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  • Each patient’s Crohn’s disease manifests itself differently. The symptoms are less similar than is seen with UC. A patient might have a great deal of abdominal pain, but no diarrhea; a child might not have any pain or diarrhea, just fatigue and poor growth. A patient could experience a great amount of diarrhea and nausea. The problem with which a patient suffers depends on: The location of the inflammation The length of intestine involved The severity of disease History of surgery Presence of strictures Other symptoms Most commonly, patients with Crohn’s have diarrhea, which can vary from a few loose stools to more than 20 stools per day. However, about 10 % of patients with Crohn’s do not experience any diarrhea.
  • The appearance of Crohn’s, when seen through a scope, can have several features which are characteristic of Crohn’s. However, it may also look like UC, so much so that it can be impossible in some cases to distinguish the two diseases endoscopically. The classic appearance of Crohn’s includes definite ulcerations with normal, healthy-appearing intestinal lining in the surrounding tissue. Typically there are long, linear ulcerations (sometimes called bear claw ulcerations because it looks as if a bear was scrounging around in the intestines scraping deeply as he moves along his way). “Cobble-stoning” is a characteristic finding, with deep ulcerations criss-crossing, leaving nubs of normal tissue (the cobblestones). Crohn's can also cause the development of a tight stricture, a narrowed, fibrotic area, which might not allow the scope to pass through. These strictures develop over a long period of time, usually years, and result from chronic inflammation and the body’s attempt to heal. Slow gradual scarring can continue to tighten over years. Also, as mentioned, Crohn’s can have a diseased area followed by an abrupt change to normal and then a diseased segment. Detecting a small fistula by colonoscopy can be difficult, though larger fistula can be occasionally seen. They appear through the scope as a nub of inflamed tissue and a central opening.
  • As in UC, Crohn’s can develop a variety of complications in the intestines including perforation, stricture or bleeding. Cancer has been emphasized as a potential complication of UC, but patients with Crohn’s colitis can have an equal risk of developing colon cancer and should undergo similar screening. Two problems, more specific to Crohn’s disease, are the development of a fistula or an abdominal abscess. As many as one-third of patients with Crohn’s will eventually develop an abscess at some point during their life. An abscess is an infection within a closed place that, not having any point to drain, develops into a collection of pus and debris from the infection. This abscess can cause abdominal pain (often severe) and fever. The abscess in Crohn’s develops, presumably, from a deep ulceration or fissure burrowing through the wall of the intestine which causes a small perforation or opening into the abdominal cavity. This focal opening into the abdominal cavity sets up a localized infection that, in turn, develops into an abscess. Usually an abscess, unless very small, requires antibiotics, drainage and, most often, surgery to remove the perforated part. Another complication is the development of a fistula, a process and problem particular (though not unique) to Crohn’s disease.
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  • Revised 10-30-2000 mwa
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    1. 1. Stephen B. Hanauer, MD Professor of Medicine & Clinical Pharmacology Chief, Gastroenterology University of Chicago
    2. 2. Credentials <ul><li>Clinician with 6000+ patient database </li></ul><ul><li>Crohn’s & Colitis Foundation of America </li></ul><ul><ul><li>Scientific Cabinet, Chair Clinical Research Alliance, Research Initiatives </li></ul></ul><ul><li>American Gastroenterological Association </li></ul><ul><ul><li>Ex-Chair Immunology, Inflammation, IBD Section </li></ul></ul><ul><ul><li>Ex-Chair Clinical Practice Section </li></ul></ul><ul><ul><li>Chair, Consensus Conference on Biologics ( Gastroenterology July 2007) </li></ul></ul><ul><li>American College of Gastroenterology </li></ul><ul><ul><li>Governing Board </li></ul></ul><ul><li>International Organization for Inflammatory Bowel Disease </li></ul><ul><ul><li>Chairman </li></ul></ul><ul><li>FDA GI Advisory Board </li></ul><ul><ul><li>Ex-Chair &Member </li></ul></ul>
    3. 3. Conflicts of Interest <ul><li>Elan/Biogen </li></ul><ul><ul><li>Consultant & Clinical Research </li></ul></ul><ul><li>Millenium </li></ul><ul><ul><li>Consultant </li></ul></ul><ul><li>Centocor </li></ul><ul><ul><li>Consultant, Clinical Research, Lectures </li></ul></ul><ul><li>Abbott </li></ul><ul><ul><li>Consultant, Clinical Research, Lectures </li></ul></ul><ul><li>UCB </li></ul><ul><ul><li>Consultant, Clinical Research </li></ul></ul><ul><li>Genentech </li></ul><ul><ul><li>Consultant, Clinical Research </li></ul></ul><ul><li>BMS </li></ul><ul><ul><li>Consultant, Clinical Research </li></ul></ul><ul><li>PDL </li></ul><ul><ul><li>Consultant, Clinical Research </li></ul></ul><ul><li>GSK </li></ul><ul><ul><li>Consultant, Clinical Research </li></ul></ul><ul><li>Novartis </li></ul><ul><ul><li>Consultant </li></ul></ul><ul><li>P&G, Shire, Prometheus Labs, Salix, TAP, Astra Zeneca </li></ul><ul><ul><li>Consultant, Clinical Resarch, Lectures </li></ul></ul>
    4. 4. Presentation Summary <ul><li>Crohn’s Disease </li></ul><ul><li>Crohn’s Patients </li></ul><ul><li>Therapeutic Need </li></ul><ul><li>Therapeutic Risks </li></ul><ul><li>Likely Prescribers </li></ul>
    5. 5. The Spectrum of IBD 1-2 Million Americans Indeterminate colitis 10-15% <ul><li>CROHN’S DISEASE </li></ul><ul><ul><li>Patchy inflammation </li></ul></ul><ul><ul><li>Mouth to anus involvement </li></ul></ul><ul><ul><li>Full-thickness inflammation </li></ul></ul><ul><ul><li>Variable involvement </li></ul></ul><ul><ul><li>Fistulas </li></ul></ul><ul><ul><li>Strictures </li></ul></ul><ul><ul><li>Extraintestinal manifestations </li></ul></ul><ul><li>ULCERATIVE COLITIS </li></ul><ul><ul><li>Continuous inflammation </li></ul></ul><ul><ul><li>Colon only </li></ul></ul><ul><ul><li>Superficial inflammation </li></ul></ul><ul><ul><li>Variable involvement </li></ul></ul><ul><ul><li>Risk of cancer </li></ul></ul><ul><ul><li>Strictures (cancer) </li></ul></ul><ul><ul><li>Extraintestinal manifestations </li></ul></ul>
    6. 6. Common Symptoms of Crohn’s Disease <ul><li>Diarrhea </li></ul><ul><li>Abdominal pain and tenderness </li></ul><ul><li>Loss of appetite and weight </li></ul><ul><li>Fever </li></ul><ul><li>Fatigue </li></ul><ul><li>Rectal bleeding and anal ulcers </li></ul><ul><li>Stunted growth in children </li></ul>
    7. 7. Crohn’s Disease: Colonoscopic Appearance Cobblestone Discrete Ulcer Stricture (Narrowing)
    8. 8. Crohn’s Disease: Intestinal Complications Perforation Stricture Cancer Fistula Abscess
    9. 9. + IBD Subtype: UC 1 2 3 4 1 2 3 4 CD/UC Traditional Clinical Parameters: “ Crohn’s Diseases” & “Ulcerative Colitides”: CD 1 2 3 Individualized “Reagent Grade” Intervention Genetic Markers Serum Immune Markers Cytokine Profile Enzyme Activity Metabolite Levels Genetic, Serologic, and Biochemical Profiles:
    10. 10. CD Activity Course Years Clinical Activity 3 8 Diagnosis Active Inactive 25% 53% 22% Munkholm et al. Scand J Gastroenterol . 1995;30:699-706.
    11. 11. Long-term Evolution of Disease Behavior in CD Cosnes J et al. Inflamm Bowel Dis . 2002;8:244. 240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0 0 10 20 30 40 50 60 70 80 90 100 Cumulative Probability (%) Patients at risk: Months 2002 552 229 95 37 N = Penetrating Stricturing Inflammatory Progression Toward Surgery
    12. 12. Cumulative Probability of Surgical Intervention in CD Munkholm P et al. Gastroenterology . 1993;105:1716. Years Probability (%) Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1 0 20 40 60 80 100 0 2 5 8 11 14 17 20 Dx ± 2 SD
    13. 13. Postsurgical Recurrence of CD McLeod RS, et al. Gastroenterology . 1997;113:1823. N=76. 20 40 80 100 0 60 Years 0 1 2 3 4 5 6 Radiologic/endoscopic recurrence Symptomatic recurrence Patients With Recurrence (%)
    14. 14. Crohn’s Patients
    15. 15. The Crohn’s Disease Activity Index moderate CD TOTAL =307 CDAI =20 Perianal Fistula =147 Well being-avg 3/d=21x7 =70 Abdominal pain-2x7=14=5 =70 Liquid stools- 5x7 days=35x2 10 Liquid stools Moderate Pain Abdominal Mass Arthralgias, Weight loss, Anemia= 450 CDAI
    16. 16. Definitions of CD Activity <ul><li>Moderate-Severe </li></ul><ul><li>Non-responders to treatment for mild-moderate disease </li></ul><ul><li>Fever, significant weight loss </li></ul><ul><li>Abdominal pain/tenderness </li></ul><ul><li>Intermittent nausea/vomiting without obstruction </li></ul><ul><li>Anemia </li></ul><ul><li>Severe-Fulminant </li></ul><ul><li>Persistent symptoms despite outpatient oral corticosteroids </li></ul><ul><li>High fever, persistent vomiting </li></ul><ul><li>Obstruction, rebound tenderness </li></ul><ul><li>Muscle mass wasting </li></ul><ul><li>Abscess </li></ul><ul><li>Toxic megacolon </li></ul><ul><ul><li>Fever, distention, frequent bloody bowel movement </li></ul></ul>Hanauer et al. Am J Gastroenterol . 2001;96:635-643.
    17. 17. SF-36 Scale Scores for Medical Conditions (Standardized Scales) Ware JE, JR., Kosinski M. SF-36(r) PHYSICAL AND MENTAL HEALTH SUMMARY SCALES: A MANUAL FOR USERS OF VERSION 1. 2ND ed, Lincoln, RI: QualityMetric Incorporated, 2001. * Baseline ENCORE data +Baseline AFFIRM data * +
    18. 18. Ware JE, JR., Kosinski M. SF-36(r) PHYSICAL AND MENTAL HEALTH SUMMARY SCALES: A MANUAL FOR USERS OF VERSION 1. 2ND ed, Lincoln, RI: QualityMetric Incorporated, 2001. General Population SF-36 Scale Scores for Medical Conditions (Standardized Scales)
    19. 19. Current “Therapeutic Pyramid” Severe Moderate Mild Crohn’s Disease Budesonide Antibiotics 5-ASA MTX AZA/6-MP Systemic Steroids Surgery Anti-TNF
    20. 20. Clinical Remission Rates in CD Patients with Conventional Therapies <ul><li>Aminosalicylates </li></ul><ul><ul><li>Mild-Moderate Disease ~45-55% </li></ul></ul><ul><li>Antibiotics </li></ul><ul><ul><li>Few controlled trials </li></ul></ul><ul><ul><li>Mild-Moderate Disease ~50% </li></ul></ul><ul><li>Budesonide </li></ul><ul><ul><li>Mild-Moderate Disease ~65-75% </li></ul></ul><ul><li>Corticosteroids </li></ul><ul><ul><li>Moderate to Severe Disease~70-80% </li></ul></ul>
    21. 21. Corticosteroids: Short & Long Term Efficacy in Crohn’s Disease Faubion WA Jr., et al. Gastroenterology . 2001;121:255-260. None 16% (n=12) Complete 58% (n=43) Partial 26% (n=19) 30-Day Responses (n=74) 1-Year Responses (n=74)* Prolonged Response 28% (n=21) Steroid Dependent 32% (n=24) Surgery 38% (n=28) *One patient lost to follow-up
    22. 22. Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting Corticosteroids Days Cumulative Probability (%) 0 20 40 60 80 100 0 30 60 90 182 365 Faubion WA Jr et al. Gastroenterology. 2001;121:255. N=77
    23. 23. Infliximab vs. Placebo in Induction and Maintenance of Remission of CD NNT = number needed to treat. NNT = 3 NNT = 5 Adapted from Bebb JR, et al. Ailment Pharmacol Ther . 2004;20:151-9. Gap Remission
    24. 24. Corticosteroid Toxicity Dose/Duration <ul><li>Moon face </li></ul><ul><li>Acne </li></ul><ul><li>Ecchymoses </li></ul><ul><li>Hypertension </li></ul><ul><li>Hirsutism </li></ul><ul><li>Petechial bleeding </li></ul><ul><li>Striae </li></ul><ul><li>Diabetes </li></ul><ul><li>Infection </li></ul><ul><li>Osteonecrosis** </li></ul><ul><li>Osteoporosis** </li></ul><ul><li>Myopathy </li></ul><ul><li>Cataracts </li></ul><ul><li>Glaucoma </li></ul><ul><li>Psychosis </li></ul>
    25. 25. Lymphoma Risk in IBD Patients on AZA/6MP Meta-Analysis <ul><li>Study Setting N Obs Exp SIR (95% CI) </li></ul><ul><li>Kinlen U.K. 321 2 0.16 12.5 (1.2 - 46) </li></ul><ul><li>Connell London 755 0 0.52 0 </li></ul><ul><li>Farrell Dublin 238 2 0.05 37.5 (3.5 - 138) </li></ul><ul><li>Fraser Oxford 626 3 0.65 4.6 (0.9 - 13.7) </li></ul><ul><li>Korelitz New York 486 3 0.61 4.9 (0.9 - 14.5) </li></ul><ul><li>Lewis* GPRD 1465 1 0.64 1.6 (0.001 - 9) </li></ul><ul><li>Pooled 3891 11 2.63 4.2 (2.1 - 7.5) </li></ul><ul><li>Sensitivity analyses: when papers with highest or lowest SIRs were excluded, </li></ul><ul><li>results remained significant (range, 3.5 - 5.2) </li></ul><ul><li>* : population-based study </li></ul>Kandiel et al, Gut 2005
    26. 26. Ex: from Risk Factors for O pportunistic I nfections in IBD A Case-Control Study of 100 Patients (1998-2003) Toruner M, et al. Presented at DDW 2006. Opportunistic infections and anti-TNF therapies : (3.31 –28.19) (1.45-4.82) (1.15-17.09) (0.36-4.11) (1.72-5.48) (1.82-6.16) (0.61-1.56) (1.98-6.08) <0.0001 9.66 Two medications 0.0014 2.65 One medication 0.03 4.43 Infliximab 0.26 4.00 MTX 0.0001 3.07 AZA/6MP <0.0001 3.35 Corticosteroids 0.94 0.98 5-ASA <0.0001 3.50 Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab) P value Odds Ratio (95% CI)
    27. 27. Warning n°2 : Meta-analysis: Risk of Malignancy in RA <ul><li>Systematic review of pooled data from 9 clinical trials </li></ul><ul><ul><li>3,493 RA patients treated with adalimumab or infliximab compared with 1,512 placebo controls </li></ul></ul><ul><li>Malignancy: pooled OR = 3.3 (95% CI: 1.2-9.1) </li></ul><ul><ul><li>11 lymphomas or leukemia </li></ul></ul><ul><ul><li>14 solid tumors </li></ul></ul><ul><ul><li>10 basal or squamous cell carcinomas </li></ul></ul><ul><li>The potential risks for these events are reflected in the product labeling for all TNF antagonists </li></ul>Bongartz T, et al. JAMA. 2006
    28. 28. Standard Gamble: Utility Scores in CD Gregor JC et al. Inflammatory Bowel Dis. 1997;3:265-276; unpublished data. *Median with interquartile range. >20% life trade-off
    29. 29. Utility Estimates for Chronic Diseases Gregor JC et al. Inflammatory Bowel Dis. 1997;3:265-276. Estimates obtained using time trade-off method.
    30. 30. Indications & Prescribers <ul><li>Patients with persisting moderate-severe symptoms with confirmed active inflammation (CRP +/- endoscopy) not responding to conventional & anti-TNF biologics </li></ul><ul><li>Prescribers are most likely to be experienced IBD & Tertiary Centers willing to pursue active safety & efficacy monitoring </li></ul>