THE USE OF FOLATES CONCOMITANTLY WITH LOW-DOSE PULSE METHOTREXATE

Over the past 15 years, methotrexate therapy for rheumatic diseases has evolved from a role as treatment for "intractable" inflammatory polyarthritis, to frequently the first choice of slow-acting remittive agents in early rheumatoid arthritis (RA). As rheumatologists have gained more experience with methotrexate, they have come to appreciate its quick and effective anti-inflammatory properties relative to alternative agents and the low incidence of serious toxicity. As a result, its uses have widened to other inflammatory rheumatic and nonrheumatic conditions, often in a role as a corticosteroid-sparing agent. Experimentation, largely by dermatologists, led to the low-dose, weekly, oral or intramuscular methotrexate therapy now used for rheumatic diseases. It has been shown that titrating the dose of methotrexate between 5 mg and 20 mg weekly is associated with increasing anti-inflammatory activity. 6,38 Experiments with higher-dose regimens have suggested efficacy of methotrexate where standard therapy has failed. 7,39,40 Unfortunately, higher doses of methotrexate also result in a higher frequency and severity of adverse events. 6,46 Despite the low frequency of serious toxicity with the standard regimen, there exist several side effects that limit methotrexate's use in certain patients or result in unwanted interruptions of therapy or a failure to titrate the dose optimally. For the most part, these adverse effects are the result of methotrexate's antifolate properties (e.g., hematologic, mucositic, and hepatic complications; alopecia). Oncologic protocols using extremely high doses of intravenous methotrexate (≤10 g) are well tolerated because of the concomitant use of folinic acid (leucovorin, citrovorum factor). 2,14 In addition, repetitive high doses of folinic acid have been used to reverse serious acute methotrexate toxicity. 2,14,20 These observations have led to the evaluation of various folate regimens to reduce the frequency or dampen the severity of adverse events associated with the low-dose weekly methotrexate therapy for rheumatic diseases. Essentially, there are two choices of agent to be used potentially as a folate supplement concomitantly with methotrexate: folic acid and folinic acid. Both have been evaluated in clinical trials and are used anecdotally in various ways. For folic acid to be effective, it must be able to compete with methotrexate as a substrate for dihydrofolate reductase so that it will be properly reduced to the biologically active form of folate necessary in the one carbon metabolism required in biosynthesis of certain amino acids (serine, methionine), de novo purine synthesis, and thymidine. In contrast, folinic acid (calcium 5-formyltetrahydrofolate) is a pharmaceutically synthesized, relatively stable, fully reduced form of folate developed to treat and prevent toxicity related to methotrexate therapy. Because it is fully reduced, it bypasses the inhibition of dihydrofolate reductase by methotrexate. 2,14,20 Given that it is synthetic and does not have as wide a use as folate in the general population, the cost per pill of folinic acid when compared to folate is substantial.