Serological Markers in IBD: Are They Ready for Prime Time?

1. Serological Markers in IBD: Are They Ready for Prime Time? Raymond Cross, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology Director, IBD Program Acting Chief, VA GI Service

2. What are the Serological Markers in IBD? • pANCA (perinuclear staining pattern) • Loss of perinuclear pattern after DNAase • Differentiate from the “other pANCAs” • Antibody against myeloperoxidase • Antibody against cathepsin G, elastase, lysozyme, and lactoferrin • ASCA (anti-Saccharomyces cerevisiae) • Both IgG and IgA • Recognize mannose in the cell wall mannan of Saccharomyces cerevisiae

3. What are the Serological Markers in IBD-2? • Omp C • IgG only • Recognize outer membrane porin C protein in E. coli • I2 • IgA only • Recognizes novel homologue of bacterial transcription-factor families from a Pseudomonas fluorescens-associated sequence • Cbir 1 flagellin • IgG

4. Why Use Serological Markers in Clinical Practice? • Differentiate IBD from functional bowel disorders • Accurately diagnose Crohn’s or UC in a patient with: • Severe colitis • Indeterminate colitis • Predict disease course or complications in IBD • CD phenotype • Severity of disease • Risk of pouchitis

5. Frequency of pANCA in UC Patients and Controls in a Referral Center 60% sensitive 94% specific for UC Duerr, R. H., S. R. Targan, et al. (1991). Gastroenterology100(6): 1590-6.

6. Prevalence of ASCA in Patients with CD and UC and Controls in the Different Assays Vermeire, S., S. Joossens, et al. (2001). Gastroenterology120(4): 827-33

7. Sensitivity, Specificity, and Positive and Negative Predictive Value of ASCA *Using the Prometheus Assay Vermeire, S., S. Joossens, et al. (2001). Gastroenterology120(4): 827-33

8. Accuracy of Serological Markers in Differentiating IBD from Controls Peeters, M., S. Joossens, et al. (2001). Am J Gastroenterol96(3): 730-4.

9. Utility of Serodiagnostics in Pediatric IBD: Use of a Two-Step Assay Dubinsky MC, Ofman JJ, Urman M, et al. Am J Gastroenterol 2001;96(3):758-65

10. IgA Antibody to I2 in Patients with CD or UC and Controls Sutton, C. L., J. Kim, et al. (2000). Gastroenterology119(1): 23-31.

11. Can Serological Markers Differentiate IBD from Non-IBD? • pANCA and ASCA are specific for and have high positive predictive value for UC and CD respectively • Rule in disease • The low sensitivity and negative predictive value preclude them as a screening test • Cannot rule out disease • Potential application in pediatric disease to avoid invasive work up

12. Why Use Serological Markers in Clinical Practice? • Differentiate IBD from functional bowel disorders • Accurately diagnose Crohn’s or UC in a patient with: • Severe colitis • Indeterminate colitis • Predict disease course or complications in IBD • CD phenotype • Severity of disease • Risk of pouchitis

13. Criteria for Indeterminate Colitis • No evidence of small bowel involvement, fistula, or perianal disease • Absence of diagnostic criteria for CD or UC by microscopy

14. Presentation of Ulcerative Colitis • Classic presentation • Bloody diarrhea! • Never or former smoker • Tenesmus (dry heaves of the rectum) • Red Flags • Active smoker • Perianal disease • Abdominal mass on examination

15. DISTINGUISHING FEATURES OF CROHN’S DISEASE

16. Crohn’s Disease Red Flags • Onset after stopping smoking • Bleeding only • Diverticulosis • Atherosclerosis • Prolapse

17. INDETERMINATE COLITIS

18. Sensitivity, Specificity, and Positive and Negative Predictive Value of ASCA *Using the Prometheus Assay Vermeire, S., S. Joossens, et al. (2001). Gastroenterology120(4): 827-33

19. Results of ASCA and pANCA in the Study Population Joossens, S., W. Reinisch, et al. (2002). Gastroenterology122(5): 1242-7

20. Relationship Between Marker Antibodies and CD Cohort Landers, C. J., O. Cohavy, et al. (2002). Gastroenterology123(3): 689-99

21. Conclusions-2 • pANCA and ASCA have low sensitivity in CD and UC • pANCA and ASCA have good specificity and PPV in CD and UC • In patients with indeterminate colitis, available serological markers do not accurately predict the subsequent disease course • Is indeterminate colitis a different form of IBD? • Will performance of serological markers improve with introduction of other markers?

22. Why Use Serological Markers in Clinical Practice? • Differentiate functional from organic disorders • Differentiate type of IBD • Implications for medical and surgical therapy • Predict disease course or complications in IBD • CD phenotype • Severity of disease • Pouchitis

23. Antibody Expression Stratifies Homogeneous Subgroups with Distinct Clinical Characteristics Vasiliauskas, E. A., L. Y. Kam, et al. (2000). Gut47(4): 487-96

24. Relative Contribution of Antibody Responses and Complicated Small Bowel Disease Mow, W. S., E. A. Vasiliauskas, et al. (2004). Gastroenterology126(2): 414-24

25. Disease Characteristics in Patients with Antibodies to Multiple Microbial Antigens Mow, W. S., E. A. Vasiliauskas, et al. (2004). Gastroenterology126(2): 414-24

26. Incidence of Pouchitis in pANCA+ and pANCA- Patients Fleshner, P. R., E. A. Vasiliauskas, et al. (2001). Gut49(5): 671-7

27. Conclusions-3 • Antibody profiles can predict disease behavior in IBD • ASCA and I2 generally predict small bowel disease, fibrostenotic behavior, and need for surgery • Multiple antibodies associated with an even higher risk • pANCA predicts “UC-like” behavior • pANCA+ associated with risk of pouchitis after IPAA

28. Summary • pANCA and ASCA are specific for UC and CD respectively • Neither pANCA nor ASCA are sensitive enough to exclude IBD • In patients with IC, available serological markers do not accurately predict the subsequent disease course • Antibody profiles can predict disease behavior in IBD