Aminopterine, a precursor of
methotrexate (MTX), was first used for the treatment of
rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of
cortisone and
aminopterin. Am. J. Med. Sci. 221, 169-175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of
aminopterin in
rheumatoid arthritis and
psoriasis. Am. J. Med. Sci. 221, 176-182.].
Corticosteroids, and to some extent
cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s-early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as
gold salts and
D-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral
methotrexate therapy for refractory
rheumatoid arthritis. J. Rheumatol. 11, 760-763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse
methotrexate in
rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489-496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose
methotrexate in
rheumatoid arthritis. N. Engl. J. Med. 312, 818-822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse
methotrexate and placebo in the treatment of
rheumatoid arthritis. A controlled clinical trial.
Arthritis Rheum. 28, 721-730.]. Subsequently, these four trials were included in a meta-analysis and the
drug was approved by the Food and Drug Administration for use in RA [Health and Public Policy Committee, H.P.P.C. and American College Physicians, A.C.P., 1987.
Methotrexate in
rheumatoid arthritis. Ann. Intern. Med. 107, 418-419; Paulus, H.E., 1986. FDA
Arthritis Advisory Committee meeting:
Methotrexate; guidelines for the clinical evaluation of antiinflammatory drugs;
DMSO in scleroderma.
Arthritis Rheum. 29, 1289-1290; Tugwell, P., Bennett, K., and Gent, M., 1987.
Methotrexate in
rheumatoid arthritis. Indications,
contraindications, efficacy, and safety. Ann. Intern. Med. 107, 358-366.]. Since then, rheumatologists have become aware of what Pincus et al. have called "the side effects" of RA comparing the morbidity and mortality caused by RA with that potentially caused by medications used to treat this disease [Pincus, T. and Callahan, L.F., 1993. The "side effects" of
rheumatoid arthritis: joint destruction, disability and early mortality. Br. J. Rheumatol. 32, 28-37.]. Thus, during the 1990s the use of MTX for the treatment of RA became generalized [O'Dell, J.R., 1997.
Methotrexate use in
rheumatoid arthritis. Rheum. Dis. Clin. N Am. 23, 779-796 (a); Bannwarth, B., Vernhes, J., Schaeverbeke, T., and Dehais, J., 1995. The facts about
methotrexate in
rheumatoid arthritis. Rev. Rhum. 62, 471-473 (b); Bologna, C., Jorgensen, C., and Sany, J., 1997a.
Methotrexate as the initial second-line disease modifying agent in the treatment of
rheumatoid arthritis patients. Clin. Exp. Rheumatol. 15, 597-601; Bologna, C., Viu, P. (ABSTRACT TRUNCATED)