Diagnostic Testing in IBD       IU GI Update 2012Michael Chiorean, MD      Associate Professor of Medicine   Indiana Unive...
Disclosures•    Given, Inc.•    Abbott Immunology•    Janssen•    UCB
Objectives•    Understand diagnostic paradigms in IBD•    Review the evidence for the use of serum and    fecal biomarkers...
Diagnostic Levels in IBD•    Initial diagnosis                                                    Identifying disease    –...
The Role of Serum Inflammatory        Markers in IBD
CRP and ESR in IBD v. IBS                    ESR     CRP                ESR ≥ 10mm/hr                 ≥10mm/hr ≥ 6mg/L    ...
Limitations of Serum Inflammatory                  Markers•     Limited accuracy     –         Non-specific     –         ...
CRP in predicting CD course     Likelihood of relapse at 2 years                       CRP < 0.5                          ...
9         Corticosteroid-Free ClinicalRemission at Week 26 by Baseline CRP in SONIC                            Post-hoc su...
Fecal Inflammatory Biomarkers in           IBD Diagnosis
Fecal Inflammatory Biomarkers in               IBD Diagnosis•    Calprotectin     –         Ca and Zn binding protein in c...
Fecal Inflammatory Markers       •           Advantages                •                                         Disadvant...
Accuracy of Fecal Calprotectin in             IBD Diagnosis•    Pooled data from 30 studies/5983 patients,    IBD vs. Cont...
Fecal Calprotectin in Suspected IBD•    Meta-analysis of 6 studies (adults + peds) with    suspected IBD based on symptoms...
Correlation of Biomarkers with            Disease Activity                           Endoscopic      Lactoferrin    Calpro...
Fecal Calprotectin in Predicting IBD           Exacerbations                                   Calprotectin   Relapse with...
Time to Relapse Curve after     Infliximab Withdrawal in STORI          n=115 patients with Crohn’s in remission on combin...
Predictors of Relapse after    Withdrawal of Infliximab in STORI                                     Complete Multivariate...
IBD Serological Markers
ASCA and pANCA in Differential             Diagnosis of IBD•      Meta-analysis of 60 studies with 7860 patients•      ASC...
ASCA and pANCA in Differential             Diagnosis of IBD•      Crohn’s disease vs. UC (IgA and IgG ASCA+, pANCA-)      ...
ASCA and pANCA in Differential             Diagnosis of IBD•      UC vs. Crohn’s disease (pANCA+)       –           Sensit...
ASCA and pANCA in Differential             Diagnosis of IBD•      Pediatric Population       –           ASCA+ less sensit...
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 serologic...
The Role of Capsule Endoscopy inthe Diagnosis of Crohn’s Disease
Capsule Endoscopy Has the Highest Yield in Patients with Suspected and Established             Crohn’s Disease•    Meta-an...
Small Bowel Ultrasound for the         Diagnosis of Crohn’s Disease•    Advantages    –        Accessible    –        Non-...
Role of Ultrasound in the Detection         of Crohn’s Disease•    Meta-analysis of 7 studies in adult patients (282 CD an...
Contrast-Enhanced US for the        Assessment of Crohn’s Disease•    47 consecutive patients (30 active CD by CDAI)•    U...
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):    –     ...
Ultrasound Elastography for Detecting     Intestinal Inflammation and Fibrosis•     Ultrasound-based technology that ident...
Ultrasound Elastography for Detecting     Intestinal Inflammation and Fibrosis•     Able to differentiate acutely inflamed...
CT Enteroclysis and Enterography•  Has been the SB imaging “gold” standardin the US    –        Initial diagnosis    –    ...
CT Enteroclysis and Enterography•    Correlates fairly well with biologic and    endoscopic disease activity    –        C...
CT Enteroclysis and Surgical                 Pathology•    Predictors of histological inflammation    –        Wall thickn...
Limitations of CTE•    Invasive (enteroclysis) and poorly tolerated    –        >90% of patients prefer enterography in 1 ...
Limitations of CTE•    Stricture false-negatives: 5-50%    –        Higher for isolated short strictures < 2 cm•    Series...
CTE vs. MRE
CT vs. MR Enterography              in Crohn’s Disease•    CTE                      •                                 MRE•...
CT vs. MRE for Crohn’s Disease                  Diagnosis•    Retrospective cohort of 44 patients    undergoing CTE, MRE a...
Interobserver Agreement for CTE       and MRE in Crohn’s Disease                              MRE                CTESmall ...
Conclusions•    Serum and fecal biomarkers have a role in the    diagnosis and monitoring disease activity in    patients ...
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11 chiorean ibd

  1. 1. Diagnostic Testing in IBD IU GI Update 2012Michael Chiorean, MD Associate Professor of Medicine Indiana University School of Medicine
  2. 2. Disclosures• Given, Inc.• Abbott Immunology• Janssen• UCB
  3. 3. 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
  4. 4. Diagnostic Levels in IBD• Initial diagnosis Identifying disease – High accuracy – Cost-effective• Response to therapy: Assessing response to therapy – Mucosal healing – Structural damage – Post-operative recurrence Defining disease phenotype Assessing lack of response or• Diagnosis of complications: unexplained symptoms – Structural damage • Strictures, fistulas, abscesses
  5. 5. The Role of Serum Inflammatory Markers in IBD
  6. 6. CRP and ESR in IBD v. IBS ESR CRP ESR ≥ 10mm/hr ≥10mm/hr ≥ 6mg/L & CRP ≥ 6mg/LSensitivity, % 79 77 50Specificity, % 67 70 84PPV, % 42 42 50NPV, % 91 91 84 Dolwani et al. Aliment Pharmacol Ther 2004; 20: 615–621
  7. 7. 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 recurrenceLanghorst et. al. Am J Gastroenterol 2008;103:162-169Lewis JD Gastorenterology 2011; 140:1817-1826
  8. 8. CRP in predicting CD course Likelihood of relapse at 2 years CRP < 0.5 CRP > 0.5 Boirivant et al. J Clin Gastroenterol 1988;10:401–5
  9. 9. 9 Corticosteroid-Free ClinicalRemission at Week 26 by Baseline CRP in SONIC Post-hoc sub-analysis 100 Proportion of Patients (%) p=0.121 p<0.001 80 p=0.503 p=0.314 p=0.004 p=0.027 60 40 20 0 25/71 27/67 35/69 27/9848/10161/96Colombel et al. – NEJM ’10; appendix
  10. 10. Fecal Inflammatory Biomarkers in IBD Diagnosis
  11. 11. 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
  12. 12. Fecal Inflammatory Markers • Advantages • Disadvantages• Sensitive • Non-specific• Full bowel screen • NSAIDs• Detect inflammation • Infections in patients without • Malignancy elevated CRP• Stool studies routinely collected in IBD (C Diff)
  13. 13. 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
  14. 14. 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 patientsVan Rheenan et. al. BMJ 2010; 341:c3369.
  15. 15. Correlation of Biomarkers with Disease Activity Endoscopic Lactoferrin Calprotectin CRP Study Patients Index (correlation) (correlation) (correlation)Sipponen ‘08 CD CDEIS 0.77 0.73 0.55D’Inca ’07 CD SES-CD 0.19 0.48D’Inca ’07 UC Mayo 0.35 0.51Hanai ’04 UC Matt 0.81Siponnen ’08 CD SES-CD 0.63 0.64 0.52Fagerberg ’07 IBD - 0.52Roseth ’97 UC Mayo 0.57Jones ’08 CD SES-CD 0.76 0.72 0.46Sipponen ’08 CD CDEIS 0.87 0.83 0.5Schoepfer ’09 UC Rachmilewitz 0.83 0.5Schoepfer ’10 CD CDEIS 0.75 0.53
  16. 16. Fecal Calprotectin in Predicting IBD Exacerbations Calprotectin Relapse with low Relapse with high Study Population threshold Calprotectin (%) Calprotectin (%)Gisbert ’09 UC 150 9 31Tibble ’00 UC 50 10 85Tibble ’00 CD 50 15 85Costa ’05 UC 150 10 81Costa ’05 CD 150 57 87D’Inca ’08 UC 130 30 79Sipponen ’10 UC+CD 100 25 39Walkiewicz ’08 CD 400 11 56 Pooled Δ relapse with low and high: 14-75% (average: 47%)
  17. 17. Time to Relapse Curve after Infliximab Withdrawal in STORI n=115 patients with Crohn’s in remission on combination therapy at time “0”• Louis et al. – Gastro ‘12
  18. 18. Predictors of Relapse after Withdrawal of Infliximab in STORI Complete Multivariate Simplified Model Risk factor Model HR (95% CI) p-value HR (95% CI) p-valueCorticosteroid use before baseline 3.5 (1.1–10.7) 0.03No previous surgical resection 4.0 (1.4–11.4) 0.01 4.2 (1.5–11.6) 0.005Male sex 3.7 (1.9–7.4) 0.001 3.5 (1.7–7.0) 0.001Hgb < 14.5 g/dL 6.0 (2.2–16.5) 0.001 5.5 (2.0–15.5) 0.001WBC count > 6 x 109/L 2.4 (1.2–4.7) 0.01 1.9 (1.0–3.5) 0.05CDEIS > 0 2.3 (1.1–4.9) 0.04hsCRP > 5 mg/L 3.2 (1.6–6.4) 0.001 2.7 (1.3–5.3) 0.005Infliximab trough level > 2 mg/L 2.5 (1.1–5.4) 0.005Fecal calprotectin > 300 mcg/g 2.5 (1.1–5.8) 0.04 3.1 (1.3–7.2) 0.01• Louis et al. – Gastro ‘12
  19. 19. IBD Serological Markers
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. Cost of Biomarkers• CBC $28• CRP $35• Fecal markers: $40-60• IBD7 panel: $425
  25. 25. 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.
  26. 26. The Role of Capsule Endoscopy inthe Diagnosis of Crohn’s Disease
  27. 27. 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 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• Dionisio et al. – Am J Gastro ‘10
  28. 28. Small Bowel Ultrasound for the Diagnosis of Crohn’s Disease• Advantages – Accessible – Non-invasive – No radiation – Inexpensive• Disadvantages – Limited availability in the US
  29. 29. Role of Ultrasound in the Detection of Crohn’s Disease• Meta-analysis of 7 studies in adult patients (282 CD and 975 controls) Overall Wall thickness Wall thickness >3 mm >4 mm Sensitivity 75-94% 88% 75% Specificity 67-100% 93% 97%• Fraquelli et al. – Radiology ‘05
  30. 30. 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
  31. 31. Contrast-Enhanced US for the Assessment of Crohn’s Disease• Migaleddu et al. – Gastro ‘09
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. CT Enteroclysis and Enterography• Has been the SB imaging “gold” standardin the US – Initial diagnosis – Disease extent – Disease phenotype • Inflammatory • Fibro-stenotic • Penetrating – fistulizing – Complications
  36. 36. 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
  37. 37. 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
  38. 38. 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. –
  39. 39. 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
  40. 40. CTE vs. MRE
  41. 41. CT vs. MR Enterography in Crohn’s Disease• CTE • MRE• Advantages • Advantages – Widely available – No radiation – Fast – Extensive image• Disadvantages processing – Radiation exposure – “Functional” imaging • Disadvantages – Slower – Limited expertise – Cost
  42. 42. 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 al. – IBD ‘11 Fiorino et
  43. 43. 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
  44. 44. 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

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