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Diagnostic Testing in IBDIU GI Update 2012
Michael Chiorean, MDAssociate Professor of Medicine
Indiana University School of Medicine
Disclosures
• Given, Inc.• Abbott Immunology• Janssen• UCB
Objectives
• Understand diagnostic paradigms in IBD
• Review the evidence for the use of serum and fecal biomarkers in IBD
• Review the role and limitations of imaging studies in IBD diagnosis
Diagnostic Levels in IBD
• Initial diagnosis– High accuracy– Cost-effective
• Response to therapy:– Mucosal healing– Structural damage– Post-operative recurrence
• Diagnosis of complications:– Structural damage
• Strictures, fistulas, abscesses– Malignancy
Identifying disease
Assessing responseto therapy
Defining disease phenotypeAssessing lack of response or
unexplained symptoms
The Role of Serum Inflammatory Markers in IBD
CRP and ESR in IBD v. IBS
Dolwani et al. Aliment Pharmacol Ther 2004; 20: 615–621
ESR ≥10mm/hr
CRP≥ 6mg/L
ESR ≥ 10mm/hr & CRP ≥ 6mg/L
Sensitivity, % 79 77 50
Specificity, % 67 70 84
PPV, % 42 42 50
NPV, % 91 91 84
Limitations of Serum Inflammatory Markers
• Limited accuracy– Non-specific– CRP non-reactive in 10% of individuals– ESR has long half-life
• No role in the diagnosis of complications• No data in post-operative recurrence
Langhorst et. al. Am J Gastroenterol 2008;103:162-169Lewis JD Gastorenterology 2011; 140:1817-1826
Boirivant et al. J Clin Gastroenterol 1988;10:401–5
CRP in predicting CD course
Likelihood of relapse at 2 years
CRP < 0.5
CRP > 0.5
Corticosteroid-Free Clinical Remission at Week 26 by Baseline CRP in SONIC
9
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)p<0.001
p=0.004 p=0.027
p=0.121
p=0.503 p=0.314
25/71 27/67 35/69 27/9848/10161/96
Post-hoc sub-analysis
Colombel et al. – NEJM ’10; appendix
Fecal Inflammatory Biomarkers in IBD Diagnosis
Fecal Inflammatory Biomarkers in IBD Diagnosis
• Calprotectin– Ca and Zn binding protein in cytosol of neutrophils– Stable up to 7 days at room temperature– Concentration in stool correlates with neutrophil
infiltrate in the bowel mucosa (whole bowel)• Lactoferrin
– Iron binding protein found in neutrophil granules and serum
– Requires freezing after 24 h d/t degradation
Lewis J – Gastro ‘11
Fecal Inflammatory Markers
• Advantages
• Sensitive• Full bowel screen• Detect inflammation
in patients without elevated CRP
• Stool studies routinely collected in IBD (C Diff)
• Inexpensive
• Disadvantages
• Non-specific• NSAIDs• Infections• Malignancy
Accuracy of Fecal Calprotectin in IBD Diagnosis
• Pooled data from 30 studies/5983 patients, IBD vs. Controls
• Different studies using different thresholds (50-100 mcg/g)
• Sensitivity 89-98%• Specificity 81-91%
• Von Roon – Am J Gastro ‘07
Fecal Calprotectin in Suspected IBD
• Meta-analysis of 6 studies (adults + peds) with suspected IBD based on symptoms
• Pre-test probability 42%• Fecal Calprotectin:
– sensitivity 93% and specificity 96%• Conclusions:
– Use of calprotectin would prevent a large number of patients from undergoing further testing
– Delayed diagnosis would occur in 6% of patients
Van Rheenan et. al. BMJ 2010; 341:c3369.
Correlation of Biomarkers with Disease Activity
Study Patients Endoscopic Index
Lactoferrin (correlation)
Calprotectin (correlation)
CRP(correlation)
Sipponen ‘08 CD CDEIS 0.77 0.73 0.55
D’Inca ’07 CD SES-CD 0.19 0.48
D’Inca ’07 UC Mayo 0.35 0.51
Hanai ’04 UC Matt 0.81
Siponnen ’08 CD SES-CD 0.63 0.64 0.52
Fagerberg ’07 IBD - 0.52
Roseth ’97 UC Mayo 0.57
Jones ’08 CD SES-CD 0.76 0.72 0.46
Sipponen ’08 CD CDEIS 0.87 0.83 0.5
Schoepfer ’09 UC Rachmilewitz 0.83 0.5
Schoepfer ’10 CD CDEIS 0.75 0.53
Fecal Calprotectin in Predicting IBD Exacerbations
Study Population Calprotectin threshold
Relapse with low Calprotectin (%)
Relapse with high Calprotectin (%)
Gisbert ’09 UC 150 9 31
Tibble ’00 UC 50 10 85
Tibble ’00 CD 50 15 85
Costa ’05 UC 150 10 81
Costa ’05 CD 150 57 87
D’Inca ’08 UC 130 30 79
Sipponen ’10 UC+CD 100 25 39
Walkiewicz ’08 CD 400 11 56
Pooled Δ relapse with low and high: 14-75% (average: 47%)
Time to Relapse Curve after Infliximab Withdrawal in STORI
• Louis et al. – Gastro ‘12
n=115 patients with Crohn’s in remission on combination therapy at time “0”
Predictors of Relapse after Withdrawal of Infliximab in STORI
• Louis et al. – Gastro ‘12
Risk factorComplete Multivariate
Model Simplified Model
HR (95% CI) p-value HR (95% CI) p-value
Corticosteroid use before baseline 3.5 (1.1–10.7) 0.03
No previous surgical resection 4.0 (1.4–11.4) 0.01 4.2 (1.5–11.6) 0.005
Male sex 3.7 (1.9–7.4) 0.001 3.5 (1.7–7.0) 0.001
Hgb < 14.5 g/dL 6.0 (2.2–16.5) 0.001 5.5 (2.0–15.5) 0.001
WBC count > 6 x 109/L 2.4 (1.2–4.7) 0.01 1.9 (1.0–3.5) 0.05
CDEIS > 0 2.3 (1.1–4.9) 0.04
hsCRP > 5 mg/L 3.2 (1.6–6.4) 0.001 2.7 (1.3–5.3) 0.005
Infliximab trough level > 2 mg/L 2.5 (1.1–5.4) 0.005
Fecal calprotectin > 300 mcg/g 2.5 (1.1–5.8) 0.04 3.1 (1.3–7.2) 0.01
IBD Serological Markers
ASCA and pANCA in Differential Diagnosis of IBD
• Meta-analysis of 60 studies with 7860 patients• ASCA and pANCA status• IBD vs. Non-IBD (ASCA+ and/or pANCA +)
– Sensitivity 62.6%– Specificity 92.6%– pANCA had higher overall accuracy (likelihood ratio)– If ASCA+ and pANCA+
• Sensitivity 6%• Specificity 97%
Reese et. al. Am J Gastroenterol 2006;101:2410-2422
ASCA and pANCA in Differential Diagnosis of IBD
• Crohn’s disease vs. UC (IgA and IgG ASCA+, pANCA-)– Sensitivity 55%– Specificity 93%
• For patients with Crohn’s colitis:– Sensitivity 36%– Specificity 90%– pANCA+ in 15-25% of patients (non-specific)
• 50% of ASCA+ and pANCA+ will develop classic CD• 50% will evolve into UC or remain IC
Reese et. al. Am J Gastro ‘06;101:2410-2422; Joossens et al. – Gastro ‘02
ASCA and pANCA in Differential Diagnosis of IBD
• UC vs. Crohn’s disease (pANCA+)– Sensitivity 55%– Specificity 88%
• Combination pANCA+ and ASCA-– Sensitivity 51%– Specificity 94%
Reese et. al. Am J Gastroenterol 2006;101:2410-2422
ASCA and pANCA in Differential Diagnosis of IBD
• Pediatric Population– ASCA+ less sensitive and more specific for CD
• 42% and 96% respectively– pANCA+, ASCA- more sensitive and specific
• 70% and 93% respectively• DNAse Usage (used in the IBD-7 panel)
– Improvement in sensitivity but drop in specificity• Disease behavior (8 studies)
– 7 showed no difference among inflammatory, stenosing or penetrating phenotypes
Reese et. al. Am J Gastroenterol 2006;101:2410-2422
Cost of Biomarkers
• CBC $28• CRP $35• Fecal markers: $40-60• IBD7 panel: $425
Summary
• Fecal markers of inflammation are helpful in the diagnosis of IBD.
• The low sensitivity of the serological markers precludes their use in diagnosis of IBD.
• The IBD7 panel is more expensive and less accurate than fecal markers.
The Role of Capsule Endoscopy in the Diagnosis of Crohn’s Disease
Capsule Endoscopy Has the Highest Yield in Patients with Suspected and Established
Crohn’s Disease• Meta-analysis of 30 trials (1008 patients)
comparing VCE with alternate modality
• Dionisio et al. – Am J Gastro ‘10
Comparison Incremental Yield 95% CI
CE vs. Push Enteroscopy 0.42 0.31, 0.53
CE vs. SBFT 0.37 0.29, 0.45
CE vs. CTE 0.39 0.27, 0.50
CE vs. Colonoscopy 0.15 0.07, 0.24
CE vs. MRE 0.07 -0.04, 0.17
Small Bowel Ultrasound for the Diagnosis of Crohn’s Disease
• Advantages– Accessible– Non-invasive– No radiation– Inexpensive
• Disadvantages– Limited availability in the US
Role of Ultrasound in the Detection of Crohn’s Disease
• Meta-analysis of 7 studies in adult patients (282 CD and 975 controls)
• Fraquelli et al. – Radiology ‘05
Overall Wall thickness>3 mm
Wall thickness>4 mm
Sensitivity 75-94% 88% 75%
Specificity 67-100% 93% 97%
Contrast-Enhanced US for the Assessment of Crohn’s Disease
• 47 consecutive patients (30 active CD by CDAI)• Underwent baseline US, Doppler and contrast-
enhanced US (sulfur-hexafluoride-filled micro-bubbles)– Morphology (thickness, layering, length)– Contrast enhancement and perfusion– Vascular pattern
• Comparison with endoscopy and histology• Determined correlation with CDAI
• Migaleddu et al. – Gastro ‘09
Contrast-Enhanced US for the Assessment of Crohn’s Disease
• Migaleddu et al. – Gastro ‘09
Contrast-Enhanced US for the Assessment of Crohn’s Disease
• Baseline US (thickness, layering, length):– Sensitivity 70-90% (highest for thickness)– Specificity 80-100%
• CE-US showed the highest accuracy and best correlation with CDAI:– Sensitivity and specificity: 94%– r=0.74
• CD-US had similar accuracy with CE-US
Ultrasound Elastography for Detecting Intestinal Inflammation and Fibrosis
• Ultrasound-based technology that identifies the degree of strain (stress) in tissues based on speckle tracking– Hard tissues less compression less strain
• Stidham et al. – Gastro ‘11
Ultrasound Elastography for Detecting Intestinal Inflammation and Fibrosis
• Able to differentiate acutely inflamed vs. chronically fibrotic bowel wall in 11 rats and 7 human subjects
• Requires minimal training (software-generated score)
• Stidham et al. – Gastro ‘11
CT Enteroclysis and Enterography
• Has been the SB imaging “gold” standard in the US
– Initial diagnosis– Disease extent– Disease phenotype
• Inflammatory• Fibro-stenotic• Penetrating – fistulizing
– Complications
CT Enteroclysis and Enterography
• Correlates fairly well with biologic and endoscopic disease activity– CRP higher in patients with peri-enteric
inflammation and mesenteric stranding– Bowel enhancement correlates with endoscopic
(Spearman r=0.39) and histological (r=0.38), but not with CRP (r=0.06)
• Colombel et al. – Gut ‘06
CT Enteroclysis and Surgical Pathology
• Predictors of histological inflammation– Wall thickness– Mucosal enhancement0– Comb sign*– Adenopathy*
• Predictors of fibrosis– Stricture severity (r=0.43, p<0.007)– Pre-stenotic dilation0
• Chiorean et al. – Am J Gastro ‘07
Limitations of CTE
• Invasive (enteroclysis) and poorly tolerated– >90% of patients prefer enterography in 1 study
• Radiation exposure• Lack of standards for disease severity and
definition of complications– Sensitivity for strictures: 30-90%– Specificity: 30-60%
• Voderholzer et al. – Gut ’05; Chiorean et al. – Am J Gastro ‘07
Limitations of CTE
• Stricture false-negatives: 5-50%– Higher for isolated short strictures < 2 cm
• Series of 56 patients evaluated for CD with CTE vs. capsule endoscopy– 15 were excluded d/t strictures at baseline CTE– Of 41 remaining patients, 2 retained the capsule
proximal to missed strictures
• Voderholzer et al. – Gut ‘05
CTE vs. MRE
CT vs. MR Enterography in Crohn’s Disease
• CTE
• Advantages– Widely available– Fast
• Disadvantages– Radiation exposure
• MRE
• Advantages– No radiation– Extensive image
processing– “Functional” imaging
• Disadvantages– Slower– Limited expertise– Cost
CT vs. MRE for Crohn’s Disease Diagnosis
• Retrospective cohort of 44 patients undergoing CTE, MRE and colonoscopy
• No difference in accuracy for– Localization– Bowel wall thickening and enhancement– Fistulas, abscesses– Lymphadenopathy and mesenteric fat
enhancement• MRE significantly superior in detecting
strictures– Sensitivity 92% vs. 85% (p=0.04)
• Fiorino et al. – IBD ‘11
Interobserver Agreement for CTE and MRE in Crohn’s Disease
MRE CTESmall bowel CD 0.48 (0.32-0.63) 0.64 (0.47-0.77)
Bowel wall thickening 0.43 (0.27-0.58) 0.56 (0.40-0.70)
Bowel wall enhancement 0.50 (0.34-0.65) 0.72 (0.56-0.83)
Creeping fat 0.39 (0.22-0.47) 0.43 (0.26-0.60)
Stenosis 0.71 (0.44-0.86) 0.54 (0.31-0.72)
• Jensen et al. – IBD ‘11
Conclusions
• Serum and fecal biomarkers have a role in the diagnosis and monitoring disease activity in patients with IBD
• VCE is probably the most sensitive test for detecting SB Crohn’s disease
• Competing safer technologies are likely to challenge the role of CTE in the diagnosis of Crohn’s disease and associated complications