Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial

Background Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. Methods 358 patients were randomly assigned leflunomide (100 mg daily on days 1–3, then 20 mg daily), placebo, or sulphasalazine (0·5 g daily, titrated progressively to 2·0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigatorʹs and patientʹs overall assessments. Analyses were by intention to treat. Findings The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9·7, -4·3, and -8·1 for tender joint count; -7·2, -3·4, and -6·2 for swollen joint count; -1·1, -0·3, and -1·0 for physicianʹs overall assessment; and -1·1, -0·4, and -1·1 for patientʹs overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0·0001 for joint counts; p<0·001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0·01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. Interpretation Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a diseasemodifying antirheumatic drug.