Like throwing oil on a fire or prescribing a high cholesterol diet for heart patients, gastroenterologists traditionally have believed that it would not be a good idea to stoke up the body’s immune system to treat Crohn’s disease. Most treatments for Crohn’s, an autoimmune disorder, are geared to suppress the immune response, but a new study demonstrates that stimulating innate immunity also is effective at improving symptoms in many patients with the intestinal disorder.
Reporting this week in the New England Journal of Medicine, researchers from Washington University School of Medicine in St. Louis, Massachusetts General Hospital and other institutions found that treatment with GM-CSF (granulocyte macrophage colony stimulating factor) alleviated symptoms of Crohn’s disease and improved patients’ quality of life. Patients who received the drug also had significantly less inflammation in the mucosal linings of their intestines.
“That’s very significant,” says first author Joshua R. Korzenik, M.D., who did much of the research at Washington University and now is co-director of the Crohn’s and Colitis Center at Harvard-affiliated Massachusetts General Hospital. “We have clear, clinical evidence that patients feel better and have less pain and other problems related to Crohn’s disease. Endoscopic evidence also seems to demonstrate the drug helps with underlying inflammation.”
Crohn’s affects about half a million people in the United States. A typical Crohn’s disease patient deals with diarrhea, abdominal pain and intra-abdominal infections. Frequently, scar tissue closes off sections of the intestine, and patients need surgery to eliminate those blockages.
Korzenik and co-principal investigator Brian K. Dieckgraefe, M.D., Ph.D., a Washington University gastroenterologist and staff physician at Barnes-Jewish Hospital, have been investigating the treatment of Crohn’s disease by enhancing the body’s innate immunity since the mid-1990s.
“The idea of priming the immune system in patients with Crohn’s disease sounds a bit crazy at first,” says Dieckgraefe, an assistant professor of medicine. “But there are two types of immunity, and we’re only dealing with half of the immune system. We’re priming early immune cells, such as neutrophils and macrophages, not the T cells and B cells that are suppressed by other Crohn’s disease therapies.”
The strategy appears to help a significant number of patients. In 2002, Korzenik and Dieckgraefe published results from a preliminary15-patient, open-label study in The Lancet reporting that GM-CSF treatment improved symptoms of Crohn’s disease in the majority of patients with moderate to severe forms of the disorder.
Following that study, Washington University applied for and received a patent covering the use of colony-stimulating factors for the treatment of Crohn’s disease. The technology then was licensed by Washington University to Berlex Laboratories Inc.
In this larger, phase II clinical study, Korzenik, Dieckgraefe and a team of researchers from around the country followed 124 patients at 28 centers to determine whether GM-CSF, commercially known as Leukine® (sagramostim), would help patients with moderate to severe Crohn’s disease.
In the study, 81 participants got daily injections of GM-CSF, which stimulates the activity of certain cells in the immune system. Another 43 received an inactive placebo. The investigators wanted to see whether patients on the drug would experience a decrease in the Crohn’s Disease Activity Index (CDAI), which registers severity of Crohn’s disease symptoms on a scale from one (mild) to 600 (severe).
After eight weeks of treatment, 48 percent of those who received GM-CSF had a 100-point improvement in their CDAI score. Only 26 percent of those who received the placebo had a similar improvement. In all, 40 percent of those who received the drug went into remission, compared to 19 percent of the placebo group.
The researchers also measured quality of life with the Inflammatory Bowel Disease Questionnaire. Scores on that test range from a low of 32 to a high of 224. After eight weeks, scores improved an average of 28 points in the group receiving treatment, compared to a 16-point improvement in the placebo group.
There were minor side effects to treatment — some patients developed soreness at the injection site or reported bone pain — and a handful of more serious side effects, including migraines, weakness and lethargy. Dieckgraefe says it is important to remember that powerful medications can sometimes have serious side effects, so studies must continue to ensure GM-CSF is not used in patients it might harm.
The investigators believe if research continues to demonstrate the drug is effective and safe for most patients, using GM-CSF earlier in the course of Crohn’s disease might be especially beneficial.
“Our study population included many people who were very sick: more than 80 percent of these patients already had been treated with steroids, and about 70 percent had been on some type of immune system inhibitor,” Korzenik says. “Response rates might be higher in patients whose disease is milder and who haven’t been on so many other treatments.”
“And as we move forward, we’d like to learn whether improving symptoms now can improve long-term outcomes and prevent some of the abscesses, fistulas and surgeries that are so common in many Crohn’s patients,” Dieckgraefe adds.
Berlex Laboratories Inc., the pharmaceutical firm that owns Leukine, initiated the multicenter study that just concluded. The success of the treatment strategy in this study has led them to begin a phase III trial as part of an effort to petition the Food and Drug Administration for approval of GM-CSF as a treatment for Crohn’s disease.
A U.S. patent entitled “Stimulating Neutrophil Function to Treat Inflammatory Bowel Disease (6500418)” was issued on Dec. 31, 2002. Brian K. Dieckgraefe and Joshua R. Korzenik are the inventors. The patent is owned by Washington University School of Medicine in St. Louis and licensed by Berlex Laboratories. Dieckgraefe, Korzenik and Washington University School of Medicine’s Department of Medicine are entitled to a share of the royalties received by the University from the licensed technology. The terms of these arrangements were deterimined in accordance with the University’s conflict-of-interest policies (http://www.wustl.edu/policies/conflictclinical.html).
This research was supported by a General Clinical Research Center grant from the National Institutes of Health and by funding from Berlex, Inc., a member of Sheering AG, Germany Group. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or the writing of the report.
Korzenik JR, Dieckgraefe BK, Valentine JF, Hausman DF, Gilbert MJ and the Leukine in Crohn’s disease study group. Sagramostim (Granulocyte-macrophage colony-stimulating factor) for active Crohn’s disease. New England Journal of Medicine, vol. 352:21, pp. 31-39, May 26, 2005.
Dieckgraefe BK, Korzenik JR. Treatment of active Crohn’s disease with recombinant human granulocyte-macrophage colony-stimulating factor. The Lancet, vol. 360,
pp. 1478-1481, Nov. 9, 2002.
Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.