Presentation on theme: "Biomarkers Managing IBD"— Presentation transcript:
1 Biomarkers Managing IBD Stephen B. Hanauer, MDUniversity of Chicago
2 Traditional Clinical Parameters: Genetic markersSerum immune markersCytokine profileEnzyme activityMetabolite levelsGenetic, Serologic, and Biochemical Profiles:+123Crohn’s DiseasesandUlcerative ColitidesCDUCFigure 1CD/UCIBD subtype:14234132
3 Role of Biomarkers in IBD Disease ClassificationDisease ActivityPrognosis
4 Names based on mechanisms Defining IBDCDUC20th CenturyClassic namesIBD1IBD2IBD3IBD4Severe DiseaseMild Disease21st CenturyNames based on mechanismsAbreu MT, et al. Clin Perspect Gastroenterol. May/June 2001;
6 Differential Diagnosis: Serological Markers 10080604020ASCA Specific for CDAnti-saccharomyces cervisiae antibody (ASCA)Perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)ANCA SensitiveFor Colitis% Patients with Positive ASCAand ANCA Test ResultsCD UC Miscellaneous Controls (n=100) (n=101) non-IBD (n=163) (n=28)Quinton J-F et al. Gut. 1998;42:788.
7 Accuracy of ANCA and ASCA to Differentiate UC from CD SensitivitySpecificityPPV1009795949191888078696060Percentage (%)5650404420ASCA+(CD)pANCA+(UC)ASCA+/pANCA-(CD)pANCA+/ASCA-(UC)Peeters M, et al. Am J Gastroenterol. 2001;96:
8 The Value of Serologic Markers in Indeterminate Colitis (IC) Study Design:97 patients with IC from 3 centers analyzed for pANCA and ASCAPatients prospectively analyzed since 1996Follow-up time from inclusion 1 year for each patientMean disease duration at time of publication, 10.7 yearsMarkerDiagnosisSensitivitySpecificityPPVNPVASCA+/ pANCA–CD67%78%80%64%ASCA–/ pANCA+UCJoossens S, et al. Gastroenterology. 2002;122:
9 The Value of Serologic Markers in IC pANCA+/ASCA–ASCA+/ pANCA–Standard Markers70%UC67%CDPPVDiagnosis83%75%PPVpANCA+/ ASCA-/ OmpC- /I2-OmpCNew Markers72% remain ICJoossens 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 CDHigh titers associated with risk of pouchitisASCA is specific for “classic” (small bowel) Crohn’sRarely positive in indeterminate colitis without small bowel disease
14 Antibody Sum and Disease Behavior NPNSP trend <*2.21.05.09.5IP*1.71.04.26.1P trend <SSurgeryFrequency of Disease Behavior %N=1991N=2622N=1943N=57* Odds RatioNumber of Immune ResponsesDubinsky et al, Gastroenterology 2007; 132: 82
15 Proportion Acquiring First Surgery ASCA and Surgery1.000.75P < 0.001Proportion Acquiring First Surgery0.500.25Either ASCA negativeEither ASCA positive0.0050010002000Time in DaysSignificant difference in time to first surgery observed in patients ASCA positiveAmre et al, Am J Gastroenterol. 2006;101:645.
16 High Level Pre-operative pANCA Predicts Chronic Pouchitis 78 %Incidence of Pouchitis (%)41 %22 %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-IBDDoes NOT provide individual probabilitiesNot clinically intuitivee.g. Low titer OmpC + alone may predict UC?
18 New serologic markers: carbohydrate antigens 913 well-characterized patientsAnti-glycan antibodies:Anti-laminaribioside carbohydrate (ALCA)Anti-chitobioside carbohydrate (ACCA)Anti-mannobiodside (AMCA)IgG gASCAIgA OmpOnly gASCA 43.9%ALCA 8.9%2.7%8.0%4.9%Ferrante--from Leuven groupLaminaribioside, chitobioside mannobiodside is found in cell walls of pathogenic bacteria and fungi6.8%15.9%gASCA positive CD n=5158.9%ACCAAMCAFerrante M, et al. DDW 2006, Los Angeles. Abstract #129
19 Serological markers can be used to discriminate IBD vs non-IBD Individual markersgASCAALCAACCAAMCASensSpecPPVCD vs UC56909518932185822884IBD vs non-IBD GI459810015991926IBD vs HC868991Combined scoresCSS ≥1.0CSS ≥1.5CSS ≥2.0CSS ≥2.5SensSpecPPVCD vs UC746186548391379394209796IBD vs non-IBD GI668298451003016IBD vs HC99HC= healthy controlsNon-IBD GI--intestinal inflammation, no IBDGot score of 0, 0.5 or 1 for each Ab marker depending on whether negative, intermediate or high respectivelyCombinations of ASCA plus these new anti-carbohydrate markers improves the ability of tests to discriminate b/w Crohn’s disease and ulcerative colitis, inflammatory bowel disease vs. non-Inflammatory bowel disease intestinal inflammation. As the number and level of serologic markers increases, sensitivity decreases but specificity and PPV improvesFerrante M, et al. DDW 2006, Los Angeles. Abstract #129
20 Complicated disease course Need for abdominal surgery Serological markers to carbohydrate Ags can be used to predict CD courseComplicated disease courseNeed for abdominal surgeryOR: 1.96 p=0.010OR: 2.81 p<0.001% patientsOR: 2.00 p=0.001OR: 1.45 p=0.072OR: 1.76 p=0.006OR: 1.56 p=0.033Ferrante--from leuven group913 Crohn’s disease patients; 81% had complete phenotypic informationFor the 5 antibodies they assigned a score of 0 for negative, 0.5 for intermediate, 1 for high level for the highest score of 5-- COMPLICATED DISEASE COURSE means developing fistulas or stricturesScore <1.5Score 1.5 or 2.0Score 2.5 or 3.0Score >3.0Score <1.5Score 1.5 or 2.0Score 2.5 or 3.0Score >3.0Ferrante M, et al. DDW 2006, Los Angeles. Abstract #129OR=odds ratio; p-value (Chi-square)
21 Serologic Markers: Current Status pANCA is sensitive for colitis and high titers are bad prognosis for pouchitisASCA is specific for small bowel Crohn’s disease and high titers are bad prognosis for transmural complicationsOmpC, Anti-Flagellin and I2 add sensitivity and specificity for Crohn’s diseasePredictive value is too low for clinical utility
22 ECCO RecommendationsNo 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 ProteinHigh CRP better separates placebo from drug respondersNatiluzimab, CDP-571, CDP-870, Infliximab, Adalimumab, HuZafNo distinct cut-off for CRPOther biologic markers if low CRPFistula 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 Baseline CDAI150200250300350400450500Log CRP mg/L0.010.1110100Low CDAI-High CRPHigh CDAI-High CRPULNLow CDAI-Low CRPHigh CDAI-Low CRP
26 How to assess/treat these patients? CDAI/CRP at Baseline Baseline CDAI150200250300350400450500Log CRP mg/L0.010.1110100HighResponderLow CDAI-High CRPHigh CDAI-High CRPULNLow CDAI-Low CRPHigh CDAI-Low CRP
27 How to assess/treat these patients? CDAI/CRP at Baseline Baseline CDAI150200250300350400450500Log CRP mg/L0.010.1110100Low CDAI-High CRPHigh CDAI-High CRPULNHigh PlaceboResponseLow CDAI-Low CRPHigh CDAI-Low CRP
28 How to assess/treat these patients? CDAI/CRP at Baseline Baseline CDAI150200250300350400450500Log CRP mg/L0.010.1110100Low CDAI-High CRPHigh CDAI-High CRPClinicalRemissionULNLow CDAI-Low CRPHigh CDAI-Low CRP
29 How to treat these various patients? CDAI/CRP at Baseline Baseline CDAI150200250300350400450500Log CRP mg/L0.010.1110100EarlyRelapseLow CDAI-High CRPHigh CDAI-High CRPULNLow CDAI-Low CRPHigh CDAI-Low CRP
30 Conclusions CRP CRP is a predictor of placebo response Efficacy signals in recent clinical trails may have been obscured by placebo responses in CRPlow 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).