Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Antiperinuclear factor and disease activity in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy.

OBJECTIVE: To study the correlation between antiperinuclear factor (APF) titer and disease activity variables in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) or azathioprine (AZA) and to investigate whether changes are dependent on the drug used. METHODS: Serial measurements of APF titers (2-fold dilutions) and disease activity variables in a 48-week double blind trial comparing MTX and AZA in 64 patients with RA. APF titers at baseline and during followup, and correlations between APF titers and disease activity variables and their changes from baseline were studied in the patient group as a whole and in the 2 treatment groups. RESULTS: The prevalence of the APF at baseline in the MTX group and in the AZA group with undiluted serum was 15/31 (48%) and 19/33 (58%), respectively. With serum diluted 1:10 this was about 25% higher. The APF titer ranged from 1/10 to 1/640. No sustained changes in APF titers were observed during followup. Statistically significant correlations were found between APF titers and 2 of the 4 disease activity variables, as well as for their changes from baseline at some time points and were most pronounced in the AZA group. However, no consistent correlation between APF titers and disease activity variables could be established. APF changed from negative to positive during followup in 4 patients (6.3%) and from positive to negative in 4 (6.3%). Changes in APF titer between 2 consecutive measuring points did not exceed 2 dilution steps. CONCLUSION: The APF titer showed no sustained change during the followup period. There was no consistent correlation between APF titer and disease activity variables. We conclude that serial measurements of the APF in longitudinal studies do not give additional information.