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  • 1. Novel Diagnostic Strategies in Inflammatory Bowel Disease Mark H. Flasar, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology

2. The Short List

  • Laboratory testing
    • Serologic markers
    • Genetic testing
    • Metabolite monitoring
    • Markers of disease activity (serum, stool)
  • Radiography
    • Enterography (CT, MRI)
    • Pelvic imaging (MRI)
    • Ultrasound
  • Endoscopy
    • Chromoendoscopy
    • Advanced endoscopic imaging
    • Rectal EUS for fistulae

3. All That in 30 Minutes??? THATSUN-POSSIBLE! 4. Serology: The Two Jakes

  • ASCA:The Crohns Disease Ab
    • + in60% of CD 1-3
    • IgA + IgGvs. cell wall ofS. cerevisiae
  • pANCA:The Ulcerative Colitis Ab
    • + in 40-80% UC, 2-28% CD (UC-like CD) 4
    • Newer assay more specific for UC
      • Loss of perinuclear stain after DNAse

5. Other CD Abs: OmpC and CBir1

  • Anti-OmpC *
    • IgA + in 55% of CD 5
    • Vs.E. coliouter membrane porin C protein
  • Anti-Cbir1
    • IgA + in 50-55% CD 6,7
    • 40% Ab- CD pts are + for anti-CBir1 7
  • Anti-I2
    • + in 54% CD 8-9
    • Vs. bacterial DNA in LP monocytes

6. Other Abs: PAB and anti-Glycans

  • Anti-Glycan Abs 11,12
    • Vs. bacterial/fungal cell wall carbo hydrate s
    • ALCA, ACCA, AMCA + in 18-38% CD
  • Anti pancreatic Ab (PAB)
    • + in 30% CD 10
    • unknown relevance in CD

7. Serology: What is it Good For?

  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response

8. ASCA, pANCA for IBD vs. Healthy 13. Vermeire S, et al. Gastroenterology 2001;120:827 60% sensitive94% specific for UC Duerr R. H. et al. Gastroenterology 1991;100:1590 pANCA+ 9. ASCA, pANCA for IBD vs. Healthy 14. Peeters M, et al. Am J Gastroenterol 2001;96:730 10. Utility of Serodiagnostics in Pediatric IBD: Use of a Two-Step Assay 15. Dubinsky MC, et al. Am J Gastroenterol 2001;96:758 11. Summary: IBD vs. Functional/healthy

  • pANCA and ASCA are specific for UC and CD respectively
    • Can HELP rule in disease (if high PTP)
  • The moderate sensitivity and low negative predictive value preclude them as a screening test
    • Unable to rule out disease
  • Potential application in pediatric disease to avoid invasive work up
    • Not in recent algorithm

12. Serology: What is it Good For?

  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response

13. ASCA for CD vs. UC 16. Vermeire S, et al. Gastroenterology 2001;120:827 14. Diagnosis: CD vs. UC

  • 97 IC pts for ASCA/pANCA and followed 17
  • 31/97 (32%) Declared themselves
  • 48% pts had all Abs
    • 85% of these, dx remained IC
  • Adding anti-OmpC and anti-I2 in did not help 18

80% 64% 67% 78% UC ASCA-/ANCA+ 64% 80% 78% 67% CD ASCA+/ANCA- NPV PPV Specificity Sensitivity 15. Diagnosis: CD vs. UC (IC)

  • 238 UC pts for IPAA had preop serology 19
    • anti-OmpC, anti CBir1, ASCA, pANCA
    • 16 (7%) developed CD after IPAA
      • MV analysis ASCA+ 3-fold risk CD
  • Glycan panel gASCA, ALSA, ACCA 11
    • 1 Ab+: sens 77%, spec 90%, PPV 91%, NPV 77%
    • 2+ Abs+ increased specificity/PPV
      • At expense of sens/NPV.

16. Summary: CD vs. UC (IC)

  • Most specific test is combining ASCA/ANCA 20, 21
    • PPV ranges 77-96% in several studies 22-24
  • IC is likely a distinct clinical entity
    • Serology as adjunct
    • Newer markers may help (CBir1)
      • 44% pANCA+ CD. vs 4% of pANCA+ UC pts 25

17. Prevalence effects on PPV, NPV 18. Serology Panel: Effects of Prevalence UC CD IBD 97% Spec 93% Sens 98% Spec 88% Sens 95% Spec 93% Sens 99% 98% UC NPV 73% 89% UC PPV 100% 93% CD NPV 74% 96% CD PPV 99% 90% NPV 75% 96% PPV 15% Prevalence 59% Prevalence 19. Serology: What is it Good For?

  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response

20. Diagnosis: Pre-clinical markers

  • pANCA variably present in UC relatives 26-29
  • ASCA+ in CD relatives 5x more than controls 30,31
  • Study of 40 IBD patients banked sera 32
    • 31% of CD pts were ASCA+ prior to dx
      • No ASCA+ controls
    • 25% UC pts were pANCA+
      • No pANCA+ controls
      • No UC pts were ASCA+

21. Serology: What is it Good For?

  • Diagnosis
    • IBD vs. Functional/Healthy
    • CD vs. UC
    • Pre-clinical marker
  • Predict disease course or complications in IBD
    • CD and UC phenotype
    • CD and UC progression/aggression
    • Risk of pouchitis after IPAA for UC
    • Following disease activity/treatment response

22. Relationship Between Marker Antibodies and CD Cohort

  • Analyzed immune response heterogeneity in 330 pts 33
    • Found ASCA 56%, OmpC 55%, I2 50%, and pANCA 23%
    • Described 4 distinct immune response phenotype clusters
      • ASCA+, OmpC and I2 +, pANCA+, All negative
  • 15-20% had all neg Abs

23. Antibody Expression Correlates with Clinical Characteristics 34. Vasiliauskas EA, et al. Gut 2000;47:487 24. CD progression/phenotype

  • ASCA+more aggressive, complicated disease
    • Higher levelsearlier disease onset 35,36
    • In adult CD
      • FS, IP, SB resection, early surgery 34,37-41,45
      • Higher long-term health care costs 46
    • In peds CD
      • 3x odds relapse in children 42
      • early onset, fistula/abscess recurrence, repeat surgery, SB dz 43,44
  • ASCA+/pANCA-
    • SB involved more often than colon alone 34

25. CD progression/phenotype

  • pANCA+ identifies 34,35,47,48
    • UC-like subgroup, good therapy response , later onset
  • anti-OmpC
    • Levels assoc w/disease progression (non-FS/IP FS IP) 39,49
    • Assoc w/FS, IP and SB surgery 3, 34,38,47,49
    • Assoc w/FS, IP