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  • ASCA:
    Sacch=brewer’s yeast
    Simple ELISA, standardized, easy to run
    Poor correlation with mucosal S. cerevesiae Mallant-Hent RC, et al. World J Gastroenterol 2006;12:292
    ANCA:
    ANCA IgG, pANCA IIF, DNASE sens pANCA IIF
    Results variable based on assay, personnel experience. ELISA+IFE--?60%, IFE alone0-40%
  • OmpC
    less + in peds (24% in pediatric-onset CD) Zholudev A, et al. Am J Gastroenterol 2004;99:2235
    CBir1
    Induces colitis in animal models
    40% CD pts - for all other Abs are + for anti-CBir1 (suggesting possible unique CD phenotype)
    I2
    assoc w/ Pseudomonas flouresciens
  • Low correlation between presence of AMCA, ACCA, ALCA
    suggests different microorganism targets for each
    Anti-laminaribocide Ab (ALCA)
    Anti-chitobioside (ACCA)
    Anti-mannobioside (AMCA)
  • IBD vs. functional/healthy: Use when low index suspicion and want to avoid endoscopy/expensive testing
  • How about ASCA alone?
    Here, test characteristics examined as a secondary aim, looking at population with high prevalence CD (36%).
    Not a very good screening test
  • How about ASCA AND ANCA?
    The aim of this study was to see how well ACSA, ANCA and combination could tell IBD from controls.
    (n = 582: 407 CD, 147 UC, and 28 indeterminate colitis), patients with non-IBD diarrheal illnesses (n = 74), and healthy controls (n = 157).
    CONCLUSIONS: Specificity of serological markers for IBD is high, but low sensitivity makes them less useful as diagnostic tests.
    The combination of tests is probably more powerful, although, clinical subgroups still need to be defined.
  • Used different algorithm, with more sensitive cutoffs, then traditional testing.
    Serial testing such as this supposed to increase specificity. Prev=45%
    Here, SENS=69% spec=95% ppv=90% npv=80%
    Sens not sig. better (81% overall). Allowed 81% reduction in FP, thus possibly avoiding unneeded testing in some.
    Other studies had conflicting results Khan K, et al. Inflamm Bowel Dis 2002;8:325
    50% new CD pts had – serology
    ASCA+ also often had + routine markers inflammation
    Accounting for rectal bleeding, markers of inflam and serology, Only 76% identified as possibly having IBD prior to an endoscopy
    Thus, - serology may not preclude an endoscopic exam
  • North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America
  • How did ASCA do?
    Secondary aim of study that looked at performance of different assays in a known population.
    Again, if ASCA+, especially in a high-prev population, it is CD. Otherwise, it offers little help.
  • What about ASCA/ANCA?
    97 pts w/u extensively for IC, still couldn’t tell which.
    Serology applied, then followed to see if declared. over 9.9 year f/u
    32% declared by about 6 years. No more into about 10 yrs f/u (longer IC, longer stay in IC).
    1/3 ASCA+/ANCA-, ¼ ASCA-/ANCA+, small amount both+, 48% all -
  • differentiate ANCA+ UC-like CD (CBir1+) from ANCA+ UC (CBir1-)
  • Mean interval from serology to detection was 38 months
  • Eighty-five percent responded to at least 1 antigen
    only 4% responded to all 4
    Among microbial antigens, 78% responded to at least 1, and 57% were double positive, but only 26% responded to all 3.
    The level of response was stable over time and with change in disease activity.
    Among patients with the same qualitative antigen-response profiles, quantitative response differed.
    Cluster analysis of these antibody responses yielded 4 groups
    CONCLUSIONS: Rather than global loss of tolerance, there seem to be patient subsets with differing responses to selected microbial and autoantigens
  • This study looked at Sera from 156 consecutive CD patients and compared to clinical profiles.
    higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours.
    Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour.
  • Retrospective evaluation of 303 pts
  • 797 pt. prospective pediatric CD cohort; assessed for:
    CARD15 mutations
    Anti-CBir1, anti-OmpC, ASCA
  • Appears to be “dose dependent” for cumulative incidence pouchitis
  • No ASCA/ANCA relation to TNF in in 279 Belgian CD pts52
    Subanalysis of RCT in moderate ileal +/- R colon CD for budesonide/FLagyl
  • Crohn’s With Neo-TI & Colonic Disease
    Better evaluation of colon than with SIFT
  • 259 pts randomized to CC vs CE (indigo carmine)
    995 consecutive patients evaluated with CC vs indigo-carmine CE+mag.
    260 pts randomized to pan-CE vs. targeted CE
  • 165 UC pts: methylene blue
  • Suggests random bx not very efficient
  • PowerPoint Slides

    1. 1. Novel Diagnostic Strategies in Inflammatory Bowel Disease Mark H. Flasar, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology
    2. 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. 3. All That in 30 Minutes??? “THAT’S UN- POSSIBLE!”
    4. 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. 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. 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. 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. 8. ASCA, pANCA for IBD vs. Healthy 13. Vermeire S, et al. Gastroenterology 2001;120:827 0 10 20 30 40 50 60 70 Norm al UC UC w ith C olectom yCollagenous Colonic CD Infectious IBS M isc %ofPatients 60% sensitive 94% specific for UC Duerr R. H. et al. Gastroenterology 1991;100:1590 pANCA+
    9. 9. ASCA, pANCA for IBD vs. Healthy 14. Peeters M, et al. Am J Gastroenterol 2001;96:730
    10. 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. 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. 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. 13. ASCA for CD vs. UC 16. Vermeire S, et al. Gastroenterology 2001;120:827
    14. 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 help18 Sensitivity Specificity PPV NPV ASCA+/ANCA- CD 67% 78% 80% 64% ASCA-/ANCA+ UC 78% 67% 64% 80%
    15. 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. 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. 17. Prevalence effects on PPV, NPV
    18. 18. Serology Panel: Effects of Prevalence 59% Prevalence 15% Prevalence IB D 93% Sens PPV 96% 75% 95% Spec NPV 90% 99% CD 88% Sens CD PPV 96% 74% 98% Spec CD NPV 93% 100% UC 93% Sens UC PPV 89% 73%
    19. 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. 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. 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. 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. 23. Antibody Expression Correlates with Clinical Characteristics 34. Vasiliauskas EA, et al. Gut 2000;47:487
    24. 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. 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. 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. 27. “Dose response” of + Ab in CD Number of + Abs (ASCA, OmpC, I2) 0 1 2 3 SB Disease 44% 51% 56% 82% Progression 24% 52% 73% 87% FS 29% 55% 54% 71% SB Surgery 32% 57% 52% 89% 39. Arnott ID, et al. Am J Gastroenterol 2004;99:2376
    28. 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. 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. 30. UC progression/phenotype pANCA+ higher probability of – severe L-sided dz – treatment-resistance – aggressive course with earlier surgery51 – pouchitis after IPAA35,52
    31. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 44. CT Enterography Abscess seen better after positive oral contrast
    45. 45. CT Enterography Normal Terminal Ileum
    46. 46. CT Enterography Active Disease
    47. 47. CT Enterography
    48. 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
    49. 49. Performance of Various Imaging Modalities vs.Ileoscopy in CD Patients Sensitivity Specificity Bodily KD, et al. Radiology 2006;238:505 CTE 70% 97% Wold PB, et al. Radiology 2003;229:275 CTE 78% 83% CT enteroclysis 75% 100% SBFT 62% 90% Diagnostic Yield of Various Imaging Modalities in CD Patients Yield Hara AK, et al. Radiology 2006;238:128 WCE 71% Ileoscopy 65% CTE 53% SBFT 24%
    50. 50. CT Enterography CTE compared to operative findings in 36 CD patients103 CTE correctly identified – 100% strictures (83% accuracy) – 100% abscesses – 94% fistulae (86% accuracy for # fistulae) – 97% inflammatory mass Overestimated or underestimated disease extent in 31% – Stricture, fistula, inflammatory mass, abscess counts
    51. 51. Chromoendoscopy (CE) Conventional Colonoscopy (CC) surveillance – 2-4 bx every 10cm in colon, q5cm in rectum – Known miss rates for even for visible exophytic lesions » Tandem endoscopy studies 15-24% adenomas <1 cm missed55-6 » Similar results for colectomy specimens vs. preop colonoscopy57
    52. 52. Chromoendoscopy (CE) – Flat and depressed lesions have premalignant importance58 » Can look like normal mucosa endoscopically (easy miss) » Depressed can become invasive early on » Only 20-50% intraepithelial neoplasia detected with CC59 – Even miss rate for CRC » 4% CRC colectomy pts had “normal” colonoscopy in preop 6-36mo60
    53. 53. Chromoendoscopy (CE) Chromo= dyes applied to mucosa during endoscopy – highlight and better characterize specific mucosal changes – Allows visualization of otherwise invisible mucosal changes » enhancing detection and accuracy – Absorptive, reactive, and contrast staining dyes » Indigo carmine: nonabsorbed; collects in mucosal depressions » Methylene blue: absorbed in normal cytoplasm; irregularities pale » Cresyl violet: taken up in crypts of Leibeukuhn; appears as dots/pits. Pit patterns have histologic correlates. Can be used with the above 2 stains
    54. 54. Chromoendoscopy (CE) CC poorly detects flat/depressed lesions – Requires more meticulous training and examination Chromo +/- mag. detection of flat/raised neoplasia – In R colon and in pts w/multiple adenomas61 – In non-IBD pts with hx adenomas62 – In screening population adenomas randomized to CC vs. CE63 » Better detection of adenomas with pan-CE (espec. diminutive lesions)
    55. 55. Chromoendoscopy in IBD HRCE better detection (esp. flat) in 85 UC patients64 165 UC pts randomized to CC vs CE65 – CE better an defining degree/extent inflammation – CE better at dysplasia detection than CC (32 v 10 lesions) 100 UC surveillance pts got sequential CC and CE65 – Pan-CE with target bx after standard CC bx protocol » CC: ALL 2,904 random bx neg; 2/43 target bxdysplasia » CE: 7/114 target bxdysplasia
    56. 56. Chromoendoscopy in IBD 350 UC pts had HMCE matched to UC controls w/CC66 – Target bx AND 4-quadrant randoms HMCE – Detected sig. more lesions – Alone detected 79% of dysplasia – 0.16% random bx + – 8% targeted bx + CC – 0.14% random bx + – 1.6% target bx +
    57. 57. Chromoendoscopy in IBD Dye spraying adds about 10 minutes to colonoscopy67 Abandoning random bx will shorten procedure Should be pretty even in terms of time after learning curve Recent CCFA committee on IBD CRC/dysplasia surveillance endorses CE in “appropriately trained endoscopists”68
    58. 58. Rectal EUS 20-30% CD develop perianal disease103 – Diagnostics include MRI, fistolography (radiating, inaccurate vs surgery, painful, cannot delineate relation to perianal structures), CT (radiating, limited for fistula), EUA EUS has emerging role – Accurate imaging of perianal region preoperatively » Road-mapping; theoretically reduce risk incontinence – Therapeutic (abscess drainage) – Safe – Can assess response to therapy » Superficial fistula closure may not herald deep tract closure
    59. 59. Rectal EUS Can accurately delineate EAS, IAS, and pathologic defects Identified 82% fistula c/w EUA in unblinded series – Better performance than fistulography105 EUS detected 82% fistula vs 24% by CT c/w EUA+fistulography – No difference in abscess detection106 Anal endosonography (AES) 100% sensitive vs. 55% for MRI in detecting perianal abscesses found at EUA – AES 89% sensitive vs. 48% for MRI in fistula detection107
    60. 60. Rectal EUS Prospective, blinded study of EUS, MRI, EUA vs. “consensus gold standard” – Accuracy EUS 91%, MRI 87%, EUA 91% – Combination of any 2 modalities increased accuracy to 100%108 To assess medical response: – IFX trial: AES at entry and 10 weeks in 30 perianal CD pts109 » 54% had week 10 clinical closure; only 18% closed by AES » Those with week 10 closure on AES had sig. lower relapse rates – 21 perianal CD pts with baseline, serial EUS during surgical/medical rx110 » 52% showed no persistent fistula activity; 64% of these able to stop rx
    61. 61. Rectal EUS Future: – Contrast-enhanced EUS: 3% Hydrogen peroxide – 3D-EUS – Both methods likely comparable111
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