Methotrexate, a folic-acid antagonist and well-known anticancer drug, was first used to treat rheumatoid arthritis in the early 1950s [2.2] Because of growing interest in the use of immunosuppressive drugs in the treatment of rheumatoid arthritis, methotrexate received increasing attention in the late 1970s and early 1980s as a third-line agent [2.1, 2.3] for use in patients with disease refractory to first-line (nonsteroidal anti-inflammatory agents) and second-line agents (antimalarials, gold salts, or D-penicillamine).
Four placebo-controlled clinical trials [2.2, 3.11] have been published documenting the short-term clinical benefit of methotrexate. However, the benefits of long-term treatment are still unclear [3.22], and