SAN ANTONIO, Texas – Patients with rheumatoid arthritis (RA) who receive leflunomide in combination with methotrexate are at no more risk of serious health consequences than are patients who take leflunomide as a monotherapy, according to University of Washington investigators who presented a five-year, prospective study.

"This was the largest five-year prospective cohort study focusing on leflunomide's safety to date," said principal investigator Kent T. Ta, MD, Senior Fellow in Rheumatology at the University of Washington School of Medicine in Seattle, Washington. "After studying over 5000 patients on either combination therapy with methotrexate or on leflunomide monotherapy, we found no increased risk of mortality or serious adverse events associated with the combination regimen."

The group included 3036 patients placed on leflunomide (10 mg or 20 mg/ daily) and 1977 on a leflunomide/methotrexate combination. The monotherapy and combination therapy patients received treatment for an average of 25 and 26 months, respectively.

Over the five-year study period, 85 patients taking the leflunomide/methotrexate combination therapy (4.3%) died, compared to 163 patients on leflunomide alone (5.4%). A partial list of causes of death showed that, in the combination group, 8 died of pneumonia, 26 of cardiovascular disease, 25 of pulmonary disease, and 9 each of cancer or infection.

In the monotherapy group, 20 patients died of pneumonia, 49 of cardiovascular disease, 58 of pulmonary disease, 13 from cancer, and 17 from infection. No patients died of hepatic failure that was related to treatment, Dr. Ta reported.

The rate of treatment-associated mortality in the combination group was similar to the rate in the monotherapy group, with a hazard ratio of 0.8.

The most common adverse events that required withdrawal of treatment (combination therapy vs. monotherapy) were diarrhea (85 vs. 165), alopecia (40 vs. 103), nausea (31 vs. 69), rash (24 vs. 65), and abnormal liver function test (26 vs. 42) . The rates for these events were statistically similar between the groups, Dr. Ta reported.

Seventeen patients in the combination group were hospitalized for pneumonia, compared with 27 in the monotherapy group. The investigators noted that no patients in the combination group were hospitalized for hepatitis, compared with three in the monotherapy arm due to abnormal liver function.

The study population was drawn from a cohort of 5 013 adult patients with RA who were followed from 1998 to 2003. Patients' demographic details, as well as clinical and adverse events data, were collected every six months through questionnaires. Dr. Ta and his investigative team confirmed deaths by reviewing medical records, death certificates, and the National Death Index, and they used both mortality and reported adverse events as safety outcome measures.

Reference:

Ta KT, Cartwright V, Michaud K, Wolfe F . Safety data comparing combination therapy of leflunomide plus methotrexate to leflunomide alone: a five-year prospective study. Presented at: Annual Meeting of the American College of Rheumatology; October 20, 2004; San Antonio, Texas. Abstract 1466.