An infamous drug proves to be important therapy for Crohn’s

A new study by University researchers 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.

Crohn’s disease, a chronic and often debilitating condition in which inflammation of the intestines leads to severe diarrhea, abdominal pain and weight loss, affects an estimated 200,000 people in the United States, primarily young adults.

Fourteen patients who completed a 12-week study performed at the University of Chicago Hospitals and at Sunnybrook Hospital in Toronto, Canada, responded to the treatment.

Almost two-thirds of those patients had a clinical remission, and more than half of them 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, Assistant Professor in Clinical Medicine 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.”

The study involved 22 patients with Crohn’s disease who did not respond to anti-inflammatory medications or treatment with steroids.

Fourteen of the 22 patients completed 12 weeks of treatment. All 14 had a reduction in disease activity or dramatic improvement of fistulas, which are small leaks from the intestine that can extend to the skin of the abdomen. Five patients had complete closure of their fistulas.

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. Its use resulted in more than 10,000 severe birth defects, deformities of the limbs or internal organs, in exposed newborns.

In July 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 know to inhibit tumor necrosis factor, one component of the immune response. Two patients who did not respond to infliximab, an antibody directed at tumor necrosis factor that was 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 pressures. Several patients had their doses reduced from 200 to 300 mg per day down to as low as 50 to 100 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, which was reported by two patients in the study.

A smaller, low-dose study 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.

“This drug must be carefully controlled and monitored, especially for use in women of child-bearing age,” noted 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 between 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 Clinical Research Center.

Additional authors of the study include professors in the University’s Inflammatory Bowel Disease Center, Stephen Hanauer, Professor in Medicine, Sunanda Kane, Assistant Professor in Medicine, and Russell Cohen, Assistant Professor in Medicine, and Lawrence Cohen of Sunnybrook Hospital, Toronto, Canada. Dr. Eric Vasiliauskas of Cedars-Sinai directed the lower-dose study.