Crohn’s Disease: Managing and Monitoring Mucosal Healing in the

Small Bowel

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Mucosal Healing• Mucosal healing after one year of treatment is

predictive of reduced subsequent disease activity and decreased need for active treatment1

• These results strengthen the use of mucosal healing as a clinical indicator and treatment goal in inflammatory bowel disease (IBD)1

• Results from an endoscopic substudy of ACCENT 1 (A Crohn’s disease Clinical trial Evaluating infliximab in a New long term Treatment regimen) suggest that objective endpoints such as mucosal healing may end up being clinically meaningful, and that treatment directed toward such endpoints may result in improved long-term outcomes in Crohn’s disease (CD)2

1. Froslie KF et al. Gastroenterology. 2007;133(2):412-422.2. Loftus EV. Rev Gastroenterol Disord. 2007;7(suppl 2):S8-S16.

Mucosal Healing: Long-term Outcomesin Crohn’s Disease

• Mucosal healing by long-term maintenance infliximab treatment was associated with an improved long-term outcome of disease, especially with a lower need for hospitalization and major abdominal surgeries

Schnitzler R et al. Inflamm Bowel Dis. 2009;15(9):1295-301.

Does Mucosal Healing Matter?

• In most recent pharmaceutical trials, the documentation of endoscopic healing has become a critical component of outcome measurement

• Additionally, studies are needed to demonstrate that mucosal healing, in addition to symptom control, should be a primary goal of therapy for CD• Capsule endoscopy (CE) may play a role in

demonstrating/monitoring mucosal healing

Shergill AK et al. World J Gastroenterol. 2008;14(17):2670-2677.

Capsule Endoscopy Images of Mucosal Healing Before and After Therapy

• The aim of this study was to evaluate the efficacy of infliximab as a treatment of chronic refractory pouchitis complicated by ileitis as diagnosed by CE• Short-term treatment with infliximab determined clinical remission in

90% of patients with chronic refractory pouchitis and/or ileitis• Endoscopic/histologic healing of lesions in 80% of patients with

refractory pouchitis and/or ileitis• Only one patient’s disease was unresponsive to therapy

Calabrese et al. Aliment Pharmacol Ther. 2008;27(9):759-764.

Before Therapy After TherapyCapsule Endoscopy Images:

Mucosal Healing Measured by Capsule Endoscopy: Published Trial

• Efthymiou et al assessed correlation between clinical response and mucosal healing of the small bowel using CE

• In this small study (n=40), the number of large ulcers showed statistically significant improvement after treatment (p=.01)

• In this study, the endoscopic lesions of 42.5% of patients would not have been able to be assessed by ileocolonoscopy alone (the lesions were more proximal SB)

• CE was able to detect more small bowel lesions and monitor their healing more than would have been possible with ileocolonoscopy alone

Efthymiou A et al. Inflamm Bowel Dis. 2008;14(11):1542-1547.

Endoscopic Parameters Before and After Treatment

Before Treatment

After Treatment

p

Number of large ulcersa 8.3 ± 1.4 5.0 ± 0.8 .01

Number of aphthous ulcersa

26.5 ± 7.5 12.7 ± 2.3 .07

Time percentage of lesions visiblea

22.0 ± 3.1 17.8 ± 2.5 .08

a Mean ± SEM.

Efthymiou A et al. Inflamm Bowel Dis. 2008;14(11):1542-1547.

Mucosal Healing Measured by Capsule Endoscopy: Case Study

• Female patient diagnosed with CD using CE after other modalities failed to identify moderate to severe disease limited to the small bowel• Only reported symptoms of obscure GI bleeding and

occasional loose stools

• Complete mucosal healing observed by CE after 7 months of treatment with 6-mercaptopurine and mesalamine

• Monitoring response to therapy necessitated serial CE to demonstrate mucosal healing over time

Akhtar RY et al. Am J Gastroenterol. 2009;104(4):1065-1067.

Clinical Impact of Capsule Endoscopy Findings of Mucosal Healing in the Management of Crohn’s

Disease

• Multiple studies determined that CE can detect subtle mucosal abnormalities of the small bowel (fissures, aphthous ulcers) that may be missed by other modalities1 • CE is a valuable tool not only in the evaluation of CD,

but also in the evaluation of its endoscopic severity1

• High diagnostic yield of CE influences disease management and clinical outcomes2,3

• As a result of CE findings, CD therapy was changed in 64% of cases3

1. Efthymiou et al. Inflamm Bowel Disease 2008;14(11):1542-1547.2. Toy E et al. Am J Gastroenterol. 2008;103(12):3022-3028.3. Lorenzo-Zúñiga V et al. Dig Dis Sci. 2010;55(2):411-4.

Need for a Capsule Endoscopy Scoring Index

• Lack of unified method of categorizing findings of CE considered a limitation of early adoption • No standard when describing small bowel

inflammatory lesions in terms of their extent and severity

• No one language for findings, no severity scale of mucosal disease activity or threshold for disease diagnosis

• Capsule Endoscopy Scoring Indices• Capsule Endoscopy Crohn's Disease Activity Index

(CECDAI)• Lewis Score

Lewis B. World J Gastroenterol. 2008;14(26):4137-4141.

Capsule Endoscopy Crohn's Disease Activity Index (CECDAI)

• Scoring system for CECDAI • Endoscopic score based on:

• Inflammation score • Extent score • Stricture score • The proximal and distal segments are evaluated

separately • The total score is the sum of proximal and distal scores

• Simple, easy to learn, and has a strong inter-observer correlation

• May serve as a convenient, reliable, and reproducible diagnostic and follow-up tool for use by experienced endoscopists in the evaluation of patients with CD of the small bowel

Gal E et al. Dig Dis Sci. 2008;53(7):1933-1937.Gralnek IM et al. Aliment Pharmacol Ther. 2008;27(2):146-154.Gurudu SR et al. Inflamm Bowel Dis. 2009;15(10):1607-8.

Lewis Score• Developed to assess mucosal change in the small bowel

detected by direct visualization with CE• Objective measure of disease activity used to monitor therapy

and measure mucosal healing

• Based on Crohn’s Disease Endoscopic Index of Severity (CDEIS)

• Score provides a common language to quantify mucosal changes associated with any inflammatory process

• Differentiates normal small bowel from diseased states • May help establish the diagnosis of small bowel CD when

combined with other clinical signs and symptoms, including patient history, clinical presentation, and laboratory values

• Could potentially be used to measure and document mucosal healing in response to therapy

• Can provide one more point of evaluation with other patient data to assist in determining appropriate disease managementGralnek IM et al. Aliment Pharmacol Ther. 2008;27(2):146-154.

Lewis B. World J Gastroenterol. 2008;14(26):4137-4141.

Scoring Indices Key Points

• Symptom assessment is a poor indicator of severity and extent of disease• Clinical response does not correlate with mucosal healing

or staging of disease• Mucosal healing may be associated with better long-term

outcomes

• Before CE there was no good direct measure of mucosal disease activity in the small intestine• Early clinical scoring systems were based on report of

symptoms and not on endoscopic findings or evidence of mucosal healing

• Lewis Score was developed to assess mucosal change in the small bowel detected by direct visualization with CE• Provides a common language to quantify mucosal changes

associated with any inflammatory process

Mucosal Healing and CE Key Points

• CE was able to detect more small bowel lesions and monitor their healing more than would have been possible with conventional ileocolonoscopy alone

• In a case study of a patient diagnosed with CD, serial CE exams with Lewis Score demonstrated the utility of monitoring response to therapy

• High diagnostic yield of CE influences disease management and clinical outcomes

• Mucosal healing after one year of treatment is predictive of reduced subsequent disease activity and decreased need for active treatment• Healing is associated with less need for hospitalization

and major abdominal surgeries