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Serologic markers in the diagnosis of irritable bowel disease

Serologic markers in the diagnosis of irritable bowel disease. 7 September 2006 Roni J Bollag. To evaluate the utility of serologic markers in the diagnosis of IBD. Background on IBD Current criteria for IBD diagnosis Evidence for serology in IBD Case study at MCG

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Serologic markers in the diagnosis of irritable bowel disease

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  1. Serologic markers in the diagnosis of irritable bowel disease 7 September 2006 Roni J Bollag

  2. To evaluate the utility of serologic markers in the diagnosis of IBD • Background on IBD • Current criteria for IBD diagnosis • Evidence for serology in IBD • Case study at MCG • Serology: adjunct or screening tool • Conclusion

  3. IBD • Spectrum of chronic relapsing disorders affecting GI tract • Crohn disease • Ulcerative colitis • Indeterminate colitis • Lifelong disease beginning in youth (15-30) • Prevalence: 15 -20% (North America) • Immunologically mediated disease in genetically susceptible hosts

  4. IBD – consensus criteria • Chief symptom: abdominal pain with altered bowel habits • Rome criteria

  5. IBD - Rome III criteria • Rule out “Alarm” feature

  6. Epidemiology of IBD

  7. UC vs CD

  8. Pathophysiology • Aberrant immune response with loss of tolerance to normal GI flora leading to chronic inflammation of the GI tract • Genetic susceptibility: multifactorial CARD15/NOD2 in Crohn - increased severity: fibrostenotic small bowel • IBD5, DLG5 • Chr 1, 3, 5, 7, 10, 12, 16

  9. Hypothesized Etiologies

  10. Differential Diagnosis

  11. Antibodies in IBD

  12. IBD Serologies • ANCA – antineutrophilic cytoplasmic abx • pANCA, cANCA (Wegener’s) • Atypical pANCA = not myeloperoxidase • ASCA – anti-Saccharomyces cerevisiae abx • IgG, IgA • Increased titers indicates ileal involvement • Antibodies against bacterial antigens (E. coli) • OmpC, Hup-B • I2 (bacterial sequence in CD) • PAB (antibodies to pancreatic antigens) Lee: IBD2006

  13. pANCA • Produced by B-cells in IBD patients • 70% UC patients pANCA positive • 30% Crohn disease pANCA positive • Left sided colonic disease requiring colectomy • Reduced rate of response to anti-TNF Lee: IBD2006

  14. ANCA immunofluorescence

  15. ASCA ELISA • ASCA – anti-Saccharomyces cerevisiae antibody • Usually measured with IgA or IgG • Increased titers indicates ileal involvement • Crohn Disease 50-60%

  16. Serologic associations

  17. Serologic associations

  18. IBD SCREENING TEST • Modified ANCA / ASCA - lowered threshold • Positive test confirmed by higher titer test • 95% non-IBD patients negative (74 patients) • 69% of IBD patients positive (54 patients) • False negatives will continue with symptoms • Positives confirmed with imaging / scoping • Important in indeterminate colitis - pouch Lee: IBD2006

  19. Serology in CD • Prospective study in children with CD • Children with more severe (internal penetrating / stricturing) disease had increased levels of antibodies • Anti-OmpC, anti I2, anti-CBir1,ASCA,

  20. UptoDate

  21. Prometheus

  22. UptoDate – re: Prometheus • accuracy and predictive value in diagnosis of IBD unclear • prevalence of antibodies in patients with a variety of inflammatory diseases affecting the gut not well studied • ASCA present in 50 % of patients with celiac disease • may reflect a non-specific immune response in small bowel disease • ASCA association with cystic fibrosis • at the present time antibody tests should only be used as an adjunct to conventional testing and clinical diagnosis.

  23. Correlations I • P-ANCA+/ASCA-  UC • P-ANCA-/ASCA+  CD • Positive IBD panel modestly increases pre-test probability for IBD • Positivity for multiple serological markers correlates with disease severity • Negative IBD panel has no clinical relevance

  24. Correlations II • Strongest risk factor for IBD is having a relative with disease – good correlation with serology • Possibility as ‘pre-clinical’ markers in familial IBD • Correlation of ASCA levels with increased severity in CD • No correlation between ANCA levels and UC severity

  25. Diagnosis of IBD • IBD was once a diagnosis of exclusion • With symptom-based approach, IBD now a diagnosis of inclusion • Role of serology?

  26. Diagnosis of IBD • History & physical • Radiological evidence • Endoscopy • IBD inclusion – CD vs UC discrimination Pathology

  27. Pathology • Time honored diagnostic criteria for ulcerative colitis are being questioned • Rectal involvement • Contiguous disease • Non-contiguous UC • Rectal sparing, especially in children Lee IBD2006

  28. Pathology • Non-contiguous distribution in UC • Rectal sparing not uncommon (peds) • One colonoscopy with biopsies should not establish the extent of disease • UC skip lesions do not warrant a diagnosis change to Crohn disease Lee: IBD2006

  29. Viewpoints Rutgeerts, Vermeire Hoffenberg, Fidanza, Sauaia Canani et al Lerner, Schoenfeld

  30. The Insurance angle • Position echoed on four insurance policy statements

  31. Case history – RMD request for Prometheus IBD panel • 11-year-old male with weight loss and diarrhea who developed an intra-abdominal abscess • patient underwent a small-bowel resection at an outside institution • per report specimen was not diagnostic for CD • Peds GI unable to scope the patient due to his recent surgery and requested the Prometheus panel in the interim.   • Patient kept in-house; endoscopy after 4 days

  32. Case history – continued • Case deferred for pathology … PATHOLOGY • Specimen A: The findings are suggestive, but not diagnostic of celiac disease. Repeat biopsy after a trial of gluten-free diet may be helpful. • Specimens D-E: While inflammatory bowel disease is a possible cause of the chronic active colitis, the histologic features are not diagnostic of this disease. No granulomas are identified.

  33. Case history – continued • Case sent for Prometheus panel

  34. Case history – conclusion

  35. Differential Diagnosis

  36. Final Dx • It looks like a duck, walks like a duck, quacks like a duck (see comment) Comment: favor duck; correlate with serologies

  37. Bibliography • Bossuyt, X.(2006) Clin. Chem 52:171-181 • Abreu, M.T. (2002) Inflamm Bowel Dis 8:224-6 • Canani, R.B et al. (2006) J Ped Gastroenterol Nutr 42:9-15 • Reumaux. D. et al. (2003) Best Pract Res Clin Gastroenterol 17:19-35 • Dubinsky , M et al. (2006) Am J Gastroenterol 101:360-367 • Ruemmele et al. (1998) Gastroenterology 115:822-829 • Hoffenberg et al. (1999) J. Pediatr. 134:447-452 • Lerner, A., Schoenfeld, Y. (2002) Eur J. Gastroentero Hepat 14:103-105 • Malagelada, J-R (2005) Int J Clin Pract 60:57-63 • Cash, B.D., Chey, W.D. (2004) Aliment Pharmacol Ther 19:1235-1245 • Lee, J.L. (2006) IBD2006 (powerpoint) • Medscape • UptoDate • Harrison’s Principles of Internal Medicine, 15th ed., 2005

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