Arthritis News – 1999

Many patients with RA have suboptimal responses to treatment with a single therapeutic agent such as methotrexate, leflunomide (Arava), and etanercept (Enbrel). Therefore, there has been increasing interest in recent years in combining several treatments in order to achieve better control of the arthritis. A concern has been whether the toxicity will also be increased. In a recent report in Arthritis and Rheumatism, Weinblatt et al¹ reported the results of a small, open-label study to determine the safety of combining methotrexate and leflunomide for the treatment of RA. Both of these agents inhibit DNA synthesis, albeit by different molecular mechanisms, and both have the potential for causing liver inflammation. The study was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17 + 4 mg/week for > 6 months were given leflunomide, 10-20 mg/day. Patients were evaluated for adverse effects as well as clinical responses using the ACR 20 response criteria. Twenty-three patients completed 1 year of treatment. The combination therapy was generally well tolerated clinically. The most common adverse events reported were gastrointestinal (diarrhea, nausea) and respiratory (cough, shortness of breath), and were generally rated as mild to moderate in severity. The most common laboratory abnormality was asymptomatic elevation of liver enzymes. Two to three-fold elevations of transaminases occurred in approximately 20% of subjects, and higher (> 3-fold) elevations occurred in 7% (AST) and 17% (ALT) of patients. Three subjects were withdrawn from the study because of persistent enzyme elevation. Three subjects who had persistent enzyme elevations underwent liver biopsy. No evidence of marked fibrosis or cirrhosis were observed; 2 biopsies were scored as Roenigk grade IIIA mild fibrosis) and 1 as grade 1 (normal). Sixty (60%) percent of subjects met ACR 20 criteria for clinical response.

These data suggest that the combination of methotrexate and leflunomide may represent a relatively safe and effective treatment for rheumatoid arthritis. However, because of the open-label nature of this clinical trial, these results must be interpreted with caution. Currently, a double-blind, placebo-controlled trial is in progress to confirm or refute these preliminary results.

¹Weinblatt ME, Kremer JM, Coblyn JS, et al. Arthritis and Rheumatism 42:1322-28, 1999.