Ann Rheum Dis 2001;60:729-735 ( August )

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Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

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	Methotrexate in rheumatoid arthritis

Methotrexate (MTX) is a folate analogue originally synthesised in the 1940s and designed to inhibit dihydrofolate reductase.¹ Reduced folate (tetrahydrofolate) is the proximal single carbon donor in several reactions involved in the de novo synthetic pathways for purine and pyrimidine precursors of DNA and RNA required for cell proliferation. Furthermore, tetrahydrofolate plays a part in a second important biochemical step: the methionine-homocysteine cycle, which is necessary to provide a methyl group for several downstream reactions such as methylation of DNA, RNA proteins, and others. Therefore, MTX has been used extensively for treatment of neoplastic diseases. In 1951 the rationale for the introduction of MTX for the treatment of rheumatoid arthritis (RA) was that it inhibited proliferation of the lymphocytes and other cells responsible for inflammation in the joint.² No further studies on clinical experience with MTX in RA were published until the early 1980s, when several uncontrolled trials were reported.^3-8

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