Hepatotoxicity of prolonged methotrexate therapy for rheumatoid arthritis1

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Sixty patients with severe rheumatoid arthritis (RA), who were being treated with methotrexate (MTX) (mean duration of therapy, 48 months; mean weekly dosage, 8.67 mg), underwent liver biopsy performed to assess hepatic toxicity. Liver biopsies of 25 comparably severe RA patients not receiving MTX served as controls. All pathologic findings were grades I and II. Fatty infiltration was present in 50% of patients treated with MTX and 44% of controls. Fatty liver occurred more frequently in older patients and in consumers of alcohol. Round-cell portal inflammatory infiltrates were present in 18% of patients treated with MTX and 20% of controls, more frequently if Sjögren’s syndrome was present. No portal fibrosis (grade III) was found, but fibrous expansion of portal zones (grade II) was noted in 1 patient treated with MTX (1.7%) with Sjögren’s syndrome. At these low dosages, MTX exerts a minor and clinically unimportant hepatotoxic effect during two to eight years of chronic maintenance therapy.