scholarly journals Effects of JAK1-Preferential Inhibitor Filgotinib on Circulating Biomarkers and Whole Blood Genes/Pathways of Patients With Moderately to Severely Active Crohn’s Disease

2021 ◽  
Author(s):  
Xavier Roblin ◽  
Adrian Serone ◽  
Oh Kyu Yoon ◽  
Luting Zhuo, ◽  
Ethan Grant ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Whole Blood ◽  
Janus Kinase ◽  
Oncostatin M ◽  
Circulating Biomarkers ◽  
Amyloid A ◽  
Pro Inflammatory Cytokines

Abstract Background Pro-inflammatory cytokines are dysregulated in Crohn’s disease (CD) and could serve as surrogate markers to improve diagnostic and therapeutic approaches, potentially addressing an unmet need. We profiled circulating biomarkers and whole blood transcriptional pathway activity to identify those associated with CD using data from the phase 2 FITZROY study with filgotinib, an oral preferential janus kinase-1 inhibitor. Methods Patients with serum and whole blood samples taken from the induction period were included. Serum cytokines were measured (ELISA), whole blood RNA sequenced, and stool samples taken to measure fecal calprotectin (FC). Spearman’s Rank correlations were assessed between biomarkers and baseline disease activity; post-treatment endoscopic improvement was measured by the Simplified Endoscopy Score for CD (SES-CD), FC and the Crohn’s Disease Activity Index. Effect of filgotinib on circulating biomarkers was also evaluated. Results Serum biomarkers (n = 168) and whole blood RNA sequencing (n = 104) were assessed. Moderate correlation between serum analytes with SES-CD and FC was noted; most highly correlated were acute phase proteins CRP (rho = 0.35 [SES-CD] and 0.47 [FC]), serum amyloid A (rho = 0.40 and 0.39, respectively) and pro-inflammatory cytokines interleukin (IL)-6 (rho = 0.31 and 0.30, respectively), IL-22 (rho = 0.36 and 0.35, respectively), and oncostatin M (rho = 0.35 and 0.33, respectively). Filgotinib treatment was associated with reduction of many candidate biomarkers, particularly in patients with treatment response. Early changes in IL-6 and IL-10 may be prognostic for endoscopic response. Conclusions Several circulating factors with potential as CD activity biomarkers were identified. Larger studies are necessary to investigate the best utility of these markers for CD.

scholarly journals TGR 5 signalling inhibits the production of pro‐inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Immunology ◽  
2013 ◽  
Vol 139 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Kazuaki Yoneno ◽  
Tadakazu Hisamatsu ◽  
Katsuyoshi Shimamura ◽  
Nobuhiko Kamada ◽  
Riko Ichikawa ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Cytokines ◽  
Pro Inflammatory Cytokines

scholarly journals P535 Effects of the Janus Kinase 1 (JAK1)-selective inhibitor filgotinib on circulating cytokines and whole-blood genes/pathways of patients with moderately to severely active Crohn’s disease (CD)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S457-S458
Author(s):  
X Roblin ◽  
A Serone ◽  
O K Yoon ◽  
L Zhuo ◽  
E Grant ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Whole Blood ◽  
Enrichment Analysis ◽  
Selective Inhibitor ◽  
Janus Kinase ◽  
Gene Set Enrichment Analysis ◽  
Mucosal Inflammation ◽  
Illumina Hiseq ◽  
Circulating Cytokines

Abstract Background A Phase 2 study of the JAK1-selective inhibitor filgotinib (FIL) dosed at 200 mg once daily for 10 weeks in moderately to severely active CD (FITZROY, ClinicalTrial.gov #NCT02048618) demonstrated significantly higher clinical remission rates compared with placebo,1 and early decrease in systemic and mucosal inflammation biomarkers that was more pronounced in endoscopic responders.2 We investigated baseline (BL) correlation of whole-blood transcriptome pathway activities with clinical disease indexes and circulating cytokines. The effect of FIL on changes in disease-related pathways in responders and nonresponders was also explored. Methods PAXgene blood samples were collected from 104 CD patients at BL and Week 10 (W10). RNA was sequenced (Illumina HiSeq 2500) after globin depletion (ThermoFisher GlobinClear). Differential gene expression analysis was performed using the limma R package,3 and Hallmark pathway4 activity scores were calculated using a single-sample Gene Set Enrichment Analysis (ssGSEA).5 All correlations were performed using the Spearman method. Results At BL, pathways with activity scores positively correlated with Simple Endoscopic Score for Crohn’s Disease (SES-CD) were immune (IL6/JAK/STAT3, inflammatory response), metabolic, and reactive oxygen species (ROS). These were also positively correlated with systemic inflammation (CRP, SAA, IL6, and OSM) and epithelial turnover (IL22, C4M2, and C3M) markers. Ten weeks of FIL treatment led to significant decreases in these pathways in endoscopic responders (50% reduction in SES-CD) (Figure), whereas there were no significant changes by placebo treatment. While interferon (IFN) response pathway scores showed a weak correlation (rho < 0.2) with SES-CD at BL, they are significantly reduced by FIL treatment, particularly in FIL responders. Conclusion In whole blood, inflammation, metabolic, and ROS pathways are reduced by FIL in endoscopic responders at W10, while a reduction in IFN response pathways was observed in all patients regardless of endoscopic response. References

scholarly journals Systemic Molecular Mediators of Inflammation Differentiate Between Crohn’s Disease and Ulcerative Colitis, Implicating Threshold Levels of IL-10 and Relative Ratios of Pro-inflammatory Cytokines in Therapy

2019 ◽  
Vol 14 (1) ◽  
pp. 118-129 ◽  
Author(s):  
Miranda G Kiernan ◽  
J Calvin Coffey ◽  
Shaheel M Sahebally ◽  
Paul Tibbitts ◽  
Emma M Lyons ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Cytokines ◽  
Healthy Controls ◽  
Mediators Of Inflammation ◽  
Faecal Diversion ◽  
Inflammatory Bowel ◽  
Circulating Fibrocytes ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims Faecal diversion is associated with improvements in Crohn’s disease but not ulcerative colitis, indicating that differing mechanisms mediate the diseases. This study aimed to investigate levels of systemic mediators of inflammation, including fibrocytes and cytokines, [1] in patients with Crohn’s disease and ulcerative colitis preoperatively compared with healthy controls and [2] in patients with Crohn’s disease and ulcerative colitis prior to and following faecal diversion. Methods Blood samples were obtained from healthy individuals and patients with Crohn’s disease or ulcerative colitis. Levels of circulating fibrocytes were quantified using flow cytometric analysis and their potential relationship to risk factors of inflammatory bowel disease were determined. Levels of circulating cytokines involved in inflammation and fibrocyte recruitment and differentiation were investigated. Results Circulating fibrocytes were elevated in Crohn’s disease and ulcerative colitis patients when compared with healthy controls. Smoking, or a history of smoking, was associated with increases in circulating fibrocytes in Crohn’s disease, but not ulcerative colitis. Cytokines involved in fibrocyte recruitment were increased in Crohn’s disease patients, whereas patients with ulcerative colitis displayed increased levels of pro-inflammatory cytokines. Faecal diversion in Crohn’s disease patients resulted in decreased circulating fibrocytes, pro-inflammatory cytokines, and TGF-β1, and increased IL-10, whereas the inverse was observed in ulcerative colitis patients. Conclusions The clinical effect of faecal diversion in Crohn’s disease and ulcerative colitis may be explained by differing circulating fibrocyte and cytokine responses. Such differences aid in understanding the disease mechanisms and suggest a new therapeutic strategy for inflammatory bowel disease.

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