Theory for Root Cause Of Crohn's Gains Support
By PETER LANDERS
Staff Reporter of THE WALL STREET JOURNAL
Two scientists in St. Louis say their radical theory about Crohn's disease is vindicated by a study in which an immune-system booster drug helped some patients get relief from diarrhea, abdominal cramps and other typical Crohn's symptoms.
Crohn's disease, named after a New York doctor, Burrill Crohn, who described its symptoms in 1932, afflicts an estimated 500,000 Americans. Patients often have to use the bathroom as much as 10 times a day, and may end up undergoing surgery to remove part of their intestines.
The disease is generally thought to be the result of a hyperactive immune system that attacks bacteria in the gut unnecessarily, causing inflammation. One of the newest treatments is Remicade, a Johnson & Johnson drug that treats Crohn's and rheumatoid arthritis by blocking a stimulator of immune response.
CROHN'S DISEASE
Affects about 500,000 Americans
Risk of developing the disease is 30 times greater if a sibling has it
Major symptoms: persistent diarrhea, abdominal cramping
More common in rich countries
More common in whites, especially Jews of European ancestry; less common in Hispanics and Asians
Source: Crohn's and Colitis Foundation of America
But two doctors at Washington University in St. Louis believe the root cause of Crohn's disease is an inadequate immune response. They say a defect in the body's initial response to bacteria causes infection to get out of control, forcing the second-line responders in the immune system to go into overdrive.
"It's a failure of the early step: The excessive response is a reflection of the earlier failure," says Brian Dieckgraefe of Washington University. Dr. Dieckgraefe and colleague Joshua Korzenik developed the theory after finding Crohn's-like symptoms in patients with two rare genetic disorders that cause immune deficiency.
Now the doctors have tested their theory in a clinical trial involving 124 patients. Two-thirds of the patients took Leukine, a drug owned by Schering AG of Berlin that is used in cancer patients to boost the body's initial line of immune defenses. The other one-third took a placebo. In the trial, 48% of the patients taking the drug showed a significant reduction in Crohn's symptoms, compared with 26% on placebo.
"This is a marvelous proof of concept," Dr. Dieckgraefe said. "It's going to change how people view the disease."
But Stephan Targan, a Crohn's disease expert who is head of gastroenterology at Cedars-Sinai Medical Center in Los Angeles, called the results "unimpressive" and said the two St. Louis doctors "had better get some better data than this." Dr. Targan said the modest response rate to the drug suggests that the new theory at most applies to only a minority of Crohn's patients.
Dr. Targan also questioned whether the therapy used in the trial was a realistic option for most patients because it requires them to take a shot every day for eight weeks. The drug is injected into the abdominal area and can leave a welt around the spot.
Drs. Korzenik and Dieckgraefe said their study was aimed more at showing the legitimacy of their theory and predicted that they could improve the response rate by refining the dose and administration of the drug. But they agreed that their theory might not apply to all Crohn's patients.
One patient in the study, Mike Harris, said taking Leukine has helped him stay symptom-free for the first time in seven or eight years. Mr. Harris, a 45-year-old lawyer in St. Louis, had suffered from loss of appetite but says he was "eating like a horse" after taking the drug. He also stopped having to rush to the bathroom several times a day.
The two doctors first proposed their theory in a 2000 article in a specialist journal. Dr. Dieckgraefe said a bigger journal rejected the paper, calling the theory "preposterous." An initial study with Leukine, published last year in Lancet, a major British journal, showed that 12 of 15 patients taking the drug showed a significant decrease in Crohn's symptoms. That study didn't have a placebo arm, to provide a base as a comparison.
The doctors' theory also appears to mesh with the discovery in 2001 of a gene that significantly increases the risk of developing Crohn's disease. That gene, called Nod2, encodes a protein that helps the immune system's first line of defense respond to some kinds of bacteria. The mutated form found in Crohn's patients reduces the immune system's responsiveness.
Write to Peter Landers at peter.landers@wsj.com |
