Nakase Hiroshi, Danese Silvio, Reinisch Walter, Ritter Timothy, Liang Yan, Wendt Emily, Levesque Barrett G, Yoon Oh Kyu, Tian Yuan, Zhuo Luting, Karouzakis Emmanuel, Bauer Yasmina, Oortwijn Alessandra, Kaise Toshihiko, Malkov Vladislav A, Hibi Toshifumi
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Milan, Italy.
Inflamm Bowel Dis. 2025 Apr 10;31(4):1095-1108. doi: 10.1093/ibd/izae278.
We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects.
Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed.
The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores.
Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects.
CLINICALTRIALS.GOV IDENTIFIER: NCT02914522.
我们利用大型2b/3期SELECTION试验中的患者样本，以识别溃疡性结肠炎（UC）的循环生物标志物以及非戈替尼治疗效果的潜在早期介导因子。
在SELECTION试验的基线期和诱导期收集样本。评估的生物标志物包括血清和粪便蛋白（通过酶联免疫吸附测定法测量）、全血细胞计数以及通过探索性因子分析确定的全血RNA测序衍生基因表达因子。通过基线疾病严重程度（内镜检查/出血/粪便和梅奥诊所评分）和生物制剂使用状态（初治与经治）评估生物标志物水平。评估了非戈替尼对生物标志物水平的影响，包括可能介导第10周临床改善的第4周生物标志物变化。
生物标志物分析集包括598例生物制剂初治患者和592例生物制剂经治患者。全身炎症生物标志物（C反应蛋白[CRP]、白细胞介素-6[IL-6]、血清淀粉样蛋白A[SAA]和血小板细胞计数）与基线UC疾病严重程度的正相关性最强。与生物制剂初治患者相比，生物制剂经治患者的CRP、IL-6、SAA和中性粒细胞活化生物标志物（包括中性粒细胞明胶酶相关脂质运载蛋白[NGAL]、肿瘤坏死因子ɑ和制瘤素M[OSM]）以及血小板、中性粒细胞和单核细胞计数增加。基因表达衍生的浆母细胞和细胞增殖因子与疾病严重程度呈正相关；B细胞、T细胞活化和浆细胞样树突状细胞因子呈负相关。非戈替尼降低了几乎所有与基线UC疾病活动相关的促炎生物标志物；第4周时SAA、CRP、IL-6、NGAL和OSM的降低被确定为第10周临床评分改善的介导因子。
非戈替尼显著影响与UC病理相关的循环生物标志物。几种促炎和中性粒细胞活化生物标志物可能是非戈替尼治疗效果的早期介导因子。
NCT02914522。
