Weighing the Evidence in Chronic GI Diseases: A Case-based Audience-Interactive Symposium

At an industry-sponsored symposium held in conjunction with the American College of Gastroenterology’s 2002 Annual Scientific Meeting, leaders in the field of gastroenterology and the treatment of inflammatory bowel disease discussed strategies for inducing and maintaining remission in Crohn’s disease (CD), and the impact of CD on patients’ quality of life. In addition, the panel reviewed optimal goals of therapy in Barrett’s esophagus.

This program was sponsored by the Postgraduate Institute for Medicine. This program was supported
by an unrestricted educational grant from AstraZeneca.

This material represents a compilation from a series of industry-sponsored educational symposia presented October 18–23, 2002 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient.

The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.

Strategies for Inducing and Maintaining Remission in Crohn’s Disease

The natural history of the disease and the efficacy and safety of potential induction medications should be considered when determining appropriate medical therapy for patients with active Crohn’s disease (CD), according to William J. Sandborn, MD, Professor of Medicine at the Mayo Medical School, and Head of the Inflammatory Bowel Disease Interest Group at the Mayo Clinic in Rochester, Minnesota. Developing a long-term maintenance strategy also is important.

The natural history of CD is characterized by periodic relapses, as illustrated by a Danish population-based study, which found that over a 5-year period, approximately 20% of patients continue to have inactive disease, while about 25% have active CD. The remaining 50% of patients have cycles of active and inactive disease (Figure 1) (Munkholm P, et al. Scand J Gastroenterology. 1995;30:699).

The efficacy of 5-ASA agents (eg, mesalamine) in initial therapy has not been consistent, Dr. Sandborn reported, with some studies indicating that mesalamine has superior efficacy to placebo, while others finding no difference between the two (Singleton JW, et al. Gastroenterology. 1993;104:1293; Singleton J. Gastroenterology. 1994;107: 632; Hanauer SB, et al. Gastroenterology. 2001;120:A453). One study concludes that budesonide, a steroid with high first-pass hepatic metabolism, exhibits better efficacy than Pentasa® (mesalamine) in reducing CD activity index (CDAI) scores (Thomsen OO, et al. N Engl J Med. 1998;339:370). With its relatively rapid onset of action and substantially different activity profile, budesonide may be a suitable alternative to mesalamine, Dr. Sandborn believes.

Prednisolone is used to treat moderate-to-severe CD and has been shown to be slightly more efficacious than budesonide. However, prednisolone also is associated with greater steroid-related toxicity (Rutgeerts P, et al. N Engl J Med. 1994;331:842; Campieri M, et al. Gut. 1997;41:209; Kane SV, et al. Aliment Pharmacol Ther. 2002;16: 1509).

In a European study examining the effects of long-term use of steroids on bone loss (Schoon E, et al. Am J Gastroenterol. 2002;97(suppl):S272. Abstract), patients were randomly assigned to receive budesonide 9 mg/day or prednisolone 40 mg/day. The dosages were gradually tapered. The patients then received budesonide or prednisolone for 2 years at doses adjusted to control disease activity. In steroid-naïve patients, bone loss with budesonide treatment was 1%, which was not statistically significant over a 2-year period. Prednisolone-treated patients, in contrast, experienced an almost 4% loss in bone density. Patients who had previously received steroids but were not current users, and patients who were steroid dependent, had low baseline bone density scores, indicating developing or existing osteopenia. Bone loss did not substantially worsen in these groups with additional budesonide or prednisolone treatment, but additional conventional corticosteroid therapy (eg, prednisolone) in these patients would not be advisable, remarked Dr. Sandborn.

Reviewing maintenance strategies, Dr. Sandborn cited a 1997 study totaling 1,400 patients that concluded that mesalamine was not effective in maintaining medically induced remission (Camma C, et al. Gastroenterology. 1997;113:1465). Budesonide 6 mg/day prolongs remission, but by the end of 1 year, the difference in remission rates
between budesonide and placebo is not significant (Greenberg GR, et al. Gastroenterology. 1996;110:45). Infliximab (Hanauer S, et al. Lancet. 2002;359: 1541) and azathioprine (Feagan BG, et al. N Engl J Med. 2000;342:1627) are effective in maintaining remission in moderate-to-severe CD, but azathioprine is associated with toxicity, such as bone marrow depression and possible immunosuppression-related lymphoma.

Considering the limitations of the various strategies, Dr. Sandborn proposed that budesonide, which is effective for induction, be used for initial treatment. He added that relapses may be re-treated with budesonide, followed by azathioprine therapy.

According to a population-based study of patients with Crohn’s disease (CD), 50%-60% of patients require surgery within 10 years of diagnosis (Munkholm P, et al. Scand J Gastroenterology. 1995;30:699), reported Bret A. Lashner, MD, Director, Center for Inflammatory Bowel Disease at the Cleveland Clinic Foundation in Cleveland, Ohio. Furthermore, the probability of patients remaining in remission also decreases over time, with recurrence rates approaching 100% at 10-15 years of disease.

In terms of 30-year survival rates among patients with CD, the curves for expected and overall survival are virtually overlapping (Loftus EV, et al. Gastroenterology. 1998;114:1161). Thus, “patients with CD rarely die of their disease, but do die with the disease,” explained Dr. Lashner. Another population-based study found markedly high rates of death resulting from infectious diseases among patients with CD compared with individuals without the disease (Jess T, et al. Gastroenterology. 2002;122:1808). This highlights the need for judicious use and careful monitoring of immunosuppressive therapies in patients with CD, believes Dr. Lashner.

Surgical interventions contribute to most of the costs in managing CD: in any given year, 1% of patients undergoing surgery account for 44% of the costs (Silverstein, MD, et al. Gastroenterology. 1999;117:49). Of the patients who do not have surgery, 27% are being treated with 5-aminosalicylate therapy, amounting to 29% of overall costs.

What Is the Best Medical Therapy to Induce Remission in Mild-to-Moderate Active Crohn’s Disease?
Sulfasalazine and mesalamine are the most common agents used to treated mild-to-moderate CD, although the National Cooperative Crohn’s Disease Study (NCCDS) found that sulfasalazine was marginally more effective than placebo (Summers RW, et al. Gastroenterology. 1979;77:846). Singleton (Singleton JW, et al. Gastroenterology. 1993;104:1293) found that mesalamine 4 g produced a statistically significant response rate (64%; placebo: 40%), but results obtained in other trials have not been consistent (Hanauer S. Gastroenterology. 2001;120:2308).

Steroids are effective for initial therapy (Summers RW, et al. Gastroenterology. 1979;77:846; Faubion WA, et al. Gastroenterology. 2001;121:255), but over 1 year, only 32% of patients remain in remission, and 28% become steroid dependent (Greenberg GR, et al. N Engl J Med. 1994;331:836). Furthermore, steroids are associated with significant adverse effects.

Budesonide 9 mg/day produced significantly greater response rates than did placebo in an 8-week trial (Greenberg GR, et al. N Engl J Med. 1994;331:836), and is slightly less effective than (Rutgeerts P. N Engl J Med. 1994;331: 842) or comparable to (Campieri M, et al. Gut. 1997;41:209) prednisolone. Prednisolone, however, is associated with greater steroid-related toxicity than is budesonide. Neither agent may be appropriate for long-term use, Dr. Lashner observed.
Remission rates of 65% and 40% have been obtained with budesonide 9 mg/day and mesalamine 4 g/day, respectively, at 8 weeks (P = 0.001) (Thompson OO, et al. N Engl J Med. 1998;339:370). Antibiotics are not consistently effective in active CD, whereas methotrexate and infliximab induce remission in patients with mild-to-moderate and severe CD, respectively.

Given these data, Dr. Lashner prefers a paradigm shift in the first-line treatment of flares and mild-to-moderate
ileocolonic CD, with greater use of budesonide rather than mesalamine.

What Are the Optimal Goals of Therapy in Barrett’s Esophagus?

Richard E. Sampliner, MD, Professor of Medicine at the University of Arizona Health Sciences Center, Chief of Gastroenterology, Southern Arizona VA Health System, in Tucson, Arizona, reported that the primary treatment goals in Barrett’s esophagus are similar to those for all patients with gastroesophageal reflux, namely elimination of gastroesophageal reflux symptoms and maintenance of healed mucosa. Unique to the treatment of Barrett’s esophagus is the goal of preventing esophageal adenocarcinoma. Dr. Sampliner addressed several patient-driven questions in the management of Barrett’s esophagus.

How Often Is Surveillance Endoscopy Required?
The data regarding appropriate intervals for surveillance endoscopy are limited. Cancer develops in only about 7% of patients with low-grade dysplasia, and some studies have found no difference in the development of cancer among patients with low-grade dysplasia and those with no dysplasia. Thus, in patients with no dysplasia on two consecutive endoscopies with systematic biopsies, current guidelines recommend a 3-year follow-up interval. If low-grade dysplasia is found, the endoscopy should be repeated to confirm that this is the highest grade of dysplasia in the esophagus. Subsequently an annual endoscopy is sufficient until no dysplasia is found on two consecutive endoscopies (Table 1).

The risk of cancer is higher in patients with high-grade dysplasia and guidelines for these patients are more controversial. Determining the time course of progression from one level of dysplasia to the next is difficult. Low-grade dysplasia can progress to cancer over a 4-year interval, and in patients with high-grade dysplasia, cancer may develop over an average period of 3 years. In some patients, cancer may develop over an average of 6 years without any recognizable intermediate stages of dysplasia.

If any lesions or mucosal irregularities are observed in patients with high-grade dysplasia, endoscopic resection is recommended to determine the degree of esophageal involvement. Intensive surveillance endoscopy is appropriate for focal high-grade dysplasia. Whether patients with multi-focal high-grade dysplasia should continue with intensive surveillance, receive endoscopic therapy, or undergo surgery depends on factors such as comorbidity, and patient age and preferences.

Are Biomarkers Helpful in Identifying the Risk for Progression to Cancer?
Several biomarkers could potentially be utilized for determining the risk of cancer. Among patients with histologic evidence of low-grade or indefinite dysplasia who had no flow cytometry abnormalities and no increases in the DNA content or 4N fraction, the 5-year incidence of cancer was 0 (CI: 0-0.47%) (Reid BJ, et al. Am J Gastroenterol. 2000;122: A292). Loss of 17p heterozygosity, which indicates a p53 mutational change, may be used to predict the likelihood of developing cancer. Further, patients with increased expression of cyclin D1 at baseline have markedly raised odds of developing adenocarcinoma (Bani-Hani K, et al. J Natl Cancer Inst. 2000;92:1316), whereas a p53 mutation at baseline in this study was not significantly related to the development of adenocarcinoma.

Can Proton Pump Inhibitors Prevent Progression to Cancer?
Proton pump inhibitors effectively treat reflux symptoms in patients with Barrett’s esophagus, but whether they influence the natural history of the disease process is unclear. In a 2-year trial, patients with Barrett’s esophagus who were treated with omeprazole 40 mg BID had mean 24-hour pH values of <4 for only 1.4 minutes (Peters FT, et al. Gut. 1999;45:489). Despite this excellent control of esophageal pH, the changes in the length and surface area of Barrett’s esophagus were just 6% and 8%, respectively — statistically but probably not clinically significant, according to Dr. Sampliner.

Among patients hospitalized for reflux symptoms, those who did not undergo surgery had a six-fold increased risk (standardized incidence ratio) of esophageal adenocarcinoma, compared with a control population without reflux symptoms (Ye W, et al. Gastroenterology. 2001;121:1286). With patients who underwent surgery, the risk increased
14-fold (Ye W, et al. Gastroenterology. 2001;121:1286). Thus, surgery does not appear to be more effective than
other therapies in reducing the risk of esophageal adenocarcinoma.

Should Patients With Barrett’s Esophagus Be Taking Cyclooxygenase-2 Specific Inhibitors?
Emerging data suggest that hyper-expression of cyclooxygenase-2 (COX-2) correlates with progression to neoplasia in patients with Barrett’s esophagus (Kaur BS, et al. Am J Physiol Gastrointest Liver Physiol. 2002;283:G327; Morris CD, et al. Am J Gastroenterol. 2001;96: 990). Two COX-2 specific inhibitors, sulindac and celecoxib, are approved for use in familial adenomatous polyposis. In a rat model of Barrett’s esophagus, sulindac and an experimental COX-2 specific inhibitor significantly reduced the development of cancer (Buttar NS, et al. Gastroenterology. 2002;122:1101). Similarly, epidemiologic studies demonstrated a 36% to 90% reduction in the development of esophageal cancer (Corey KE, et al. Gastroenterology. 2002;122:A292; Funkhouser EM, et al. Cancer. 1995;76:1116). Prospective, placebo-controlled, multicenter studies using this chemopreventive approach are underway.

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