Inflammatory Bowel Disease A Aljebreen, MD, FRCPC Oct 2010

Objectives At the end of this lecture you should know The definition of ulcerative colitis (UC) and Crohn's disease (CD) The clinical, pathological, radiological and endoscopic features of each disease How diagnose a patient with UC or CD and how to differentiate between them How do you manage those patient and what are the main medications used for each disease

Inflammatory Bowel Disease: IBD 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.

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

CD and UC CD is a condition of 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 UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon.

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

IBD in Saudi Arabia Male to Female ratio is 1: 1.48 (169 VS 114) 89 % from Urban areas The average age at diagnosis is 25.8 years Prevalence of CD is 22 per 100,000 An annual incidence of 4.8 per 100,000

A1=16 or younger A2= 17-40 A3= over 40 years

Genetics Studies suggested that 1st 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.

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? Infectious? ? Possibly non-pathogenic commensal enteric flora

CD: PATHOLOGY Early Findings: Late 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.

Transmural inflammation with predominance of the inflammation in the mucosa and submucosa.

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.

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

Distinguishing characteristics of CD and UC 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 50-75% Granulomas

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

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

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

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…

DDX of UC Infectious Drug induced Microscopic colitis

UC: Presentation Mild attack: Moderate 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

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

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, fever 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.

CD ilitis: DDx Lymphoma Yersinea Enterocolitis and TB

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

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.

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.

Complications of IBD Bleeding Toxic mega-colon Cancer Stricture Fistula Multiple abdominal abscess

How to diagnose IBD History Physical examinations Labs (CBC, ESR, CRP, U & E, LFT, serology) Radiology (CT abdomen, SBFT, MRI enterocolysis and MRI pelvis) Endoscopy Histopathology

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?

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?

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

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

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.

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.

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

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. Dose-related BM suppression is uniformly observed

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

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

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.

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.

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

IBD Sequelae 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.

IBD conclusion It is a chronic disorders Need to exclude other possibilities 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.