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Biomarkers Managing IBD Stephen B. Hanauer, MD University of Chicago.

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Presentation on theme: "Biomarkers Managing IBD Stephen B. Hanauer, MD University of Chicago."— Presentation transcript:

1 Biomarkers Managing IBD Stephen B. Hanauer, MD University of Chicago

2 + IBD subtype: UC CD/UC Crohn’s Diseases and Ulcerative Colitides Traditional Clinical Parameters: CD Genetic markers Serum immune markers Cytokine profile Enzyme activity Metabolite levels Genetic, Serologic, and Biochemical Profiles:

3 Role of Biomarkers in IBD Disease Classification Disease Activity Prognosis

4 Defining IBD CDUC 20 th Century Classic names Abreu MT, et al. Clin Perspect Gastroenterol. May/June 2001; IBD1IBD2IBD3IBD4 Severe Disease Mild Disease 21 st Century Names based on mechanisms

5 IBD Serologies pANCA ASCA OMPc Anti-I2 CBir1

6 Differential Diagnosis: Serological Markers Quinton J-F et al. Gut. 1998;42:788. % Patients with Positive ASCA and ANCA Test Results CDUCMiscellaneousControls (n=100) (n=101) non-IBD (n=163) (n=28) Anti-saccharomyces cervisiae antibody (ASCA) Perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) ASCA Specific for CD ANCA Sensitive For Colitis

7 Percentage (%) Accuracy of ANCA and ASCA to Differentiate UC from CD Peeters M, et al. Am J Gastroenterol. 2001;96: ASCA+ (CD) pANCA+ (UC) ASCA+/pANCA- (CD) pANCA+/ASCA- (UC) 0 SensitivitySpecificityPPV

8 The Value of Serologic Markers in Indeterminate Colitis (IC) Study Design: 97 patients with IC from 3 centers analyzed for pANCA and ASCA Patients prospectively analyzed since 1996 Follow-up time from inclusion  1 year for each patient Mean disease duration at time of publication, 10.7 years MarkerDiagnosisSensitivitySpecificityPPVNPV ASCA + / pANCA – CD67%78%80%64% ASCA – / pANCA + UC78%67%64%80% Joossens S, et al. Gastroenterology. 2002;122:

9 The Value of Serologic Markers in IC pANCA+/ ASCA – ASCA+/ pANCA – Standard Markers 70%UC 67%CD PPVDiagnosis 83% 75% PPV pANCA+/ ASCA-/ OmpC- /I2- OmpC New Markers 72% remain IC Joossens SB, et al. Gastroenterology. 2003;124(suppl1):A-323. Abstract M1174.

10 Summary of pANCA/ASCA pANCA is sensitive for “colitis” –Does not differentiate UC from CD –High titers associated with risk of pouchitis ASCA is specific for “classic” (small bowel) Crohn’s –Rarely positive in indeterminate colitis without small bowel disease

11 AntibodyAntigen Non- IBD (%) CD (%) UC (%) DNase Sensitive pANCA Histone H 1, bacterial antigen? <5% 10– 25% 50– 65% ASCA Anti- Saccharomyces cerevisiae antibody 5% 55– 65% 5% OmpCE. coli<5% 38– 50% 2% Anti-I2 Pseudomonas fluorescens <5%54%2% Anti-FlagellinCBir 1 Antigen8-14%50%6% IBD Specific Serologic Immune Markers

12 Interrelationships of Serum Immune Responses to Microbial Antigens in CD ASCA + I 2 + OmpC + Landers et al, Gastro. 123: , 2002 All Negative 22% 12% 2% 7% 26% 9% 13% CBir1 ???

13 Serology as a predictor of Disease Behavior

14 Frequency of Disease Behavior % Number of Immune Responses Antibody Sum and Disease Behavior NPNS IP S * Odds Ratio 0 N=199 1 N=262 2 N=194 3 N=57 Surgery P trend < * 2.2 * 1.0 * 5.0 * 9.5 * 1.7 * 1.0 * 4.2 * 6.1 P trend < Dubinsky et al, Gastroenterology 2007; 132: 82

15 ASCA and Surgery Amre et al, Am J Gastroenterol. 2006;101:645. Significant difference in time to first surgery observed in patients ASCA positive Time in Days Proportion Acquiring First Surgery P < Either ASCA negative Either ASCA positive

16 78 % 22 % High Level Pre-operative pANCA Predicts Chronic Pouchitis Incidence of Pouchitis (%) 41 % P=0.03 Fleshner PR et al., Gut 2001;49

17 IBD-7 Panel Combines pANCA/ASCA/OmpC/Anti- I2/CBir1 profiles Provides composite prediction of UC/CD patterns vs. non-IBD Does NOT provide individual probabilities Not clinically intuitive –e.g. Low titer OmpC + alone may predict UC?

18 New serologic markers: carbohydrate antigens Anti-glycan antibodies: Anti-laminaribioside carbohydrate (ALCA) Anti-chitobioside carbohydrate (ACCA) Anti-mannobiodside (AMCA) IgG gASCA IgA Omp ALCA 8.9% 2.7% 4.9% 8.0% 15.9% AMCA 6.8% ACCA gASCA positive CD n=515 Ferrante M, et al. DDW 2006, Los Angeles. Abstract # well-characterized patients Only gASCA 43.9% 8.9%

19 Serological markers can be used to discriminate IBD vs non-IBD gASCAALCAACCAAMCA SensSpecPPVSensSpecPPVSensSpecPPVSensSpecPPV CD vs UC IBD vs non-IBD GI IBD vs HC CSS ≥1.0CSS ≥1.5CSS ≥2.0CSS ≥2.5 SensSpecPPVSensSpecPPVSensSpecPPVSensSpecPPV CD vs UC IBD vs non-IBD GI IBD vs HC Individual markers Combined scores Ferrante M, et al. DDW 2006, Los Angeles. Abstract #129

20 Serological markers to carbohydrate Ags can be used to predict CD course Complicated disease course OR: 2.00 p=0.001 OR: 1.96 p=0.010 Ferrante M, et al. DDW 2006, Los Angeles. Abstract #129 % patients Need for abdominal surgery OR: 1.56 p=0.033 OR: 1.45 p=0.072 OR: 2.81 p<0.001 Score <1.5 Score 1.5 or 2.0 Score 2.5 or 3.0 Score >3.0 Score <1.5 Score 1.5 or 2.0 Score 2.5 or 3.0 Score >3.0 OR=odds ratio; p-value (Chi-square) OR: 1.76 p=0.006

21 Serologic Markers: Current Status pANCA is sensitive for colitis and high titers are bad prognosis for pouchitis ASCA is specific for small bowel Crohn’s disease and high titers are bad prognosis for transmural complications OmpC, Anti-Flagellin and I2 add sensitivity and specificity for Crohn’s disease Predictive value is too low for clinical utility

22 ECCO Recommendations No evidence based recommendation can be made with regards to the routine clinical use of: - genetic tests - stool markers - serologic markers (ASCA, ANCA,…ompC, I2, flagellin) - permeability testing - Phenotype driven classifications (5,D)

23 C-Reactive Protein High CRP better separates placebo from drug responders –Natiluzimab, CDP-571, CDP-870, Infliximab, Adalimumab, HuZaf No distinct cut-off for CRP Other biologic markers if low CRP –Fistula response, mucosal healing? Currently not a regulatory criteria but improves “efficiency” of trials

24 CDAI and CRP Relationship at Baseline (logarithmic scale)

25 How to assess/treat these patients? CDAI/CRP at Baseline ULN High CDAI-High CRP High CDAI-Low CRP Low CDAI- High CRP Low CDAI- Low CRP

26 How to assess/treat these patients? CDAI/CRP at Baseline ULN High CDAI-High CRP High CDAI-Low CRP Low CDAI- High CRP Low CDAI- Low CRP High Responder

27 How to assess/treat these patients? CDAI/CRP at Baseline ULN High CDAI-High CRP High CDAI-Low CRP Low CDAI- High CRP Low CDAI- Low CRP High Placebo Response

28 How to assess/treat these patients? CDAI/CRP at Baseline ULN High CDAI-High CRP High CDAI-Low CRP Low CDAI- High CRP Low CDAI- Low CRP Clinical Remission

29 How to treat these various patients? CDAI/CRP at Baseline ULN High CDAI-High CRP High CDAI-Low CRP Low CDAI- High CRP Low CDAI- Low CRP Early Relapse

30 Conclusions CRP CRP is a predictor of placebo response Efficacy signals in recent clinical trails may have been obscured by placebo responses in CRP low patients

31 ECCO Recommendations Regarding CRP Serum levels of CRP are useful to assess the patients’ risk for a relapse (B). High CRP levels are indicative of active disease (B) or a bacterial complication (C). CRP levels can be assessed to guide therapy and follow up (B).


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