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Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis
  1. M CUTOLO,
  2. A SULLI,
  1. Division of Rheumatology
  2. Department of Internal Medicine
  3. University of Genova
  4. Viale Benedetto XV,6
  5. 16136 Genova, Italy
  6. Laboratory of Neuroendocrinoimmunology
  7. Department of Internal Medicine
  8. University Medical Centre
  9. 93042 Regensburg, Germany
  1. Professor Cutolo mcutolo{at}

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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

Finally, four well designed, blinded, placebo controlled studies published in 1984 and 1985 introduced the use of MTX in the treatment of RA.9-12

The early indications for MTX use in the rheumatic diseases were first reported in a large review in 1984.13 From the considerable experience obtained over the past 15 years, several lines of evidence clearly suggest that MTX does not act simply as a cytotoxic (antiproliferative) agent for the cells responsible for the joint inflammation in RA.14 As a matter of fact, it would be difficult to understand how a drug that diminishes inflammation by preventing proliferation of immune cells might work at effective concentrations for only a very short time and once a week. In addition, the rapid clinical remission and the short term effect on the acute phase reactants, as seen with low dose MTX administration in most patients with …

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