GAINESVILLE, Fla. --- Nearly half the patients with an often debilitating form of inflammatory bowel disease saw their symptoms disappear within six weeks of starting a medication usually reserved for cancer patients, researchers report in the May 26 issue of The New England Journal of Medicine.
The patients had Crohn's disease, an incurable disorder that primarily affects the small intestine and colon but can cause problems throughout the digestive tract. The condition is frequently painful and often causes bouts of diarrhea.
Researchers from Harvard Medical School, the University of Florida and Washington University School of Medicine helped lead the national multicenter study of the drug sargramostim, also known by the trade name Leukine. The medication is typically used to boost the recovery of white blood cells, the body's defenders against foreign invaders such as bacteria. White blood cell levels can drop dramatically during chemotherapy, leaving patients prone to infection.
The findings could lead to renewed debate over the cause of Crohn's disease and the best way to treat it, which actually might be to stimulate the immune system, not suppress it, said Dr. John F. Valentine, an associate professor of gastroenterology, hepatology and nutrition at UF's College of Medicine and the Malcom Randall Veterans Affairs Medical Center.
"If the drug really works the way we think it works, it's 180 degrees in the opposite direction of everything else we do to treat Crohn's disease," he said. "We still don't really know what causes Crohn's disease. The traditional theory has been it's an overactive or inappropriate immune response against bacteria in the intestine. Now a theory has come forward that perhaps the problem isn't that the immune system is overactive, it's that the initial cells that stimulate the immune system to deal with injurious agents to the bowel are not active enough, which then leads to the chronic inflammation."
Crohn's disease afflicts 1 million people worldwide, about half of them Americans. About 20 percent of these patients have a blood relative with some form of inflammatory bowel disease.
Traditionally, doctors have used drugs such as steroids and other immunosuppressants to treat Crohn's disease. And while these medications result in similar remission rates, about 40 percent, they suppress the immune system and can be associated with other side effects.
"While some patients have gotten remarkable results with these agents, we still don't have the drug we're really looking for, one that has fewer side effects and is an effective therapy for most patients," Valentine said.
Admissions of patients with a diagnosis of inflammatory bowel disease to Shands at UF medical center have tripled in the past 12 years, he said, adding that he believes the disease is increasingly prevalent nationwide. The U.S. Congress passed the Inflammatory Bowel Disease Act last year, which required the Centers for Disease Control and Prevention to study the disease's prevalence in the United States and gather the demographic characteristics of these patients. The effort seeks to determine the environmental and genetic factors that spur development of the disease. In addition, a Florida bill seeks funding for similar research, to help practitioners learn how common Crohn's disease is in Florida and whether patients are being treated appropriately to manage the condition, Valentine said.
In the study, conducted at 35 medical centers, 124 patients with moderate to severe Crohn's disease who were not taking immunosuppressants were randomly assigned to receive either sargramostim, which is a version of a naturally occurring protein, or a placebo. Study participants on sargramostim received the drug in a daily injection for eight weeks. Neither the researchers nor the patients knew who was receiving the drug or the placebo while the study was under way.
Nearly half the patients treated with sargramostim, 48 percent, had a decrease of at least 100 points on the Crohn's Disease Activity Index, a standard measure of treatment effectiveness, during the treatment period. Twenty-six percent of those receiving a placebo noted a similar decrease. Lower scores correlate with less severe disease. In addition, compared with those on placebo, nearly twice as many patients on sargramostim went into remission.
"While it's not a therapy that puts everybody in remission, 40 percent of patients went into remission, which is as good as virtually any therapy we have," Valentine said. Nineteen percent of those receiving a placebo went into remission.
Significantly greater improvement was reported in quality of life scores for patients on the treatment compared with those on placebo, which continued for at least 30 days after treatment. A month after stopping the drug, more than 80 percent of the patients who entered remission were still in remission. The most common side effects associated with sargramostim were mild to moderate reactions at the site of injection and bone pain, and these diminished over time.
"Crohn's disease can be a devastating condition and current treatment options are not as effective in many patients and can have side effects as difficult for the patient to endure long-term as the disease itself," said lead investigator Dr. Joshua Korzenik, an assistant professor at Harvard Medical School and co-director at Massachusetts General Hospital Crohn's and Colitis Center, in a prepared statement. "Although there is currently no cure for Crohn's disease, we are encouraged by these data because they show sargramostim's potential as an alternative treatment option that does not involve suppressing the immune system and that improves Crohn's symptoms without steroid treatment."
The study was funded by Berlex Inc., a U.S. affiliate of Schering AG, Germany. Valentine worked with company officials on the design and conduct of the study and has received consulting and lecture fees from the company.
Further studies are needed before the Food and Drug Administration decides whether to approve sargramostim for the treatment of Crohn's disease.
"The approach with sargramostim is unique in that this agent is a growth factor that stimulates many different white blood cells instead of inhibiting them and demonstrates some significant clinical benefits in patients with Crohn's disease," said Dr. Stephen Hanauer, a professor of medicine and clinical pharmacology and chief of gastroenterology at the University of Chicago. "But I would emphasize that not all patients improved, the long-term safety of this agent has not been established and exactly how this drug works in Crohn's disease hasn't been defined. This is by no means a definitive therapy. It was effective in less than half the patients treated, and we don't know the profile of who responded versus who didn't, and there were significant side effects that included injection site reactions and bone pain in a significant number of patients."
Researchers would like to determine whether sargramostim helps patients who also take steroids and whether they eventually could stop taking steroids, which pose long-term risks, Valentine said. Another study will duplicate the most recent trial and include a re-treatment phase for patients who discontinue therapy but whose symptoms recur.
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