Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial

The folic acid antagonist methotrexate (n-10-methyl-aminopterin) is useful in low doses (2.5 to 20 mg/wk) for treating chronic inflammatory diseases [1-7]. Many trials have established the efficacy of methotrexate in rheumatoid arthritis [7-13]. Comp... show more

The folic acid antagonist methotrexate (n-10-methyl-aminopterin) is useful in low doses (2.5 to 20 mg/wk) for treating chronic inflammatory diseases [1-7]. Many trials have established the efficacy of methotrexate in rheumatoid arthritis [7-13]. Compared with other disease-modifying drugs, methotrexate has the highest probability of drug continuation at 10 years. Dose response-related toxic effects have been reported in 30% to 90% of patients given methotrexate [13]. Toxic effects include gastrointestinal intolerance, hematologic abnormalities, alopecia, hepatotoxicity, and pulmonary toxicity [14-22]. Some side effects of methotrexate administration, such as gastrointestinal intolerance, mimic complicated folate deficiency [23]. Folate deficiency occurs frequently in patients with rheumatoid arthritis; further, folate stores are decreased in patients with rheumatoid arthritis who take methotrexate, suggesting that impaired folate status is related to toxicity [24-26]. Folic acid supplementation has been reported anecdotally to lessen toxicity in patients receiving methotrexate treatment [27, 28]. In a 6-month, double-blind, placebo-controlled trial, 7 mg of folic acid weekly (1 mg/d or 2265 nmol/d) decreased methotrexate toxicity without affecting efficacy [29]. This was confirmed by Stewart and colleagues [30] in a retrospective chart review. Folinic acid (leucovorin, citrovorum factor) is a one-carbon-substituted, fully reduced folate that has also been administered during methotrexate therapy [31-36]. Low doses of the vitamin (1 to 7 mg/wk) have decreased methotrexate toxicity [35, 36]. Higher doses negate efficacy and lessen toxicity [31, 32]. Thus, the folinic acid dose may critically affect the efficacy of methotrexate therapy. The influence of the folic acid dose on methotrexate toxicity and efficacy remains controversial, and the effects of different doses of folic acid are not known [37, 38]. Some investigators argue that if toxic effects occur, the most rational approach is to reduce the dose of methotrexate rather than to provide folic acid supplements [37]. We designed a larger and longer study to evaluate different doses of folic acid, assuming that toxicity could be reduced without changing the efficacy of methotrexate. Methods Participants Patients aged 19 to 78 years who fulfilled the American College of Rheumatology's revised criteria for rheumatoid arthritis consented to participate in the trial [39]. Enrollment criteria included rheumatoid arthritis diagnosed more than 6 months previously, onset after the age of 16 years, and at least three of the following signs or symptoms: 3 or more swollen joints, 6 or more tender joints, at least 45 minutes of morning stiffness, and a Westergren erythrocyte sedimentation rate 28 mm/h. Referring rheumatologists and the principal investigator did the screening. Exclusion criteria included serious concomitant medical illnesses, liver enzyme levels twice the upper limit of normal, leukocyte counts less than 3.5 109/L or platelet counts less than 150 109/L, and use of methotrexate within the past 6 months. Gold salts were stopped for at least 10 days before the trial. This short washout period mirrors actual rheumatology practice. Patients remained under the care of their rheumatologists, abstained from alcohol use, did not become pregnant, and received stable doses of aspirin and nonsteroidal anti-inflammatory drugs. If prednisone was taken at entry, the dose could not exceed 10 mg/d. Hydroxychloroquine therapy was allowed during the study. Study Design Figure 1 shows the trial design. To maintain the double-blind status of the trial, the statistician carried out the randomization using a computer program in which the algorithm was transparent and a coded vial number represented the treatment assignment. Patients were assigned to treatment groups by a sequential treatment assignment process designed to balance the sample with respect to baseline features, including age, sex, folate-containing vitamin use, rheumatoid factor status, and prednisone use [40]. Patients agreed to discontinue therapy with folate-containing vitamins during the trial. Rheumatoid factor was considered positive if the level was more than 30 IU/mL or if the titer was more than 1:160. Patients received either visually identical placebo or 5 mg (low-dose folic acid group) or 27.5 mg folic acid (high-dose folic acid group) each week, prepared by the Hospital Investigational Drug Service. Spectrophotometric analysis indicated that the mean SD folic acid content was 1 0.15 mg (2.3 0.3 mol) and 5.5 0.3 mg (12.5 0.7 mol) per capsule in the low-dose and high-dose folic acid groups, respectively. Lederle Laboratories provided the methotrexate (Rheumatrex; Pearl River, New York), which was started in a median oral dose of 16.5 mol (7.5 mg) per week and increased in 5.5-mol (2.5 mg) increments at the rheumatologist's discretion. Methotrexate was taken either in an undivided or a divided dose (that is, every 12 hours for three doses). The methotrexate dosing regimens were identical among the study groups. Folic acid supplements were given 5 days per week when methotrexate was not ingested. Compliance with the regimen was reinforced using a digital reminder cap (Counter Cap; Senetics, Boulder, Colorado). All participants and investigators were blinded to vitamin capsule content until the study was complete. Figure 1. Study design for the double-blind, placebo-controlled trial. Clinical Assessment Patients were evaluated immediately before methotrexate initiation at a mean of 13, 26, 39, and 53 weeks (Figure 1). Each patient was assessed by the same physician-nutritionist (SLM). Two research assistants (JSA or WHV) did the joint evaluations. In most cases, patients were examined by the same observer throughout the study. The joint counts for tenderness and swelling were not significantly different between the two observers (P = 0.6 for tenderness; P = 0.9 for swelling). The fo show less