Retrospective analysis of 23 rheumatoid arthritis patients receiving low-dose methotrexate (MTX) demonstrated an association between the mean corpuscular volume (MCV) and hematologic toxicity. All 6 patients who developed hematologic toxicity were folate deficient, and 4 of 6 had marked macrocytosis. Furthermore, the mean MCV of the patients who developed toxicity was significantly higher than that of the controls without toxicity (P < 0.02). This difference in MCV was associated with an increased probability of developing toxicity with time (P < 0.005). These results suggest that sustained elevation in the MCV may be a predictor of impending hematologic toxicity due to folate depletion.Weekly low-dose methotrexate (MTX) has been shown to be an effective treatment in patients with active rheumatoid arthritis (RA) (1-5). Hematologic toxicity has rarely occurred during the use of weekly low-dose MTX. An antifolate compound, MTX inhibits the enzyme dihydrofolate reductase, preventing the formation of metabolically active reduced folates. However, acute folate deficiency leading to bone marrow toxicity has rarely occurred during prolonged treatment with low-dose MTX. MTX can lead to a reduction in erythrocyte folate concentrations in psoriasis patients (6) and to alterations in folate-mediated amino acid metabolism in RA patients (7). Macrocytosis, or elevation in the mean corpuscular volume (MCV), has been observed infrequently during low-dose MTX therapy (8). There are, however, several cases of marked macrocytosis followed by severe megaloblastic anemia that have been observed in psoriatic patients treated with low-dose MTX (9,lO). We have identified 6 RA patients who experienced hematologic toxicities during the course of long-term weekly low-dose MTX therapy, and noted that most of these patients with toxicity had marked macrocytosis for at least 6 months prior to the occurrence of the toxic episode. We report the association between severe, prolonged macrocytosis and hematologic toxicity due to MTX therapy.Patients and methods. A retrospective comparative analysis of 6 patients with hematologic toxicity and 17 additional RA patients was performed to test the hypothesis that marked macrocytosis is a risk factor for hematologic toxicity associated with MTX therapy. Among the 17 controls, 15 were enrolled in a long-term prospective study of MTX (4), and 2 additional patients who were undergoing prolonged weekly MTX therapy were followed by 1 of the investigators (PF).All study subjects fulfilled the 1987 American Rheumatism Association criteria for the diagnosis of rheumatoid arthritis (1 1) and were followed regularly at the Robert Brigham Arthritis Center of the Brigham and Women's Hospital. The medical records of the 23 patients were reviewed to ascertain their sex, the duration of MTX treatment, and the MCV and serum creatinine levels at the most recent laboratory deter-
