Thursday, March 4, 2004

Research Encouraging For Crohn's Maintenance
By Mike Upchurch

Researchers from the U.S, Israel, and Europe, including the DCRI’s Dr. Jane Onken, have found encouraging data for patients with a debilitating gastrointestinal disease. Their results, published last week in the New England Journal of Medicine, show that infliximab holds promise in mitigating some of the worst complications of Crohn’s disease.

Jane E. Onken, MD

Crohn’s is an inflammatory disease of the gastrointestinal tract whose causes are not well understood. Consequently, it can be difficult to treat. Crohn’s patients frequently suffer severe diarrhea, vomiting, abdominal pain, weight loss, and fistulas. Fistulas are abnormal erosions that open passages between two normally separated organs. In Crohn’s patients, these happen most often in the intestines and the anus.

Fistulas severely impair a patient’s quality of life and often lead to the need for surgical removal of the colon and the placement of a colostomy. They occur in 17%-43% of all cases of Crohn’s.

Though infliximab, which works by inhibiting an inflammation-promoting protein called tumor necrosis factor, has shown to be effective in newly diagnosed Crohn’s, it hasn’t been fully explored in patients who have already developed fistulas. Early short-term trials showed that the drug could close fistulas, but little was known about its long-term potential for keeping them closed.

ACCENT II (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen in Patient’s with Fistulizing Crohn’s Disease) enrolled 306 patients at 45 sites in North America, Europe, and Israel. The patients were all given an infusion of infliximab, and those who responded—defined as closure of at least 50% of the fistula after 14 weeks—were randomized to receive either infliximab maintenance therapy or a placebo. The patients were followed for just over 1 year total.

In all, 195 patients had a response to the initial therapy and 87 did not. All of these patients were randomized to 1 of the 2 treatment arms.

For patients who had a response to the first infliximab infusion, news was good. The average time until their fistulas stopped responding to maintenance therapy was 14 weeks in the placebo group versus just over 40 weeks for those on infliximab. Overall, 62% of the patients on placebo had an eventual loss of response, compared with 40% in the infliximab group.

The majority of patients were deemed to have a loss of response due to a need for changing their standard Crohn’s treatment, not because of a reappearance of their fistulas. In the placebo group, 22% saw their fistulas open again and 16% of the infliximab group experienced reopened fistulas.

At the end of the study, the infliximab group was still seeing benefits. Compared with 23% of the placebo group, 46% of infliximab patients were still responding to the medicine at week 54.

For patients who did not have a response upon initial infliximab treatment, the numbers were not as dramatic, though the medication still had an advantage over placebo. Overall, 16% of these patients on placebo responded to treatment, compared with 21% of infliximab patients. This group of patients was much smaller, however, and the statistical power of the difference between the two was accordingly lower.

The ASSENT II authors concluded that infliximab is an effective treatment for keeping fistulas closed in Crohn’s disease patients who respond to an initial infusion.

“Nearly twice as many patients who received infliximab maintenance therapy, as compared with placebo maintenance therapy, had complete and durable closure of fistulas over the 54-week study,” write Dr. Onken and her coauthors. “In addition, as previously reported in patients with Crohn’s disease without fistulas, superior control of disease activity and an improved quality of life were associated with infliximab maintenance therapy.”

Joining Dr. Onken was lead author Dr. Bruce Sands of Harvard Medical School. The senior author was Dr. Sander van Deventer of the Acadernisch Medisch Centrum in Amsterdam.