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Targan SR, Feagan B, Vermeire S, Panaccione R, Melmed GY, Landers C, Li D, Russell C, Newmark R, Zhang N, Chon Y, Hsu YH, Lin SL, Klekotka P. A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn's Disease. Am J Gastroenterol 2016; 111:1599-1607. [PMID: 27481309 DOI: 10.1038/ajg.2016.298] [Citation(s) in RCA: 284] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 06/21/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To assess the safety and efficacy of brodalumab, a human anti-interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn's disease (CD). METHODS Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700 mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn's disease activity index (CDAI) remission (≤150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of ≥100) at week 6 and change from baseline in CDAI at week 6. RESULTS The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210 mg), 15% (350 mg), 9% (700 mg), and 3% (placebo) and CDAI response occurred in 16% (210 mg), 27% (350 mg), 15% (700 mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was -8.7 (95.3) (210 mg), -35.4 (105.6) (350 mg), -0.6 (105.9) (700 mg), and -28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups. CONCLUSIONS Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD.
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Affiliation(s)
- Stephan R Targan
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Brian Feagan
- Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Severine Vermeire
- Department of Gastroenterology, University Hospitals KU Leuven, Leuven, Belgium
| | | | - Gil Y Melmed
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Carol Landers
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dalin Li
- Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | | | - Nan Zhang
- Amgen, Thousand Oaks, California, USA
| | - Yun Chon
- Amgen, Thousand Oaks, California, USA
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Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 2015; 5:10918. [PMID: 26039416 PMCID: PMC4454150 DOI: 10.1038/srep10918] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 05/05/2015] [Indexed: 12/28/2022] Open
Abstract
Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. However, the role of opioids in sepsis progression has not been well characterized. The present study demonstrated that morphine alone altered the gut microbiome and selectively induced the translocation of Gram-positive gut bacteria in mice. Using a murine model of poly-microbial sepsis, we further demonstrated that morphine treatment led to predominantly Gram-positive bacterial dissemination. Activation of TLR2 by disseminated Gram-positive bacteria induced sustained up-regulation of IL-17A and IL-6. We subsequently showed that overexpression of IL-17A compromised intestinal epithelial barrier function, sustained bacterial dissemination and elevated systemic inflammation. IL-17A neutralization protected barrier integrity and improved survival in morphine-treated animals. We further demonstrated that TLR2 expressed on both dendritic cells and T cells play essential roles in IL-17A production. Additionally, intestinal sections from sepsis patients on opioids exhibit similar disruption in gut epithelial integrity, thus establishing the clinical relevance of this study. This is the first study to provide a mechanistic insight into the opioid exacerbation of sepsis and show that neutralization of IL-17A might be an effective therapeutic strategy to manage Gram-positive sepsis in patients on an opioid regimen.
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Wang YL, Fang M, Wang XM, Liu WY, Zheng YJ, Wu XB, Tao R. Proinflammatory effects and molecular mechanisms of interleukin-17 in intestinal epithelial cell line HT-29. World J Gastroenterol 2014; 20:17924-17931. [PMID: 25548490 PMCID: PMC4273142 DOI: 10.3748/wjg.v20.i47.17924] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 08/24/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the proinflammatory effects and molecular mechanisms of interleukin (IL)-17 in intestinal epithelial cell line HT-29. METHODS HT-29 cells were cultured with IL-17, tumor necrosis factor (TNF)-α, or the combination of both IL-17 and TNF-α. Real-time PCR and Western blot were used to measure the gene expression levels of neutrophil chemokines CXCL1, CXCL2, CXCL5, CXCL6, IL-8 and TH-17 cell chemokine CCL20, the phosphorylation levels of p38 and TNF-α, and the expression level of IL-8, after using the p38 inhibitor in HT-29 cells. The stable Act1 knockdown HT-29 cell line was established to further test the phosphorylation changes of p38, after using IL-17 and TNF-α. RESULTS After HT-29 cells were cultured with IL-17 and TNF-α, the expression levels of neutrophil chemokines (CXCL1, CXCL2, CXCL5, CXCL6, IL-8) and Th17 chemokine (CCL20) significantly improved (24.96 ± 2.53, 28.47 ± 2.87, 38.08 ± 2.72, 33.47 ± 2.41, 31.7 ± 2.38, 44.37 ± 2.73, respectively), and the differences were all statistically significant (P < 0.01). Western blot results showed that IL-17 obviously enhanced the phosphorylation level of p38, which was induced by TNF-α. Compared with the control group, the expression level of IL-8 significantly declined (9.47 ± 1.36 vs 3.06 ± 0.67, P < 0.01) when TH-29 cells were cultured with IL-17 and TNF-α. p38 inhibition assay showed that the p38 pathway played an essential role in the inflammatory response induced by IL-17. p38 phosphorylation levels could not be changed after using IL-17 and TNF-α in the stable Act1 knockdown HT-29 cell line. CONCLUSION IL-17 significantly promoted the gene expression levels of TNF-α-induced neutrophil chemokines and Th17 cell chemokine. It is obvious that IL-17 and TNF-α have synergistic effects on p38.
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Wan SS, Cao Q. Immunoregulatory role of Th17 cells in development of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2013; 21:574-578. [DOI: 10.11569/wcjd.v21.i7.574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is associated with an exaggerated Th1 or Th2 cell response. Recent studies have shown that there is also enhanced synthesis of cytokines by Th17 cells in IBD. Interleukin-23 (IL-23) induces the differentiation of naïve CD4+ T cells into highly pathogenic helper Th17 cells that produce IL-17, IL-6 and TNF-α and cause colitis. We here review the new progress in understanding the immunoregulatory role of Th17 cells and the related cytokines in IBD.
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