Antirheumatic — leflunomide

Rheumatoid arthritis (RA) is a painful and progressive inflammatory disease of the joints that causes considerable functional disability. The standard treatment is with NSAIDs (non-steroidal antiinflammatory drugs), which give symptomatic relief but do not modify or check the progressive nature of the disease. Other antirheumatic drugs such as gold and sulphasalazine have a different and more prolonged action, and by suppressing the inflammatory processes of RA, may delay to some extent the progressive nature of the illness.

Such agents are sometimes distinguished as disease-modifying antirheumatic drugs (DMARDs) as RA is considered to be an autoimmune disease.

There is increasing evidence that activated T-cell lymphocytes and derived cytokines play an important part in the pathophysiology of RA, mediated by the biosynthesis of pyrimidine, and that they are linked with the inflammation and joint damage characteristic of the disease.¹

The rate-limiting factor in the production of pyrimidine is the enzyme dihydroorolate dehydrogenase, and an inhibitor of this enzyme should be able to prevent the proliferation of T-cells, and so break the vicious process of inflammation and eventual joint destruction that is a feature of rheumatoid arthritis.

In the search for a new type of DMARD with the required pattern of activity, attention was directed towards compounds known to have an inhibitory effect on some cytokines, and subsequently the isoxozole derivative leflunomide² was selected for further study.

Leflunomide has already been used as an immunomodulator in transplant surgery, and has also been studied in animals with adjuvant-induced arthritis.

It was found that leflunomide could suppress such induced arthritis, and also had the effect of blocking the spread of inflammation to uninvolved joints, a response considered to be linked with the inhibition of pyrimidine synthesis.

A favourable response was seen in preliminary clinical trials in patients with RA, who were given leflunomide in doses of 20mg indicated the clinical potential of the drug, and subsequent double-blind randomised multicentre clinical trials have shown that leflunomide is both effective and well-tolerated in the treatment of active RA.³ Extended trials are now necessary to determine whether the drug has a cumulative action, and that the initial response is maintained during long-term therapy.