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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Turning the Corner on Crohn's Disease: Evolving Strategies for Disease Management and Patient Care


GOAL
To provide gastroenterologists and gastroenterology fellows with the most up-to-date information on the treatment of Crohn’s disease.

TARGET AUDIENCE
This activity is designed for gastroenterologists and gastroenterology fellows.
No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, participants should be able to:

  • Discuss the etiology of Crohn’s disease (CD) and the social, psychological, and economic implications of this disease.
  • Identify the role of tumor necrosis factor (TNF)-a in CD and the potential benefits of treatment with TNF-a antagonists.
  • Evaluate alternative approaches and combination therapies for the treatment of CD.
  • Assess methods of maximizing patient-physician communication with specific focus on patient education and medication compliance.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. The estimated time to complete this educational activity: 2 hours.

Release date: October 15, 2005.
Expiration date: October 15, 2007.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from UCB Pharma.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Directors and Participating Faculty reported the following:

PROGRAM DIRECTOR

Theodore M. Bayless, MD
Professor of Medicine, Department of Gastroenterology
Director, Meyerhoff Inflammatory Bowel Disease Center
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Bayless reports serving as a consultant to Centocor, Inc, and Procter & Gamble; receiving honoraria from AstraZeneca LP, Centocor, Inc, and Procter & Gamble; and previously holding stock in AstraZeneca LP and Merck & Co, Inc.

PARTICIPATING FACULTY

Stephen B. Hanauer, MD
Professor of Medicine and Clinical Pharmacology
Chief, Section of Gastroenterology, Hepatology, and Nutrition
University of Chicago
Chicago, Illinois
Dr Hanauer reports receiving grants/ research support from and serving as a consultant to Abbott Laboratories, Centocor, Inc, and UCB Pharma; and receiving honoraria from Centocor, Inc, and UCB Pharma.

William J. Sandborn, MD
Professor of Medicine
Division of Gastroenterology and Hepatology
Mayo Clinic College of Medicine
Rochester, Minnesota
Dr Sandborn reports receiving grants/ research support from Abbott Laboratories, Amgen Inc, Centocor, Inc, Serono SA, and UCB Pharma; serving as a consultant to Abbott Laboratories, Centocor, Inc, Serono SA, and UCB Pharma; and receiving honoraria from Abbott Laboratories, Centocor, Inc, and UCB Pharma.

Notice: The audience is advised that articles in this CME activity contain no reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Bayless—adalimumab, certolizumab pegol (CDP-870), etanercept, onercept.

Dr Hanauer—adalimumab, certolizumab pegol (CDP-870).

Dr Sandborn—adalimumab, alicaforsen, CDP-S71, certolizumab pegol (CDP-870), etanercept, granulocyte macrophage colony stimulating factor, MLN-02, natalizumab, onercept.

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Turning the Corner on Crohn's Disease: Evolving Strategies for Disease Management and Patient Care
Theodore M. Bayless, MD*

Crohn’s disease (CD) is a chronic, immunologically mediated disorder with varied clinical manifestations that can involve any segment of the gastrointestinal tract from the mouth to the anus. Epidemiologic studies have suggested that the prevalence of CD has increased during the last 2 to 4 decades. An analysis of the incidence and prevalence of CD in Olmstead County, Minnesota for the period from 1940 to 1993 found that the prevalence rate increased 46% between 1980 and 1991, and that the incidence rate for the period between 1989 and 1993 was significantly higher than during the period before 1964.1 Similarly, a recent systematic review of the CD prevalence literature found that more recent studies reported higher prevalence rates.2 CD is associated with considerable physical and emotional distress, and it also requires 1 or more surgical procedures for approximately 40% to 60% of patients.3,4

The medical management of CD consists of both short-term and maintenance treatments. In recent years, delineation of the role of cytokines such as tumor necrosis factor (TNF)-a and the interleukins has identified a number of novel therapeutic targets for the treatment of CD. As described in many review articles and editorials, TNF-a in particular has emerged as an important modulator of several physiological processes that contribute to the pathogenesis of CD.5-7 TNF-a regulates the expression of other proinflammatory cytokines, and also stimulates the expression of cell-surface adhesion molecules that are used by lymphocytes to migrate from the circulation to sites of tissue inflammation.8

Nearly a decade ago, the first large randomized trial demonstrated that infliximab, a monoclonal antibody against TNF-a, significantly improved clinical outcomes in patients who were resistant to other treatments.9 Since that time, a number of other studies have shown that infliximab improves the clinical course of CD, as well as quality of life and the need for surgery and hospitalization.10 Infliximab-induced remission of CD has even been associated with improvement in employment status.11 Infliximab is recommended for the treatment of CD in treatment guidelines developed by the American College of Gastroenterology and the British Society of Gastroenterology.12,13

Infliximab does possess important limitations in the treatment of CD. A significant proportion of patients either fail to respond to treatment or exhibit only a partial or temporary response.14 Infliximab is a “chimeric” monoclonal antibody that includes a substantial number of murine residues. Antibodies against infliximab are detected in as many as 60% of treated patients and contribute to infusion reactions.14 Antibodies to infliximab have also been shown to reduce the effectiveness of infliximab treatment.15 Immunosuppression produced by infliximab therapy increases the risk of infections, including sepsis and tuberculosis.16 In response to these concerns, a variety of alternative approaches are currently in development. Humanized or fully human antibodies with fewer murine components may effectively target TNF-a but with lower rates of immunogenicity. Potential members of this family of agents include certolizumab pegol (CDP-870), etanercept, onercept, and adalimumab.6 Novel treatments that are designed to interfere with other inflammatory pathways are also being evaluated in rigorously designed clinical trials. Combined with traditional medications such as 5-aminosalicyclic acid, corticosteroids, antibiotics, and immunomodulatory agents, these approaches hold new promise for affected patients.

This issue of Advanced Studies in Medicine reviews the latest information on treatment strategies for CD, including practical techniques for selecting and dosing therapy, as well as emerging strategies for optimizing patient outcomes. William J. Sandborn, MD, reviews the mechanisms of action of several new biologic agents that have recently been evaluated in randomized clinical trials. Dr Sandborn also reviews the use of the inflammation marker C-reactive protein in the management of CD. Stephen B. Hanauer, MD, reviews the incorporation of anti-TNF therapies into clinical practice, and also summarizes the psychosocial impact of CD, role of nutritional therapy and support, and the importance of improving clinician-patient interaction.

REFERENCES

1. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn’s disease in Olmsted County, Minnesota, 1940-1993: Incidence, prevalence, and survival. Gastroenterology. 1998;114:1161-1168. Erratum in: Gastroenterology. 1999;116:1507.

2. Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: A systematic review. Aliment Pharmacol Ther. 2002;16:51-60.

3. Agrez MV, Valente RM, Pierce W, Melton LJ 3rd, van Heerden JA, Beart RW Jr. Surgical history of Crohn’s disease in a well-defined population. Mayo Clin Proc. 1982;57:747-752.

4. Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn’s disease: Markov model analysis of a population-based cohort. Gastroenterology. 1999;117:49-57.

5. van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40:443-448.

6. Lim WC, Hanauer SB. Emerging biologic therapies in inflammatory bowel disease. Rev Gastroenterol Disord. 2004;4:66-85.

7. Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 2005;34:819-836.

8. Sands BE. Why do anti-tumor necrosis factor antibodies work in Crohn’s disease? Rev Gastroenterol Disord. 2004;4(suppl 3):S10-S17.

9. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337:1029-1035.

10. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology. 2005;128:862-869.

11. Lichtenstein GR, Yan S, Bala M, Hanauer SB. Remission in patients with Crohn’s disease is associated with improvement in employment and quality of life and a decrease in hospitalizations and surgeries. Am J Gastroenterol. 2004;99:91-96.

12. Hanauer SB, Sandborn WJ; Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2001;96:635-643.

13. Carter MJ, Lobo AJ, Travis SP; IBD Section of the British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53(suppl 5):V1-V16.

14. Rutgeerts PJ. Challenges in Crohn’s disease. Rev Gastroenterol Disord. 2004;4(suppl 3):S1-S2.

15. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601-608.

16. Remicade (infliximab). Prescribing information. Malvern, Pa: Centocor, Inc; 2005.

*Professor of Medicine, Department of Gastroenterology; Director, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to: Theodore M. Bayless, MD, Blalock 461 Gastroenterology, 600 N Wolfe St, Baltimore, MD 21287.
E-mail:
tbayless@jhmi.edu.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.