Table 1.

Characteristics of included studies of patients with rheumatoid arthritis for more than 18 years.

StudyMethods/DurationParticipantsInterventionsOutcomes
Buckley 1990Randomized, controlled, double-blind clinical trial. A crossover study design. 48 weeksTwenty patients (11/9 placebo/folinic acid, respectively), treated with low dose of MTX (< 20 mg/week). 7 males, 13 females, mean age 57.5 yrsFolinic acid or placebo weekly for 24 weeks, then crossed over to receive the alternate treatment. The dose of folinic acid was about equal to the dose of MTX, between 5 and 15 mg per week (mean dose: 9.9 mg/week)Reduction of MTX toxicity (GI and hematologic side effects).
Reduction of MTX efficacy (joint count, 50-foot walk time, grip strength, rheumatoid factor, ESR, patient and physician assessment)
Morgan 1990Randomized, controlled, double-blind clinical trial. A parallel study design. 24 weeksThirty-two patients (16/16 placebo/folic acid, respectively) treated with low dose of MTX (< 20 mg/week). Six males, 26 females. Mean age 52.0 and 50.9 yrs for the folic acid and placebo group, respectivelyFolic acid 1 mg/d or placebo. The median dose of MTX was 7.5 mg/week (2.5–15 mg/week).Reduction of MTX toxicity (GI, hepatic, and hematologic side effects). Reduction of MTX efficacy (SJC, TJC, joint swelling index, joint tenderness index, joint pain (VAS), patient global assessment of disease activity, duration of morning stiffness, grip strength). The definition of elevated liver enzymes was AST or ALP ≥ 2 × baseline values
Morgan 1994Randomized, controlled, double-blind clinical trial. A parallel study design. 48 weeksSeventy-nine patients (28/25/26 placebo/low-dose folic acid/high-dose folic acid, respectively) treated with low-dose MTX (< 20 mg/week). Twenty males and 59 females. Mean age 54.4 years for the folic acid group and 52.2 for the placebo groupFolic acid or placebo weekly. The dose of folic acid was 5 mg/week or 27.5 mg/week. The mean dose of MTX was 9.16 mg/week. Only the patients receiving low-dose (5 mg/wk) folic acid or placebo were included in the study (25 and 28 patients)Reduction of MTX toxicity. GI and hematological side effects
Shiroky 1993Randomized, controlled, double-blind clinical trial. A parallel study design. 52 weeksNinety-two patients (48/44 placebo/folinic acid, respectively) treated with low-dose of MTX (< 20 mg/week). Thirty males, 62 females, with a mean age of 53.1 and 53.4 years for the folinic acid and placebo groups, respectivelyFolinic acid 2.5–5 mg/wk or placebo. The mean dose of MTX was 13.6 mg/week (2.5–30 mg/week)Reduction of MTX toxicity (GI, hepatic, and hematologic side effects). Reduction of MTX efficacy (SJC, TJC, patient global assessment, physician assessment of disease activity, duration of morning stiffness, grip strength, 50-foot walk time, morning stiffness, and HAQ). Side effectsrelating to toxicity were reported in the no. clinic visits at which the side effect occurred, not by no. patients. The no. patients suffering particular side effects were reported when severe enough to result in withdrawal from the study protocol. We used the latter data in the review. We extracted liver enzyme elevation data defined in the study as “moderate” or “severe” derangement, which was AST or ALT ≥ 2 × ULN
Van Ede 2001Randomized, controlled, double-blind clinical trial. A parallel study. 48 weeksFour hundred eleven patients (137/133/141 placebo/folic acid/folinic acid). One hundred twenty-one males, 291 females. Mean age 56.3, 54.5, and 57.1 yrs for the folic acid, folinic acid, and placebo groups, respectivelyFolic acid 1 mg/d, folinic acid 2.5 mg/wk, or placebo. Mean dose of MTX 13.6 mg/week (2.5–20 mg/week)Reduction of MTX toxicity (GI, hepatic, and hematologic side effects). Reduction of MTX efficacy (SJC, TJC, Ritchie index, pain score, patient global assessment, physician assessment of disease activity, and ESR). Liver toxicity data extracted was reported as “moderate” or “severe” and was defined as values ≥ 3 × ULN
Weinblatt 1993Randomized, controlled, double-blind clinical trial. A parallel design. 8 weeksSixteen patients (8/8 placebo/folic acid, respectively), treated with low dose of MTX (< 20 mg/week). Six males, 10 females. Mean age 55.9 years for the folinic acid group and 62.3 for the placebo groupFolic acid 1 mg/wk or placebo. Mean dose of MTX 13.6 mg/week (2.5–20 mg/week)Reduction of MTX toxicity (GI and hematologic side effects). Reduction of MTX efficacy (SJC, TJC, patient global assessment, physician assessment of disease activity, duration of morning stiffness, grip strength, 50-foot walk time, morning stiffness, and HAQ)
  • MTX: methotrexate; GI: gastrointestinal; ESR: erythrocyte sedimentation rate; SJC: swollen joint count; TJC: tender joint count; VAS: visual analog scale; AST: aspartate aminotransferase; ALT: alanine aminotransferase; HAQ: Health Assessment Questionnaire; ULN: upper limit of normal.