Research Update: Looking for the Answers Ted Denson, M.D. Schubert-Martin Inflammatory Bowel Disease Center Research Support: NIH/NIDDK, CCFA, BMRP
Figure 2 Approach to Improve Outcomes for our IBD Patients Quality improvement to standardize care and establish platform for translational studies Translational patient-based studies to discover associations between genes, microbes, and clinical outcomes Collaborative animal model and enteroid studies to test mechanisms and new therapies Translation of biomarkers to the clinic to better target therapies and assess healing Clinical trials of new therapies
Figure 1 Optimizing Sustained Remission Rates to Focus Translational Studies 2012 2013 2014 2015 2016 2017 ICN Self-Management Program: Kevin Hommel & Erin Holbrook CD64 Biomarker for Intestinal Healing: Phil Minar K23 project testing in ICN RCT Therapeutic Drug Monitoring: Michael Rosen & Chelly Dykes ICN study Peter Margolis & Sander Vinks
Multi-factorial Causes of IBD Genetic Predisposition n=200+ IBD Gut Bacteria, Fungi & Viruses: Microbes Environmental Factors: Diet & Antibiotics
Figure 1 Increasing trend of IBD in industrialized countries since the 19th century and in industrializing countries since the 20th century Gastroenterology 2017 152, 313-321.e2DOI: (10.1053/j.gastro.2016.10.020) Kaplan & Ng Gastro 2017
Global Prevalence of IBD : 6 Million+ North-South gradient in North America & Europe UC increased first in Asia CD now in Japan Recent US estimate of 3 million including 100,000 children Cosnes et al Gastro 2011
Percent of Cases Age of Onset of IBD 25 20 15 10 5 0 Years 0 10 20 30 40 50 60 70 80 years Incidence has doubled in the pediatric age group over the past decade. 100,000 affected in the U.S. 60% males Loftus, Gastroenterology 2003; 124:abstract 278 Benchimol, Gut 2009, IBDJ 2014
IBD Risk Genes and Chances of Developing IBD Uhlig et al IBDJ 2016
Factors Influencing IBD Development and Flares Copyright 2015 Inflammatory Bowel Diseases. Published by Lippincott Williams & Wilkins.
Figure 2 Environmental and Microbial Triggers for IBD Gastroenterology 2017 152, 313-321.e2DOI: (10.1053/j.gastro.2016.10.020) Kaplan & Ng Gastro 2017
Figure 2 Dietary Approaches for IBD Symptoms Gastroenterology 2017 152, 313-321.e2DOI: (10.1053/j.gastro.2016.10.020) Lewis IBDJ 2017
Gut Bacteria Billions of bacteria in the intestine Bacteria change with genes, food, antibiotics Bacteria are different in IBD patients, and are the main activator of the immune system Beneficial bacteria promote gut health & are lower in IBD patients
Intestinal Bacterial Shifts are Associated with Symptoms We will now test a prebiotic dietary supplement to expand the noninflammatory bacteria Gevers et al Cell Host Microbe 2014
Figure 2 Intestinal Bacteria Promote Gut Function in Health and Drive Inflammation in IBD Health: IBD: Gastroenterology 2017 152, 327-339.e4DOI: (10.1053/j.gastro.2016.10.012) Sartor & Wu Gastro 2017
Figure 1 Can We Predict & Change the Natural History of IBD? Gastroenterology 2017 152, 351-361.e5DOI: (10.1053/j.gastro.2016.09.046) Colombel et al Gastro 2017
Are Specific Genes & Microbes Associated with Disease Severity and Treatment Responses? 2 mm Intestinal Biopsy Normal ileum (Peyer s patches) 16S DNA Sequencing: Mucosal Microbes RNA Sequencing: Patient Gene Expression Identified Biologic Pathways associated with Clinical Severity and Outcomes Crohn s Ileitis (linear ulcers, exudate)
The RISK & PROTECT Studies 1112 children with CD at diagnosis between 2008-2012 432 children with UC at diagnosis between 2013-2015 Follow-up to 2017 Clinical & Demographic Genotype Environmental Exposures Immune Serology Microbial Community/Gene Expression Patient outcomes: Steroid-free remission Surgeries
Genes Signatures and Clinical Outcomes
Therapeutic Targets 1: Intestinal damage NO Proteases 2: White cell activation by bacteria MHC Class II B7 ROM TCR CD4 CD28 CTLA4 Diet or fecal transplant to change microbes? LTB 4 Selectins PMN 4: White cell recruitment to the intestine Integrins ICAM-1 Monocyte MAdCAM-1 Resting Mo 3: Inflammatory proteins Lymphocyte Activated Mo IL-8 IL-23 IFNg TNF CD4 + T cell IL-12 IL-17 Naive T cell IL-2 CD40L IL-4 CD40 Th1 Th2 IL-5 Th17 Biologic medications to block inflammatory proteins and now white cell recruitment B cell
Figure 1 Cytokine Signaling Blockade with Biologics and Small Molecules Biologics: monoclonal anti-cytokine antibodies (anti-tnf, anti-il12/23, anti-a4b7) Small molecules: specific oral inhibitors (JAK1/2/3 kinase activity; SMAD7 antisense) Gastroenterology 2017 152, 374-388.e4DOI: (10.1053/j.gastro.2016.10.018) Sandborn et al Gastro 2017
Biologic Therapy: Antibody Blockade of Tumor Necrosis Factor Inflammatory Protein
Therapeutic Targets 1: Intestinal damage NO Proteases 2: White cell activation by bacteria MHC Class II B7 ROM TCR CD4 CD28 CTLA4 Diet or fecal transplant to change microbes? LTB 4 Selectins PMN 4: White cell recruitment to the intestine Integrins ICAM-1 Monocyte MAdCAM-1 Resting Mo 3: Inflammatory proteins Lymphocyte Activated Mo IL-8 IL-23 IFNg TNF CD4 + T cell IL-12 IL-17 Naive T cell IL-2 CD40L IL-4 CD40 Th1 Th2 IL-5 Th17 B cell
Targeting White Cell Recruitment to the Gut 1: Intestinal damage NO Proteases LTB 4 2: White cell activation by bacteria MHC Class II B7 ROM TCR CD4 CD28 CTLA4 Selectins PMN 4: White cell recruitment to the intestine Integrins ICAM-1 Monocyte MAdCAM-1 Resting Mo 3: Inflammatory proteins Lymphocyte Activated Mo IL-8 IL-23 IFNg TNF CD4 + T cell IL-12 IL-17 Naive T cell IL-2 CD40L IL-4 CD40 Th1 Th2 IL-5 Th17 B cell
Vedolizumab anti-adhesion molecule (a4b7) a4b7 adhesion molecules are specifically needed for white cell intestinal recruitment FDA approval for adults with Crohns and UC in 2014 Sandborn et al NEJM 2013 Feagan et al NEJM 2013
Targeting The IL-12 and IL-23 Inflammatory Proteins 1: Intestinal damage NO Proteases LTB 4 2: White cell activation by bacteria MHC Class II B7 ROM TCR CD4 CD28 CTLA4 Selectins PMN 4: White cell recruitment to the intestine Integrins ICAM-1 Monocyte MAdCAM-1 Resting Mo 3: Inflammatory proteins Lymphocyte Activated Mo IL-8 IL-23 IFNg TNF CD4 + T cell IL-12 IL-17 Naive T cell IL-2 CD40L IL-4 CD40 Th1 Th2 IL-5 Th17 B cell
Ustekinumab Blocks the IL-12 and IL-23 Inflammatory Proteins & Provides Clinical Benefit for Two-Thirds of Patients With Crohn s Disease Refractory to Anti Tumor Necrosis Factor Agents 6 mg/kg IV loading dose 90 mg SC q 8 wks A clinical benefit was defined as a significant improvement in CDrelated clinical symptoms and laboratory tests assessed by the patient s physician leading to continued ustekinumab treatment, associated with complete weaning from steroids if they were being taken at inclusion, without surgery, or immunosuppressant introduction. Wils et al Clin Gastro Hep 2015
Therapeutic Drug Monitoring to Optimize Long Term Benefit of Biologic Medications Therapeutic Drug Monitoring of Antitumor Necrosis Factor Agents in Patients with Inflammatory Bowel Diseases Yarur, Andres J.; Rubin, David T. Inflammatory Bowel Diseases. 21(7):1709-1718, July 2015. doi: 10.1097/MIB.0000000000000380 Copyright 2016 Inflammatory Bowel Diseases. Published by Lippincott Williams & Wilkins. 27
Association Between Response to Etrolizumab which Blocks White Cell Retention in the Gut and Expression of Biomarkers in Colon Biopsies of Patients With Ulcerative Colitis: Companion Diagnostics Tew et al Gastro 2015
Gut Bacteria Shift Towards Normal with Resolution of Inflammation with Either Nutritional or anti-tnf (Remicade) Therapy Lewis et al Cell Host Microbe 2015
Figure 4 Treatment of IBD by Altering Microbial Composition or Function Gastroenterology 2017 152, 327-339.e4DOI: (10.1053/j.gastro.2016.10.012) Sartor & Wu Gastro 2017
The Specific Carbohydrate Diet Clinical and Mucosal Improvement With Specific Carbohydrate Diet in Pediatric Crohn Disease Cohen, Stanley A.; Gold, Benjamin D.; Oliva, Salvatore; Lewis, Jeffery; Stallworth, Angela; Koch, Bailey; Eshee, Laura; Mason, David Journal of Pediatric Gastroenterology and Nutrition. 59(4):516-521, October 2014. doi: 10.1097/MPG.0000000000000449 Improved symptoms and intestinal inflammation after 3 and 12 months Improved weight after 12 months Copyright 2016 Journal of Pediatric Gastroenterology and Nutrition. Published by Lippincott Williams & Wilkins. 31
Fecal MicrobiotaTransplant Healthy donor screened for infectious agents Filtered diluted fecal preparation administered as enema, ND tube, scope CDiff infection and IBD (mainly UC) McMasters University: first randomized controlled trial in adult UC with negative results 7/31 remission compared to 2/30 Anderson et al Alim Pharm Ther 2012 DeLeon Clin Gastro Hep 2013
Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial Remission rate: FMT 24% versus placebo 5% p=0.03 Moayyedi et al Gastro 2015
Figure 2 Butyrate-Producing Microbes Boost Intestinal Epithelial Function 2 -fucosyllactose (2 -FL) prebiotic induces healthy bacteria to make SCFA 2 -FL clinical trial in IBD patients receiving anti- TNF therapy Gastroenterology 2017 152, 327-339.e4DOI: (10.1053/j.gastro.2016.10.012) Sartor & Wu Gastro 2017
IBD: New Therapies New agents are being tested in over 100 clinical trials in the United States : www.ccfa.org, www.clinicaltrials.gov Small Molecule Therapies: Targeting the Over-active Immune System: Xeljanz Boosting beneficial microbes: 2 -FL