Conflict of Interest. Inflammatory Bowel Disease. Road Map. Scope of the Disorder (United States) Age-Specific Incidence of IBD*

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1 Inflammatory Bowel Disease Conflict of Interest No conflicts of interest Sonia Friedman, M.D. Assistant Professor of Medicine Gastroenterology Division Brigham and Women s Hospital Road Map Background Differential diagnosis Presentation Medical Treatment Surgical Treatment Extraintestinal Manifestations Cancer Risk Overview of Inflammatory Bowel Disease (IBD) ULCERATIVE 1 COLITIS IBD >1 million persons in US INDETERMINATE COLITIS 2 1%-2% of IBD patients Proctitis 28% Pancolitis 47% % at time of diagnosis Left-sided disease 25% Ileitis 22% CROHN S DISEASE 3 Ileocolitis 45% Colitis 32% 1. Loftus EV, et al. Gut. 2;46: ; 2. Marion JF, et al. In: Kirsner JB, ed. Inflammatory Bowel Disease. 5th ed. Philadelphia, Pa: WB Saunders Co; 2: ; 3. Loftus EV, et al. Gastroenterology. 1998;14: Age-Specific Incidence of IBD* Incidence / 1, Ulcerative Colitis Crohn s s Disease Age (yrs) Age (yrs) *Per 1, population Reprinted with permission from Lashner BA. In: Stein SH and Rood RP, eds. Inflammatory Bowel Disease A Guide for Patients and Their Families. Philadelphia, Pa: Lippincott-Raven Publishers; 1999: Scope of the Disorder (United States) 7, physician visits per year 1, hospitalizations per year Crohn s disease accounts for twothirds

2 UC: Presenting Symptoms Bloody diarrhea Abdominal cramping Tenesmus Weight loss Fevers Symptoms depend upon extent and severity of inflammation UC: Differential Diagnosis Infectious Ischemic Malignant Diversion Radiation Solitary rectal ulcer syndrome Irritable bowel syndrome Crohn s disease Endoscopic Spectrum of Severity UC Spectrum of Disease CD: Presentation Normal Moderate Mild Severe Diarrhea Chronic abdominal pain and tenderness Weight loss Fever Perianal disease Symptoms vary with location of disease Reprinted with permission from AGA Clinical Teaching Project. IBD. 3rd ed. 22. CD: Clinical Features Inflammation Obstruction Fistulization CD: Differential Diagnosis Abdominal pain Tenderness Diarrhea Weight loss Cramps Distention Vomiting Diarrhea Pain Air/feces in urine Types Enteroenteric Enterovesical Retroperitoneal Enterocutaneous Lymphoma Yersinia TB or MAI CMV Herpes Ischemia UC Adapted with permission from AGA Gastroenterology Teaching Project. 3rd ed. 22.

3 Risk for Developing CD 6 Empiric Risk for Developing Crohn's Disease (%) Offspr Both Parents Sib Ashk Jew Offspr Ashk Jew 4.6 <4. Sib Non-Jew <.2.1 Heterozygote NOD2 MZ Twin Parent DZ Twin Homozygote NOD2 General Population

4 Epidemiologic Risk Factors UC CD Appendectomy Negative Positive Smoking Negative Positive OCP?? Breast feeding?? High level of sanitation in childhood? Positive Chemical Structure of 5- Aminosalicylate (Mesalamine) and Its Prodrugs: Sulfasalazine, Balsalazide, and Olsalazine 5-aminosalicylic acid Balsalazide Sulfasalazine Olsalazine Rectal Preparations Rowasa (mesalamine) Canasa (mesalamine) Approved 5-ASA Formulations Azobonded Pro-drug Azulfidine (sulfasalazine) Dipentum (olsalazine) Colazal (balsalazide capsules) Moisture Dependent Pentasa (mesalamine) Delayed Release Asacol (mesalamine) Lialda (mesalamine) Delayed + Extended Release APRISO (mesalamine) Meta-Analyses of Rectal 5- ASA in UC Rectal 5-ASA vs Rectal Corticosteroids Improvement: Symptomatic Endoscopic Histologic Remission: Symptomatic Endoscopic Histologic Pooled Odds Ratio Corticosteroids better 5-ASA better Adapted from Marshall JK, Irvine EJ. Gut. 1997;4: with permission from the BMJ Publishing Group. Rectal Corticosteroid Therapy Hydrocortisone Retention Enemas 5% symptomatic response in distal colitis Hydrocortisone Foam Enemas Reaches sigmoid colon Less volume than enema preparation Hydrocortisone Suppositories Useful in proctitis Metronidazole in IBD Proven efficacy in perianal CD May be helpful in enteric CD No proven benefit in acute UC Potential neuropathy (parasthesias of distal extremities) Ciprofloxacin also effective Rifaximin may be effective

5 Oral/IV Corticosteroids Role Induction of Remission in UC and CD Toxicity Metabolic Musculoskeletal Osteoporosis Avascular necrosis Arthralgias Neuropsychiatric Ocular Immunologic Growth Failure Remission Rates at 8 Weeks (%) Remission Rate in Acute Crohn s Studies With Budesonide CIR Bud CIR 9 mg QD Average across 3 studies BID Pentasa 2 g BID Prednisolone 4 mg Rutgeerts P, et al. N Engl J Med. 1994;331: ; Thomsen OØ, et al. N Engl J Med. 1998;339:37-374; Greenberg GR, et al. N Engl J Med. 1994;331: Cumulative Probability of Remission Oral Budesonide: Efficacy as Maintenance Therapy Days Budesonide 6 mg Budesonide 3 mg 3 Pharmacology of Thiopurines Azathioprine 6-MP mg/kg 1mg 2 : mg/kg 5mg Adapted from Greenberg GR, et al. Gastroenterology. 1996;11:45 with permission from American Gastroenterological Association. Cuffari C, et al. Aliment Pharmacol Ther. 2;14: Thiopurines are not indicated for IBD. Effectiveness of Thiopurines 6-MP Response Rates in Crohn s Disease % Patients * 67 26/ /44 1 6/39 3/39 Clinical Steroid Discontinuation *P<.1. Improvement or Reduction With clinical improvement maintained. 6-MP 6-MP: Toxicity Bone marrow suppression Pancreatitis Allergic reaction Liver toxicity Can now monitor metabolite levels to determine correct dosage Present DH, et al. N Eng J Med. 198;32: Copyright 198 Massachusetts Medical Society. All rights reserved. Thiopurines are not indicated for IBD.

6 Remission (%) Induction and Maintenance of Remission with Methotrexate Induction 1 Maintenance 2 Methotrexate 25 mg IM Weekly 19.1 * 39.4 Treatment Group Remission (%) % of 45% Responders = 3% Overall P=.4 Methotrexate Weeks Since Randomization N=4 65% N=36 39% Intravenous Cyclosporine in Severe, Refractory UC Steroid-resistant patients 4mg/kg/day 82% response rate Mean time to response: 7 days IM = intramuscular. *P=.25 vs placebo. 1. Feagan et al. N Engl J Med. 1995;332: Feagan et al. N Engl J Med. 2;342: Cyclosporine in IBD: Toxicity Renal insufficiency Seizures with low serum cholesterol Hair growth Hypertension Bone marrow suppression Liver toxicity Infliximab in Moderate to Severe UC: The ACT 1 and 2 Trials 5 Patients in Clinical Remission and Discontinuing Corticosteroids ACT 1 ACT Week 3 Week 54 Week 3 Infliximab 5 mg/kg Infliximab 1 mg/kg Rutgeerts P et al. N Engl J Med. 25;353:2462. Infliximab Maintenance of Remission in Crohn s s Disease: ACCENT I Clinical Remission at Week 3* 21 * Week 2 responders (primary end point). **P=.3 vs placebo; P=.2 vs placebo. Hanauer et al. Lancet. 22;359: ** 39 Infliximab 5 mg/kg Every 8 Week 45 Infliximab 1 mg/kg Every 8 Week

7 Fistula Response at Week 54 with Infliximab: ACCENT II* Infliximab 5 mg/kg 5 ** Fistula Response Complete Response *Randomized responders (secondary end point). **P=.1 vs placebo; P=.9 vs placebo. Sands et al. N Engl J Med. 24;35: Main Extension SONIC Study Design Randomization of Patients Azathioprine 2.5 mg/kg Infliximab 5 mg/kg Infliximab 5 mg/kg + placebo infusions + placebo capsules + Azathioprine 2.5 mg/kg Visits Week * Week 2 Week 6 Week 1 Week 14 Week 18 Week 22 Week 26* Primary Endpoint (Corticosteroid-free Remission at Week 26) Week 3 Week 34 Week 38 Week 42 Week 46 Week 5 Secondary Endpoint (Week 5) Week 54 Infusions * Endoscopy performed at Weeks & 26 Colombel JF, et al. N Engl J Med. 21;362(15): Proportion of SONIC Clinical Remission Without Corticosteroids: Week Colombel JF, et al. N Engl J Med. 21;362(15): p=.9 p<.1 45 p= /17 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA 4 Anti-TNF Engineered Antibodies Anchoring ACCENT I, CHARM, and PRECiSE 2 Results Chimeric monoclonal antibody Human recombinant antibody Humanized Fab' fragment VL VH Week 2 Response ACCENT I* (infliximab) 39. Week 3 Remission 22.8 Overall Remission Week 3 Mouse Human IgG1 IgG1 No Fc PEG PEG Infliximab Adalimumab Certolizumab pegol CH Week 4 Response CHARM** (adalimumab) 4 Week 26 Remission 24 Overall Remission Week Week 6 Response PRECiSE 2 (certolizumab) 47.9 Week 26 Remission 3.7 Overall Remission Week 26 PEG = polyethylene glycol *5 mg/kg dose. **Maintenance trial with 8/4 mg induction dosing. Randomized responders = CR-7 at week 4. Week 26 remission among randomized responders on 4 mg every other week dosing.

8 Disease Complications Can Early Highly Effective Therapy Alter CD Course? Natural Course Induce and maintain gastrointestinal healing Prevent strictures and penetrating complications Prevent extraintestinal complications Decrease hospitalization and/or surgery Decrease long-term cost of care Crohn s Disease Do We Treat Everyone with Early Combined TNF Antagonist Therapy? No! Years High Risk Patients Should be Considered for Early Treatment with a TNF Antagonist Complex fistula Deep ulceration on endoscopy Young age (< 4) Steroid-dependence/resistance High risk anatomy (foregut disease, extensive disease, perianal disease) Severe disease activity (weight loss, low albumin and/or hemoglobin) 45 General TNF Class-Effect Adverse Events* Infection Tuberculosis Opportunistic infections Serious infections Immunogenicity Infusion reactions Injection site reactions Altered pharmacokinetics +/- loss of response Autoimmunity Demyelinating disease Congestive heart failure (very rare) Hepatotoxicity (very rare) Malignancy Lymphoma Death *See workbook for supplemental information. Sustained Clinical Remission with Natalizumab: ENACT-2* P=.3 44 P< Primary End Point Natalizumab Start ENACT-2 Weeks * ENACT-1 responders (secondary end point). Sandborn et al. N Engl J Med. 25;353: UC Indications for Surgery Exsanguinating hemorrhage Toxicity and/or perforation Dysplasia/ Cancer Growth retardation Systemic complications Intractable disease

9 Crohn s Disease: Indications for Surgery Failure to respond to medical therapy Management of complications Dysplasia/ Cancer Strictures Perforation Fistulae Perianal disease EIMs of IBD: Epidemiology and Etiology 1+ EIM occurs in >6% of patients Clinical activity may follow bowel activity More common with colonic involvement More common in women than in men Herald relapse Wagtmans MJ, et al. Am J Gastroenterol. 21;96: Liver and bile duct inflammation Skin lesions Eye inflammation* Lower bone density* Gallstones *Higher incidence in women. IBD: Systemic Complications Growth failure in children Kidney stones Subfertility* Ovaries Uterus Arthritis and joint pains

10 Musculoskeletal Disorders in IBD Peripheral arthritis Sacroiliitis Reprinted with permission from Berens DL. Roentgen Features of Ankylosing Spondylitis. Clin Ortho. 1971;74:2-33. Ankylosing spondylitis Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, Used by permission of the American College of Rheumatology. Bone Disease in Inflammatory Bowel Disease Prevalence of osteoporosis (T < -2.5) using DXA: 5-4% Prevalence of osteopenia (T 1. to -2.49): 16-77% Corticosteroid use is strongly associated with osteoporosis AGA medical position statement. Gastroenterology 23 AGA Recommendations for Managing Osteoporosis IBD patient: Any of: -Prolonged steroid use (>3mo consec or recurrent courses) -Low trauma, fragility fracture -Postmenopausal or male age >5 -Hypogonadism Gastroenterology 23;124: T score >-1 DXA T score -2.5 to -1 T score <-2.5 Vert Fracture Regardless of DXA Basic Prevention: -Ca/Vit D -exercise -smoking cessation -avoid alcohol -minimize corticosteroids -treat hypogonadism Prevention and: -repeat DXA 2 years -Prolonged CS consider BP and DXA 1 year Prevention and: -Screen other causes low BMD -Bisphosphonate therapy or -Refer to bone specialist Relative Risk of Colon Cancer Based on Extent of UC Relative Risk of Colon Cancer All Cases Proctitis Left-Sided Pan-colitis Ekbom A, et al. N Engl J Med. 199;323:

11 Risk of Colon Cancer in Crohn s Colitis The same as UC given equal extent and duration of disease ASGE and AGA recommend screening and surveillance colonoscopy as in UC Risk Factors for Colon Cancer in IBD Strictures that cannot be passed Extensive colitis Long duration of disease Young age at diagnosis Primary sclerosing cholangitis Family history of colon CA Take Home Messages IBD is a chronic disease IBD requires life-long medical therapy Most IBD medications have side effects Most IBD patients have a normal life expectancy Complications of IBD include extraintestinal manifestations and an increased risk of colon cancer. Who should have a DEXA scan to assess bone density? A. Men 5 and above with IBD B. Women under 5 with Crohn s disease who have never been on steroids C. IBD patients who have been on steroids > 3 months D. IBD patients who had have a fragility fracture E. A, C, and D Who should have a DEXA scan to assess bone density? A. Men 5 and above with IBD B. Women under 5 with Crohn s disease who have never been on steroids C. IBD patients who have been on steroids > 3 months D. IBD patients who had have a fragility fracture E. A, C, and D In which Crohn s patient should combination anti- TNF/immunomodulator therapy be considered? 45 year woman with mild ileitis 16 year old teen with Crohn s colitis responding to 6-MP 38 year old woman with complex perianal fistulizing disease 24 year old man with ileocolitis responding well to entocort

12 In which Crohn s patient should combination anti- TNF/immunomodulator therapy be considered? 45 year woman with mild ileitis 16 year old boy with Crohn s colitis responding to 6-MP 38 year old woman with complex perianal fistulizing disease 24 year old man with ileocolitis responding well to entocort 1. Farraye FA, Odze RD, Eaden J, Itzkowitz SH; AGA institute Medical Position Panel on Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease, McCabe RP, Dassopoulos T, Lewis JD, Ullman TA, James T 3rd, McLeod R, Burgart LJ, Allen J, Brill JV. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 21 Feb;138(2): Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-1 receptor. N Engl J Med. 29 Nov 19;361(21): Kaser A, Zeeissig S, Blumberg RS. Inflammatory Bowel Disease. Annu Rev Immunol 21;28: Kornbluth A, Sachar DB. Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 21 Jan Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn's disease in adults.am J Gastroenterol. 29 Feb;14(2):465-83; quiz 464, 484. Epub 29 Jan 6.