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Novel Diagnostic Strategies in Inflammatory Bowel Disease

Novel Diagnostic Strategies in Inflammatory Bowel Disease Mark H. Flasar, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology The “Short” List Laboratory testing Serologic markers Genetic testing Metabolite monitoring Markers of disease activity (serum, stool)

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Novel Diagnostic Strategies in Inflammatory Bowel Disease

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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??? “THAT’S UN-POSSIBLE!”

  4. Serology: “The Two Jakes” • ASCA: The “Crohn’s Disease Ab” • + in ≈ 60% of CD1-3 • IgA + IgG vs. cell wall of S. 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 CD5 • Vs. E. coli outer membrane porin C protein • Anti-Cbir1ŧ • IgA + in 50-55% CD6,7 • 40% Ab- CD pts are + for anti-CBir17 • Anti-I2 • + in 54% CD8-9 • Vs. bacterial DNA in LP monocytes

  6. Other Abs: PAB and anti-Glycans • Anti-Glycan Abs11,12 • Vs. bacterial/fungal cell wall carbohydrates • ALCA, ACCA, AMCA + in 18-38% CD • Anti pancreatic Ab (PAB) • + in 30% CD10 • 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. pANCA+ 60% sensitive 94% specific for UC Duerr R. H. et al. Gastroenterology 1991;100:1590 ASCA, pANCA for IBD vs. Healthy 13. Vermeire S, et al. Gastroenterology 2001;120:827

  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 followed17 • 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 help18

  15. Diagnosis: CD vs. UC (IC) • 238 UC pts for IPAA had preop serology19 • anti-OmpC, anti CBir1, ASCA, pANCA • 16 (7%) developed CD after IPAA • MV analysis ASCA+ 3-fold risk CD • Glycan panelgASCA, ALSA, ACCA11 • 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/ANCA20, 21 • PPV ranges 77-96% in several studies22-24 • IC is likely a distinct clinical entity • Serology as adjunct • Newer markers may help (CBir1) • 44% pANCA+ CD. vs 4% of pANCA+ UC pts25

  17. Prevalence effects on PPV, NPV

  18. Serology Panel: Effects of 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 relatives26-29 • ASCA+ in CD relatives 5x more than controls30,31 • Study of 40 IBD patients’ banked sera32 • 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 pts33 • 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 levels  earlier disease onset35,36 • In adult CD • FS, IP, SB resection, early surgery34,37-41,45 • Higher long-term health care costs46 • In peds CD • 3x odds relapse in children42 • early onset, fistula/abscess recurrence, repeat surgery, SB dz43,44 • ASCA+/pANCA- • SB involved more often than colon alone34

  25. CD progression/phenotype • pANCA+ identifies34,35,47,48 • “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 surgery3, 34,38,47,49 • Assoc w/FS, IP in pediatrics44 • Anti-I2 • assoc w/ FS and SB surgery34,47-8 • Anti-CBir1 • assoc w/FS, IP dz and SB surgery6,7

  26. “Dose response” of + Ab in CD • Number and level of + Abs correlate w/severity • ↑ immune reactivity may = ↓ immune tolerance • ASCA+/anti-OmpC+anti-I2+ assoc w/↑ risk vs. all -Abs • FS, IP and surgery (3-8x)38 • 196 pt prospective peds cohort had similar results44 • ASCA+/anti-OmpC+/anti-I2+/anti-CBir1+ • 11x risk IP or FS w/subsequent surgery if all 4+ vs. all 4- • Time to complication significantly less if ANY + Ab

  27. “Dose response” of + Ab in CD 39. Arnott ID, et al. Am J Gastroenterol 2004;99:2376

  28. “Dose response” of + Ab in CD • CD behavior from presence AND level of markers38 • “Quartile sum” (dose-response) of I2, ASCA, OmpC • Higher quartileshigher FS, SB dz, SB surg, IP and lower UC-like

  29. CD progression/phenotype • Aggressive pediatric CD predicted by Abs50 • If Anti-CBir1+/anti-OmpC+/ASCA+: • 6x odds FS, 9x odds IP and 3x odds SB dz • Same pattern seen for higher Ab response levels • MV analysis • Anti-CBir1, anti-OmpC assoc w/IP • ASCA, anti-CBir1 assoc. w/FS

  30. UC progression/phenotype • pANCA+ higher probability of • severe L-sided dz • treatment-resistance • aggressive course with earlier surgery51 • pouchitis after IPAA35,52

  31. Follow-up/treatment response • no corr. pANCA+, titer and UC activity49 • Titer same after colectomy32 • ASCA stable/independent of CD activity32,35,48 • ACCA, ALCA stable as well11 • No corr. ASCA to anti-TNF response52 • Trend to poorer response to ASCA-/pANCA+ pts • CD w/anti-OmpC+/I2+ • better response to budesonide + Cipro/Flagyl • while abs – better to budesonide alone54

  32. Summary: progression/phenotype • Antibody profiles can predict CD behavior • Stratify to therapy regimens • Multiple antibodies associated with higher risks • pANCA+ associated with pouchitis after IPAA in UC

  33. Conclusion: Serology • Helpful if positive in correct population • Can help Rule IN disease if high PTP • Can help Rule OUT disease if low PTP • Diagnostic ADJUNCT • Possible alternative in certain populations • Future hope for UC vs. CD • Pre-clinical? • Associated with phenotype/complications

  34. Thiopurine ADRs • Dose dependent (usually 2/2 toxic metabolites) • Hemotoxicity • Leukopenia: 3.8-11.5% • Pancytopenia: 0.4-2% • Thrombocytopenia: 1.2% • Hepatotoxicity: 0.3-9.9% • 4.6% of 173 adult IBD patients69 • Infections: 7.4-14.1% • Malaise, nausea: 11%

  35. Thiopurine ADRs • Dose-independent (hypersensitivity) • Flu-like symptoms (including fever):2-6.5% • GI distress: 4.6% • Pancreatitis:1.2-4.9% • NRH, HVOD, AIN, pneumonitis: rare/case reports • Malignancy:? • Purported 4x lymphoma risk in IBD70 • Benefits outweigh risks in decision analysis71

  36. Metabolite Monitoring • 6-TG corresponds with clinical efficacy while 6-MMP corresponds with hepatotoxicity72-3 • Peds clinical efficacy related to 6-TGN > 235 pmol/8x10e8 RBC • Hepatotoxicity corr w/6-MMP> 5700 pmol/8x10e8 RBC (3x risk)

  37. Metabolite Monitoring • Monitoring of 6-TG + 6-MMP levels may allow prediction of toxicity and guide dose titration • Mixed results from studies73,77-8

  38. Metabolite Monitoring: CON • No diff in 6-TGN between responders and NR79-82 • No diff in 6-TGN between remission and NR78, 81, 83-85

  39. Metabolite Monitoring: PRO • Correlation between 6-TG and remission72-3, 86-91 • Higher 6-TGN levels assoc. with greater clinical response73, 90, 92-3 • Meta-analysis showed higher 6-TG assoc w/sig higher levels remission94 • 6-TGN >230-260 pmol/8x10e8 RBC more likely to be in remission (OR 3.27, 95% CI 1.71-6.27) • Cost-effective analysis suggested MM may decrease costs and improve outcomes vs. usual care95

  40. Metabolite Monitoring • Controversy whether monitoring good for predicting toxicity • Recent retrospective study reports poor test characteristics of 6-MMP levels in predicting hepatotoxicity at 5,300 and 9,800 cutoffs69

  41. Summary: Metabolite Monitoring • Useful in pts not achieving expected results despite appropriate dose and time intervals • Very low 6-TG and 6-MMPnoncompliance • Very rarely poor absorption form short gut • 6-MMP:6-TG>10-11 suggests preferential shunting to 6-MMP • Suggests unfavorable metabolism, unlikely to be clinically effective89,96 • Suboptimal 6-TG levels (<230-260 pmol/8x10e8 RBC and no shunting to 6-MMP), doses could be pushed to get optimal levels • Likely not useful for toxicity

  42. CT Enterography • Allows visualization of lumen, mucosa, bowel wall and extraluminal pathology • Traditional oral contrast has similar attenuation to enhancing mucosa • Multidetector CT scanner • 1-2L of Low Houndsfield-unit oral contrast (<30 HU) • Water +/- methylcellulose, lactulose, PEG • barium/sorbitol (improves distension) • Traditional IV contrast

  43. CT Enterography • problematic in cases of suspected infection or perforation • Fluid collections/abscesses appear similar to bowel • Mucosal enhancement on CTE correlates with endoscopically and histologically active mucosal disease97-8

  44. CT Enterography Abscess seen better after positive oral contrast

  45. CT Enterography Normal Terminal Ileum

  46. CT Enterography Active Disease

  47. CT Enterography

  48. CT Enterography • Enteroclysis • 100% agreement with surgical findings of fistula and stricture99-100 • SBFT • Reported 85-95% sensitivity/specificity for identification of stricture, fistula and mucosal abnormalities101 • Incorrectly identified stricture number in 31% vs. operative findings102

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