1. Radiology in IBD: Appropriate Indications and Response to Findings Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, USA

2. Just Another December in Rochester

3. “My Husband Went to Florida and All I Got Was This Lousy Snowblower”

4. Assessment Of Efficacy Of Medical Therapy: CDAI Versus CDEIS During Treatment With Prednisolone Lack of correlation between CDAI (primarily symptom-based) and endoscopic inflammation Symptoms and signs of Crohn’s are neither sensitive nor specific Modigliani R et al, Gastroenterology 1990 r = 0.13; p = NS

5. Paradigm Shift for Making Treatment Decisions in Patients with Inflammatory Bowel Disease OLD: Treat based on symptoms But: symptoms are insensitive and non-specific for bowel inflammation NEW: Treat based on objective markers of inflammation Serologic (CRP reduction) Endoscopic (mucosal healing) Radiographic (CTE/MRE improvement) Goal should be “mucosal healing” or absence/reduction in inflammation This will be the only way we can hope to alter the natural history of Crohn’s disease

6. CT Enterography Combines high-resolution CT scanning with some of the concepts of barium radiography Ingestion of large volume of a negative contrast agent (either PO or via NJT) to distend loops water or diluted PEG or diluted methylcellulose or highly diluted barium sulfate in sorbitol Intravenous contrast, scan after 70 seconds (venous phase) Thin slices on helical CT Radiation exposure More appropriate for advanced disease and complications (abscess, fistula)

7. CT Scans in Crohn’s disease Lumen Routine CT (bright lumen) CTE (dark lumen) Lumen Mucosal enhancement Submucosal edema

8. CTE: Mural Thickening Wall thickening > 3mm lumen distended frequently asymmetric

9. CTE: Small-Bowel Mucosal Hyperenhancement 58 HU 92 HU

10. Mural Stratification Trilaminar: Mucosa, Submucosa, Serosa

11. Crohn’s and Mesenteric Fat Intramural fat Fibrofatty proliferation Fibrofatty proliferation Increased fat density Increased fat density

12. Peri-Enteric Fat Stranding

13. Extraluminal Findings (About 18% – 20%) Penetrating disease Hepatobiliary — stones, portal vein clot, abscess, primary sclerosing cholangitis Pancreatitis Sacroiliitis Nephrolithiasis Avascular necrosis Bruining DH et al. Inflamm Bowel Dis. 2008;14:1701.

14. Small-Bowel Imaging in Crohn’s Disease: Prospective Blinded 4-Way Study With Consensus Reference Standard CTE and CE were equally sensitive but CE was less specific than other 3 modalities. Patients (%) 82 83 74 65 89 53 100 94 85 67 86 79 0 100 CTE (n=41) CE (n=27) Ileocolonoscopy (n=36) SBFT (n=38) Sensitivity SpecificityAccuracy Solem CA et al. Gastrointest Endosc. 2008;68:255.

15. Capsule vs Enterography: Another View 93 pts with known or suspected Crohn’s Ileoscopy and/or surgery was reference standard 6 patients excluded from CE due to stenosis SensitivitySpecificity CE100% 91% CTE 76% 85% MRE 81% 86% Jensen MD et al, Clin Gastroenterol Hepatol 2011;124-9.

16. Clinical Benefit of CTE Higgins PDR, et al. Inflamm Bowel Dis 2006; 13:262 Clinical Review & Pre-CTE Clinical Assessment Post-CTE Clinical Assessment CTE CTE did not replicate original impression (poor correlation) No strictures at CTE in about half the pts with clinical suspicion CTE findings changed impression of steroid benefit in 61%

17. Alterations to Clinical Management Plans Based on CT Enterography Findings: Prospective Study of 273 Patients Established CD (n=145) Suspected CD (n=128) CT enterography- related changes 70 (48.3%)69 (53.9%) Exclude CDNA49 (38.3%) Exclude active small- bowel diseases 20 (13.8%)NA Add new medication21 (14.5%)4 (3.1%) Remove medication13 (9.0%)6 (4.7%) Surgical referral5 (3.4%)5 (3.9%) Other11 (7.6%)5 (3.9%) Bruining DH et al, Inflamm Bowel Dis 2012;18:219-25.

18. Total (n=273) Established Crohn’s Disease (n=145) Suspected Crohn’s Disease (n=128) CTE-related LOC Δ 247 (90.5%) 135 (93.1%)112 (87.5%) Any Significant LOC Δ 212 (77.6%) 124 (85.5%)88 (68.8%) Active Disease Significant LOC Δ 138 (50.4%) 76 (52.4%)62 (48.4%) Stricturing Disease Significant LOC Δ 127 (46.5%) 79 (54.5%) 48 (37.5%) Fistula Significant LOC Δ 109 (39.9%) 64 (44.1%)45 (35.2%) Abscess Significant LOC Δ 92 (33.7%)55 (37.9%)37 (68.8%) CTE-Related Change in Level of Confidence (LOC) For CD or Complications (n=273) Bruining DH et al, Inflamm Bowel Dis 2012;18:219-25.

19. CTE Healing: Example 1 Resolution of Penetrating Disease Successful resolution with antibiotics followed by infliximab + azathioprine 3/27/06 3/18/07 Bruining DH et al, Clin Gastroenterol Hepatol 2011;9:679-83.

20. CTE Healing: Equivalent to Mucosal Healing at Endoscopy? Resolution of intramural inflammation on maintenance infliximab 3/25/2005 10/11/2006 Bruining DH et al, Clin Gastroenterol Hepatol 2011;9:679-83.

21. 8/17/2006 2/1/2007 CTE to Monitor Response to Anti-TNF Therapy Marked decrease in wall thickness and enhancement Bruining DH et al, Clin Gastroenterol Hepatol 2011;9:679-83.

22. Using CT Enterography to Monitor Crohn’s Disease Patients Receiving Anti-TNF Therapy Retrospective study of patients evaluated at Mayo 2002-08 who were treated with infliximab and had >1 CTE (n = 63) Before and after infliximab start After infliximab start but at least 6 months apart Response determined by radiographic healing of lesions Complete response: all lesions improved Partial response: some lesions improved No response: worsening or no changes Median interval between 1 st and 2 nd CTE: 356 days (IQR, 215 – 630) Bruining DH et al, Clin Gastroenterol Hepatol 2011;9:679-83.

23. CTE Enterography Detects Intestinal Wall Changes: Results ResponsePer Lesion (n = 105) Per Patient (n = 63) Complete52 (50%)28 (44%) Unchanged or Partial11 (10%)12 (19%) None42 (40%)23 (37%) Fair to poor agreement with symptoms, endoscopic improvement, and c- reactive protein at time of 2 nd scan Suggests that CTE was providing information not otherwise obtained from symptoms and endoscopy Bruining DH et al, Clin Gastroenterol Hepatol 2011;9:679-83.

24. Radiation Exposure in a Population-Based IBD Cohort: Olmsted County, Minnesota, 1990 – 2001 (n=215) Crohn’s DiseaseUlcerative Colitis Median total effective dose (mSv)26.610.5 Upper quartile range (mSv)47.9–279.226.8–251.4 Annualized median ED (mSv/year) 3.11.2 After adjusting for duration of disease, CD patients had 2.46 times greater total effective doses than UC patients (95% CI: 1.5, 4.1; P=0.001) CT scans accounted for 51% of ED in patients with Crohn’s disease; 40% in patients with ulcerative colitis This study led to a change in practice—30% dose reduction for CTE Peloquin JM et al. Am J Gastroenterol 2008; 103:2015-22

25. Radiation Concerns with Serial CTE? Controversial—little proof that diagnostic medical imaging increases risk of cancer Low-dose CTE may be better option Mayo study showed that low-dose CTE had sufficient sensitivity and specificity Findings have been replicated by other groups Assuming the linear-no threshold cancer risk model, it is still cost-effective to perform serial CTE (vs. MRE) in patients over age 35 to 50 years. If CTE effective dose is <6 mSv, then serial CTE at all ages is more cost-effective than MRE Siddiki H et al, Inflamm Bowel Dis 2011;17(3):778-86. Craig O et al, Digestive Disease Week 2011 abstract. Cipriano L et al, Inflamm Bowel Dis 2011 Online Early.

26. Review of Indications for CTE in Patients Under Age 35 Years (n = 2022) 99% of first-time examinations met appropriateness criteria 9.7% of patients required more than one examination 73% had Crohn’s For approximately half of these repeat exams, MR enterography would have been appropriate Guimaraes LS et al, Inflamm Bowel Dis 2010; 16:226

27. Ileosigmoid Fistula: CT vs. MR Enterography CTEMRE

28.    Panes J et al, Aliment Pharmacol Ther 2011;34:125 MRE: Wall Thickening, Contrast Enhancement, Ulcers

29. Crohn’s Disease MRE Findings Enhancement Wall thickening Comb sign Courtesy of Jeff Fidler, MD

30. CTE vs. MRE – Mayo Clinic TechniqueSensitivitySpecificityInterobserver Agreement CTE (n=33) Consensus 95.2%88.9%0.76 MRE (n=30) Consensus 90.5%66.7%0.63 Siddiki H et al. AJR 2009; 193:113-121

31. §    §   Derivation CohortValidation Cohort VariableCoefficient*p p Wall thickness 1.313 ± 0.4550.0041.209 ± 0.3170.01 RCE 0.029 ± 0.0110.0100.032 ± 0.007<0.001 MR edema 5.86 ± 2.00.047.08 ± 1.22<0.001 MR ulcers 11.22 ± 1.97<0.00111.29 ± 1.13<0.001 * Coefficients expressed as values ± SE MRE Predictors of CDEIS - Barcelona RCE: relative contrast enhancement Ordas I et al, Digestive Disease Week 2010 Rimola J et al, Inflamm Bowel Dis 2011;17:1759

32.          MRE Predictors of CDEIS MaRIA s = 1.5 * wall thickness (mm) + 0.02 * RCE + 5 * edema + 10 * ulcers  Σ MaRIA (segment) Ordas I et al, Digestive Disease Week 2010 Rimola J et al, Inflamm Bowel Dis 2011;17:1759

33. 403020100   150 100 50 0 R linear = 0.8   Global correlation MaRIA-CDEIS Ordas I et al, Digestive Disease Week 2010 Rimola J et al, Inflamm Bowel Dis 2011;17:1759

34.   –    –  Changes on MRI Index of Activity According to Endoscopy Response (30 Patients Treated with Steroids or ADA) Changes on MRI Index of Activity According to Endoscopy Response (30 Patients Treated with Steroids or ADA)      MaRIA per segments Ordas I et al, Digestive Disease Week 2011 Courtesy of Ingrid Ordas, M.D.

35.  T2 Axial  T2 Axial  12 T2 Axial  12 T2 Axial Ordas I et al, Digestive Disease Week 2011 Courtesy of Ingrid Ordas, M.D.

36.               Ordas I et al, Digestive Disease Week 2011 Courtesy of Ingrid Ordas, M.D.

37.                         Endoscopic healing (absence of ulcers) MRI healing (MaRIAs < 11) Endoscopic healing (absence of ulcers) MRI healing (MaRIAs < 11) kappa = 0.80 ± 0.056 p < 0.001 kappa = 0.80 ± 0.056 p < 0.001     Ulcers Endoscopy Ulcers Endoscopy Ordas I et al, Digestive Disease Week 2011 Courtesy of Ingrid Ordas, M.D.

38. ACTIF Study: MR Enteroclysis in Patients Treated with Infliximab: Belgium, Germany, UK, Netherlands Serial MR enteroclysis at weeks 0, 2, 26 MICD to score activity (range, 0 to 14) Inflammatory (0 to 8) Wall thickening, contrast enhancement, extramural involvement Obstructive (0 to 6) Narrowing, prestenotic dilation Primary endpoint: 2 point decrease in MICD score 17% at week 2 32-40% at week 26 MICD correlated well with CDAI but not CRP Van Assche G et al, Digestive Disease Week 2011

39. ©2010 MFMER | slide-39 Conclusions There is often a disconnect between patient symptoms and the degree of inflammation as demonstrated by serum, fecal and endoscopic markers Crohn’s disease patients with demonstrable inflammation seem to have a better response in many RCTs CT enterography is a noninvasive method of diagnosing or assessing disease activity in suspected or known Crohn’s Complementary to SBFT, but potentially more sensitive MRI enterography is rapidly improving - no radiation Both appear promising as monitoring tools for Crohn’s disease patients receiving anti-TNF therapy