- Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis, both characterized by chronic inflammation of the gastrointestinal tract. The causes are not fully understood but involve immune dysfunction and genetic factors. - Crohn's disease can affect any part of the GI tract and cause transmural inflammation and complications like strictures and fistulas. Ulcerative colitis primarily involves only the inner mucosal layer of the colon and rectum. - Treatment depends on disease severity and includes medications to induce and maintain remission as well as surgery for complications. The goals are to control symptoms, improve quality of life, and prevent disease progression.

1. Inflammatory Bowel Disease Dr. Mohammad Shaikhani CABM,FRCP. 2/2010

2. Introduction A group of related conditions characterized by idiopathic inflammation of GIT. The 2 most common types are Crohn's disease & ulcerative colitis, both of which cause macroscopic inflammation. Microscopic colitis is less common& does not cause significant macroscopic abnormalities. The pathophysiology is not well understood but most likely involves immune dysfunction, genetically mediated, that causes inappropriate immune activation in response to luminal microorganisms. Although several features may differentiate Crohn's disease from ulcerative colitis, there is significant overlap. Even after diagnostic evaluation, 10% have disorders that cannot be classified(indeterminate colitis).

4. Less common colitis forms are: Microscopic colitis (collagenous& lynphocytic) Others Diversion colitis after clostomies. Radiation colitis Drug induced colitis Infectious colitis Ischemic colitis

5. Introduction CD is a condition of chronic inflammation potentially involving any location of the GIT from mouth to anus. UC is an inflammatory disorder that affects the rectum & extends proximally to affect variable extent of the colon.

6. Epidemiology CD: 1 st peak 15-30 years of age, 2 nd peak around 60 y UC: High incidence areas: US, UK, northern Europe Young adults, commoner in females

7. Genetics 1 st degree relatives have a *4-20 risk 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. 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-.

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

12. Environmental Precipitants Smoking increases the risk of Crohn's disease, but not the risk of ulcerative colitis. Arthritis, ophthalmologic disorders& dermatologic diseases are common extraintestinal manifestations of IBD. Patients with IBD have an increased risk of developing intestinal dysplasia& colorectal cancer.

13. 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.

15. 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 & a chronic inflammatory infiltrate.

16. UC

17. Distinguishing characteristics of CD and UC UC CD Feature Only colon (rarely “ backwash ileitis ” SB or colon Location Continuous, begins distally Skip lesions Anatomic distribution Involved in >90% Rectal spare Rectal involvement Universal Only 25% Gross bleeding Rare 75% Peri-anal disease No Yes Fistulization No 50-75% Granulomas

18. Endoscopic features of CD and UC UC CD Feature Continuous Discontinuous Mucosal involvement Rare Common Aphthous ulcers Abnormal Relatively normal Surrounding mucosa Rare Common Longitudinal ulcer No In severe cases Cobble stoning Common Uncommon Mucosal friability distorted Normal Vascular pattern

19. Pathologic features of CD and UC UC CD Feature Uncommon Yes Transmural inflammation No 50-75% Granulomas Rare Common Fissures No Common Fibrosis Uncommon Common Submucosal inflammation

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

21. Comparison of Features in Ulcerative Colitis and Crohn's Disease Crohn's Disease Ulcerative Colitis Feature Transmural Mucosal Depth of inflammation Skip areas Contiguous Pattern of disease Mouth to anus Colorectum Location Less common Usual Rectal involvement Common Backwash ileitis (15%–20% of patients ) Ileal disease Common Rare Fistulas Common Rare Perianal disease 10%–30% of patients Unlikely Granulomas Less common Usual Overt bleeding More common Unlikely Malnutrition Colorectal cancer, small bowel cancer (depending on disease location ) Colorectal cancer, cholangiocarcinoma (if primary sclerosing cholangitis is present ) Cancer risk Harmful Protective Tobacco use

22. UC

23. CD

25. Presentation UC typically involves the rectum & extends proximally with contiguous inflammation that is generally limited to the mucosa of the colon & rectum. Patients usually present with bloody diarrhea associated with rectal discomfort, fecal urgency& cramps. Although most patients have bloody diarrhea, those with proctitis can present with constipation. Patients with mild ulcerative colitis may have no abnormal physical findings. Fever, weight loss, tachycardia, dehydration& significant abd tenderness or rebound indicate more severe disease. Hypoactive bowel sounds or abdominal distention suggests perforation or megacolon.

26. Presentation CD may affect any segment of the GIT, is often discontinuous & may cause CD commonly present with abdominal pain, diarrhea& weight loss. Disease involving the small intestine often causes nonbloody diarrhea, whereas hematochezia is more likely when the colon is involved. Diarrhea may be due to bacterial overgrowth, bile acid malabsorption, or steatorrhea, depending on the extent of disease, the presence of complications (e.g., strictures)& whether or not intestinal resection was performed. CD may also present with bowel obstruction due to inflammation or fibrosis. Those with fistulizing disease may have pneumaturia, fecaluria, & recurrent or &vaginal drainage of feces (due to enterovaginal fistulas), or seepage of bowel contents through the skin (caused by enterocutaneous fistulas).

27. Presentation Patients with upper GI involvement may have nausea, vomiting, dyspepsia, DU or gastric outlet obstruction. Abdominal exam may demonstrate tenderness or a mass that most often occurs in the right lower quadrant. High fever suggests an abscess or peritonitis. Malnutrition may be present&growth failure is common in children. Perianal examination may reveal skin tags, inflammation, induration, or fistulas.

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

29. DDX of UC Infectious Drug induced Microscopic colitis

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

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

32. 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.

33. CD ilitis: DDx Lymphoma Yersinea Enterocolitis TB

34. 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

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

36. Extra-intestinal manifestations of IBD occur in 10% Arthritis is the most frequent & can be axial or peripheral. The most common types of axial arthritis are sacroiliitis& ankylosing spondylitis. Ophthalmologic / dermatologic manifestations are also fairly common. Episcleritis /uveitis occur in patients with either CD or UC. Erythema nodosum is more frequent CD& causes tender skin nodules, especially on the legs. Pyoderma gangrenosum occurs more often in UC& can range from small indurated lesions to large ulcers.

37. Extra-intestinal manifestations of IBD Primary sclerosing cholangitis occurs in 5% of patients with UC&to a lesser extent CD. Patients may present incidentally with jaundice, portal hypertension, or lab findings indicative of cholestasis. Patients with UC&primary sclerosing cholangitis are at an even higher risk of developing colon cancer than are those with ulcerative colitis alone. Metabolic bone disease is common , especially those with CD,can occur independent of corticosteroid use& is associated with an increased risk of fractures. Patients with prolonged IBD, malabsorption, a history of using corticosteroids for >3 months, cigarette smoking, older age, history of fractures, or a family history of osteoporosis should be evaluated for the presence of metabolic bone disease. Kidney stones / gallstones are other extraintestinal manifestations of inflammatory bowel disease.

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

44. Complications of IBD Bleeding Stricture Fistula Toxic megacolon Cancer: Patients with either UC or CD have an increased risk of intestinal dysplasia & CRC that is related to the duration, extent& severity of the inflammation,so those with extensive/longstanding disease should undergo regular colonoscopic examinations with mucosal biopsies to detect these complications.

45. Complications of IBD UC: 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. Need for colonoscopic screening after 8 years CD: True incidence of cancer is uncertain, but could be as high as UC Need the same screening policy.

46. Complications of IBD

47. Standard Diagnostic Evaluation for Suspected IBD: Colonoscopy with intubation of the terminal ileum& biopsies of the involved mucosa Stool analysis for ova / parasites & Clostridium difficile toxin plus stool culture Barium radiographs of small bowel, CT enterography&/or capsule endoscopy if Crohn's disease is suspected Plain abd radiographs if bowel obstruction, toxic megacolon, or perforation is suspected Abdominopelvic CT scan if abscess or fistula is suspected

48. Dignosis/assessing severity & extent: Lab, endoscopic,histologic findings assist in diagnosing /assessing severity. Stool examination is needed for all patients to exclude an infectious cause. The presence of significant anemia, acidosis, leukocytosis, or hypoalbuminemia indicates severe disease. Evidence of malnutrition / vitamin deficiencies occurs more commonly in CD than in UC.

49. Dignosis/assessing severity of extent: Colonoscopic fingings in UC At presentation, 40% of patients with ulcerative colitis have proctitis, 40% have left-sided colitis (up to the splenic flexure)& 20% have pancolitis. Endoscopic findings can be subtle in patients with mild disease&may show only mucosal edema / erythema. increased inflammation causes friability, ulceration& bleeding Histologic studies show distorted crypt architecture with acute / chronic inflammation & crypt abscesses.

54. Dignosis/assessing severity of extent: Colonoscopic fingings in CD 30% with CD have isolated small bowel disease, 40% have ileocolitis, 25% have colitis alone, 5% have primarily upperGI or perianal disease. Endoscopic examination may show aphthous ulcers or large ulcers that can coalesce and cause a “cobblestone” appearance. Rectal sparing is common& areas of disease activity may be separated by areas of normal mucosa (“skip areas”). Histologic findings are similar to those in ulcerative colitis. Granulomas are often absent but, when present, suggest Crohn's disease.

61. Dignosis/assessing severity of extent: Imaging Abd XRs are helpful in diagnosing bowel obstruction / dilatation in patients with CD & UC. Radiographs of small bowel are more useful for evaluating CD. Barium radiographs, enteroclysis, CT enterography, capsule endoscopy are also helpful. Although no single test is ideal, CT enterography is being used more often because this study can assess various signs of inflammation & detect extraluminal findings such as fistulas & abscesses. Capsule endoscopy is a sensitive test for identifying small bowel ulcers but should not be used in patients with obstructive symptoms because the capsule can be retained in the intestine.

62. Treatment :outline Goals of therapy Induce / maintain remission. Ameliorate symptoms Improve pts quality of life Adequate nutrition Prevent complication of both the disease & medications Divided into active &maintenance strategies. Specific treatment choices depend on the type, extent& severity of the disease

63. Treatment :Active UC Topical therapy is appropriate for distal disease. Options include cortisone foam & mesalamine or corticosteroid suppositories for proctitis & hydrocortisone or mesalamine enemas for left-sided colitis. Oral 5-aminosalicylates, including sulfasalazine, mesalamine, balsalazide& olsalazine, are appropriate for distal disease that does not respond to topical therapy or for mild to moderate pancolitis. Oral prednisone is used when symptoms do not respond to 5-aminosalicylates. Because prednisone & other corticosteroids have many acute / chronic toxic effects that are dose-/ duration-dependent, the lowest effective dose should be given for the shortest time. Azathioprine (AZA) or 6-mercaptopurine (6-MP) may be used for patients who have incomplete disease remission while on corticosteroids,but both have delayed onset of action,so concomitant use of either AZA or 6-MP together with a 3- to 4-month course of prednisone is often necessary.

64. Treatment :Active UC IV corticosteroids (equi to 40-60 mg of methylprednisolone) are indicated for treatment of severe ulcerative colitis unless the patient has fulminant disease or a complication that requires urgent surgery. IV corticosteroids should only be used for 7 - 10 days. If the patient does not respond, surgery, infliximab, or cyclosporine should be considered. Although cyclosporine is generally effective, its use is limited because of its potential toxic effects. Narcotics / anticholinergic agents should be avoided in order to reduce the risk of precipitating megacolon. Infliximab is effective for treating UC that is refractory to other therapies & favored by some because of a perception of fewer side effects with infliximab than with cyclosporine.

65. Treatment :Active UC Surgery is indicated for patients with refractory disease or corticosteroid dependence & for those with complications such as perforation, dysplasia, or malignancy. Total proctocolectomy with ileal pouch–anal anastomosis is favored for younger patients& end-ileostomy is recommended for older patients.

66. Treatment :Maintain remission in UC Patients with mild distal disease may not need maintenance therapy. Patients with more severe disease should most likely continue treatment to prevent relapse. The same medication used to achieve remission can often be given successfully for maintenanceas oral or topical 5-aminosalicylate. Because 5-aminosalicylates have dose-dependent efficacy, tapering the dose during maintenance may increase the chance of relapse. Topical & systemic corticosteroids are neither effective nor safe for use as maintenance therapy. Patients whose acute symptoms responded to oral corticosteroids may receive maintenance 5-aminosalicylates for milder disease or AZA/6-MP for more severe ulcerative colitis. AZA/6-MP may also be used for patients who did not respond to a 5-aminosalicylate alone. If a 5-aminosalicylate is used for maintenance therapy, corticosteroids should be tapered over several weeks,but disease flares during corticosteroid taper indicate the need for AZA/6-MP followed by slow tapering of corticosteroids over a 3- to 4-month period. When remission is achieved with IV corticosteroids, changing to oral prednisone & AZA/6-MP is appropriate.

67. Treatment :Active CD Treatment for Crohn's disease is similar to that for ulcerative colitis with the following exceptions: 1) smokers should be encouraged to stop; 2) 5-aminosalicylates are less effective for treating CD 3) metronidazole is an option for induction therapy. Drugs targeting the colon, as sulfasalazine, balsalazide, olsalazine, are ineffective for treating small-bowel CD. Instead, mesalamine may be used for mild disease of the small bowel (Asacol® for ileal delivery and Pentasa® for more proximal delivery Patients who do not respond to this regimen are treated as for those with moderate disease.

68. Treatment :Active CD Patients with moderate disease (presence of fever, weight loss, abdominal tenderness without rebound, nausea or vomiting without obstruction, significant anemia) require corticosteroids. Budesonide is an option for disease limited to the distal ileum and right colon because this corticosteroid is designed to deliver drug to this area of the bowel& has limited toxicity as a result of extensive metabolism in the liver. Prednisone is used for more diffuse disease. Patients who have an incomplete response or become corticosteroid-dependent should be given AZA/6-MP or methotrexate, especially if surgery is contraindicated. Patients with severe Crohn's disease (presence of high fever, persistent vomiting, obstruction, abdominal tenderness with rebound, cachexia) in whom infection has been excluded require hospitalization and the same treatment used for those with severe ulcerative colitis. Infliximab should be considered when there is no response to IV corticosteroids.

69. Treatment :Active CD Surgical resection is an option for patients with medically refractory disease, especially if large segments of small intestine are not involved. Other indications for surgery include obstruction, fistulas, abscess, hemorrhage, dysplasia, cancer.

70. Treatment :Maintain remission in CD Mesalamine & AZA/6-MP are used for maintenance after medically induced remissions. 5-aminosalicylates, which are used for maintenance treatment of UC, are less effective for maintaining remissions in patients with Crohn's disease. Patients with more severe disease may benefit from infliximab. Mesalamine /AZA/6-MP may be effective for maintaining postoperative remissions, but the benefit is either minimal.

71. Treatment :Perineal CD Small, minimally symptomatic fistulas may not require treatment. More troublesome fistulas are treated with antibiotics, most commonly metronidazole / ciprofloxacin, with drainage of any abscesses. Recurrence is common when antibiotics are stopped, and prolonged therapy may be needed. Although AZA and 6-MP are effective for healing fistulas, these agents have mostly been replaced by infliximab. Drains may be needed while fistulas are being treated medically. Surgical diversion or proctectomy is indicated for refractory perianal Crohn's diseas

72. Infliximab - mucosal healing Baseline Week 10 Week 54 Rutgeerts et al. DDW 2002: [abstract] W1367.

74. Microscopic colitis Characterized by chronic diarrhea, often with abdominal pain & mild weight loss. Elderly persons (70 years of age / older) are affected most often. A possible association with certain medications, including nonsteroidal anti-inflammatory drugs, has been suggested. Colonoscopy with biopsies is required for diagnosis. The colonic mucosa appears normal on gross examination; histologic studies show surface epithelial lymphocytosis and a mixed inflammatory infiltrate. Microscopic colitis is further classified into subtypes based on whether a thickened subepithelial collagen band is present (collagenous colitis) or absent (lymphocytic colitis). Unlike the histologic findings in UC/CD, crypt architectural distortion is not present in microscopic colitis. Collagenous colitis is more common in women, whereas lymphocytic colitis affects men & women almost equally. Coexisting celiac sprue should be considered in patients with microscopic colitis that is refractory to therapy.

75. Microscopic colitis: treatment Lopeamide, diphenoxylate, bismuth subsalicylate, either alone or in combination, are effective,well-tolerated as initial therapy. If this initial regimen is ineffective, cholestyramine or a 5-aminosalicylate should be tried, although the latter drug is useful in only a minority of patients. Patients who do not benefit from a 5-aminosalicylate may respond to corticosteroids. Corticosteroids should only be used to induce remission,& one of the drugs used for initial therapy should also be used for maintenance. Budesonide is effective for most patients with collagenous colitis. If this drug is not beneficial, the diagnosis should be reconsidered. If no other cause for symptoms is found, AZA/6-MP or surgery (diverting ileostomy or proctocolectomy) is an option.

76. 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

77. 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.

79. 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.

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

82. Anti-TNF Therapy: Infliximab It is a chimeric monoclonal antibody, binds soluble TNF. Prompt onset, effects takes 6weeks to max of 6m. Indicated in fisulizing crohns, refractory CD and refractory UC Complications (it is safe and usu 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.

83. Infliximab: side effects Increase risk of upper respiratory infections. Reactivation/dissemination of TB causing death. Any patient suspected of having a pyogenic complication of CD or any serious infection should undergo adequate drainage & treatment with antibiotics before starting infliximab.