1. Overview of Inflammatory Bowel Disease Crohn’s Disease and Ulcerative Colitis

2. Definitions “Inflammatory bowel disease (IBD) is an idiopathic and chronic intestinal inflammation.” Harrison’s Textbook of Internal Medicine Ulcerative Colitis (UC) is a mucosal disease that usually involves the rectum and extends proximally to involve part of or the entire colon. Crohn’s Disease (CD) is a disease that can effect any portion of the luminal GI tract and usually presents in two patters: obstructive/fibrostenotic and penetrating/fistulizing

3. IBD - Epidemiology Men = Women ; Jews > non-Jews Peak incidence is 15 - 25 years old Incidence is 5-15/100,000 but prevalence is much higher (133-181/100,000) and rising (Crohn’s/UC) 17% of UC and 23% of Crohn’s patients have a relative with IBD (usually same type of IBD)

4. UC

5. Terminal Ileum

6. Ulcerative Colitis Inflammatory disease of the colon mucosa affecting the rectum and to varying degrees extending proximally to the cecum Presents with bloody diarrhea (rarely constipation) and abdominal pain 77% (Danish cohort) experience chronic relapsing disease 30% will undergo colectomy over 30 years Approximately 18% (Mayo Clinic data) will develop colon cancer over 30 years Up to 4% will develop Primary Sclerosing Cholangitis 6-11% will develop osteopenia, venous thrombosis, arthritis/arthralgias, pyoderma, E. nodosum, iritis, uveitis, hepatobiliary complications, asymptomatic abnormal PFTs

7. UC

8. UC- Endoscopic

9. Mucosal Inflammation in UC

10. Crohn’s Disease A pan-enteric transmural inflammatory disease involving the terminal ileum and right colon, terminal ileum alone or colon alone (in a patchy distribution) Abdominal pain and diarrhea in > 70% 2 subtypes: inflammatory/obstructive, penetrating/fistulous 80% will need surgery by 15-30 years

11. Transmural Inflammation

12. The Elusive Granuloma

13. CD- endoscopic

14. Crohn’s

15. Etio-pathogenesis in IBD Abnormal function of the gut mucosal barrier results in chronic intestinal inflammation Genetic susceptibility conferred by mutations at distinct chromosomal loci Dysregulation of mucosal proinflammatory immunity (Th1 responses) with resulting overactivity of effector immune mechanisms Decreased regulatory T cell populations (suppressor T cells) lead to unfettered Th1 inflammatory responses to luminal antigens (loss of tolerance) Microbial antigens can lead to self-perpetuating inflammation in genetically susceptible hosts

19. Bacteria Antigen presenting cell Macrophage Type 1 helper T cell Macrophage migration inhibitor factor Interleukin-12 Interleukin-18 Tumor necrosis factor Interleukin-1 Interleukin-6 Normal epithelium Epithelial barrier Interferon-γ

20. Toll-like receptor Bacterial LPS NOD2 TNF and receptor Interleukin-1 and receptor NFk -B Anti-apoptosis NIK, MEKK1, or MEKK3 IKK complex Receptor-interacting protein 2 Gene transcription IkB

21. Environmental Influences Clean Kid hypothesis Crohn’s > UC are smokers; are s/p appendectomy IBD more common in cold climates IBD more common in industrialized areas Active disease increases risk to fetus and mother in pregnancy; relapse not increased by pregnancy

22. Symptoms

23. Infectious Mimics of IBD Bacteria: Shigella species, Enterohemorrhagic E. coli, Enteroinvasive E. coli, Campylobacter jejuni, Salmonella (gastroenteritis and typhoid fever), Yersinia enterocolitica, MTB, C. difficile, Vibrio parahaemolyticus, Chlamydia (lymphogranuloma venereum serotypes) Parasites: Entamoeba histolytica, Schistosoma species, Balantidium coli, Trichinella spiralis Viruses: Cytomegalovirus Causing proctitis: Neisseria gonorrhoeae, Herpes simplex virus, Chlamydia trachomatis, Treponema pallidum, Cytomegalovirus

24. Colorectal Cancer in Ulcerative Colitis Increased risk above general population (5%) 1-3% at 10 yrs and 18% at 30 years with pancolitis Flat or depressed adenomas—fields of dysplasia. Increased risk with: –Disease proximal to splenic flexure –> 8 years duration; young age at diagnosis –Primary sclerosing cholangitis (1-4% of IBD patients) –Family history of CRC –Pseudopolyps at colonoscopy 5-ASA treatment is protective

26. Capsule Endoscopy

27. CD in Small Bowel

28. Common extraintestinal manifestations Musculoskeletal: Arthritis, ankylosing spondylitis, clubbing, periostitis, osteoporosis, aseptic necrosis, polymyositis Skin and mouth: erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruption, necrotizing vasculitis, fissures and fistulas, oral Crohn's disease, drug rashes, nutritional deficiencies, vitiligo, psoriasis, amyloidosis, epidermolysis bullosa acquisita Hepatobiliary: Primary sclerosing cholangitis and bile duct carcinoma, autoimmune chronic active hepatitis, pericholangitis, portal fibrosis and cirrhosis, granulomatous inflammation, fatty liver, gallstones associated with ileal Crohn's disease Ocular: Uveitis (iritis), episcleritis, scleromalacia, corneal ulcers, retinal vascular disease Metabolic: Growth retardation in children and adolescents, delayed sexual maturation, osteoporosis, vitamin D deficiency

29. Obstruction in CD

30. Fistulae in CD

31. Current Expectations for IBD Therapy Induce clinical remission Maintain clinical remission Improve patient quality of life PLUS Heal mucosa Decrease hospitalization/surgery and overall costs Minimize disease-related and therapy-related complications

32. IBD Therapeutic Pyramid Severe Moderate Mild Aminosalicylates / Antibiotics Budesonide/ Oral prednisone Azathioprine / 6-MP IV Corticosteroids Infliximab / anti-TNF Rx Cyclosporine Tacrolimus Surgery Methotrexate Refractory

33. AMINOSALICYLATES

34. Steroid Toxicities Ocular – cataracts, glaucoma Skin – striae, atrophy, acne Endocrine – growth failure (pediatric), hypothalamic-pituitary-adrenal (HPA) axis suppression; glucose intolerance Cardiovascular – hypertension Other – Infection (abcess); myopathy Mortality, increased hospitalization (outcomes studies ??confounders)

35. ORAL BUDESONIDE IN ACTIVE CROHN’S DISEASE

36. IBD Therapeutic Pyramid Severe Moderate Mild Aminosalicylates / Antibiotics Budesonide/Oral prednisone Azathioprine / 6-MP Systemic Corticosteroids Infliximab / anti-TNF Rx Cyclosporine Tacrolimus Surgery Methotrexate Refractory

37. 6-MERCAPTOPURINE IN ACTIVE CROHN’S DISEASE

41. Biologic Therapy

42. Infliximab

43. TNF- α Inhibitors

44. Infliximab for UC

45. INDICATIONS FOR SURGERY IN ULCERATIVE COLITIS

46. SURGICAL OPTIONS IN ULCERATIVE COLITIS

47. INDICATIONS FOR SURGERY IN CROHN’S DISEASE