非肿瘤坏死因子靶向生物制剂与第二种抗肿瘤坏死因子药物治疗对第一种抗肿瘤坏死因子药物反应不足的类风湿关节炎患者：一项随机临床试验。

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

作者信息

Gottenberg Jacques-Eric, Brocq Olivier, Perdriger Aleth, Lassoued Slim, Berthelot Jean-Marie, Wendling Daniel, Euller-Ziegler Liana, Soubrier Martin, Richez Christophe, Fautrel Bruno, Constantin Arnaud L, Mariette Xavier, Morel Jacques, Gilson Melanie, Cormier Gregoire, Salmon Jean Hugues, Rist Stephanie, Lioté Frederic, Marotte Hubert, Bonnet Christine, Marcelli Christian, Sellam Jeremie, Meyer Olivier, Solau-Gervais Elisabeth, Guis Sandrine, Ziza Jean-Marc, Zarnitsky Charles, Chary-Valckenaere Isabelle, Vittecoq Olivier, Saraux Alain, Pers Yves-Marie, Gayraud Martine, Bolla Gilles, Claudepierre Pascal, Ardizzone Marc, Dernis Emmanuelle, Breban Maxime A, Fain Olivier, Balblanc Jean-Charles, Aberkane Ouafaa, Vazel Marion, Back Christelle, Candon Sophie, Chatenoud Lucienne, Perrodeau Elodie, Sibilia Jean, Ravaud Philippe

机构信息

Department of Rheumatology, National Reference Center for Systemic Autoimmune Diseases, Strasbourg University Hospital, Université de Strasbourg, Strasbourg, France.

Department of Rheumatology, Centre Hospitalier Princesse Grâce, Monaco.

出版信息

JAMA. 2016 Sep 20;316(11):1172-1180. doi: 10.1001/jama.2016.13512.

DOI:10.1001/jama.2016.13512

PMID:27654603

Abstract

IMPORTANCE

One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists.

OBJECTIVE

To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor.

DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013.

INTERVENTIONS

Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician.

MAIN OUTCOMES AND MEASURES

The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections.

RESULTS

Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003).

CONCLUSIONS AND RELEVANCE

Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT01000441.

摘要

重要性

三分之一的类风湿关节炎患者对肿瘤坏死因子α（TNF-α）抑制剂反应不足；对于选择下一步治疗几乎没有指导意见。

目的

比较非TNF靶向生物制剂（非TNF）与第二种抗TNF药物对TNF抑制剂反应不足的患者的疗效。

设计、地点和参与者：总共300例类风湿关节炎患者（于2009年至2012年进行研究），有持续性疾病活动（28个关节疾病活动评分-红细胞沉降率[DAS28-ESR]≥3.2[范围为0-9.3]）且对抗TNF治疗反应不足，纳入一项为期52周的多中心、实用、开放标签随机临床试验。最终随访日期为2013年8月。

干预措施

患者被随机分配（1:1）接受非TNF靶向生物制剂或与其先前治疗不同的抗TNF药物。每个随机分组内所开生物制剂的选择由治疗医生决定。

主要结局和测量指标

主要结局是根据欧洲抗风湿病联盟（EULAR）量表在第24周时达到良好或中等反应的患者比例。次要结局包括第12周和第52周时的EULAR反应；第12周、24周和52周时的DAS28-ESR、低疾病活动度（DAS28≤3.2）、缓解（DAS28≤2.6）；严重不良事件；以及严重感染。

结果

在300例随机分组的患者中（243例[83.2%]为女性；平均[标准差]年龄为57.1[12.2]岁；基线DAS28-ESR为5.1[1.1]），269例（89.7%）完成了研究。在第24周时，非TNF组146例患者中的101例（69%）和第二种抗TNF组76例患者中的76例（52%）达到了良好或中等的EULAR反应（比值比，2.06；95%置信区间，1.27-3.37；P = 0.004，采用缺失数据插补法；绝对差异，17.2%；95%置信区间，6.2%至28.2%）。非TNF组的DAS28-ESR低于第二种抗TNF组（根据基线差异调整后的平均差异为-0.43；95%置信区间，-0.72至-0.14；P = 0.004）。在第24周和第52周时，非TNF组比第二种抗TNF组有更多患者表现出低疾病活动度（第24周时为45%对28%；比值比，2.09；95%置信区间，1.27至3.43；P = 0.004，第52周时为41%对23%；比值比，2.26；95%置信区间，1.33至3.86；P = 0.003）。