Background and aims Histological outcomes and JAK-STAT signaling 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). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior 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 to 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 to responders (0.4%, IQR 0.1-2.1). Conclusions Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

中文翻译：

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接受托法替布治疗的溃疡性结肠炎患者的组织学结果和 Jak-Stat 信号转导

背景和目的 在使用托法替布（一种口服 Janus 激酶 (JAK) 抑制剂）治疗 8 周后，对前瞻性溃疡性结肠炎 (UC) 患者队列进行组织学结果和 JAK-STAT 信号传导评估。方法 40 名 UC 患者接受托法替布 10 mg，每天两次，持续 8 周。治疗反应定义为组织内镜下粘膜改善（HEMI）。组织学缓解定义为 Robarts 组织病理学指数 (RHI) ≤ 3 分，组织学缓解定义为 RHI 下降 50%。使用免疫组织化学 (IHC) 评估 JAK1-3、酪氨酸激酶 2 (TYK2) 和总信号转导子和转录激活子 (STAT) 1-6 的粘膜表达。结果 基线时，中位 RHI 为 14（四分位数间距 (IQR) 10-19）。 40 名患者中的 26 名 (65%) 患有严重内镜疾病（内镜 Mayo 评分 3），31/40 (78%) 之前的抗 TNF 治疗失败。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%) 出现组织学缓解。应答者(p＜0.001)中RHI平均下降14点(IQR 9-21)，无应答者(p＝0.002)中RHI平均下降6点(IQR 0-13)。整个队列中 STAT1、STAT3 和 STAT5 表达水平显着下降。与无反应者相比，有反应者在第 8 周的 STAT1 表达水平较低（0.2%，IQR 0.1-2.8 vs 4.3%，IQR 1.2-11.9，p = 0.001），表明 STAT1 阻断更深入。与应答者（0.4%，IQR 0.1-2.1）相比，托法替布无应答者（2.7%，IQR 0.1-7.7）观察到基线 JAK2 表达较高的趋势。结论 托法替尼治疗使大多数 UC 患者的组织学得到改善，并且 STAT1、STAT3 和 STAT5 表达显着降低。 HEMI 与 STAT1 更严重的抑制有关。