Elsevier

The Lancet

Volume 353, Issue 9149, 23 January 1999, Pages 259-266
The Lancet

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

https://doi.org/10.1016/S0140-6736(98)09403-3Get rights and content

Summary

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 investigator's and patient's 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 physician's overall assessment; and -1·1, -0·4, and -1·1 for patient's 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.

Introduction

Rheumatoid arthritis is a progressive disease associated with severe morbidity, functional decline, permanent disability, and an increase in mortality.1 Disease progression is rapid in the early phases.2, 3 There has therefore been a growing trend for early, aggressive treatment with disease-modifying antirheumatic drugs (DMARDs).4 A recent investigation found consistent use of DMARDs in patients with moderate or long-standing rheumatoid arthritis.5 However, only a few DMARDs have been unequivocally shown to retard radiographically assessed disease progression;6, 7 sulphasalazine is one of these DMARDs.8, 9, 10, 11, 12 Furthermore, DMARDs can rarely be given for long periods in rheumatoid arthritis owing to lack of sustained efficacy or to toxicity.10, 13, 14 Therefore, there is a need for new agents with a high ratio of efficacy to toxicity that decrease clinical signs and symptoms of rheumatoid arthritis, retard disease progression, prevent new joint erosions, and improve functional ability and quality of life.

The primary action of leflunomide, an immunomodulatory agent, is inhibition of de-novo pyrimidine synthesis by selective inhibition of dihydro-orotate dehydrogenase, a key enzyme in the process.15, 16, 17 Cells such as activated T lymphocytes that predominantly synthesise pyrimidines via the de-novo pathway seem to be especially sensitive to the effect of leflunomide.17 Hypotheses on the pathogenesis of rheumatoid arthritis invoke an important role of activated T lymphocytes.18, 19, 20

Leflunomide effectively inhibits the progression of arthritis in studies in animals, including the rat adjuvant and the MRL/lpr mouse models.21 The efficacy and safety of leflunomide were investigated in comparison with placebo in a dose-finding phase II study of patients with rheumatoid arthritis.22 Although DMARDs show better efficacy than placebo, they can differ in their efficacy and toxicity profiles.8, 10, 14 We therefore undertook a phase III study to compare leflunomide with placebo and with sulphasalazine, a DMARD known to be effective,8, 9, 10, 11, 12 in the management of patients with active rheumatoid arthritis.

Section snippets

Patients

Eligible participants had a diagnosis of active rheumatoid arthritis based on the revised criteria of the American College of Rheumatology23 and were of functional class I, II, or III, according to the classification of the American College of Rheumatology. Active disease was defined by the presence of six or more tender joints, and six or more swollen joints, based on 28-joint count;24 overall assessments by the physician and patient of rheumatoid arthritis activity as fair, poor, or very

Baseline characteristics of participants

The demographic characteristics of the treatment groups were similar (table 1). The mean age was 58 years (SD 12), and 72% of patients were women. The mean disease duration was 7 years; 41% of patients had had rheumatoid arthritis for 2 years or less. 93% of patients were of American College of Rheumatology functional class II or III. Across treatment groups, 40% to 53% of the patients had no history of DMARD treatment. The three groups were similar in terms of use of NSAIDs and corticosteroids

Discussion

In this study, leflunomide and sulphasalazine effectively and safely alleviated signs and symptoms of active rheumatoid arthritis.

Leflunomide inhibits de-novo pyrimidine synthesis, and may act selectively on activated autoimmune lymphocytes, such as those involved in the pathogenesis of rheumatoid arthritis.15, 16, 17 However, other modes of action may also be involved,32, 33 and further studies are needed to elucidate the in-vivo mechanism of action in rheumatoid arthritis. During the short

European Leflunomide Study Group

I Andreasson (Gothenburg, Sweden); P Andresen (Gråsten, Denmark); P Beck (Frederiksberg, Denmark); HA Bird (Leeds, UK); D Brackertz (Mainz, Germany); S Brighton (Pretoria, South Africa); H Bröll (Vienna, Austria); AK Clarke (Bath, UK); O Duke (Surrey, UK); W Graninger (Vienna, Austria); R Grigor (Auckland, New Zealand); B Hazleman (Cambridge, UK); P Jones (Rotorua, New Zealand); JR Kalden (Erlangen, Germany); AA Kalla (Cape Town, South Africa); GH Kingsley (London, UK); R Kreuzeder (Vienna,

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