1. Inflammatory Bowel Disease

2. Overview – Ulcerative colitis and Crohn’s disease are two main forms of IBD, can be differentiated on basis of genetic predisposition, risk factors, and clinical, endoscopic and histologic features – Exact etiology of IBD is unknown, though thought to be related to dysregulated mucosal immune response to commensal gut flora in genetically susceptible individuals

3. Pathophysiology Exact mechanism for IBD not well understood, though to be related to combination of factors in gut, including: – Damage to epithelial mucin proteins and tight junctions, – Breakdown of homeostatic balance between host’s mucosal immunity and enteric microflora – Genetic polymorphisms in toll-like receptors (TLRs) – Disrupted homeostatic balance between regulatory and effector T-cells

4. Ulcerative colitis Epidemiology Higher incidence than CD – More commonly seen in North America and Europe Bimodal incidence pattern – Onset 15-30 years or 50-70s year olds Genetic factors: Family history very important – Ashkenazi Jews have 3-5x higher risk Environmental factors – Smoking associated with paradoxically lower risk, milder disease – Hx of prior GI infections, e.g. Shigella, Salmonella, Campylobacter, during adulthood double risk of developing UC, thought to be 2/2 changes in gut flora triggering chronic inflammatory process – Weak associations between NSAIDs, OCPs and increased risk of UC – No data supports psychological stress as trigger for onset or relapse

5. Ulcerative Colitis Clinical Presentation Common presenting symptoms include rectal bleeding, diarrhea, urgency, tenesmus, abdominal pain – More rarely can see fistulas, weight loss, more common in CD – In severe or advanced cases, patients may present with fever Clinical course characterized by alternating periods of remission and relapse Montreal classification used to categorize extent and severity of disease – E1 (proctitis): inflammation limited to the rectum – E2 (left-sided; distal): inflammation limited to the splenic flexure – E3 (pancolitis): inflammation extends to the proximal splenic flexure – S0 (remission): no symptoms – S1 (mild): four or less stools per day (with or without blood), absence of systemic symptoms, normal inflammatory markers – S2 (moderate): four stools per day, minimum signs of systemic symptoms – S3 (severe): six or more bloods per day, pulse rate of ≥90 beats per min, temperature ≥37·5°C, ESR >30 Extraintestinal manifestations are more commonly seen in UC than CD – include aphthous oral ulcers, iritis/uveitis/episcleritis, seronegative arthritis, ankylosing spondylitis, sacroiliitis, erythema nodosum, pyoderma gangreosum, autoimmune hemolytic anemias and primary sclerosing cholangitis

6. Ulcerative Colitis Diagnosis Based on clinical symptoms confirmed by objective findings from endoscopic and histologic examinations Initial w/u must r/o infectious and non-infectious causes of diarrhea Endoscopic features – loss of vascular pattern, erythema, granular and friable mucosa, erosions, ulcerations and spontaneous bleedings Pathologic features – distortion of crypt architecture, crypt abscess, infiltration of lamina propria w/ plasma cells, eosinophils, lymphocytes, lymphoid aggregates and mucin depletion

7. Ulcerative Colitis Treatment Treatment should be tailored to disease activity and extent of disease activity – 5-ASA drugs: E.g. mesalazine, sulfasalazine – Corticosteroids – Immunosuppresants: E.g. azathioprine, 5- mercaptopurine – Biologics: E.g. infliximab, adalimumab

8. Ulcerative Colitis Treatment Surgical treatment required in approximately 20- 30% of patients. Surgery is generally curative in UC. – Emergency: Life-threatening complications related to fulminant disease unresponsive to medical treatment – Urgent: Severe disease admitted to hospital and not responding to intensive medical treatment – Elective: Refractory disease intolerant to long-term maintenance treatments or colorectal cancer.

9. Ulcerative Colitis Prevention/Screening UC patients at increased risk of colorectal cancer – 2% after 10 years, 8% after 20 years and 18% after 30 years Screening colonoscopy beginning at 8 years after disease onset Following initial colonoscopy, subsequent screening depends on extent of disease – Proctitis/proctosigmoditis: Follow specific age guidelines for surveillance of colorectal cancer – Left-sided colitis/pancolitis: Every 1-2 years – UC w/ PSC: Annually from time of dx of PSC Risk factors for CRC – Duration and extent of disease – Endoscopic and histologic severity of inflammation

10. Crohn’s Disease Epidemiology Genetic factors – Family hx well established as one of the strongest risk factors for development for CD Environmental factors – Lifestyle factors such as tobacco use, sedentary lifestyle, exposure to air pollution, and consumption of western diet Infectious factors – CD often occurs after infectious gastroenteritis

11. Crohn’s Disease Clinical Presentation Unlike in UC, Crohn’s disease can affect any portion of the GI tract Common presenting symptoms – abdominal pain, bloody or watery diarrhea, incontinence, fistulas and perianal symptoms. Extracolonic GI involvement associated with aphthous ulcers, dysphagia, upper abdominal pain and vomiting. Patients with CD may have hx of other autoimmune disorders, Montreal classification used to categorize CD – L-classification: Defines extent of disease L1: Disease confined to terminal ileum L2: Disease confined to clon L3: Disease involving ileum and colon L4: Disease involving upper GI tract L4+L3: Disease involving upper GI tract and distal disease – B-classification: Defines phenotype B1: Without stricture formation, non-penetrating B2: Stricturing B3: Penetrating B3p: Perinally penetrating

12. Crohn’s Disease Diagnosis Clinical diagnosis based on H&P findings with objective findings from history and laboratory studies As with UC, must r/o important non-infectious causes (IBS, Behcet’s syndrome) and infectious causes (Yersinia, enteroviruses etc.) that mimic CD Endoscopy is gold standard for diagnosis Radiologic tests may assist in diagnosis – CT/MRI enterography or enteroclysis – Abdominal U/S Biomarkers can also be used – CRP, lactoferrin and calprotectin

13. Crohn’s Disease Treatment All patients with CD should be counseled to quit smoking As with UC, initial medical treatment depends on phenotype, disease activity, comorbidities and other individual characteristics of patient – In most cases, short course of antibotics, steroids, or anti-TNF agent, e.g. infliximab, adalimumab, combined with thiopurines or methotrexate for long-term maintenance – 5-ASA derivatives, which are mainstay of UC, have shown to be less useful in treatment of CD Superiority of combination of thiopurines and TNF blockers No current consensus on optimal length of therapy Unlike in UC, surgery is not curative in CD

14. Crohn’s Disease Prevention/Screening Regular screen for active infection – tuberculosis, infections hepatitis, CMV, HIV and C. difficile Colorectal cancer screening – In patients with more than a third of colon affected (Montreal classification L3), first screening colonoscopy should occur 8 years after onset, repeated every 1-2 years once remission achieved, and every 1-3 years once normal. – Patients with PSC should undergo annual screenings

15. References Ordás I1, Eckmann L, Talamini M, et al. Ulcerative colitis Lancet. 2012 Nov 3;380(9853):1606-19. Baumgart DC1, Sandborn WJ. Crohn's disease. Lancet. 2012 Nov 3;380(9853):1590-605.