接受托法替尼治疗的溃疡性结肠炎患者的组织学结果和Jak-Stat信号转导

Sara van Gennep, Ivan C N Fung, Djuna C de Jong, Rishand K Ramkisoen, Esmé Clasquin, Jitteke de Jong, Leonie C S de Vries, Wouter J de Jonge, Krisztina B Gecse, Mark Löwenberg, John C Woolcott, Aart Mookhoek, Geert R D'Haens
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引用次数: 0

摘要

背景和目的:在前瞻性溃疡性结肠炎(UC)患者队列中,对口服Janus激酶(JAK)抑制剂托法替尼治疗8周后的组织学结果和JAK-STAT信号转导进行评估:40名溃疡性结肠炎患者接受了为期8周、每天两次、每次10毫克的托法替尼治疗。治疗反应定义为组织内镜粘膜改善(HEMI)。组织学缓解定义为罗巴茨组织病理学指数(RHI)≤3分,组织学应答定义为RHI下降50%。采用免疫组化(IHC)方法评估了粘膜中JAK1-3、酪氨酸激酶2(TYK2)和总信号转导及激活转录(STAT)1-6的表达:基线时,RHI 的中位数为 14(四分位数间距 (IQR) 10-19)。40名患者中有26名(65%)患有严重的内镜疾病(内镜下梅奥评分3分),31/40(78%)的患者之前未接受抗肿瘤坏死因子治疗。第 8 周时,15 名患者(38%)出现 HEMI,23 名患者(58%)出现组织学缓解,34 名患者(85%)出现组织学应答。应答者的 RHI 中位数下降了 14 个点(IQR 9-21)(p 结论:托法替尼治疗能显著改善患者的病情:托法替尼治疗使大多数 UC 患者的组织学状况得到改善,STAT1、STAT3 和 STAT5 的表达大幅下降。HEMI与STAT1的抑制作用更强有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Histological Outcomes and JAK-STAT Signalling in Ulcerative Colitis Patients Treated with Tofacitinib.

Background and aims: Histological outcomes and JAK-STAT signalling were assessed in a prospective ulcerative colitis [UC] patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase [JAK] inhibitor.

Methods: Forty UC patients received tofacitinib 10 mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement [HEMI]. Histological remission was defined as a Robarts Histopathology Index [RHI] ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, tyrosine kinase 2 [TYK2], and total signal transducer and activator of transcription [STAT] 1-6 were assessed using immunohistochemistry [IHC].

Results: At baseline, the median RHI was 14 (interquartile range [IQR] 10-19). Of 40 [65%] patients, 26 had severe endoscopic disease [endoscopic Mayo score 3] and 31/40 [78%] failed prior anti-tumour necrosis factor [anti-TNF] treatment. At Week 8, 15 patients [38%] had HEMI, 23 patients [58%] histological remission, and 34 [85%] histological response. RHI decreased by a median of 14 points [IQR 9-21] in responders [p <0.001] and by 6 points [IQR 0-13] in non-responders [p = 0.002]. STAT1, STAT3, and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower Week 8 STAT1 expression levels compared with non-responders [0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p = 0.001], suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders [2.7%, IQR 0.1-7.7] compared with responders [0.4%, IQR 0.1-2.1].

Conclusions: Tofacitinib treatment resulted in histological improvement in the majority of UC patients and in a substantial decrease of STAT1, STAT3, and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

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