Thalidomide effective against refractory Crohn's disease
December 1, 1999
A study in the December issue of Gastroenterology shows that thalidomide, a drug that became infamous in the 1960s for causing thousands of severe birth defects, can be an effective short-term treatment for Crohn's disease--even for patients whose disease has not responded to other therapies.
All 14 of the patients who completed the 12-week study, performed at the University of Chicago Hospitals and at Sunnybrook Hospital in Toronto, responded to the treatment; almost two-thirds of those patients had a clinical remission. More than half of the patients began to improve within four weeks.
"We were impressed by the number of patients with truly difficult-to-manage Crohn's disease who responded to thalidomide and with the speed of the drug's effect in some of these patients," said Eli Ehrenpreis, MD, assistant professor of clinical medicine at the University of Chicago and director of the study. "Our results suggest that thalidomide has a very potent effect on Crohn's disease and could play an important role as a steroid-sparing agent."
Crohn's disease is a chronic and often debilitating condition in which inflammation of the intestines leads to severe diarrhea, abdominal pain, and weight loss. It affects an estimated 200,000 people in the United States, primarily young adults. About 30 percent of patients develop fistulas, small leaks from the intestine that can extend to the skin of the abdomen.
The study involved 22 patients with Crohn's disease that did not respond to anti-inflammatory medications and was resistant to treatment with steroids. Before beginning the study, nine patients had severe intestinal symptoms, and 13 had perianal fistulas. Their median score on the Crohn's Disease Activity Index, a measure of disease severity, was 371. (CDAI scores range from 150, disease in remission, to 500.)
Fourteen of the 22 patients completed 12 weeks of treatment. All 14 had either a 150-point or greater reduction in disease activity or dramatic improvement of fistulas. Five patients had complete closure of their fistulas.
The median CDAI score improved from 371 at the trial's start, to 210 at four weeks, to 175 at 12 weeks. Three patients were able to stop taking steroids entirely and the median daily steroid dose fell more than 70 percent, from 26 mg down to 7.5 mg.
Although never approved for use in the United States, thalidomide was widely used in the late 1950s and early 1960s in Europe, Canada, and Japan to treat nausea and sleeplessness in pregnant women suffering from morning sickness. Its use resulted in more than 10,000 severe birth defects and deformities of the limbs or internal organs in the exposed newborns.
In July of 1998, however, thalidomide won FDA approval for the treatment of leprosy. It has been tested recently against several other disorders--especially autoimmune diseases--because it is known to inhibit tumor necrosis factor (TNF), one component of the immune response. Two patients who did not respond to infliximab--an antibody directed at TNF and recently approved for treating Crohn's disease--did respond to thalidomide therapy.
All patients in this study had to practice reliable birth control to prevent any risk of birth defects. Thalidomide has several side effects in addition to causing birth defects. All patients reported sleepiness, and several dropped out of the study--primarily because of drowsiness. Others complained of a diffuse rash or constipation or had elevated blood pressure. Several patients had their doses reduced from 300 to 200 mg. per day down to as low as 100 to 50 mg. per day. The lower doses did not appear to reduce the drug's benefits.
The most serious concern was mild symptoms of peripheral neuropathy, a loss of sensation or discomfort in the hands and feet, reported by two patients in the study.
A smaller low-dose study, sponsored by the drug manufacturer (Celgene), was conducted at Cedars-Sinai Medical Center in Los Angeles and published in the same journal. Seven of the 10 patients who completed this study responded to the drug; two had clinical remissions. All 10 were able to reduce their steroid doses by at least 50 percent, and two were able to discontinue steroid use.
"Together, these two small, open-label studies provide preliminary data that suggest a beneficial effect of thalidomide in Crohn's disease," wrote Drs. Bruce Sands and Daniel Podolsky from the Massachusetts General Hospital in an editorial accompanying the Gastroenterology articles.
"This drug must be carefully controlled and monitored, especially for use in women of childbearing age," notes Dr. Ehrenpreis, "but it would be unconscionable to withhold thalidomide from seriously ill patients if controlled trials confirm the safety and efficacy of this treatment in patients with refractory Crohn's disease."
A controlled clinical trial comparing the response to two different doses of thalidomide and placebo is being planned.
Funding for the Chicago study was provided by the Gastrointestinal Research Foundation, Chicago, and the University of Chicago's Clinical Research Center.
Additional authors of the study include Drs. Stephen Hanauer, Sunanda Kane and Russell Cohen of the University of Chicago Inflammatory Bowel Disease Center, and Lawrence Cohen of Sunnybrook Hospital, Toronto. The lower-dose study was directed by Eric Vasiliauskas, MD of Cedars-Sinai.
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