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The Patient With Small Bowel Crohn’s Disease

The Patient With Small Bowel Crohn’s Disease. David T. Rubin, MD Associate Professor of Medicine Program Director, The Fellowship in Gastroenterology, Hepatology, and Nutrition Co-Director, The Inflammatory Bowel Disease Center University of Chicago Medical Center Chicago, Illinois. :00.

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The Patient With Small Bowel Crohn’s Disease

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  1. The Patient With Small Bowel Crohn’s Disease David T. Rubin, MD Associate Professor of MedicineProgram Director, The Fellowship in Gastroenterology, Hepatology, and NutritionCo-Director, The Inflammatory Bowel Disease CenterUniversity of Chicago Medical CenterChicago, Illinois

  2. :00 Answer Now Audience Question 1 What is your first-line approach to treating moderately-to-severely active CD of the ileum? • Mesalamine • Budesonide • Prednisone • AZA/6-MP • Anti-TNF therapy • AZA/6-MP + anti-TNF combination therapy • MTX + anti-TNF combination therapy Answer 3

  3. :00 Answer Now Audience Question 1 What is your first-line approach to treating moderately-to-severely active CD of the ileum? • Mesalamine • Budesonide • Prednisone • AZA/6-MP • Anti-TNF therapy • AZA/6-MP + anti-TNF combination therapy • MTX + anti-TNF combination therapy Answer 3

  4. :09 Answer Now Audience Question 2 For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy? • Discontinue AZA/6-MP, and then initiate anti-TNF therapy • Continue AZA/6-MP indefinitely in combination with anti-TNF therapy • Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it Answer 3

  5. :09 Answer Now Audience Question 2 For a CD patient in whom AZA/6-MP treatment fails, how would you initiate anti-TNF therapy? • Discontinue AZA/6-MP, and then initiate anti-TNF therapy • Continue AZA/6-MP indefinitely in combination with anti-TNF therapy • Continue AZA/6-MP for a period of time while starting anti-TNF therapy, and then discontinue it Answer 3

  6. Case Study: TimPresentation to PCP • 18-year-old male high school student • Abdominal pain, 6-month duration • Weight loss, 10 pounds • 3 to 4 loose stools per day, some urgency • Doesn’t smoke cigarettes • Takes ibuprofen for prior basketball injury • 400 mg 3 or 4 times per day • No family history of CD PCP, primary care physician.

  7. TimExamination and Referral • Physical examination • Tenderness and fullness in right lower quadrant • Small perianal skin tags • Referred to gastroenterologist for diagnostic testing • MRE • Colonoscopy • Laboratory results • Hemoglobin 8.7 g/dL • WBC 10 х 109/L • Platelets 454,000 (normal range, 120,000-400,000) • CRP 25 mg/L (normal level, <4.0) CRP, C-reactive protein; MRE, magnetic resonance elastography; WBC, white blood cell.

  8. MRE Results • Long segment of terminal ileal inflammation • Some proximal colon thickening

  9. Colonoscopy Results • Colitis in ascending colon • Distorted ileocecal valve precluding intubation of the ileum

  10. TimDiagnosis • Moderate-to-severe CD of the ileum and colon with perianal involvement

  11. Natural History of CD 100 90 High potential Low potential 80 70 60 Penetrating Cumulative Probability, % 50 Inflammatory 40 30 Stricturing 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Patients at risk (N) over time → 2,002 552 229 95 37 Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.

  12. Corticosteroid dependence 32% (n=24) Surgery 38% (n=28) 0 CorticosteroidsShort- and Long-Term Efficacy in CD Complete 58% (n=43) Partial 26% (n=19) None 16% (n=12) 30-day response (N=74) Prolonged response 28% (n=21) 1-year response (N=74)a a One patient lost to follow-up. Faubion, et al. Gastroenterology. 2001;121:255-260.

  13. Placebo Budesonide 9 mg/d Mesalamine 4 g/d Prednisolone 40 mg/d Therapy for Active Crohn’s DiseaseCorticosteroids 80 66 62 60 53 51 Patients in Remission, % 40 36 20 20 0 Rutgeerts 19943N=176 P<0.12 Thomsen 19982 N=182 P<0.001 Greenberg 19941N=258 P<0.001 1. Greenberg GR, et al. N Engl J Med. 1994;331:836-841; 2. Thomsen OO, et al. N Engl J Med.1998;339:370-374; 3. Rutgeerts P, et al. N Engl J Med. 1994;331:842-845.

  14. Maintenance of Remission in CDAZA a 100 AZA 2.5 mg/kg per day (n=33) Placebo (n=30) 80 60 Patients Not Failing Trial, % 40 P=0.001 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Duration of Trial, months a Remission induced by prednisolone tapered over 12 weeks. Candy S, et al. Gut. 1995;37:674-678.

  15. Murine Human Anti-TNF AgentsStructure Certolizumab pegol IFX Adalimumab Fab IgG1 Fc PEG Monoclonal antibody PEGylated humanized Fab′ fragment containing 2x20 kDa PEG molecules Fab, fragment antigen binding; Fc, fragment crystallizable; IgG, immunoglobulin G; IFX, infliximab; PEG, polyethylene glycol.Hanauer SB. Presented at: Advances in Inflammatory Bowel Diseases Crohn’s and Colitis Foundation’s Research and Clinical Conference; Hollywood, FL; December 4-7, 2008. http://vid.imedex.com/pdf/5477/hanauer.pdf.

  16. 100 ACCENT I1 Week 54 PRECiSE 12 Week 26 PRECiSE 23 Week 26 CHARM4 Week 56 CLASSIC I5-II6 Week 24 80 60 48 Remission, % 41 36 33.3 40 29 20 13.6 20 0 Episodic IFX (N=110) Combined IFX (N=225) CertolizumabPegol (N=331) CertolizumabPegol (N=215) Adalimumab (N=172) Adalimumab (N=157) Maintenance of Remission in CD Anti-TNF Therapies Adalimumab (N=76) ACCENT, A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen; CHARM, Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance; CLASSIC, Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease; EOW, every other week; PRECiSE, Pegylated Antibody Fragment Evaluation in Crohn’s Disease.1. Hanauer SB, et al. Lancet. 2002;359:1541-1549; 2. Sanborn W, et al. NEJM. 2007;357:228-238; 3. Schreiber S, et al. NEJM. 2007;357:239-250; 4. Colombel, JF et al. Gastroenterol. 2007;132:52-65; 5. Hanauer SB, et al. Gastroenterol. 2006;130:323-333; 6. Sanborn W, et al. Gut. 2007;56:1232-1239.

  17. Certolizumab pegol Placebo Adalimumab Higher Remission Rates With Shorter Disease Duration 80 68 CHARM2 PRECiSE 21 70 70 59a n=19 60 60 55 n=39 47 n=20 50 50 44 41b 40 n=45 Patients in CDAI Remission (<150) at Week 26, % 40 40 Patients in CDAI Remission (<150) at Week 26, %2 n=131 n=233 n=57 37.1 36.4 30 30 n=35 n=22 29.1 25 20 20 23.5 n=55 n=36 17 n=98 14 10 10 n=23 n=111 0 0 <1 Year 2 to <5 Years 2 to <5 Years 1 to <2 Years ≥5 Years <2 Years ≥5 Years Disease Duration Disease Duration aP=0.002; bP<0.001.CDAI, Crohn’s Disease Activity Index. 1. Sandborn WJ, et al. Presented at: Annual Scientific Meeting of the American College of Gastroenterology; October 12-17, 2007; Philadelphia, PA; 2. Schreiber S, et al. Gastroenterol. 2007;132:A-147.

  18. Top-Down/Step-Up1 Early combined therapy Steroid-naïve Immune modifier-naïve Duration: 2 years End point: 104 weeks SONIC2 Not in remission Some patients on steroids Duration: 1 year End points: 26 weeks,52 weeks Early Biologic Trials: 2008 IFXAZA Steroids  steroids  AZA  IFX IFX + AZA IFX alone AZA alone SONIC, Study of Immunomodulator-Naïve Patients in Crohn’s Disease.1.D’Haens G, et al. Lancet. 2008;371:660-667; 2. Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.

  19. 100 80 60 40 20 0 Top-Down vs Step-Up TrialClinical Results at 2 Years Early combined immunosuppression (top-down; n=66) Conventional management (step-up; n=67) 100 P=0.0001 P=0.028 P=0.431 80 P=0.006 P=0.797 Patients Given AZA/6-MP, % 60 Patients in Remission,a % 40 20 0 14 26 52 78 104 26 52 78 104 Weeks Weeks a Remission defined as CDAI <150, no steroids, no surgery.D’Haens G, et al. Lancet. 2008;371:660-667.

  20. SONICCorticosteroid-Free Clinical Remission at Week 26 AZA + placebo IFX + placebo IFX + AZA 100 P<0.001 80 P=0.009 P=0.022 56.8 60 Patients, % 44.4 40 30.6 20 52/170 75/169 96/169 0 Sandborn W, et al. Presented at: 2008 American College of Gastroenterology Annual Scientific Meeting and Postgraduate Course. October 3-8, 2008; Orlando, FL.

  21. :10 Answer Now Audience Question 3 What would you prescribe as initial treatment for Tim? • Mesalamine • Budesonide • Prednisone • AZA/6-MP • Anti-TNF therapy • AZA/6-MP + anti-TNF combination therapy • MTX + anti-TNF combination therapy Answer 3

  22. :10 Answer Now Audience Question 3 What would you prescribe as initial treatment for Tim? • Mesalamine • Budesonide • Prednisone • AZA/6-MP • Anti-TNF therapy • AZA/6-MP + anti-TNF combination therapy • MTX + anti-TNF combination therapy Answer 3

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