Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 110th Annual Digestive Disease Week

Chicago, Illinois / May 30-June 4, 2009

Early placebo-controlled clinical trials (Gendre et al. Gastroenterology 1993;104:435-9, Singleton et al. Pentasa Crohn’s Disease Study Group. Gastroenterology 1993;104(5):1293-301) showed that the 5-aminosalicylic acid (5ASA) mesalamine induced remission and clinical response in patients with active Crohn’s disease (CD). However, a meta-analysis of previously unpublished data suggested only a minor improvement. Still, many physicians continue to use mesalamine for treatment of CD with clinical success.

Identifying Appropriate Patients

In an attempt to get a better understanding of the role of 5-ASA in CD, Dr. William J. Tremaine, Mayo Clinic, Rochester, Minnesota, and colleagues noted that the prospective trials of 5-ASA that have failed to demonstrate efficacy in CD included patients with both ileal and colonic disease. Thus it was suggested that the appropriateness of patients selected for 5-ASA therapy can influence the results. For example, the National Cooperative CD Study demonstrated efficacy for sulfasalazine in the subgroup of patients with Crohn’s colitis.

In a retrospective study of mesalamine in patients with Crohn’s colitis, Dr. Tremaine and colleagues reviewed records of patients treated with mesalamine alone. They excluded patients with disease involving more than 5 cm of the distal ileum, fistulas, previous bowel resection and current or past treatment of CD with corticosteroids.

The analysis comprised 96 patients, 83 of whom had exclusive colonic disease and 13 of whom had distal ileal disease <5 cm in length. After a median follow-up of 1.5 years, the probability of success at one and five years was 73.4% and 61.1%, respectively. The results were not significantly affected by patient sex, smoking status, family history of inflammatory bowel disease or age at diagnosis. They observed that the majority of patients who were started on or were continued on mesalamine did not require additional therapy at one and five years.

While the natural disease course of Crohn’s colitis may in part explain these findings, they warrant a prospective trial of mesalamine for mildly to moderately active CD limited to the colon.

Efficacy in Mild to Moderate Disease

According to Faubion et al. (Gastroenterology 2001; 121:255-66), 43% of CD patients experience a mild disease course and never receive steroids. With the more aggressive top-down treatment strategy being studied in the medical community, patients may be subject to overtreatment. Thus, identifying factors that predict a mild clinical course of the disease can delay moving patient to more toxic therapies. In order to identify these factors, Dr. Wolfgang Kruis, Evangelisches Krankenhaus, Köln-Kalk, Germany, and colleagues analyzed data from patients with newly diagnosed, endoscopically and histologically proven CD treated at 12 German gastroenterology clinics. The patients were followed for a minimum of 12 months.

The study included 103 patients who were followed for a median of 46 months. The study population comprised 28 patients who received only mesalamine over the entire follow-up period or who received only one initial course of steroid therapy, and 75 patients who were started on steroids or immunosuppressants at diagnosis or who had step-up therapy during follow-up.

Comparing demographic and clinical characteristics in the two subgroups of patients, investigators identified three factors that predicted a mild, uncomplicated clinical course of CD: older age at diagnosis (P=0.027), lower level of C-reactive protein at diagnosis (P=0.019) and minor endoscopic lesions (P=0.03).

The investigators reviewed a subgroup of 42 patients who received mesalamine monotherapy at diagnosis. Ultimately, 20 of the 42 patients remained on mesalamine for at least 48 months without step-up therapy. They observed that more than a quarter of patients with CD diagnosed and treated with mesalamine only in an outpatient setting experienced long-term mild disease and did not require any step-up therapy.

Long-term Disease Control

In the Danish Crohn Colitis Database, it was established that at eight years from diagnosis, 44% and 36% of patients were characterized with a mild and moderate disease course, respectively.

An analysis of outcome was performed in patients treated with 5-ASA monotherapy by Dr. Pia S. Munkholm, Herlev University Hospital, Copenhagen, Denmark, and led by Dr. Dana Duricova, Charles University, Prague, Czech Republic. Findings added to evidence that appropriately selected patients can obtain long-term disease control with mesalamine.

Investigators retrospectively reviewed records on 345 patients, 165 (48%) of whom began therapy with 5-ASA monotherapy. Of these patients, 75% had a complete or partial response, 47% had a prolonged response and 31% maintained response on monotherapy. The median duration of 5-ASA therapy was 34 months in patients who had prolonged responses, 63 months in those who remained on a 5-ASA agent alone, and 5 months in nonresponders. Women were significantly more likely (OR 2.68, P=0.03) to have prolonged responses or remain on 5-ASA monotherapy.

Investigators concluded that the right phenotype of CD patients might profit from 5-ASA treatment, as 78% of initial responders obtained long-term benefit and 31% became 5-ASA-dependent, resulting in remissions lasting from 5 to 28 years.

5-ASA, Steroid Therapy

German investigators led by Dr. Andreas Tromm, Evangelisches Krankenhaus, Hattingen, reported findings from a prospective randomized study comparing a polymer-coated formulation of mesalamine (1.5 g t.i.d.) vs. two dosing schedules of the corticosteroid budesonide (3 mg t.i.d. and 9 mg q.d.) continued for eight weeks.

The study involved 311 patients with moderately active CD. Of those, 307 were available for intention-to-treat (ITT) analysis and 253 for per-protocol analysis.

The primary end point was the proportion of patients in each treatment group who achieved clinical remission, defined as a CD Activity Index (CDAI) score <u><</u>150. Clinical remission rates at eight weeks were 71.8% and 67.1% with budesonide t.i.d. and q.d. doses, respectively, and 62.1% with 5-ASA.

In both the ITT and per-protocol analyses, the budesonide groups demonstrated numerical superiority to polymer-coated 5-ASA therapy, but differences failed to meet the 10% threshold investigators established for non-inferiority. No patient developed unexpected or serious drug-related adverse events.

Researchers concluded that budesonide was numerically but not statistically superior to the polymer-coated 5-ASA high daily dose of 1.5 g t.i.d. tablets. The budesonide 9 mg q.d. dose appeared equally effective as the current standard dose regimen of 3 mg t.i.d. Authors characterized high-dose 5-ASA tablets (4.5 g/day) as achieving an impressive clinical remission rate.

Dr. Gary R. Lichtenstein, University of Pennsylvania, Philadelphia, analyzed data on 812 CD patients treated with delayed-release mesalamine in a real-world clinical practice setting. Patients were treated for as long as 5.2 years with doses ranging from 0.4 to 7.2 g/day. Twenty-nine per cent achieved remission on 5-ASA with no concomitant corticosteroid use. In the maintenance phase of this study, 69% maintained clinical remission with no concomitant use of corticosteroids.

The high, long-term remission rate observed with no concomitant use of steroids suggested that mesalamine could be effective if used in the appropriate patient at the right dose, and should be considered before placing patients on potentially more toxic therapies, especially for long periods of time.

Summary

Results from clinical trials and real-life practice settings demonstrated that treatment with a 5-ASA agent such as mesalamine is safe and effective for patients with mild or moderately severe CD. A substantial proportion of patients will have uncomplicated clinical courses, suggesting that many of them might achieve lasting benefits with 5-ASA therapy. These study findings indicated that 5-ASA therapy warrants consideration prior to initiating potentially more toxic therapies, especially in the maintenance setting.