Mucosal p-STAT1/3 correlates with histologic disease activity in Crohn's disease and is responsive to filgotinib.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Walter Reinisch, Adrian Serone, Xavier Hébuterne, Tanja Kühbacher, Maria Kłopocka, Xavier Roblin, Jens Brodbeck, Kim Etchevers, René Galien, Ethan Grant, Chantal Tasset, Oh Kyu Yoon, Shiva Zaboli, Séverine Vermeire
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引用次数: 0

Abstract

The validity and relevance of histologic disease activity in Crohn's disease (CD) is unclear, owing to disconnects with endoscopic pathology. Here, we explore relationships between endoscopic, histologic, and molecular activity. This post hoc analysis of the Phase 2 FITZROY trial (NCT02048618) assessed baseline and week 10 (W10) inflammation across matched ileal and colonic segments in CD patients receiving filgotinib 200 mg (n = 42) vs placebo (n = 18). Macroscopic and microscopic disease were assessed by Simple Endoscopic Score for CD ulceration subscore (uSES-CD) and Global Histologic Activity Score activity subscore (aGHAS), respectively. Molecular activity was quantified by phosphorylated signal transducer and activator of transcription (pSTAT)1 and pSTAT3 in epithelium and nonepithelium. Segments were classified as "low" or "high" activity; correlations and concordance were calculated. Logistic regression identified W10 outcome predictors. Overall, 300 segments in 60 patients were assessed. Baseline uSES-CD and aGHAS correlations were 0.72 and 0.53 in colon and ileum, respectively. pSTAT levels had poor-to-moderate concordance with uSES-CD (κ range, 0.11-0.49) but moderate-to-good concordance with aGHAS (0.43-0.77). With filgotinib vs placebo, uSES-CD and aGHAS decreased in significantly more segments with high baseline uSES-CD and aGHAS, and significantly more segments with high baseline pSTAT improved at W10. pSTAT1 was more sensitive to change than uSES-CD and aGHAS. Low baseline pSTAT3 in colon nonepithelium predicted W10 low uSES-CD (P = .044). There was better concordance between histologic and molecular disease activity associated with higher sensitivity to change vs endoscopic severity in ileocolonic CD. Our results suggest histologic activity be included in the assessment of CD inflammatory burden.

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粘膜p-STAT1/3与克罗恩病的组织学疾病活动相关,并对非戈替尼有反应。
克罗恩病(CD)的组织学疾病活动性的有效性和相关性尚不清楚,因为与内窥镜病理脱节。在这里,我们探讨内窥镜,组织学和分子活性之间的关系。这项2期FITZROY试验(NCT02048618)的事后分析评估了接受非戈替尼200 mg (n = 42)和安慰剂(n = 18)治疗的CD患者回肠和结肠匹配段的基线和第10周(W10)炎症。肉眼和显微镜下的病变分别采用简单内镜下CD溃疡评分(uSES-CD)和全局组织学活动评分(aGHAS)进行评估。通过磷酸化信号传导和转录激活因子(pSTAT)1和pSTAT3在上皮细胞和非上皮细胞中的分子活性进行量化。细分市场被划分为“低”或“高”活动;计算相关性和一致性。逻辑回归确定了W10结局预测因子。总共评估了60名患者的300个节段。结肠和回肠的基线uSES-CD和aGHAS相关性分别为0.72和0.53。pSTAT水平与uSES-CD的一致性较差至中等(κ范围,0.11-0.49),但与aGHAS的一致性中等至良好(0.43-0.77)。与安慰剂相比,非戈替尼在W10时,使用use - cd和aGHAS的高基线段明显减少,使用use - cd和aGHAS的高基线段明显增加。pSTAT1比uSES-CD和aGHAS对变化更敏感。结肠非上皮低基线pSTAT3预测W10低uSES-CD (P = 0.044)。在回肠结肠CD中,组织学和分子疾病活动与内镜下病变严重程度的高敏感性之间有更好的一致性。我们的研究结果表明,组织学活动可纳入CD炎症负担的评估。
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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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