丹麦哥本哈根关节炎研究中心Merete Lund Hetland团队比较了早期类风湿关节炎采用积极常规治疗和三种不同的生物治疗的效果。2020年12月2日，该研究发表在《英国医学杂志》上。

为了评估和比较三种具有不同作用方式的生物疗法与积极常规疗法治疗早期类风湿关节炎患者的利弊，2012-2018年，研究组在瑞典、丹麦、挪威、芬兰、荷兰和冰岛的29个风湿病科进行了一项随机、开放标签、评估者盲、多臂、临床IV期研究。

研究组招募18岁及以上，初发类风湿性关节炎，症状持续时间小于24个月，中至重度疾病活动，类风湿性因子或抗瓜氨酸蛋白抗体阳性，或C反应蛋白增高的患者，根据国家（地区）、性别和抗瓜氨酸蛋白抗体状态分层，按1：1：1：1进行随机分组。分别接受甲氨蝶呤联合（a）积极常规治疗，（b）聚乙二醇结合赛妥珠单抗，（c）阿巴西普，或（d）托珠单抗治疗。主要结局为24周时校正后的临床疾病活动指数缓解（CDAI≤2.8）。

共有812例患者接受了随机分组，平均年龄为54.3岁，女性占68.8％。28个关节的基线疾病活动性评分为5.0分。积极常规治疗组校正后的24周CDAI缓解率为42.7％，聚乙二醇结合赛妥珠单抗组为46.5%，阿巴西普组为52.0%，托珠单抗组为42.1%。与积极常规治疗相比，聚乙二醇结合赛妥珠单抗组的相应绝对差异为3.9％，阿巴西普组为9.4％，托珠单抗组为-0.6％。关键的次要结局显示四种疗法之间没有重大差异。

积极常规治疗组与聚乙二醇结合赛妥珠单抗组和托珠单抗组的CDAI缓解率差异仍在预先确定的15％的非劣效范围内，但阿巴西普组除外。积极常规治疗组中共发生13例严重不良事件（5.6%），聚乙二醇结合赛妥珠单抗组有20例（8.4％），阿巴西普组有10例（4.9％），托珠单抗组有10例（4.9％）。阿巴西普组有11例患者较早停止了治疗，其他组各有20-23例。

研究结果表明，四种治疗方法均达到了较高的缓解率。与积极常规治疗相比，阿巴西普治疗获得了较高的CDAI缓解率，而聚乙二醇结合赛妥珠单抗或托珠单抗治疗则未观察到。积极常规治疗不逊于聚乙二醇结合赛妥珠单抗或托珠单抗，但逊于阿巴西普。

附：英文原文

Title: Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Author: Merete Lund Hetland, Espen A Haavardsholm, Anna Rudin, Dan Nordstrm, Michael Nurmohamed, Bjorn Gudbjornsson, Jon Lampa, Kim Hrslev-Petersen, Till Uhlig, Gerdur Grondal, Mikkel stergaard, Marte S Heiberg, Jos Twisk, Kristina Lend, Simon Krabbe, Lise Hejl Hyldstrup, Joakim Lindqvist, Anna-Karin Hultgrd Ekwall, Kathrine Lederballe Grn, Meliha Kapetanovic, Francesca Faustini, Riitta Tuompo, Tove Lorenzen, Giovanni Cagnotto, Eva Baecklund, Oliver Hendricks, Daisy Vedder, Tuulikki Sokka-Isler, Tomas Husmark, Maud-Kristine Aga Ljos, Eli Brodin, Torkell Ellingsen, Annika Sderbergh, Milad Rizk, sa Reckner Olsson, Per Larsson, Line Uhrenholt, Sren Andreas Just, David John Stevens, Trine Bay Laurberg, Gunnstein Bakland, Inge C Olsen, Ronald van Vollenhoven

Issue&Volume: 2020/12/02

Abstract:

Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.

Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.

Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.

Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.

Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.

Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.

Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval 5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and 0.6% (10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.

Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.

DOI: 10.1136/bmj.m4328

Source: https://www.bmj.com/content/371/bmj.m4328