Clinical trial of Etanercept for Wegener's disease shows no benefit

January 26, 2005

A Johns Hopkins-led study designed to evaluate the ability of etanercept to maintain disease remissions in a serious autoimmune disorder has failed to show any benefit. Etanercept, also called Enbrel, is a common treatment for rheumatoid arthritis and other types of joint inflammation.

"We had hoped that this approach to the treatment of Wegener's granulomatosis would be useful in preventing disease relapses," says John H. Stone, M.D., associate professor of medicine, director of the Johns Hopkins Vasculitis Center, and lead investigator of the study published in the Jan. 27, 2005, issue of the New England Journal of Medicine.

"The study results, however, demonstrate unequivocally that etanercept was not effective for this purpose. Because of the disease's propensity to flare following remission and the high risk of treatment complications associated with conventional therapies for Wegener's, we must continue to look for safe, effective ways of achieving and maintaining disease remissions," said Stone.

Wegener's granulomatosis is an uncommon disorder in which the body's immune system attacks its own blood vessels, damaging vital organs by limiting the flow of blood to lungs, kidneys, upper airways and other organs. The disease can affect people of any age and occurs in men and women with equal frequency.

Although current medications used to treat Wegener's halt the disease temporarily in most patients, 60 to 80 percent of patients eventually suffer from disease flares. The need to treat many patients repeatedly with medications such as glucocorticoids (prednisone), cyclophosphamide, and methotrexate leads to mounting morbidity from treatments. At the same time, each disease flare has the potential to cause irreversible damage. Wegener's granulomatosis frequently leads to kidney failure, hearing loss, damage to the respiratory tract, peripheral nerve injury, and other complications, according to Stone.

Etanercept, the first of a class of drugs called tumor necrosis factor inhibitors approved by the U.S. Food & Drug Administration for the treatment of rheumatoid arthritis, is also known to be effective in psoriasis, psoriatic arthritis, and juvenile rheumatoid arthritis. To test the effectiveness of etanercept at preventing flare-ups for Wegener's patients, Stone and colleagues from seven other academic medical centers enrolled 180 patients with the disease into a randomized, placebo-controlled clinical trial. All patients received standard drug therapy to treat the disease. In addition to standard therapies, 89 patients received etanercept and 91 received placebo. Patients were followed for an average of 27 months.

The researchers found no significant differences in the percentages of patients in the two groups who achieved disease remissions of at least six months duration: 69.7 percent among the etanercept-treated patients, compared with 75.3 percent in the control group. In the trial overall, fewer than 50% of the patients achieved and maintained remissions for the duration of the study. There were also no differences between groups in the numbers of patients who experienced severe or limited disease flares. Twenty-three patients in the etanercept group suffered severe flares during the trial, for example, compared with 25 in the comparison group. In both groups, disease remissions were achieved at a high cost in treatment-associated adverse effects. Most side effects of treatment were attributed to conventional medications. Solid cancers developed in six patients in the etanercept group, however, compared with none in the placebo group.

"The number of malignancies observed is too small to draw any firm conclusions," noted Stone. "There is certainly the potential for interaction between TNF inhibitors and cyclophosphamide - a drug known to cause several types of cancer. This potential association bears further scrutiny," said Stone.

Other centers participating in the study were the Beth Israel Medical Center (New York), Boston University, the Cleveland Clinic Foundation, Duke University, the University of California, San Francisco, the Mayo Clinic, and the University of Michigan.
-end-
The study was funded by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases/National Institutes of Health (NIH/NIAMS) and the Office for Orphan Products Development (U.S. Food and Drug Administration). Amgen Corporation provided etanercept and placebo for the trial.

On the Web:

www.nejm.org
http://vasculitis.med.jhu.edu/index.html

Johns Hopkins Medicine

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