了 50% 的改善，28 (5 , 48)。在 SE 阳性患者中，ACR50 差异估计值 (95% CI) 为 32 (7, 55)。在开放标签期间，阿巴西普非转换组的反应持续，并且在第 48 周时，阿达木单抗转阿巴西普转换组的总体和 SE 阳性亚群均显示出进一步改善的趋势。没有发现新的安全信号。在患有早期自身抗体阳性 RA 的 MTX-IR 患者中，阿巴西普在 24 周后与阿达木单抗相比在数值上产生更高的疗效反应，在 SE 阳性患者中治疗差异更明显。48 周后，继续使用阿巴西普的患者的反应持续，而转用阿巴西普的患者总体上和 SE 阳性患者的临床表现进一步改善。这支持将共刺激阻断作为早期自身抗体阳性 RA 患者，尤其是 SE 阳性患者的有效治疗策略。NIH 美国国家医学图书馆，NCT02557100。2015 年 9 月 23 日注册。