Serum and red blood cell methotrexate (MTX) levels, as well as hepatic levels of MTX and folate, were analyzed in 24 patients who had received long-term oral MTX weekly for the treatment of rheumatoid arthritis. The serum MTX level peaked rapidly and was insignificant after 24 hours. The red blood cell MTX level was not related to the interval from the last MTX dose. In hepatic tissue obtained by liver biopsy, MTX was found in a predominantly polyglutamated form with depleted hepatiic folate stores when compared with baseline specimens. A brief period of therapy with oral folinic acid repleled hepatic folate. It is possible that MTX heptotoxicity is related to reduced hepatic folate levels and formation of MTX polyglutamates.Although methotrexate (MTX) is widely used in the treatment of refractory rheumatoid arthritis (RA), little is known about its metabolism and mechanism of action in the disease. Weekly dosage schedules of MTX for the treatment of rheumatoid arthritis have been similar to those employed in psoriasis, in which long-term weekly therapy has resulted in wellestablished hepatic abnormalities (1-4). for the development of these problems, including cirrhosis, remain unclear. Although MTX accumulation and folate depletion have previously been documented in hepatic tissue from patients receiving MTX for treatment of malignancy (5), no studies of hepatic folate or MTX have been reported in RA patients receiving long-term MTX therapy.MTX has been shown to accumulate in a polyglutamated form after long-term administration in animals and in humans, in hepatic and other tissues (5,6). We document for the first time the accumulation of MTX in a predominantly polyglutamated form in the liver, in addition to a marked hepatic folate deficiency in patients with active RA who were treated weekly for 2 to 4 years with pulse oral MTX. Serum and red blood cell (RBC) MTX levels and kinetics in the same patient population are also reported. PATIENTS AND METHODS Twenty-nine patients who fulfilled the AmericanRheumatism Association criteria for definite or classic RA (7) and who had previously failed to respond t o therapy with, or had a toxic reaction to, hydroxychloroquine, gold, or penicillamine, signed informed consent and participated in a prospective trial of long-term safety and efficacy of MTX. All patients had active disease defined by 3 of the following 4 criteria: I ) 2 6 tender joints, 2) 2 3 swollen joints, 3) morning stiffness of 245 minutes, and 4) an erythrocyte sedimentation rate r 2 8 mm/hour. Patients were started on a regimen of 15 mg of MTX, taken orally in I dosage once a week. Elderly patients (>65 years old) and 2 patients who weighed 4 0 kg were started on a regimen of 7.5 mg orally in 1 dosage. The dosage of methotrexate was lowered if the patients experienced toxicity (nausea, abdominal discomfort, diarrhea, or oral ulcerations) which they rated as "moderate" (8). Patients were ingesting 7.5-15 mg (mean 12.4 mg) when serum and RBC MTX levels were measured and when liver biopsies were obtained.

No abstract