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Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

ABSTRACT: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-? (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.

SUBMITTER: West NR

PROVIDER: S-EPMC5420447 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

West Nathaniel R NR Hegazy Ahmed N AN Owens Benjamin M J BMJ Bullers Samuel J SJ Linggi Bryan B Buonocore Sofia S Coccia Margherita M Görtz Dieter D This Sébastien S Stockenhuber Krista K Pott Johanna J Friedrich Matthias M Ryzhakov Grigory G Baribaud Frédéric F Brodmerkel Carrie C Cieluch Constanze C Rahman Nahid N Müller-Newen Gerhard G Owens Raymond J RJ Kühl Anja A AA Maloy Kevin J KJ Plevy Scott E SE Keshav Satish S Travis Simon P L SPL Powrie Fiona F

Nature medicine 20170403 5

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed ...[more]

PMID: 28368383

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Project description:Introduction: Tumor necrosis factor antagonists (anti-TNF) therapies are used for the management of moderate to severe inflammatory bowel disease (IBD). Anti-TNF combination therapy, with immunomodulators, has been shown to reduce immunogenicity, especially for infliximab, improve treatment success rate and patient outcomes. We evaluated factors associated with gastroenterologists adherence to anti-TNF combination therapy. Methods: A retrospective cohort study was performed to evaluate the adherence of gastroenterologists (n = 14), at an inflammatory bowel disease center, to anti-TNF combination therapy. Records of patients who received Infliximab (n = 137) or adalimumab (n = 152) were obtained and their ordering physicians' data was analyzed. Gastroenterologists were divided into six groups according to their age and interest in IBD. The baseline characteristics of their patients were also obtained. Results: The proportion of patients on combination therapy in the young gastroenterologists group was higher than those in the senior gastroenterologists group for both infliximab (83.2 vs. 55.6%, respectively, P < 0.001) and adalimumab (59 vs. 30.8%, respectively, P < 0.001). Gastroenterologists with interest in inflammatory bowel disease (IBD interest group) had also more proportion of patients on adalimumab combination therapy compared to gastroenterologists with no interest in IBD (non-IBD interest group) (61.7 vs. 35.2%, respectively, P < 0.001). Gastroenterologists who were both young and have interest in IBD had more proportion of patients on combination therapy than those who were senior or had no interest in IBD for both infliximab (89.4 vs. 63.4%, respectively, P < 0.001) and adalimumab (75.9 vs. 33%, P < 0.001). The IBD interest group was also requesting more antidrug antibody level tests than those in the non-IBD interest group (41.4 vs. 12.3 tests, respectively, P < 0.001). Conclusion: Young gastroenterologists are more likely to prescribe anti-TNF infliximab and adalimumab combination therapy than senior gastroenterologists. In addition, gastroenterologists with IBD interest are more likely to prescribe adalimumab combination therapy than gastroenterologists with no IBD interest. Moreover, young gastroenterologists who have interest in IBD are more likely to prescribe both infliximab and adalimumab combination therapy than senior gastroenterologists or those with no IBD interest. In addition, gastroenterologists with IBD interest requested more anti-TNF serum drug concentrations and antidrug antibody level tests than those with no IBD interest.

Project description:Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the intestinal tract with currently not well-understood pathogenesis. In addition to the involvement of immune cells, increasing studies show an important role for fibroblasts in the pathogenesis of IBD. Previous work showed that glycolysis is the preferred energy source for fibroblasts in fibrotic diseases. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) is a key kinase supporting glycolysis. Increased expression of PFKFB3 in several cancers and inflammatory diseases has been previously reported, but the metabolic status of fibroblasts and the role of PFKFB3 in patients with IBD are currently unknown. Therefore, in this study, we evaluated the role of glycolysis and PFKFB3 expression in IBD. Single-sample gene set enrichment analysis (ssGSEA) revealed that glycolysis was significantly higher in IBD intestinal samples, compared to healthy controls, which was confirmed in the validation cohorts of IBD patients. Single-cell sequencing data indicated that PFKFB3 expression was higher in IBD-derived stromal cells. In vitro, PFKFB3 expression in IBD-derived fibroblasts was increased after the stimulation with pro-inflammatory cytokines. Using seahorse real-time cell metabolic analysis, inflamed fibroblasts were shown to have a higher extracellular acidification rate and a lower oxygen consumption rate, which could be reversed by inhibition of JAK/STAT pathway. Furthermore, increased expression of pro-inflammatory cytokines and chemokines in fibroblasts could be reverted by PFK15, a specific inhibitor of PFKFB3. In vivo experiments showed that PFK15 reduced the severity of dextran sulfate sodium (DSS)- and Tcell transfer induced colitis, which was accompanied by a reduction in immune cell infiltration in the intestines. These findings suggest that increased stromal PFKFB3 expression contributes to inflammation and the pathological function of fibroblasts in IBD. Inhibition of PFKFB3 suppressed their inflammatory characteristics.

Project description:ImportanceInflammatory bowel disease (IBD) is commonly treated with corticosteroids and anti-tumor necrosis factor (TNF) drugs; however, medications have well-described adverse effects. Prior work suggests that anti-TNF therapy may reduce all-cause mortality compared with prolonged corticosteroid use among Medicare and Medicaid beneficiaries with IBD.ObjectiveTo examine the association between use of anti-TNF or corticosteroids and all-cause mortality in a national cohort of veterans with IBD.Design, setting, and participantsThis cohort study used a well-established Veteran's Health Administration cohort of 2997 patients with IBD treated with prolonged corticosteroids (≥3000-mg prednisone equivalent and/or ≥600 mg of budesonide within a 12-month period) and/or new anti-TNF therapy from January 1, 2006, to October 1, 2015. Data were analyzed between July 1, 2019, and December 31, 2020.ExposuresUse of corticosteroids or anti-TNF.Main outcomes and measuresThe primary end point was all-cause mortality as defined by the Veterans Health Administration vital status file. Marginal structural modeling was used to compare associations between anti-TNF therapy or corticosteroid use and all-cause mortality.ResultsA total of 2997 patients (2725 men [90.9%]; mean [SD] age, 50.0 [17.4] years) were included in the final analysis, 1734 (57.9%) with Crohn disease (CD) and 1263 (42.1%) with ulcerative colitis (UC). All-cause mortality was 8.5% (n = 256) over a mean (SD) of 3.9 (2.3) years' follow-up. At cohort entry, 1836 patients were new anti-TNF therapy users, and 1161 were prolonged corticosteroid users. Anti-TNF therapy use was associated with a lower likelihood of mortality for CD (odds ratio [OR], 0.54; 95% CI, 0.31-0.93) but not for UC (OR, 0.33; 95% CI, 0.10-1.10). In a sensitivity analysis adjusting prolonged corticosteroid users to include patients receiving corticosteroids within 90 to 270 days after initiation of anti-TNF therapy, the OR for UC was statistically significant, at 0.33 (95% CI, 0.13-0.84), and the OR for CD was 0.55 (95% CI, 0.33-0.92).Conclusions and relevanceThis study suggests that anti-TNF therapy may be associated with reduced mortality compared with long-term corticosteroid use among veterans with CD, and potentially among those with UC.

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Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

Publications

Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.

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