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The Patient With Crohn’s Disease Complicated By Abscesses

The Patient With Crohn’s Disease Complicated By Abscesses. Gary R. Lichtenstein, MD Professor of Medicine University of Pennsylvania School of Medicine Director, Center for Inflammatory Bowel Diseases Philadelphia, Pennsylvania. 34-year-old woman Pregnant, 28 weeks Symptoms Fever 38.3 ° C

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The Patient With Crohn’s Disease Complicated By Abscesses

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  1. The Patient With Crohn’s Disease Complicated By Abscesses Gary R. Lichtenstein, MD Professor of MedicineUniversity of Pennsylvania School of MedicineDirector, Center for Inflammatory Bowel DiseasesPhiladelphia, Pennsylvania

  2. 34-year-old woman Pregnant, 28 weeks Symptoms Fever 38.3° C 1-week duration Nausea RUQ abdominal pain Constant with radiation to the back Current conditions Terminal ileal CD 4-year duration Arthralgias, loose stools No active symptoms at conception Current medications AZA 2 mg/kg + mesalamine 4 g per day Case Study: IrenePresentation AZA, azathioprine; CD, Crohn’s disease; RUQ, right upper quadrant.

  3. IreneCD History • Prior examinations • Colonoscopy • Normal colon with ileal aphthous ulcerations • Biopsies consistent with CD • Small bowel series • Active, chronic inflammatory changes of CD in distal 25 cm of ileum • 2 focal sites of stricturing without proximal dilatation • Prior treatments • Prednisone, 8-week course • 40 mg per day for 1 week, tapered by 5 mg per week • For flare that began 10 weeks prior to current visit • Mesalamine 4 grams per day • Symptoms continued • AZA added to maintenance regimen 2 months after diagnosis

  4. :00 Answer Now Audience Question 1 What complication(s) associated with CD would you suspect at this point in examining Irene? • Fistula • Abscess • Bowel obstruction • All of the above

  5. :00 Answer Now Audience Question 1 What complication(s) associated with CD would you suspect at this point in examining Irene? • Fistula • Abscess • Bowel obstruction • All of the above

  6. Answer Now Audience Question 2 How would you further assess Irene to determine the appropriate diagnosis? • Abdominal MRI • Abdominal CT scan • Small bowel series • Abdominal ultrasound • Laparotomy MRI, magnetic resonance imaging; CT, computed tomography.

  7. :10 Audience Question 2 How would you further assess Irene to determine the appropriate diagnosis? • Abdominal MRI • Abdominal CT scan • Small bowel series • Abdominal ultrasound • Laparotomy MRI, magnetic resonance imaging; CT, computed tomography.

  8. IreneAssessment • Laboratory results • Physical examination • Abdomen • Protuberant, consistent with stage of pregnancy • Soft, normal BS • RUQ tenderness • Voluntary guarding • No rebound ALT, alanine aminotransferase; AST, aspartate aminotransferase; BS, bowel sounds; Hgb, hemoglobin; Hct, hematocrit; Phos, phosphatase; Plt, platelet; WBC, white blood cell.

  9. Irene MRI of Abdomen, Pelvis • No abscess visible • No phlegmon or source ofpersistent fever • Arrow indicates terminal ileum

  10. IreneCT Scan of Abdomen, Pelvis • Performed subsequent to persistent pain, fever • 2-day duration • Marked circumferential thickening of distal ileum • Abscess in continuity with inflamed segment of bowel, abutting uterus • 30 x 36 mm

  11. Drainage1 Operative Radiologic Antibiotics2 Empiric coverage Coverage of enterobacteriaceae, enterococci, anaerobes Broaden coverage if suggested by blood cultures Intra-Abdominal AbscessTreatment Components 1. Carpenter CF, Swami A. Intra-abdominal infections. Johns Hopkins POC-IT Center. http://prod.hopkins-abxguide.org/diagnosis/surgical_infections/intra-abdominal_abscess.html?contentInstanceId=255356. Accessed April 16, 2009; 2. Malangoni MA, et al. Am J Surg. 1990;159:167-171.

  12. IreneTreatment During Pregnancy • Ultrasound-guided percutaneous drainage of abscess • Unsuccessful • Poor visualization (bowel gas) • CT-guided drainage • Not attempted in an effort to minimize fetal radiation exposure • Inpatient care • Ceftizoxime, metronidazole • TPN • Outpatient care • Amoxicillin/clavulanate Ka • Home parenteral nutrition • Both continued, monitored closely through remainder of pregnancy aPregnancy category B; approved by obstetrician.K, potassium; TPN, total parenteral nutrition.

  13. Intra-Abdominal AbscessAssociation With CD • Spontaneous abscess • Transmural extension of fissure ulcers • Postoperative abscess • Anastomic leaks • Intraperitoneal contamination during surgery • Sepsis in 7% to 28% of CD cases Ayuk R, et al. Ann R Coll Surg Engl. 1996;78:5-10.

  14. Abscess in CD • 566 operations for CD • 13% complicated by intra-abdominal sepsis • Predictors • Low albumin (<3.0) • Steroids • Abscess at laparoscopy • Fistula at laparoscopy • If 4 factors, risk 50% • If 0 factors, risk 5% Yamamoto, T et al. Dis Colon Rectum. 2000;43:1141-1145.

  15. Predictors of Disabling DiseaseRequirement for Steroids Is Turning Point Beaugerie L, et al. Gastroenterology. 2001;121:155-260.

  16. Surgical ResectionCD Patients Starting Corticosteroids 100 80 60 Cumulative probability, % 40 38 20 0 30 60 90 182 365 n=77 Days Faubion WA, et al. Gastroenterology. 2001;121:255-260.

  17. Abscess in CDPharmacologic Risk Factors 10 a Intra-Abdominal or Pelvic Abscess, OR 9 8 7 6 5 4 b 3 2 a a 1 0 Prednisone (≥20 mg Per Day) Antibiotics AZA Corticosteroid Prednisone (Continuous, ≥12 Weeks Before Presentation) a Within 3 months before development of abscess or presentation with perforating CD; b One patient was receiving budenoside 2 to 9 mg per day and was included with patients receiving prednisone <20 mg per day for this analysis. OR, odds ratio.Agrawal A, et al. Clin Gastroenterol Hepatol. 2005;3:1215-1220.

  18. IrenePostpartum Care • Healthy baby girl delivered at term • 6 weeks postpartum, small bowel series and CT scan of abdomen, pelvis performed • Changes consistent with CD • Distal 20 cm of ileum • No fistula demonstrable • IV IFX initiated • 5 mg/kg at 0, 2, and 6 weeks; then every 8 weeks • Patient in remission, no CD symptoms for 6 months • Baby doing well IFX, infliximab; IV, intravenous.

  19. TREAT RegistryCrohn’s Therapy Resource, Evaluation, and Assessment Tool • >6,000 CD patients followed for ≥5 years • Treatment at discretion of patients’ physicians • ~50% have received IFX • Usually + other CD treatments • ~50% have received other CD treatments only • Registry primarily designed to assess long-term safety of IFX in CD • “Real-world” experience • 80% community • 20% academic Lichtenstein GR. Clin Gastroenterol Hepatol. 2006;4:621-630.

  20. IFX Other treatments only TREAT RegistryPatient Characteristics a 60 49.0 50 a a a 40 31.7 30.7 b Patients, % 30 27.3 26.8 18.9 20 17.5 16.0 13.6 a 10.8 10 2.5 0.6 0 MOD-SEV SEV-FUL Immunomodulator CS Hospitalization (Previous Year) Surgery (Previous Year) Disease Severity Concomitant Medications a P<0.0001; b P=0.0005. CS, corticosteroid; FUL, fulminant; MOD, moderate; SEV, severe.Lichtenstein GR. Clin Gastroenterol Hepatol. 2006;4:621-630.

  21. TREAT RegistrySerious Infections 95% CI 3.5 3.25 3 3 2.5 2.21b 2.11b 1.91 2 HazardRatioa 1.42 1.37 1.5 1.49 1.5 1.03 1 0.99 0.75 0.5 0 6-MP/AZA/MTX IFX Prednisone Narcotic Analgesics 6-MP, 6-mercaptopurine; CI, confidence interval; MTX, methotrexate.a COX proportional hazard regression data (multivariate); b P<0.001.Lichtenstein GR. Clin Gastroenterol Hepatol. 2006;4:621-630.

  22. 43.0 18 17.1 16 14.5 14 12 10 Infection Risk, OR 8 6.2 6 5.5 5.3 4.4 4.9 3.4 4 3.1 2.9 2 1.7 1.8 1.5 1.2 0 CS IFX AZA ≥2 of IFX,CS, AZA IFX, CS, AZA vs No Drug Opportunistic Infections in IBDRisk Factors • Mayo Clinic case-control study • 100 consecutive IBD patients with opportunistic infections • For each, 2 matched controls (IBD patients without history of opportunistic infection) 95% CI IBD, inflammatory bowel disease.Toruner M, et al. Gastroenterology. 2008;134:929-936.

  23. IreneIFX Treatment • At 7 months, symptom-free interval between IFX injections ↓ to 4 weeks • Infusion reaction • Hypotension • Rash • Wheezing during infusion • Active CD symptoms re-emerged

  24. Audience Question 4 What options exist for Irene’s acute induction therapy? • Adalimumab • Certolizumab pegol • MTX • AZA/6-MP • Adalimumab and certolizumab pegol

  25. Audience Question 4 What options exist for Irene’s acute induction therapy? • Adalimumab • Certolizumab pegol • MTX • AZA/6-MP • Adalimumab and certolizumab pegol

  26. WELCOMEStudy Design • 26-week trial examining benefit and tolerability of certolizumab pegol in patients with intolerance or loss of response to IFX • 6-week open-label induction phase • Certolizumab pegol 400 mg at weeks 0, 2, and 4 • Responders: 18-week double-blind maintenance phase (weeks 6-24) • Certolizumab pegol 400 mg every 2 or 4 weeks or placebo • 1° end point: response at week 6 WELCOME, 26-Week Open-Label Trial Evaluating the Clinical Benefit and Tolerability of Certolizumab Pegol Induction and Maintenance in Patients Suffering From CD with Prior Loss of Response or Intolerance to Infliximab.Vermeire S, et al. Gastroenterology. 2008;134:A67-A68.

  27. Certolizumab pegol responsea Certolizumab pegol remissionb WELCOME StudyIFX → Certolizumab Pegol 70 62.3 61.0 61.2 57.6 60 45.7 50 39.3 35.9 40 Patients, % 30.3 30 20 10 0 All Intolerance to IFX Loss of Response to IFX Intolerance and Loss of Response to IFX N=539 n=199 n=304 n=33 a ≥100-point decrease in CDAI score; b ≥150-point decrease in CDAI score.CDAI, Crohn’s disease activity index.Abreu, et al. Presented at: Scientific Meeting of the American College of Gastroenterology, October 5-8, 2008; Orlando, Florida.

  28. Response at week 8 or earlier Remission at week 8 or earlier Certolizumab PegolAs Alternative to IFX 70 62.2a 60 55d 49.3c 50 45e 39.3b 40 Patients, % 30 20 10 0 WELCOME1 COMPAS2 Danese, et al3 N=539 n=160 n=20 a ≥100-point decrease in CDAI score; b ≥150-point decrease in CDAI score; c Clinical improvement satisfactory to both patient and investigator with patient remaining on treatment; d ≥3-point decrease in HBI score from baseline; e HBI score ≤4. COMPAS, Compassionate Use of Certolizumab Pegol in Patients with Crohn’s Disease for Whom Treatment with One or Two Anti-TNFs Failed; HBI, Harvey-Bradshaw Index.1. Vermeire S, et al. Gastroenterology. 2008;134(4 Suppl 1):A67-A68; 2. Vermeire S, et al. Am J Gastroenterol. 2007;103:S408-S555; 3. Danese S, et al. Gastroenterol. 2008;134(4 Suppl 1):A663.

  29. GAIN TrialInduction Study Design Screening period Double-blind, placebo-controlled period ≤14 days Week 0 Week 2 Week 4 n=166 Placebo Placebo N=325 Long-term open-label extension study 1° end point n=159 160 mgAdalimumab 80 mgAdalimumab GAIN, Gauging Adalimumab Efficacy in Infliximab Nonresponders.Sandborn WJ, et al. Ann Intern Med. 2007;146(12):829-838.

  30. GAIN TrialEfficacy Outcomes at Week 4 Placebo Adalimumab 80 or 160 mg a 60 52 b 50 38 40 34 a Patients, % 30 25 21 20 7 10 12/166 34/159 56/166 82/159 41/166 61/159 41/166 61/159 56/166 83/159 34/159 12/166 0 Remissionc CR-70 Response CR-100 Response aP<0.001; bP<0.01; c CDAI score <150.CR-70, 70-point decrease in CDAI score; CR-100, 100-point decrease in CDAI score. Sandborn WJ, et al. Ann Intern Med. 2007;146(12):829-838.

  31. Conclusions • In treating patient with CD, judicious use of CS is advocated when necessary given potential for complications • Abscess • Surgery • Infection • If loss of efficacy or intolerability occurs with anti-TNF therapy, consider switch to another anti-TNF • WELCOME: certolizumab pegol • GAIN: adalimumab

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