scholarly journals A Multi-mRNA Prognostic Signature for Anti-TNFα Therapy Response in Patients with Inflammatory Bowel Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1902
Author(s):  
Suraj Sakaram ◽  
Yehudit Hasin-Brumshtein ◽  
Purvesh Khatri ◽  
Yudong D. He ◽  
Timothy E. Sweeney
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Therapy Response ◽  
Gene Signature ◽  
Youden Index ◽  
Predictive Test ◽  
Forward Search ◽  
Data Repositories ◽  
Public Data ◽  
Inflammatory Bowel

Background: Anti-TNF-alpha (anti-TNFα) therapies have transformed the care and management of inflammatory bowel disease (IBD). However, they are expensive and ineffective in greater than 50% of patients, and they increase the risk of infections, liver issues, arthritis, and lymphoma. With 1.6 million Americans suffering from IBD and global prevalence on the rise, there is a critical unmet need in the use of anti-TNFα therapies: a test for the likelihood of therapy response. Here, as a proof-of-concept, we present a multi-mRNA signature for predicting response to anti-TNFα treatment to improve the efficacy and cost-to-benefit ratio of these biologics. Methods: We surveyed public data repositories and curated four transcriptomic datasets (n = 136) from colonic and ileal mucosal biopsies of IBD patients (pretreatment) who were subjected to anti-TNFα therapy and subsequently adjudicated for response. We applied a multicohort analysis with a leave-one-study-out (LOSO) approach, MetaIntegrator, to identify significant differentially expressed (DE) genes between responders and non-responders and then used a greedy forward search to identify a parsimonious gene signature. We then calculated an anti-TNFα response (ATR) score based on this parsimonious gene signature to predict responder status and assessed discriminatory performance via an area-under-receiver operating-characteristic curve (AUROC). Results: We identified 324 significant DE genes between responders and non-responders. The greedy forward search yielded seven genes that robustly distinguish anti-TNFα responders from non-responders, with an AUROC of 0.88 (95% CI: 0.70–1). The Youden index yielded a mean sensitivity of 91%, mean specificity of 76%, and mean accuracy of 86%. Conclusions: Our findings suggest that there is a robust transcriptomic signature for predicting anti-TNFα response in mucosal biopsies from IBD patients prior to treatment initiation. This seven-gene signature should be further investigated for its potential to be translated into a predictive test for clinical use.

The IBIS-Q [IBd Identification of Spondyloarthritis Questionnaire]: A Novel Tool to Detect Both Axial and Peripheral Arthritis in Inflammatory Bowel Disease Patients

2020 ◽  
Vol 14 (12) ◽  
pp. 1680-1686
Author(s):  
Angela Variola ◽  
Maria Elisabetta Zanolin ◽  
Giovanni Cipriano ◽  
Pierluigi Macchioni ◽  
Federica Martinis ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Area Under The Curve ◽  
Roc Curves ◽  
Factorial Analysis ◽  
Youden Index ◽  
Patient Identification ◽  
Asas Criteria ◽  
Inflammatory Bowel ◽  
Sensitivity Specificity

Abstract Background and Aims Both peripheral and axial spondyloarthritis [SpA] occur in inflammatory bowel disease [IBD] and represent the commonest extra-intestinal manifestation. We aimed to develop an easy and quick questionnaire through psychometric analysis, to identify peripheral and axial SpA in IBD patients within an integrated combined multidisciplinary rheumatological-gastroenterology clinic. Methods Initially, SpA-IBD experts generated a 42-item list covering SpA manifestations including spinal, articular, and entheseal involvement. The new questionnaire was administered before routine clinical IBD assessment. On the same day, rheumatological assessment, blinded to both history and questionnaire results, was performed to explore the presence of the Assessment of SpondyloArthritis International Society [ASAS] criteria for SpA, diagnostic criteria for fibromyalgia [FM], and non-specific low back pain [NSLB]. Factorial analysis of questionnaire items to identify the main factors—receiver operating characteristic [ROC] curves for sensitivity/specificity and Youden index for cut-off—were performed. Results Of the 181 consecutive patients, 56 met the ASAS SpA criteria [prevalence of 30%] with 10 new cases detected [5.5%: seven peripheral and three axial]. Through the psychometric and factorial analysis, we selected 14 items for the final questionnaire [named IBIS-Q]. The IBIS-Q was quick and performed well for detection of axial SpA and peripheral SpA (area under the curve [AUC] 0.88 with 95% confidence interval [CI] 0.830.93). A cut-off of three positive questions had a sensitivity 93% and specificity 77% for SpA patient identification. Conclusions The IBIS-Q is a useful and simple tool to use in IBD clinics for SpA detection, with a good statistical performance. Further studies are needed to validate it.

Sa1901 T Cell Expression of CD25 and TNF Receptor 2 is Associated With Anti-TNF Therapy Response in Patients With Inflammatory Bowel Disease

2012 ◽  
Vol 142 (5) ◽  
pp. S-354-S-355 ◽  
Author(s):  
Maria K. Magnusson ◽  
Hans Strid ◽  
Rahil Dahlen ◽  
Antal Bajor ◽  
Magnus Simren ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cell ◽  
Bowel Disease ◽  
Therapy Response ◽  
Tnf Receptor ◽  
Inflammatory Bowel ◽  
Cell Expression

IL6 genetic variants haplotype is associated with susceptibility and disease activity but not with therapy response in patients with inflammatory bowel disease

2020 ◽  
Author(s):  
Beatriz Piantoni Gonçalves ◽  
Tamires Flauzino ◽  
Cláudia Junko Inoue ◽  
Jaqueline Costa Castardo de Paula ◽  
Talita Cristina Galvão ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Disease Activity ◽  
Bowel Disease ◽  
Genetic Variants ◽  
Therapy Response ◽  
Inflammatory Bowel

P146 OXPHOS INDUCTION IN HEALING: A CRITICAL MISSING STEP IN INFLAMMATORY BOWEL DISEASE?

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S30-S31
Author(s):  
Neeraj Kapur ◽  
Emily Bradford ◽  
Justin Thomas ◽  
Courtney Perry ◽  
Terrence Barrett
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Epithelial To Mesenchymal Transition ◽  
Healing Process ◽  
Gene Signature ◽  
Enzymatic Digestion ◽  
Mucosal Healing ◽  
Mesenchymal Transition ◽  
Atp Production ◽  
Inflammatory Bowel

Abstract Background In Inflammatory Bowel Disease (IBD), mucosal healing represents a key outcome in clinical remission. Mitochondrial dysfunction is one of the major features of IBD, which is hallmarked by increased oxidative stress and impaired ATP production. However, partial wound healing continues even with repressed mitochondrial respiration in an inflammatory environment. In this study, we demonstrate that intestinal epithelial cells (IEC) responding to colitis produce a gene signature with downregulated mitochondrial expression associated with oxidative phosphorylation (OxPHOS) and upregulate epithelial-to-mesenchymal transition (EMT). These data were consistent with the notion that EMT induced in IEC is fueled by glycolysis (repressed OxPHOS). We also wish to determine if this OxPHOS repression is present in normal healing. Methods We are actively enrolling patients with Ulcerative Colitis (UC) and normal patients into a prospective study evaluating biopsy site healing. Biopsy samples from UC patients were collected in Allprotect® or PBS. Biopsy samples collected in PBS were processed for IEC isolation using enzymatic digestion followed by flow sorting of EpCAM+ cells. To investigate the healing process in colitis and normal patients, the sigmoid colon is tattooed at initial endoscopy and 10–12 biopsies are collected in Allprotect®. Patients are brought back a week later for a flexible sigmoidoscopy. The tattooed area is examined, and biopsies are obtained from the previous biopsy sites (“biopsy of the biopsy”) and collected in Allprotect®. RNA is extracted from Allprotect® preserved tissue or isolated IECs and analyzed with RT-PCR. Results Genes corresponding to subunits of NADH dehydrogenase (Ubiquinone) of complex I (ND1, ND2, ND3, ND4, ND5 and ND6) were consistently downregulated in ulcer sites of colitis patients as compared to “biopsy of the biopsy” sites near the tattoo in normal patients. As expected, samples from colitis patients exhibited significant upregulation of inflammatory markers (iNOS, NLRP3, CCL2, RANTES, TGF-b1, CCL20 and CXCL10) compared to “biopsy of the biopsy” sites in normal patients undergoing healing. Intriguingly, epithelial marker E-cadherin was noted to be decreased in samples obtained from colitis patients with concomitant increase in mesenchymal markers (Vimentin, Snail, Twist-1 and Zeb-1) compared to previously biopsied normal controls. Discussion Our data suggests that repressed OxPHOS observed in inflamed IEC from colitis patients may serves as an inducer of EMT governing delayed but partial healing in IBD. We found this to be in stark opposition to healing in normal patients, who exhibit enhanced OxPHOS associated with rapid healing. These important findings indicate OxPHOS metabolism may be an important target for therapeutic agents to improve healing in refractory colitis.

scholarly journals Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Sare Verstockt ◽  
Bram Verstockt ◽  
Kathleen Machiels ◽  
Maaike Vancamelbeke ◽  
Marc Ferrante ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Clinical Decision Making ◽  
Statistical Significance ◽  
Therapy Response ◽  
Clinical Decision ◽  
Serum Levels ◽  
Oncostatin M ◽  
Newly Diagnosed ◽  
Inflammatory Bowel

Abstract Background Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD. Methods We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05. Results Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages. Conclusions We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.

Sign in / Sign up

Export Citation Format

Share Document