1. Jonathan A. Leighton, MD Mayo Clinic Arizona leighton.jonathan@mayo.edu Great Debates and Updates in IBD San Francisco, CA March 2013 Small Bowel Evaluation – Choosing the Best Radiologic and Endoscopic Modalities

2. Importance of Small Bowel Evaluation in Crohn’s Disease The diagnosis of SB inflammation can be challenging when inflammation is mild and/or confined to the small bowel The diagnosis of SB inflammation can be challenging when inflammation is mild and/or confined to the small bowel A comprehensive evaluation of the entire small bowel may be indicated to: A comprehensive evaluation of the entire small bowel may be indicated to: – Make a definitive diagnosis of CD – Determine extent and severity of disease – Determine baseline disease activity to serve as a comparator for monitoring of disease Imaging Techniques Imaging Techniques Capsule Endoscopy Capsule Endoscopy CT/MR Enterography CT/MR Enterography Deep Enteroscoppy Deep Enteroscoppy CD = Crohn’s disease; C+I = colonoscopy with ileoscopy.

3. Why Might Capsule Endoscopy (CE) Be Helpful? Isolated involvement of the proximal SB can occur in as many as one third of cases Isolated involvement of the proximal SB can occur in as many as one third of cases Normal findings on ileocolonoscopy are not sufficient to exclude the diagnosis Normal findings on ileocolonoscopy are not sufficient to exclude the diagnosis Cross-sectional imaging can detect transmural inflammation but superficial mucosal inflammation may be missed Cross-sectional imaging can detect transmural inflammation but superficial mucosal inflammation may be missed CE offers a comprehensive evaluation of the SB mucosa to identify CD missed by conventional endoscopy and/or evaluate extent and severity of involvement CE offers a comprehensive evaluation of the SB mucosa to identify CD missed by conventional endoscopy and/or evaluate extent and severity of involvement Debate still exists as to its role in the diagnosis and management of Suspected and Established Crohn’s disease Debate still exists as to its role in the diagnosis and management of Suspected and Established Crohn’s disease

4. Case Study 42 yo male with history of ileal Crohn disease diagnosed in 2001 in Chicago treated with 5ASA 42 yo male with history of ileal Crohn disease diagnosed in 2001 in Chicago treated with 5ASA Recurrent episodes of abdominal pain and SBO with otherwise negative CT scans Recurrent episodes of abdominal pain and SBO with otherwise negative CT scans Presented to Mayo Clinic March 2012 with abdominal pain and black stools Presented to Mayo Clinic March 2012 with abdominal pain and black stools EGD negative EGD negative

5. Negative Colonoscopy and Ileoscopy

6. Negative MR Enterography

7. Positive CE

8. Endoscopic Skipping of the Distal Terminal Ileum 189 consecutive patients with CD 189 consecutive patients with CD 153 TI intubation 153 TI intubation 67 had normal ileoscopy67 had normal ileoscopy 67 patients with normal ileoscopy 67 patients with normal ileoscopy 36 had active small bowel CD 36 had active small bowel CD Skipped distal ileum in 11Skipped distal ileum in 11 Intramural/mesentery disease only in 23Intramural/mesentery disease only in 23 Upper GI tract in 2Upper GI tract in 2 Samuel S et al. CGH 2012;10:1253-59

9. A Prospective Multicenter Blinded Study Comparing CE vs SBFT Before Ileocolonoscopy (IC) in Suspected Crohn Disease Aim: compare diagnostic yield of CE before IC vs SBFT and IC. Aim: compare diagnostic yield of CE before IC vs SBFT and IC. Results: 80 patients were included in the analyses. Results: 80 patients were included in the analyses. Diagnostic yield of CE = IC (P=.09). Diagnostic yield of CE = IC (P=.09). Diagnostic yield CE > SBFT (P SBFT (P<.001). 25 (31.3%) had the diagnosis of CD confirmed. 25 (31.3%) had the diagnosis of CD confirmed. 11 diagnosed by CE alone/5 diagnosed by IC alone11 diagnosed by CE alone/5 diagnosed by IC alone 9 were identified by at least 2 of the 3 modalities.9 were identified by at least 2 of the 3 modalities. Conclusion: Conclusion: IC remains the diagnostic test of choice IC remains the diagnostic test of choice CE was clearly better than SBFT for SB inflammation and CD CE was clearly better than SBFT for SB inflammation and CD CE demonstrated equivalency to IC for ileocecal inflammation. CE demonstrated equivalency to IC for ileocecal inflammation. This study suggests that CE is safe and can diagnosis CD when IC is negative. This study suggests that CE is safe and can diagnosis CD when IC is negative. Leighton JA et al. Submitted for publication

10. CE and Suspected Crohn’s Disease Final Thoughts…… Although CE has greater sensitivity for mucosal inflammation than radiology, the PPV is fair at 50% Although CE has greater sensitivity for mucosal inflammation than radiology, the PPV is fair at 50% False positives and an increased risk of retention may limit the widespread use False positives and an increased risk of retention may limit the widespread use The NPV at 96% suggests that CE may be better for excluding Crohn’s disease than confirming it The NPV at 96% suggests that CE may be better for excluding Crohn’s disease than confirming it CE may play an even more important role in established CD CE may play an even more important role in established CD Tukey M et al. Am J Gastro 2009;104:2734-9 Levesque BG, et al. Clin Gastro Hep 2010;261-7 Goldfarb NI et al: Dis Manag 7:292-304, 2004 Tukey M et al. Am J Gastro 2009;104:2734-9 Levesque BG, et al. Clin Gastro Hep 2010;261-7 Goldfarb NI et al: Dis Manag 7:292-304, 2004

11. CE for Established IBD In the majority of cases, may be a better tool for monitoring disease extent and severity In the majority of cases, may be a better tool for monitoring disease extent and severity Using a standardized scoring system may aid in objectively tracking disease activity Using a standardized scoring system may aid in objectively tracking disease activity Potential Applications Potential Applications Postoperative recurrences Postoperative recurrences Indeterminate colitis Indeterminate colitis Mucosal healing Mucosal healing Doherty GA et al. GIE 2011;74:167-75

12. Impact of CE on Management of Known IBD 128 CE performed for symptomatic IBD (86 for Crohn's disease, 15 for indeterminate colitis, 23 for pouchitis. 128 CE performed for symptomatic IBD (86 for Crohn's disease, 15 for indeterminate colitis, 23 for pouchitis. Results Results In CD, 61.6% had a change in meds in the 3 months after CE, with 39.5% initiating a new IBD medication In CD, 61.6% had a change in meds in the 3 months after CE, with 39.5% initiating a new IBD medication Severe findings resulted in significant differences in Severe findings resulted in significant differences in Med changes (73.2% versus 51.1%, P = 0.04),Med changes (73.2% versus 51.1%, P = 0.04), Addition of meds (58.5% versus 22.2%, P < 0.01)Addition of meds (58.5% versus 22.2%, P < 0.01) Surgeries (21.9% versus 4.4%, P = 0.01).Surgeries (21.9% versus 4.4%, P = 0.01). CE results in management changes in the majority of cases of symptomatic IBD, regardless of the subtype of IBD CE results in management changes in the majority of cases of symptomatic IBD, regardless of the subtype of IBD Long MD et al. IBD 2011;17:1855- 62

13. CE in Patients with Perianal Disease 26 patients with perianal disease but negative endoscopic evaluation (ileocolonoscopy, SBFT, CTE/MRE) 26 patients with perianal disease but negative endoscopic evaluation (ileocolonoscopy, SBFT, CTE/MRE) Results Results 25 underwent CE 25 underwent CE 6/25 (24%) identified SB inflammation consistent with CD 6/25 (24%) identified SB inflammation consistent with CD No other variables (lab) were predictive No other variables (lab) were predictive Adler, SN et al. WJGE 2012;4:185-188

14. Bottom Line CE has a high diagnostic yield for evaluating abnormalities of the SB mucosa CE has a high diagnostic yield for evaluating abnormalities of the SB mucosa Specificity is an issue and NSAIDs should be stopped before CE; it is critical not to prematurely diagnose CD Specificity is an issue and NSAIDs should be stopped before CE; it is critical not to prematurely diagnose CD CE for suspected CD may be best suited for a subgroup of patients with negative ileocolonoscopy and a high suspicion of small bowel inflammation CE for suspected CD may be best suited for a subgroup of patients with negative ileocolonoscopy and a high suspicion of small bowel inflammation CE may also be suited for established CD for monitoring extent and severity, mucosal healing, postop recurrence, and indeterminate colitis although cost effectiveness needs to be established CE may also be suited for established CD for monitoring extent and severity, mucosal healing, postop recurrence, and indeterminate colitis although cost effectiveness needs to be established

15. Oral contrast: Neutral Oral contrast: Neutral Rate: 450 cc every 15 min Rate: 450 cc every 15 min Amt: 1350 cc over 45 min Amt: 1350 cc over 45 min Oral contrast: Neutral Oral contrast: Neutral Rate: 450 cc every 15 min Rate: 450 cc every 15 min Amt: 1350 cc over 45 min Amt: 1350 cc over 45 min CT Enterography (CTE)

16. Filtered back projection Increased noise Filtered back projection Increased noise ASIR Software Decreased noise ASIR Software Decreased noise Low Dose CT 30-50% less radiation Low Dose CT 30-50% less radiation

17. CTE Differentiating Active vs Chronic CD N = 96 pts with CTE and endoscopy Bodily K et al: Radiology 2006;238:505-516 CTE FindingSens (%) Mural hyperenhancement80 Bowel wall thickening75 Mural stratification60 Comb sign35 Inc. mesenteric fat atten10 CTE FindingSens (%) Mural hyperenhancement80 Bowel wall thickening75 Mural stratification60 Comb sign35 Inc. mesenteric fat atten10

18. Enhancement: Homogeneous Distended Bowel Wall Thickness <3 mm Enhancement: Increased Bowel Wall Thickness >3mm Small Bowel Normal vs Crohn’s Disease

19. CTE in Suspected CD with Negative Ileoscopy Retrospective study of 189 patients with CD – TI intubation in 153 Retrospective study of 189 patients with CD – TI intubation in 153 67 had normal ileoscopy 67 had normal ileoscopy 36 were found to have active SB CD 36 were found to have active SB CD Two had gastroduodenal CDTwo had gastroduodenal CD CTE was positive in 34 patients with more proximal disease (11) or intramural disease (23)CTE was positive in 34 patients with more proximal disease (11) or intramural disease (23) Samuel S et al. Clin Gastro Hep 2012;10:1253-59

20. Retrospective study of 20 pts with CD who underwent 40 CTE evaluated while blinded to clinical history Results: Disease progression or regression by CTE correlated with symptoms in 16/20 (80%) pts Disease progression or regression by CTE correlated with symptoms in 16/20 (80%) pts In 4/20 (20%) pts, symptoms progressed while CTE findings were negative (n=2) or improved (n=2) In 4/20 (20%) pts, symptoms progressed while CTE findings were negative (n=2) or improved (n=2) Endoscopy correlated with CTE findings in 12/12 and with symptoms in 9/12 Endoscopy correlated with CTE findings in 12/12 and with symptoms in 9/12 The weighted kappa was 0.57 (95%CE=0.20 to 0.94) The weighted kappa was 0.57 (95%CE=0.20 to 0.94) Retrospective study of 20 pts with CD who underwent 40 CTE evaluated while blinded to clinical history Results: Disease progression or regression by CTE correlated with symptoms in 16/20 (80%) pts Disease progression or regression by CTE correlated with symptoms in 16/20 (80%) pts In 4/20 (20%) pts, symptoms progressed while CTE findings were negative (n=2) or improved (n=2) In 4/20 (20%) pts, symptoms progressed while CTE findings were negative (n=2) or improved (n=2) Endoscopy correlated with CTE findings in 12/12 and with symptoms in 9/12 Endoscopy correlated with CTE findings in 12/12 and with symptoms in 9/12 The weighted kappa was 0.57 (95%CE=0.20 to 0.94) The weighted kappa was 0.57 (95%CE=0.20 to 0.94) Hara AK et al: AJR, 2008 Using CTE To Monitor CD Activity

21. T2 weighted image (fluid bright) T2 weighted image (fluid bright) T1 weighted image (walls bright) T1 weighted image (walls bright) Crohn’s Disease MR Enterography (MRE) Courtesy of Jeff Fidler, MD

22. MRE and CTE Correlate with Colonoscopy MRE findings compared to colonoscopy and ileoscopy: MRE correlates with CDEIS and this was validated in a subsequent study MRE findings compared to colonoscopy and ileoscopy: MRE correlates with CDEIS and this was validated in a subsequent study MRE vs CTE vs Ileocolonoscopy: CTE and MRE were equally accurate for assessing disease activity MRE vs CTE vs Ileocolonoscopy: CTE and MRE were equally accurate for assessing disease activity Rimola J et al. Gut 2009;58:1113-1120 Rimola J et al. IBD 2010 Fiorino G et al. IBD 2011;17:1073-1080 Rimola J et al. Gut 2009;58:1113-1120 Rimola J et al. IBD 2010 Fiorino G et al. IBD 2011;17:1073-1080 What we don’t know: Is mucosal healing or transmural healing or histologic remission responsible for better clinical outcomes? What we don’t know: Is mucosal healing or transmural healing or histologic remission responsible for better clinical outcomes?

23. CTE takes 10 seconds CTE takes 10 seconds MRE takes 30 minutes MRE takes 30 minutes With MRE, patients have to hold breath With MRE, patients have to hold breath Worse in obese patients or respiratory problems Worse in obese patients or respiratory problems Suboptimal MRE more common than CTE Suboptimal MRE more common than CTE CTE takes 10 seconds CTE takes 10 seconds MRE takes 30 minutes MRE takes 30 minutes With MRE, patients have to hold breath With MRE, patients have to hold breath Worse in obese patients or respiratory problems Worse in obese patients or respiratory problems Suboptimal MRE more common than CTE Suboptimal MRE more common than CTE CTEMRE CTE vs MRE

24. Bottom Line MRE and CTE show good correlation for the detection and localization of transmural CD MRE and CTE show good correlation for the detection and localization of transmural CD Compared to CE, MRE and CTE are inferior in the detection of superficial mucosal disease Compared to CE, MRE and CTE are inferior in the detection of superficial mucosal disease CE may be more sensitive than CTE or MRE, especially in proximal SB CE may be more sensitive than CTE or MRE, especially in proximal SB

25. SuspectedNoFistula/ CDstrictureStricturesabscess Ileoscopy CE CTE/MRE SBFT SuspectedNoFistula/ CDstrictureStricturesabscess Ileoscopy CE CTE/MRE SBFT Follow Known CD A A A A A A A A A A B B B B B B B B C C C C

26. Forcep channel allows biopsy and therapy Double-Balloon Enteroscopy (DBE) “Deep Enteroscopy” Tube or Balloon Assisted Enteroscopy Single-Balloon Enteroscopy (SBE) Spiral Overtube Enteroscopy

27. DBE

28. Impact of DBE on CD Prospective study of CD patients suspected of SB involvement in whom distal activity had previously been excluded Prospective study of CD patients suspected of SB involvement in whom distal activity had previously been excluded Results: Results: 35 patients (70%) showed SB lesions 35 patients (70%) showed SB lesions 23 (46%) could not be assessed by conventional endoscopy 23 (46%) could not be assessed by conventional endoscopy Step up therapy in 26 patients (74%) led to clinical remission in 23 (88%) Step up therapy in 26 patients (74%) led to clinical remission in 23 (88%) Mensink PB et al. Scan J Gastro 2010;45:483-489

29. DBE unsucessful in 26% with Crohn disease DBE unsucessful in 26% with Crohn disease 4/8 rectal DBE perforations occurred in patients with prior ileoanal or ileocolonic anastomoses 4/8 rectal DBE perforations occurred in patients with prior ileoanal or ileocolonic anastomoses In the subset of patients with available data regarding prior intestinal surgeries, perforations occurred in 6/76 (8%) patients In the subset of patients with available data regarding prior intestinal surgeries, perforations occurred in 6/76 (8%) patients Gerson L et al: DDW 2008 Complications U.S. Data

30. Diagnosis and Treatment of SB Strictures with DBE 156 patients with strictures underwent DBE Inflammatory disease in 87 and of those, Crohn’s disease in 57 Balloon dilation in 31 with long term success in 22 (71%)Balloon dilation in 31 with long term success in 22 (71%) 19 patients with symptomatic SB strictures and CD DBE detected 28 stricturesDBE detected 28 strictures 10/19 had 13 strictures from 1-4cms and underwent 15 DBE balloon dilations10/19 had 13 strictures from 1-4cms and underwent 15 DBE balloon dilations Therapeutic success was achieved in 8 patients. No complications occurredTherapeutic success was achieved in 8 patients. No complications occurred 156 patients with strictures underwent DBE Inflammatory disease in 87 and of those, Crohn’s disease in 57 Balloon dilation in 31 with long term success in 22 (71%)Balloon dilation in 31 with long term success in 22 (71%) 19 patients with symptomatic SB strictures and CD DBE detected 28 stricturesDBE detected 28 strictures 10/19 had 13 strictures from 1-4cms and underwent 15 DBE balloon dilations10/19 had 13 strictures from 1-4cms and underwent 15 DBE balloon dilations Therapeutic success was achieved in 8 patients. No complications occurredTherapeutic success was achieved in 8 patients. No complications occurred Fukumoto A et al: GI Endo 66:S108, 2007 Pohl J et al: Eur J Gastro Hep 2007;19:529-534 Fukumoto A et al: GI Endo 66:S108, 2007 Pohl J et al: Eur J Gastro Hep 2007;19:529-534

31. DBE for CE Retrieval 8/904 patients had capsule retention and caused acute SBO in 6 patients 8/904 patients had capsule retention and caused acute SBO in 6 patients All capsules were successfully removed during DBE All capsules were successfully removed during DBE 5 patients underwent elective surgery for underlying cause 5 patients underwent elective surgery for underlying cause One patient required emergency surgery because of multiple SB perforations One patient required emergency surgery because of multiple SB perforations Van Weyenberg SJB et al: GIE 2010;535-541

32. Capsule Retrieval with BAE Courtesy of Mark Stark

33. New Small Bowel Imaging Tests Complimentary Capsule Endoscopy (CE) Capsule Endoscopy (CE) Excellent mucosal detail non-invasively Excellent mucosal detail non-invasively Identifying CD missed with conventional endoscopy Identifying CD missed with conventional endoscopy Evaluating extent and severity of SB involvement Evaluating extent and severity of SB involvement CT and MR Enterography (CTE/MRE) CT and MR Enterography (CTE/MRE) Transmural assessment Transmural assessment Extraintestinal lesions Extraintestinal lesions Balloon-Assisted Enteroscopy (BAE)/ Rotational Enteroscopy Balloon-Assisted Enteroscopy (BAE)/ Rotational Enteroscopy Mucosal detail Mucosal detail Allows for biopsy and therapeutics Allows for biopsy and therapeutics

34. Obstruction Approach to Suspected Crohn’s Disease of the Small Bowel SBCD=Small Bowel Crohn’s Disease; CTE=CT Enterography; MRE=MR Enterography; SBFT=Small Bowel Follow Through Suspected Crohn’s Disease of SB Positive Ileocolonoscopy Negative Ileocolonoscopy or unsuccessful Diagnose and Treat accordingly No obstruction Capsule endoscopy Crohn’s disease of SB Possible or know obstruction CTE/MRE and/or DBE CTE/MRE and/or DBE either/or Agile patency capsule No obstruction

35. Thank You!!