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INFLAMMATORY BOWEL DISEASES 101 Anita Afzali MD, MPH UW Medicine– Harborview Medical Center February 9, 2016 LEARNING POINTS 1. 2. 3. 4. Basics of IBD Understanding your immune system Current treatments in IBD Newer therapies in IBD INFLAMMATORY BOWEL DISEASE (IBD) A group of chronic diseases that causes inflammation in the large intestines (colon) and/or small intestines Periods of relapse and remission Symptoms vary widely based on disease location and severity of inflammation 3 INFLAMMATORY BOWEL DISEASES Are Not: Are: Irritable bowel syndrome (IBS) An allergy An immune deficiency Inflammatory = activated immune system in the intestinal tract Chronic = lasts a long time (maybe a lifetime) Treatable IBD 101: TWO MAIN TYPES • • • • • Ulcerative Colitis Contiguous & circumferential, superficial inflammation Erythema, Edema Loss of vascular pattern Friability Granularity • • • • Crohn’s Disease Discontinuous, patchy, full-thickness inflammation Mouth-to-anus involvement Strictures Fistulas and abscesses 5 ILEOCOLONOSCOPY Normal findings of terminal ileum and colon UC Spectrum of Disease Normal Moderate Mild Severe 7 CD Spectrum of Disease 8 CD SPECTRUM OF DISEASE Taken from Steven Mills, MD 9 CLINICAL FEATURES OF IBD Typical Symptoms • Abdominal pain • Diarrhea • Fever • Fatigue • Rectal bleeding • Weight loss • Anorexia • Nausea Common Physical Examination Findings • Abdominal tenderness • Palpable mass • Perianal disease • Extra-intestinal manifestations: – – – – – Mouth Skin Eyes Joints Liver Common Laboratory & Radiographic Findings • Anemia • Leukocytosis • Elevated ESR/CRP** • Guaiac-positive stool • Small bowel disease • Fistulas • Strictures CRP = C-reactive protein ESR = erythrocyte sedimentation rate Podolsky DK. N Engl J Med. 2002 IMPACT OF IBD Medical Impact 85% of patients suffer from diarrhea1 51% of patients were hospitalized in the last 3 years2 • • 64% required surgery2 ~90% of CD will have surgery in their lifetime Work Disability Impact 55% missed work due to disease in the past year3 5.3% become permanently work disabled2 Emotional Impact 70% of patients report anxiety or depression, compared with 30% of population norms4 1. Knutson D, et al. Am Fam Physician. 2003. 2. Ananthakrishnan AN, et al. Am J Gastroenterol. 2008. 3. Kiebles JL, et al. Inflamm Bowel Dis. 2010. 4. Feagan BG, et al. Am J Gastroenterol. 2009. IBD CHARACTERIZED BY CHRONIC INFLAMMATION IN THE GUT Dysregulation of the immune system WHAT IS THE IMMUNE SYSTEM? • Cells (T cells, B cells, macrophages) that defend the body against attack from infections • To eradicate infection, the immune system turns on, causes inflammation • Once an infection is eliminated, the immune system knows how to turn itself off Photo courtesy of Scott Plevy, MD DYSREGULATED IMMUNE SYSTEM • In IBD, the “off” switch is broken • Inflammation is a Key Aspect of IBD CHRONIC INFLAMMATION: PROTEINS CALLED CYTOKINES ARE THE LIGHT SWITCH IL-10 TGF IFN IL-12 IL-1Ra IL-4/IL-13 IL-8 IL-1 TNF “On” “Off” Multiple Sclerosis Asthma Crohn’s Disease Ulcerative Colitis Psoriasis Rheumatoid Arthritis EXACT ETIOLOGY UNKNOWN: INAPPROPRIATE IMMUNE RESPONSE Genetics Immune System/ Inflammation Environmental Influence Luminal microbial antigens/adjuvants CD=Crohn’s disease; IBD=inflammatory bowel disease. Khor B, et al. Nature.2011. Cosnes J, et al. Gastroenterology. 2011. GENETICS IS IBD A GENETIC DISORDER? Approximately 10% of patients have positive family history for IBD 2%–10% risk for IBD if first-degree relative affected Identical twins: 40-60% that both affected “Complex” genetic disorders Yang H, et al. Inflammatory Bowel Disease. 1993. ENVIRONMENT YOU ARE ONLY 10% HUMAN = 1012 to 1013 Cells = 1013 to 1014 Intestinal Bacteria WHAT IS THE ‘MICROBIOME’? Refers to entire microbial gut composition What is the role of intestinal microbiome in good health? How does the intestinal microbiome change in IBD? Unhealthy microbiome = ‘Dysbiosis’ Role of fecal microbial transplantation (‘stool transplant’) in restoring healthy microbiome? Proposed Model Leading to IBD: Interaction of Genes and Environment Lee YK and Mazmanian SK. Science 2010 Environmental Triggers of IBD Acute infections Antibiotics IBD Diet NSAIDs Onset and Reactivation Stress Smoking Ratio Rate EFFECT ON CHANGE IN MICROBIOME? Hviid A et al. Gut 2011 U.S. INCIDENCE AND PREVALENCE Approximately 1.5 million Americans suffer from IBD Prevalence ~1/200 people have IBD in U.S. Men and women are affected equally Bimodal distribution: 20-30 and ≥60 yr Increase among different race/ethnic groups (HMC) About Crohn’s disease. CCFA Crohn’s disease. NIDDK IBD and older adults. CCFA Afzali A et al. Inflamm Bowel Dis 2016 (in press) IBD ‘MEDICINE CABINET’ Over-the-Counter Antibiotics 5-Aminosalicylates/Mesalamine Corticosteroids, Budesonide Immunomodulators – AZA/6MP, MTX Biologics - Target Protein Specific Anti-TNFs in IBD Change in Natural disease progression Infliximab approved for CD 1998 Adalimumab for CD 2002 Infliximab approved for UC 2005 Certolizumab pegol for CD 2008 Adalimumab for UC 2012 Golimumab for UC 2013 Adapted from Curr Opin Rheumat 2014 Fausel R & Afzali A. Ther Clin Risk Manag 2015 WHY DO WE NEED PERSONALIZED MEDICINE? STAGES OF RHEUMATOID ARTHRITIS Early Intermediate Late Courtesy of J. Cush, 2002 Change in Joint Damage Mean through 102 Weeks – anti-TNF Mean change from baseline through 102 weeks Placebo 3 mg/kg qw8 10 mg/kg qw8 3 mg/kg qw4 10 mg/kg qw4 14 12 10 8 6 p < 0.001 for each infliximab arm vs. placebo at week 30, 54, and 102 4 2 0 Baseline Week 30 Week 54 Week 102 90 % 75 % Respons e Remission <1 Year 1-<2 years 57 % PRECISE trial (certolizumab) 44 % n=98 24 % n=131 n=131 n=55 2-<5 years Sandborn WJ et al. Am J Gastro 2006 Colombel et al, NEJM 2007 33 % 29 % n=98 47 % n=45 36 % n=45 n=20 n=22 36 % n=20 n=35 37 % n=19 37 % 55 % n=55 50 % 62 % n=22 68 % n=35 100 % 90 % 80 % 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % n=19 % in CDAI Response or Remission RESPONSE AND REMISSION TO ANTI-TNF BY DISEASE DURATION >=5 years Placebo Response Placebo Remission WE DON’T SEE THE DEFORMITIES OF THE INTESTINES UNTIL COMPLICATION… Early Intermediate Late Courtesy of J. Cush, 2002 ANTI-TNF: ENDOSCOPIC HEALING INFLAMMATION -> FISTULA, STRICTURE Taken from M. Shaikhani MD 35 THE EVOLUTION OF CROHN’S DISEASE: INFLAMMATION LEADS TO DAMAGE Cumulative Probability (%) 100 80 70% 60 Penetrating 40 Inflammatory Stricturing 20 18% 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Over a 20-year period, 88% risk of developing stricturing (18%) or penetrating (70%) disease Cosnes J et al. Inflamm Bowel Dis. 2002 NATURAL HISTORY MOST CROHN’S PATIENTS WILL REQUIRE SURGERY Mekhjian HS et al. Gastro 1979. NATURAL HISTORY OF ULCERATIVE COLITIS 100 90 Colectomy Patients (%) 80 70 Disease activity 60 50 40 30 Remission 20 10 0 n=1161 0 Years after diagnosis 25 Risk of colectomy: 24% after 10 years ~ 30% after 20 years Significant Increased risk of cancer Adapted from Langholz E, et al. Gastroenterology 1994 TEMPORAL TRENDS OF COLECTOMY UC Kaplan GG et al. AJG 2012 Since introduction of biologic agents/anti-TNFs, decrease in total colectomy in UC patients WHAT’S NEW? IBD DRUG PIPELINE Taken from E. Loftus AIBD 2015 GY Melmed & SR Targan 2010 LYMPHOCYTE TRAFFICKING IN IBD Accumulation of excess infiltrating WBC is one of hallmarks in IBD “Gut specific” WBC causes damage in gut Multi-step adhesion cascade: Rolling -> Tethering -> Adhesion -> Migration Laroux et al. 2001 IBD Immunology 101 Taken with permission from RW Stidham IBD Immunology 101 Mucosa Submucosa Blood Vessels Taken with permission from RW Stidham IBD Immunology 101 Mucosa Submucosa Blood Vessels Taken with permission from RW Stidham IBD Immunology 101 Mucosa Submucosa Blood Vessels Taken with permission from RW Stidham Blockade of Adhesion Molecules: VEDOLIZUMAB (ENTYVIO®) Block WBC Binding to Integrins Anti-Integrin Coating BLOCKADE OF CELL-ACTIVATING SIGNALS: USTEKINUMAB (STELARA®) IL-12 Receptor IL-12/23 Ligand T-cell Interferon Dendritic cell T-cells ACTIVATED IL-17 ORAL SMAD7 ANTISENSE OLIGONUCLEOTIDE: MONGERSEN SMAD7 Mongersen Presence of Smad7: In absence of •TGFβ1Smad7: signalling blocked TGFβ1 is an effective •T-cells continue to inhibitor of promake pro-inflammatory inflammatory T-cells cytokines Adapted from Monteleone G et al. NEJM 2015 QUESTIONS ANITA AFZALI MD, MPH http://www.uwgi.org/ibd/ For appointments: 206-744-2788