Looking for Answers IBD Research 2019 March 9, 2019 Dr. Benjamin Click, MD MS Associate Staff Cleveland Clinic
Disclosures No relevant financial disclosures There is still no cure for IBD
Why me? ETIOLOGY
Kaplan G, Ng S. Gastroenterology 2017
Microbiome Genes Immune System Sartor RB. Nat Clin Pract Gastroenterol Hepatol. 2006 Environment
CD UC + + +? + + + + Kaplan G, Ng S. Gastroenterology 2017
Sugar to Blame? 83,042 Swedish pts, dietary data since 1997 Looked at risk of subsequent IBD diagnosis Sweetened beverages not associated with risk of CD or UC Not modified by age, sex, BMI, or smoking Khalili H, et al. Clin Gastroenterol Hepatol. 2018
How about Tryptophan? Tryptophan reduces colitis in mice, removal worsens 535 IBD pt compared to non- IBD controls Serum tryptophan lower in IBD (CD>UC) Level decreased with increasing IBD activity Future: Modifying intestinal tryptophan pathways? Nikolaus S, et al. Gastroenterology. 2018
It s Mom s (mitochondrial) Fault Mitochondria DNA similar to bacterial mdna release may propagate inflammation Compared IBD to controls IBD higher rates of mdna than controls Active IBD with higher levels than remission Boyapati RK, et al. Inflamm Bowel Dis. 2018
Vaccines May Decrease IBD Risk Northern Finland birth cohort (1966) IBD risk up until 2016 Increased risk: maternal smoking, perinatal antibiotics Decreased risk: TDaP (40% reduction), Polio (30%) Blomster T, et al. Digestive Disease Week. 2018 S19
PREGNANCY
Introducing the Pregnancy Pathway Mahadevan, et al. Gastroenterology 2019.
% SEROLOGIC RESPONSE Pregnancy & Biologics Vedolizumab (Entyvio): appears safe, but small numbers Preterm birth: No risk Breastfeeding: No risk of infection or delayed milestones Infection: No risk infant infection Vaccines: No difference in infant vaccine response Biologics safe in pregnancy Matro R, et al. Gastroenterology 2018. Tsao N, et al. Ann Rheum Dis 2018 Beaulieu DB, et al. Clin Gastroenterol Hepatol 2018. Chapparro M, et al. Am J Gastroenterol. 2018. Mahadevan U, et al. Aliment Pharmacol Ther 2017. H. Flu Tetanus
S Depression IBD Risk Depression associated with IBD Cause/effect, impact of antidepressants unknown 403,665 pts with depression vs. 5.3 million controls Increased risk of developing CD (AHR 2.11) and UC (AHR 2.23) SSRI and TCA use protective against CD SNRI, SSRI, TCA use protective against UC Tryptophan ut. 2018
% IN REMISSION Patient Activation and Remission Patient activation: having the knowledge, skills, and confidence to effectively manage one s care Activation questionnaire given to 1486 patients One year later eval d clinical remission Anx/depression linked to low activation High activation associated with remission Barnes EL, et al. Inflamm Bowel Dis. 2018 LOW ACTIVATION HIGH ACTIVATION
The IBD Medical Home Multidisciplinary: GI, Psych, Nutrition, SW Provided personalized, intense outpt care IMPROVED: Quality of life;stress; Anxiety; Depression; Disease Activity Regueiro M, et al. Clin Gastro Hepatol 2018.
THE MICROBIOME
SIBO in IBD SIBO: small intestinal bacterial overgrowth Symptoms: bloating, diarrhea, nausea/vomiting Treatment: 2 wks antibiotics 10x increased SIBO incidence in IBD Risks: stricturing, prior surgery (ICV) Shah A, et al. Aliment Pharmacol Ther. 2019 NO SIBO SIBO
Antibiotics Induction in Peds 63 med refractory peds pts Steroid refractory/dependent atnf loss of response Antibx lead to improved: Disease activity Inflammation markers Blood counts Breton J, et al. Inflamm Bowel Dis. 2019
Fecal Microbial Transplant (FMT) To treat C. diff? YES Donor vs. Bank vs. Capsule To treat IBD? IT S COMPLICATED UC > CD https://www.nytimes.com/2019/03/03/health/fecal-transplants-fda-microbiome.html
MEDICATIONS & PROCEDURES
When can I stop my 115 CD patients in remission on IFX + IM Stopped infliximab, continued IM 7 years follow up Outcomes: ~20% did OK ~20% major complication ~60% restarted biologic Reenaers C, et al. Clin Gastro Hepatol 2018. Perianal Disease Stopping atnf -> ~50% relapse Legue C, et al. Inflamm Bowel Dis. 2018
SURGERY COMPOSITE STEROIDS HOSP Stopping 5-ASAs after atnfs 3589 UC pts started atnf while on 5-ASA Outcomes of steroids, hospitalization, surgery No increased risk in those who stopped 5-ASA Ungaro RC, et al. Gut 2018.
COLECTOMIES Colectomy for Cancer Declining Population based Canadian cohort ID d pts who underwent colectomy for colon cancer with diagnosis of UC Time: 2003-2015 Avg colectomy rate: 1.3 per 1000 Higher in males, older pts Picardo S, et al. Gastroenterology. 2019 S63
ADV NEOPLASIA ANY NEOPLASIA Pseudopolyps Cancer Prev work suggested increased cancer risk, more freq. surveillance 462 colitis pts with pseudopolyps vs. 1120 without Mahmoud R, et al. Gastroenterology. In Press
Stem Cells for Fistulas RCT of 212 CD pts with refractory, complex perianal fistulas Picardo S, et al. Gastroenterology. 2019 S63
PARTIAL No Colectomy MAYO CRP Hyperbaric Oxygen for UC HBOT increases tissue oxygen delivery Improved wound healing Prospective multicenter RCT Hospitalized, mod-severe UC Steroids/HBOT vs steroids/sham Stopped early: low enrollment Steroids/HBOT: N=10 Steroids/Sham: N=8 Dulai P, et al. Am J Gastroenterol 2018.
Cannabis Improves Symptoms HUMAN Mouse models: YES Humans: nausea, pain But not inflammation Checkered = positive outcome MICE Couch DG, et al. Inflamm Bowel Dis. 2018
Predicting Disease Course Howell KJ, et al. Gastroenterology 2018.
Drug Pipeline
Ulcerative Colitis Crohn s Disease
The Me Too Meds Anti-TNF: oral formulation Anti-Integrin: Etrolizumab, SC Vedolizumab Anti-IL 23: Brazikumab, Risankizumab JAK Inhibitor: Filgotinib, Upadacitinib Anti-SP1: Ozanimod Hartman D et al, J Crohns Colitis. 2016;10:631 640. Hartman D et al, Crohns Colitis. 2016;10:641 649 Sands BE, et al. Gastroenterology. 2017;153(77 86) Vermeire S, et al. Lancet. 2014;384(9940):309-18 Gastroenterology Week 2018, LB03 Feagan BG, et al. Lancet. 2017;389:1699-1709 Feagan BG, et al. Lancet Gastroenterol Hepatol. 2018;10:671-680 Sandborn WJ, et al. N Engl J Med. 2016;374:1754 1762 Sandborn WJ, et al, United European
Summary IBD results from complex person and environment interactions Biologics in pregnancy: Safe for mom AND baby Mind-gut interaction important: role of multidisciplinary care Microbiome data emerging: too much, too bad, how to change Promising new interventions: stem cells, hyperbaric O2 Medication pipeline bursting: new mechanisms of action
Thank You! Questions?