Methotrexate (MTX), a stable derivative of aminopterin, is a folic acid antagonist that is specific for the S phase cell cycle by inhibiting the enzyme, dihydrofolate reductase, which is required in the pathway supplying methyl donor groups for DNA, RNA, and protein synthesis.<sup>10 Bertino J. The mechanism of action of the folate antagonists in man Cancer Res 1963 ;  23 : 1286

Cliccare qui per andare alla sezione Riferimenti</sup> It was first introduced in 1948 for the treatment of acute leukemia in children.<sup>34 Farber S., Diamond L.K., Mercer R.D. , e al. Temporary remissions in acute leukemia in children produced by folic antagonist 4-aminopteroylglutamic acid (aminopterin) N Engl J Med 1948 ;  238 : 787  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 145 Seeger D.R., Cosulich D.B., Smith J.M. , e al. Analogs of pteroylglutamic acid J Am Chem Soc 1949 ;  71 : 1753

Cliccare qui per andare alla sezione Riferimenti</sup> Following the important observation that aminopterin was effective for the treatment of psoriasis and rheumatoid arthritis (RA), <sup>48 Gubner R., August S., Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis Am J Med Sci 1951 ;  22 : 176  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> MTX, which became commercially available in the United States in 1955, has been used at lower dosages for the treatment of several nonmalignant diseases, each characterized by inflammation or cellular proliferation.<sup>68 Kevat S., Ahern M., Hall P. Hepatotoxicity of methotrexate in rheumatic diseases Med Toxicol 1988 ;  3 : 197

Cliccare qui per andare alla sezione Riferimenti</sup> With the widespread use of MTX, a well-defined toxicity profile has emerged, with hepatotoxicity being the most important potential major adverse reaction that can occur during long-term therapy. Hepatic fibrosis was originally reported in children and adults with leukemia, to whom MTX was given in high daily dosages.<sup>24 Colsky J., Greenspan E.M., Warren T.N. Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists Arch Pathol 1955 ;  59 : 198

Cliccare qui per andare alla sezione Riferimenti, 60 Hutter R.V.P., Shipkey F.H., Tan C.T. , e al. Hepatic fibrosis in children with acute leukemia: A complication of therapy Cancer 1960 ;  13 : 288

Cliccare qui per andare alla sezione Riferimenti</sup> In the late 1960s case reports appeared describing cirrhosis occurring in psoriasis patients treated with methotrexate.<sup>23 Coe R.O., Bull F.E. Cirrhosis associated with methotrexate treatment of psoriasis JAMA 1968 ;  206 : 1515

Cliccare qui per andare alla sezione Riferimenti, 31 Epstein E.H., Craft J.D. Cirrhosis following methotrexate administration for psoriasis Arch Dermatol 1969 ;  100 : 53

Cliccare qui per andare alla sezione Riferimenti, 103 Muller S.A., Farrow G.M., Martalook D.L. Cirrhosis caused by methotrexate in the treatment of psoriasis Arch Dermatol 1969 ;  100 : 523

Cliccare qui per andare alla sezione Riferimenti, 113 O'Rourke R.A., Eckert G.E. Methotrexate-induced hepatic injury in an adult Arch Intern Med 1964 ;  113 : 191

Cliccare qui per andare alla sezione Riferimenti</sup> These reports suggested that methotrexate had the potential to cause hepatotoxicity in patients with nonmalignant conditions treated with low dosages. This article reviews hepatotoxicity that occurs during MTX treatment of rheumatic diseases.