Breedveld, et al report the long-term results of a European study comparing the safety and efficacy of leflunomide (LEF) vs methotrexate (MTX). The study design is similar to a North American trial by Cohen, et al reported during the 1999 American College of Rheumatology meeting. Patients with active rheumatoid arthritis (RA) and similar demographics were randomized to receive LEF (initial dose of 100 mg qd days 1-3, then 20mg qd; n=501) or MTX (7.5 mg/week, titrated to 10 or 15 mg/week; n=320). After completion of 12 months, patients were asked to continue for an additional year of double-blind therapy (LEF, n=292; MTX, n=320).

As noted in the table below, by year 1, MTX was significantly more efficacious than LEF in all outcome measurements. However, by year 2, no statistical differences were observed when comparing the two drugs. Withdrawals due to lack of efficacy were 11% in the LEF group compared to 6% with MTX. Adverse events were reported in both LEF and MTX treatment groups (25% and 21%, respectively).

Hepatotoxicity was also compared in the absence of folate supplementation. 16.7% of patients receiving MTX compared to 2.6% of patients receiving LEF experienced a rise in SGPT (>3 x ULN).

These data indicate that LEF and MTX have comparable efficacy for long-term therapy of RA and that, in the absence of folate supplementation, MTX appears to increase the incidence of hepatotoxity.

Editorial Comments: These results differ somewhat from those of the North American trial in which LEF was found to have somewhat greater efficacy than MTX based on ACR 20 and 50% criteria for both timepoints. However, in general, both drugs demonstrate good efficacy for the treatment of RA.

This is a follow-up to an abstract reported at the American College of Rheumatology meeting in November 1999 by Cohen, et al. In this Phase III, double-blind trial, patients with active RA were randomized to receive leflunomide (LEF 100 mg/day for 3 days, then 20 mg/day), placebo, or methotrexate (MTX 7.5-20 mg/week). Due to the small sample size, patients receiving placebo were not included in the two-year comparison. The instruments used to measure improvements in functional ability and HRQOL were the Health Assessment Questionnaire (HAQ), Problem Elicitation Technique (PET), and the Medical Outcome Survey Short Form (SF-36). PET is a self-prioritized problem-elicitation tool for assessing activities most important to the patient and most desired to improve.

Results:

These data show that improvements in physical function and HRQOL resulting from LEF and MTX therapy are maintained over 24 months. Improvements were statistically significantly greater in patients receiving LEF when compared with patients receiving MTX at 24 months in HAQ Disability Index, in mean change from baseline in PET Weighted Top 5, but not in the SF-36.

Editorial Comment: Much emphasis has been placed on the ability of RA treatments to slow x-ray progression of disease. However, it is equally important that patient quality of life significantly improve with treatment also. These data complement the short-term data already published by this group (Arthritis Rheum, 1999).

The objective of the analysis was to determine if changes in the mean health assessment questionnaire (HAQ) and the modified HAQ (MHAQ) were reflective of changes in clinical parameters, and therefore, are sensitive measure of effectiveness of DMARD therapy. Data was compiled from 3 Phase III clinical trials of leflunomide (LEF), US301, MN301, and MN302 involving a total of 1,839 patients with active RA. Patients were receiving either LEF (100 mg/day for 3 days, then 20 mg per day; n=771), methotrexate (MTX; 7.5-15 mg/week; n=649), sulfasalazine (SSZ; 2 g/day; n=113), or placebo (PL; n=199). Using step-wise, backward regression analysis, the association of HAQ/MHAQ with clinical parameters was evaluated. Clinical parameters included tender and swollen joint count (TJC and SJC, respectively), pain intensity (VAS), erythrocyte sedimentation rate (ESR), patient and physician global assessment of disease activity (PGA and MDGA, respectively), ACR 20 and 50% criteria, and others.

Results: at 12 months

Changes in compiled HAQ scores with treatment DMARDs closely correlated with patients clinical response. (shown below for 12 months)

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