基线血清和粪便微生物组生物标志物可预测溃疡性结肠炎患者接受利特西替尼诱导治疗后的临床疗效和组织分子反应。

Mina Hassan-Zahraee, Zhan Ye, Li Xi, Elizabeth Dushin, Julie Lee, Jacek Romatowski, Jaroslaw Leszczyszyn, Silvio Danese, William J Sandborn, Christopher Banfield, Jeremy D Gale, Elena Peeva, Randy S Longman, Craig L Hyde, Kenneth E Hung
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引用次数: 0

摘要

背景和目的瑞替尼是一种口服 JAK3/TEC 家族激酶抑制剂,在针对中重度溃疡性结肠炎(UC)患者的 2b 期 VIBRATO 研究中,瑞替尼具有良好的耐受性和疗效。本研究旨在确定可预测后续临床疗效的基线血清和微生物组标记物,并开发无创血清特征作为利特西替尼临床疗效的潜在实时无创替代指标:在8周口服瑞替尼诱导治疗(20 mg、70 mg、200 mg或安慰剂,每天一次,N=39、41、33和18)前后,对样本进行组织和外周血蛋白质组学、转录组学和粪便元基因组学研究。线性混合模型用于确定与疗效相关的基线和纵向蛋白质标记物。通过使用置换疗效数据的逻辑模型,对这些蛋白质的综合预测能力进行了评估。粪便元基因组的差异表达用于区分应答者和非应答者:结果:外周血血清蛋白质组学确定了 4 种基线血清标记物(LTA、CCL21、HLA-E、MEGF10),它们可预测改良临床缓解(MR)、内镜改善(EI)、组织学缓解(HR)和组织分子改善的综合评分。在应答者中,37 种血清蛋白在第 8 周时与基线相比发生了显著变化(FDRC结论:血液和微生物组生物标志物对利特西替尼的内镜、组织学和组织分子反应进行了分层,这可能有助于指导未来UC治疗的精准医学方法。
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Baseline Serum and Stool Microbiome Biomarkers Predict Clinical Efficacy and Tissue Molecular Response After Ritlecitinib Induction Therapy in Ulcerative Colitis.

Background and aims: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well-tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis [UC]. The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib.

Methods: Tissue and peripheral blood proteomics, transcriptomics, and faecal metagenomics were performed on samples before and after 8 weeks of oral ritlecitinib induction therapy [20 mg, 70 mg, 200 mg, or placebo once daily, N = 39, 41, 33, and 18, respectively]. Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of faecal metagenomics was used to differentiate responders and nonresponders.

Results: Peripheral blood serum proteomics identified four baseline serum markers [LTA, CCL21, HLA-E, MEGF10] predictive of modified clinical remission [MR], endoscopic improvement [EI], histological remission [HR], and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline [false discovery rate of <0.05]; of these, changes in four [IL4R, TNFRSF4, SPINK4, and LAIR-1] predicted concurrent EI and HR responses. Faecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement.

Conclusions: Blood and microbiome biomarkers stratify endoscopic, histological, and tissue molecular responses to ritlecitinib, which may help guide future precision medicine approaches to UC treatment. ClinicalTrials.gov NCT02958865.

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