Novel Diagnostic Strategies in Inflammatory Bowel Disease - PowerPoint PPT Presentation

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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