在抗 TNF 治疗的 IBD 患者临床复发时，即使抗 TNF 药物浓度和抗药抗体检测不到，加用硫唑嘌呤转换方案：一项前瞻性随机试验。
Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.
机构信息
Department of Gastroenterology, CHU Saint-Étienne, Saint-Etienne, Rhône-Alpes, France.
Department of Gastroenterology, Hospital Lyon-South, Pierre-Benite, France.
出版信息
Gut. 2020 Jul;69(7):1206-1212. doi: 10.1136/gutjnl-2019-319758. Epub 2020 Jan 24.
OBJECTIVES
In patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.
DESIGN
Consecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn's disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable pharmacokinetics of the second anti-TNF were defined by the appearance of undetectable trough levels of anti-TNF with high antibodies (drug-sensitive assay) or by that of antibodies (drug-tolerant assay).
RESULTS
Ninety patients (48 CDs) were included, and 45 of them received AZA after randomisation. The second anti-TNF was adalimumab or infliximab in 40 and 50 patients, respectively. Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy (p<0.001; median time of clinical failure since randomisation 18 vs >24 months). At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22 versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy. Only the use of combination therapy was associated with favourable outcomes after anti-TNF switch.
CONCLUSION
In case of immune-mediated LOR to a first anti-TNF, AZA should be associated with the second anti-TNF.
TRIAL REGISTRATION NUMBER
目的
在经历肿瘤坏死因子（anti-TNF）免疫介导应答丧失（LOR）的 IBD 患者中，算法建议在不使用免疫抑制药物的情况下转换 anti-TNF。我们的研究目的是比较这些患者的两种策略：单独转换为第二种 anti-TNF 或联合使用硫唑嘌呤（AZA）。在 2 年的随访期间，比较两组之间的随机结果（临床和药代动力学失败的时间）。
设计
在免疫介导的 LOR 对单药治疗中首次优化的 anti-TNF 药物后，连续的 IBD 患者被随机分配接受 AZA 或在两个臂中均接受诱导的第二种 anti-TNF 治疗。克罗恩病（CD）的临床失败定义为 Harvey-Bradshaw 指数≥5，粪便钙卫蛋白水平>250μg/g 粪便，UC 为 Mayo 评分>5，内镜亚评分>1，或出现需要停止治疗的不良事件。第二种 anti-TNF 的不良药代动力学定义为出现无法检测到的 anti-TNF 低谷水平和高抗体（药物敏感测定）或出现抗体（药物耐受测定）。
结果
共纳入 90 例患者（48 例 CD），其中 45 例在随机分组后接受 AZA。第二种 anti-TNF 分别为阿达木单抗或英夫利昔单抗，分别为 40 例和 50 例。与联合治疗相比，单药治疗的临床失败率和不良药代动力学的发生率更高（p<0.001；随机分组后临床失败的中位时间为 18 个月 vs >24 个月）。24 个月时，无临床失败和无不良药代动力学的生存率分别为 22% vs 77%和 22% vs 78%（p<0.001 均）在单药治疗与联合治疗之间。只有使用联合治疗与抗 TNF 转换后的良好结果相关。
结论
在对第一种 anti-TNF 发生免疫介导的 LOR 后，AZA 应与第二种 anti-TNF 联合使用。
试验注册号
03580876。
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