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Jak-Stat Pathway In Inflammatory Bowel Disease PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "JAK-STAT pathway in inflammatory bowel disease”.

This medical PowerPoint presentation is about JAK-STAT pathway in inflammatory bowel disease. The JAK-STAT pathway plays a critical role in the regulation of immune responses and inflammation. In inflammatory bowel disease (IBD), which includes Crohns disease and ulcerative colitis, there is a dysregulation of the immune system, leading to chronic inflammation in the gastrointestinal tract.

Tags : JAK-STAT pathway, inflammatory bowel disease, inflammatory bowel disease, Crohns disease, ulcerative colitis, Gastroenterology, Gastroenterology PowerPoint presentation

Published on : May 02, 2023 | Views : 970 | Downloads : 1

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Describe the relationship between the JAK-STAT signaling pathway and pathogenesis of inflammatory bowel disease. Summarize the latest research developments in treatment of inflammatory bowel disease with JAK inhibitors. Incorporate evidence-based research into clinical practice. Learning Objectives JAK, Janus kinase; STAT, signal transducer and activator of transcription.
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Rationale for jak inhibitors in ibd Module 1
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Prevalence and Current Treatment of IBD 2015 prevalence data 3.1 million people (1.3%) ≥18 years have received a diagnosis of IBD(UC, CD)1 Current treatments: Aminosalicylates Immunosuppressives Corticosteroids TNF antagonists Induction and maintenance of remission remains challenging with conventional and biologic therapies2-4 ~25% patients fail to achieve response Decreased quality of life, substantial morbidity, and complications requiring hospitalizations and surgical procedures IBD, inflammatory bowel disease; TNF, tumor necrosis factor; UC, ulcerative colitis; CD, Crohn’s disease. Centers for Disease Control. https://www.cdc.gov/mmwr/volumes/65/wr/mm6542a3.htm Scott FI, et al. Curr Treat Options Gastroenterol. 2016;14:91-102. Cohen RD. Aliment Pharmacol Ther. 2002;16:1603–9. Bewtra M, et al. Clin Gastroenterol Hepatol. 2007;5:597–601.
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Pathogenesis of IBD Multifactorial pathogenesis Genetic, environmental, microbial Involves dysfunctional response from the innate and adaptive immune system Multiple inflammatory cytokines are overexpressed Amplification of the immune response leads to phenotypic expression of the disease and tissue destruction Mediate dysfunctional cell-cell interactions in innate and adaptive immune response pathways Reprinted from Translational Research, Vol 167, Bamias G, Pizarro TT, Cominelli F, Pathway-based approaches to the treatment of inflammatory bowel disease, Pages 104-115, Copyright 2016, with permission from Elsevier.
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Rationale for Targeting JAK-STAT Signaling JAKs play a role in regulating cellular proliferation, differentiation, and immune cell functions JAK-STAT is the major signaling cascade downstream from cytokine and growth factor receptors JAK family = JAK1, JAK2, JAK3 STAT family = 7 transcription factors JAKs serve to transduce signals from cytokine receptors JAK inhibitors interfere with JAK-STAT signaling Compete with ATP for binding to the kinase domain of JAKs and inhibit JAK1, JAK2, JAK3 JAK inhibitors are used effectively in other chronic inflammatory conditions(eg, rheumatoid arthritis, psoriasis) JAK inhibition is a potential therapeutic target in IBD JAK1/JAK3 involved in transduction processes of IL-2R and IL-6R (including IL-12 and IL-23) JAK, Janus kinase family; STAT, signaling transducers and activators of transcription; IBD, inflammatory bowel disease. Boland BS, et al. Gastroenterol Clin North Am. 2014;43:603-17.Villarino AV, et al. J Immunol. 2015;194:21-27. Patterson H, et al. Clin Exp Immunol. 2014;176(1):1-10.
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JAK Signaling Pathways in IBD and Therapeutic Targets of JAK Inhibitors Reprinted from Gastroenterology Clinics of North America, Vol 43, Boland BS, Sanborn WJ, Chang JT, Update on Janus Kinase Antagonists in Inflammatory Bowel Disease, Pages 603-617, Copyright 2014, with permission from Elsevier.
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Ongoing Studies of Small Molecule Inhibitors of JAK-STAT Signaling in IBD Boland BS, et al. Gastroenterol Clin North Am. 2014;43(3):603-617. www.clinicaltrials.gov UC, ulcerative colitis; CD, Crohn’s disease.
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efficacy Module 2
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Tofacitinib Efficacy in Ulcerative Colitis From The New England Journal of Medicine, Sandborn WJ, Subrata G, Panes J, et al., Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis, Volume 367, Page 616-624, Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
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Tofacitinib Efficacy in UC Sandborn WJ, et al. Abstract 767. Presented at Digestive Disease Week May 21-24, 2016; San Diego, California. Treated, tumor necrosis factor-alpha inhibitor treated; Healing, mucosal healing.
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OCTAVE Sustain Phase 3 trial of tofacitinib as maintenance therapy vs placebo in adult patients with moderate to severe UC Patients (N=593) who had completed one of the OCTAVE Induction studies and had clinical response to induction therapy Randomized to receive maintenance treatment with tofacitinib 5 mg BID, tofacitinib 10 mg BID, or placebo Remission at 52 weeks (p<0.001 for both doses vs placebo) Tofacitinib 5mg = 34.3% Tofacitinib 10 mg = 40.6% Placebo = 11.1% Sandborn WJ, et al. New Engl J Med. 2017;376(18):1723-1736.
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Filgotinib in Ulcerative Colitis: SELECTION Trial Phase 2b/3 clinical trial investigating efficacy and safety of filgotinib (100 mg, 200 mg) Induction and maintenance treatment for patients with moderately to severely active ulcerative colitis Primary endpoint: proportion achieving remission at weeks 10 and 58 Currently recruiting https://www.clinicaltrials.gov/ct2/show/NCT02914522?term=filgotinib&rank=2
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Tofacitinib Efficacy in Crohn’s Disease: Phase 2 Study Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2014;12(9):1485-1493.e1482. CDAI, Crohn’s Disease Activity Index.
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Tofacitinib Efficacy in Crohn’s Disease: Phase 2b Panes J, et al. Gut. 2017 [Epub March 2017] doi:10.1136/ gutjnl-2016-312735. CDAI, Crohn’s Disease Activity Index; *Or remission NRI, non-responder imputation.
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Filgotinib in Crohn’s Disease: FITZROY Vermeire S, et al. Lancet. 2017;389:266-275. CDAI, Crohn’s Disease Activity Index.
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Filgotinib in Crohn’s Disease: FITZROY Vermeire S, et al. Lancet. 2017;389:266-275. CDAI, Crohn’s Disease Activity Index.
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Safety Module 3
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Tofacitinib Tolerability and Side Effects (UC) Sandborn WJ, et al. N Engl J Med. 2012;367(7):616-624. Dose-dependent hyperlipidemia and viral infections noted in highest tofacitinib dose group AE, adverse event; SEA, serious adverse event.
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Tofacitinib Tolerability and Side Effects (CD) Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2014;12(9):1485-1493.e1482. AE, adverse event; TEAE, treatment-emergent adverse event; SEA, serious adverse event. Dose-dependent hyperlipidemia and viral infections noted in highest tofacitinib dose group
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Filgotinib Pooled Safety Analysis (100mg + 200mg), Week 20 Vermeire S, et al. Lancet. 2017;389:266-275. TEAE, treatment-emergent adverse event; STEAE, serious treatment-emergent adverse event.
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Clinical Implications of JAK Inhibitors Potential uses: Salvage therapy? In combinations? As substitute for corticosteroids in first-line setting? Shared decision-making is key
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Summary JAK-STAT inhibition is a promising therapeutic target in IBD Tofacitinib has shown efficacy in UC and CD Filgotinib has shown efficacy in CD Both agents demonstrate tolerability Dose dependent hyperlipidemia w/tofacitinib Several trials are ongoing Shared decision-making with patient will be key to effective use in clinical practice