PowerPoint Slides

• 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