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arthritis (Felson et al., 1990), with efficacy established in numerous trials (Morgan et al., 1994). Patients with rheumatoid arthritis are frequently reported to be folate deficient, and folate stores are decreased in patients with rheumatoid arthritis who take methotrexate (Morgan et al., 1987, 1994; Omer and Mowat, 1968). Some of the side effects of methotrexate administration, such as gastrointestinal intolerance, mimic severe folate deficiency (Jackson, 1984). When patients are also given high-folate diets or supplemental folate, there is a significant reduction in toxic side effects with no reduction in drug efficacy. It has been recommended that patients undergoing chronic methotrexate therapy for rheumatoid arthritis increase folate consumption (Morgan et al., 1994) or consider folate supplements (1 mg/day) (Morgan et al., 1997).

Other Drugs with Antifolate Activity

The following diseases have been treated with drugs having antifolate activity: malaria with pyrimethamine, bacterial infections with trimethoprim, hypertension with triamterene, Pneumocystis carinii infections with trimetrexate (Morgan and Baggott, 1995), and chronic ulcerative colitis with sulfasalazine (Mason, 1995).

Oral Contraceptives

A number of early studies of oral contraceptive agents containing high levels of estrogens suggested an adverse effect on folate status (Grace et al., 1982; Shojania et al., 1968, 1971; Smith et al., 1975). However, oral contraceptive use has not been reported to influence folate status in large-scale population surveys (LSRO/FASEB, 1984) or in metabolic studies in which dietary intake was controlled (Rhode et al., 1983).

Genetic Variations

Folic acid and its derivatives are involved in numerous biochemical reactions that are catalyzed by many different enzymes. As expected, folate metabolism is under genetic control, and genetic heterogeneity exists. To estimate the relative contribution of genetic and environmental factors in determining folate status, erythrocyte folate was measured in monozygotic and dizygotic twins (Mitchell et al., 1997); however, dietary intake was not assessed. The data were best described by a model in which 46 percent of the variance is attributable to additive genetic effects, 16 percent to age and sex,



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