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