1. Inflammatory Bowel Disease A Aljebreen, MD, FRCPC Jan 2010

2. Objectives Introduction Introduction Classifications Classifications Clinical features Clinical features Diagnosis Diagnosis Management Management Conclusion Conclusion

3. Introduction IBD characterized by a tendency for chronic or relapsing immune activation and inflammation within the gastrointestinal tract (GIT) IBD characterized by a tendency for chronic or relapsing immune activation and inflammation within the gastrointestinal tract (GIT) Crohn ’ s disease (CD) and ulcerative colitis (UC) are the 2 major forms of idiopathic IBD. Crohn ’ s disease (CD) and ulcerative colitis (UC) are the 2 major forms of idiopathic IBD.

4. Less common entities Microscopic colitis (collagenous and lynphocytic) Microscopic colitis (collagenous and lynphocytic) Others Others Diversion colitis Diversion colitis Radiation colitis Radiation colitis Drug induced colitis Drug induced colitis Infectious colitis Infectious colitis Ischemic colitis Ischemic colitis

5. CD and UC CD is a condition of CD is a condition of Chronic inflammation potentially involving any location of the GIT from mouth to anus. Chronic inflammation potentially involving any location of the GIT from mouth to anus. It is a lifelong disease arising from an interaction between genetic and environmental factors It is a lifelong disease arising from an interaction between genetic and environmental factors UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon. UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon.

6. Epidemiology CD: CD: 1 st peak 15-30 years of age, 2 nd peak around 60 y 1 st peak 15-30 years of age, 2 nd peak around 60 y There is a definite incidence surge in Saudi Arabia over the last 10 years There is a definite incidence surge in Saudi Arabia over the last 10 years UC: UC: High incidence areas: US, UK, northern Europe High incidence areas: US, UK, northern Europe Young adults, commoner in females Young adults, commoner in females

7. Genetics Studies suggested that 1 st degree relatives of an affected patient have a risk of IBD that is 4-20 times higher than that of general population. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. Having one copy of the risk alleles confers a 2 – 4-fold risk for developing CD, whereas double- dose carriage increases the risk 20 – 40-fold.

8. Etiology Mutations within the NOD2/ CARD15 gene contribute to CD susceptibility. Functional studies suggest that inappropriate responses to bacterial components may alter signaling pathways of the innate immune system, leading to the development and persistence of intestinal inflammation. Initiating pathogen? Initiating pathogen? Infectious? Infectious? ? Possibly non-pathogenic commensal enteric flora ? Possibly non-pathogenic commensal enteric flora

9. Pathogenesis The mucosa of CD patients is dominated by Th1 (T helper), which produce interferon-γ and IL-2. In contrast, UC dominated by Th2 phenotype, which produce transforming growth factor (TGF-) and IL-5. Activation of Th1 cells produce the down- regulatory cytokines IL-10 and TGF-.

10. Environmental Precipitants Factors: NSAIDs use (?altered intestinal barrier), and Early appendectomy (increase UC incidence) Smoking (protects against UC but increases the risk of CD).

11. CD: PATHOLOGY Early Findings: Aphthous ulcer. The presence of granulomas Late findings: Linear ulcers. The classic cobble stoned appearance may arise. Transmural inflammation Sinus tracts, and strictures. Fibrosis.

13. transmural inflammation with predominance of the inflammation in the mucosa and submucosa.

14. UC: PATHOLOGY The inflammation is predominantly confined to the mucosa. Non-specific (can be seen with any acute inflammation) The lamina propria becomes edematous. Inflammatory infiltrate of neutrophils Neutrophils invade crypts, causing cryptitis & ultimately crypt abscesses. Specific (suggest chronicity): Distorted crypt architecture, crypt atrophy and a chronic inflammatory infiltrate.

16. Diagnosis Exclude other possibilities (need good history, physical exam, labs, imaging and endoscopy with biopsy) Exclude other possibilities (need good history, physical exam, labs, imaging and endoscopy with biopsy) There are many distinguishing features of CD and UC. There are many distinguishing features of CD and UC. In about 5% it is classified as indeterminate because of overlapping features. In about 5% it is classified as indeterminate because of overlapping features.

17. Distinguishing characteristics of CD and UC UCCDFeature Only colon (rarely “ backwash ileitis ” SB or colonLocation Continuous, begins distally Skip lesionsAnatomic distribution Involved in >90%Rectal spareRectal involvement UniversalOnly 25%Gross bleeding Rare75%Peri-anal disease NoYesFistulization No50-75%Granulomas

18. Endoscopic features of CD and UC UCCDFeature ContinuousDiscontinuousMucosal involvement RareCommonAphthous ulcers AbnormalRelatively normal Surrounding mucosa RareCommonLongitudinal ulcer NoIn severe casesCobble stoning CommonUncommonMucosal friability distortedNormalVascular pattern

19. Pathologic features of CD and UC UCCDFeature UncommonYesTransmural inflammation No50-75%Granulomas RareCommonFissures NoCommonFibrosis UncommonCommonSubmucosal inflammation

20. Radiologic features of CD and UC UCCDFeature Collar button ulcers Nodularity granularity cobble stoning string sign of SB

25. UC: Presentation Must exclude infectious cause before making Dx. Must exclude infectious cause before making Dx. Rectal Bleeding Rectal Bleeding Diarrhea: Diarrhea: frequent passage of loose or liquid stool, often associated with passing large quantities of mucus. frequent passage of loose or liquid stool, often associated with passing large quantities of mucus. Abdominal Pain: Abdominal Pain: it is not a prominent symptom. it is not a prominent symptom. Anorexia, nausea, fever … Anorexia, nausea, fever …

26. DDX of UC Infectious Infectious Drug induced Drug induced Microscopic colitis Microscopic colitis

27. UC: Presentation Mild attack: Mild attack: Most common form, mainly left sided colitis, <4 BM/day with no blood Most common form, mainly left sided colitis, <4 BM/day with no blood Moderate attack: Moderate attack: 25% of all patients, 4-6 BM/day with blood. 25% of all patients, 4-6 BM/day with blood. Severe or fulminant colitis: Severe or fulminant colitis: ~ 15% of cases, >6BM/day, bloody, fever, weight loss, diffuse abd tenderness, elevated WBC, most refractory to medical therapy ~ 15% of cases, >6BM/day, bloody, fever, weight loss, diffuse abd tenderness, elevated WBC, most refractory to medical therapy

28. CD Anatomic distribution Anatomic distribution CD activity index CD activity index DDx (lymphoma, Yersinea Enterocolitis, TB) DDx (lymphoma, Yersinea Enterocolitis, TB)

29. CD: clinical presentations Disease of the ileum: May present initially with a small bowel obstruction. Patients with an active disease often present with anorexia, loose stools, and weight loss. Perianal disease In 24% of patients with CD. Skin lesions include superficial ulcers, and abscesses. Anal canal lesions include fissures, ulcers, and stenosis.

30. CD ilitis: DDx Lymphoma Lymphoma Yersinea Enterocolitis and Yersinea Enterocolitis and TB TB

31. CD: clinical presentations colonic disease The typical presenting symptom is diarrhea, occasionally with passage of obvious blood. proctitis May be the initial presentation in some cases of CD

32. Extra-intestinal manifestations of IBD Arthritis: Arthritis: Peripheral arthritis, usu paralels the disease activity Peripheral arthritis, usu paralels the disease activity Ankylosing Spondylitis, 1-6%, sacroiliitis Ankylosing Spondylitis, 1-6%, sacroiliitis Ocular lesions: Ocular lesions: Iritis (uvietis) (0.5-3%), episcleritis, keratitis, Iritis (uvietis) (0.5-3%), episcleritis, keratitis, Skin and oral cavity: Skin and oral cavity: Erythema nodosum 1-3% Erythema nodosum 1-3% Pyoderma Gangrenosum 0.6% Pyoderma Gangrenosum 0.6% Aphthus stomatitis, metastatic CD. Aphthus stomatitis, metastatic CD.

35. Extra-intestinal manifestations of IBD Liver and Biliary tract disease: Liver and Biliary tract disease: Pericholangitis, fatty infiltration, PSC (1-4%, more with UC), cholangiocarcinoma, gallstones Pericholangitis, fatty infiltration, PSC (1-4%, more with UC), cholangiocarcinoma, gallstones Thromboembolic disease, vasculitis, Renal disease (urolithiasis, GN), clubbing, amyloidosis. Thromboembolic disease, vasculitis, Renal disease (urolithiasis, GN), clubbing, amyloidosis.

37. Complications of IBD Bleeding Bleeding Stricture Stricture Fistula Fistula Toxic megacolon Toxic megacolon Cancer Cancer

40. How to diagnose IBD History History Physical examinations Physical examinations Labs Labs Radiology Radiology Endoscopy Endoscopy Histopathology Histopathology

41. Case scenario 1 Case scenario 1 17 year old female presented with 1 year history of intermittent abdominal cramps and increasing abdominal gases and bloating. What other history you want?

42. Case scenario 2 65 year old male presented with 6 months history of bleeding per rectum. What other history you want? What else you need?

43. Treatment Goals of therapy Goals of therapy Induce and maintain remission. Induce and maintain remission. Ameliorate symptoms Ameliorate symptoms Improve pts quality of life Improve pts quality of life Adequate nutrition Adequate nutrition Prevent complication of both the disease and medications Prevent complication of both the disease and medications

44. 5-Aminosalicylic Acids The mainstay treatment of mild to moderately active UC and CD (induction). 5-ASA may act by blocking the production of prostaglandins and leukotrienes, inhibiting bacterial peptide – induced neutrophil chemotaxis and adenosine-induced secretion, scavenging reactive oxygen metabolites

45. 5-Aminosalicylic Acids For patients with distal colonic disease, a suppository or enema form will be most appropriate. Maintenance treatment with a 5-aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohn's disease.

47. Corticosteroids Topical corticosteroids can be used as an alternative to 5-ASA in ulcerative proctitis or distal UC. Oral prednisone or prednisolone is used for moderately severe UC or CD, in doses ranging up to 60 mg per day. IV is warranted for patients who are sufficiently ill to require hospitalization; the majority will have a response within 7 to 10 days.

48. Corticosteroids No proven maintenance benefit in the treatment of either UC or CD. No proven maintenance benefit in the treatment of either UC or CD. Many and serious side effects. Many and serious side effects. Budesonide: Budesonide: less side effects, less side effects, its use is limited to patients with distal ileal and right- sided colonic disease its use is limited to patients with distal ileal and right- sided colonic disease

50. Immunosuppressive Agents These agents are generally appropriate for patients in whom the dose of corticosteroids cannot be tapered or discontinued. Azathioprine & 6-MP The most extensively used immunosuppressive agents. The mechanisms of action unknown but may include suppressing the generation of a specific subgroup of T cells. The onset of benefit takes several weeks up to six months. The onset of benefit takes several weeks up to six months. Dose-related BM suppression is uniformly observed Dose-related BM suppression is uniformly observed

51. Immunosuppressive Agents Methotrexate Methotrexate Effective in steroid-dependent active CD and in maintaining remission. Effective in steroid-dependent active CD and in maintaining remission. Cyclosporine Cyclosporine Severe UC not responding to IV steroid &need urgent proctocolectomy. Severe UC not responding to IV steroid &need urgent proctocolectomy. 50% of the responders will need surgery within a year. 50% of the responders will need surgery within a year.

52. Anti-TNF Therapy It is a chimeric monoclonal antibody, binds soluble TNF. Infleximab, Adalimumab (Humira) and Certolizumab Prompt onset, effects takes 6weeks to max of 6m. Indicated in fistulising crohns, moderate to severe CD Infleximab also indicated in severe ulcerative colitis

53. Side effects They are safe and usually tolerable Acute infusion reactions, which may include chest tightness, dyspnea, rash, and hypotension. Delayed hypersensitivity reactions, consisting of severe polyarthralgia, myalgia, facial edema, urticaria, or rash, are an unusual complication occurring from 3 to 12 days after an infusion.

54. Side effects Increase risk of infections including exacerbations of abdominal abscess or increasing upper respiratory infections. Reactivation of tuberculosis has been observed and has resulted in disseminated disease and death.

55. INDICATIONS FOR SURGERY In patients with UC: In patients with UC: Severe attacks that fail to respond to medical therapy. Severe attacks that fail to respond to medical therapy. Complications of a severe attack (e.g., perforation, acute dilatation). Complications of a severe attack (e.g., perforation, acute dilatation). Chronic continuous disease with an impaired quality of life. Chronic continuous disease with an impaired quality of life. Dysplasia or carcinoma. Dysplasia or carcinoma. In patients with CD In patients with CD Obstruction, severe perianal disease unresponsive to medical therapy, difficult fistulas, major bleeding, severe disability Obstruction, severe perianal disease unresponsive to medical therapy, difficult fistulas, major bleeding, severe disability 30 % relapse rate 30 % relapse rate

56. IBD Sequelae UC: UC: Risk of cancer begins after 8 years, risk of pancolitis 7% at 20 years and 17% at 30 years. Risk of cancer begins after 8 years, risk of pancolitis 7% at 20 years and 17% at 30 years. Increased risk: early age of onset, pancolitis. Increased risk: early age of onset, pancolitis. Need for colonoscopic screening after 8 years Need for colonoscopic screening after 8 years CD: CD: True incidence of cancer is uncertain, but could be as high as UC True incidence of cancer is uncertain, but could be as high as UC Need the same screening policy. Need the same screening policy.

57. IBD conclusion It is a chronic disorders It is a chronic disorders Need to exclude other possibilities Need to exclude other possibilities Need to differentiate between the two Need to differentiate between the two Need long term management with primary goal to induce then maintain remission and prevent complications of both the disease and drugs. Need long term management with primary goal to induce then maintain remission and prevent complications of both the disease and drugs.