Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Translational Research in Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
Aliment Pharmacol Ther. 2022 Jul;56(2):282-291. doi: 10.1111/apt.16955. Epub 2022 Apr 28.
Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking.
To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3.
Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004).
Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.
托法替布是首个获批用于溃疡性结肠炎（UC）的泛 JAK 抑制剂。已有临床疗效数据，但缺乏长期真实世界的内镜和组织学数据。
研究托法替布治疗难治性 UC 的效果，重点关注内镜、组织学和分子结局，包括在黏膜炎症的空间背景下检测 STAT3 磷酸化（pSTAT3）。
我们前瞻性监测了 59 例在两个 IBD 转诊中心接受托法替布治疗的高度难治性患者（96.7%抗 TNF 暴露，91.7%维得利珠单抗暴露），并在诱导治疗结束和治疗 48 周后评估结局。内镜改善定义为 Mayo 内镜亚评分≤1，内镜和组织学缓解定义为 Mayo 内镜亚评分 0 和 Nancy 组织学评分 0。采用多重免疫组化结合多光谱成像技术评估 pSTAT3。
分别有 24.4%和 30.5%的患者在第 8 周和第 48 周时达到内镜改善。内镜和组织学缓解率分别为 11.1%、23.7%和 16.7%、21.4%。第 8 周的内镜改善与长期治疗的延续显著相关（72.7% vs 20.6%，p=0.003）。尽管我们观察到缓解者和非缓解者的黏膜 pSTAT3 水平均逐渐降低（p<0.05），但未观察到与治疗结局相关。然而，固有层 pSTAT3 与 Nancy 组织学指数显著相关（p=0.004）。
托法替布可诱导并维持高达四分之一的高度难治性 UC 患者的内镜和组织学缓解。黏膜组织学不同部位核 pSTAT3 的纵向监测反映了独特的靶标作用，与长期治疗结局无关。
