The goal of this trial was to see if lowering the amount of supplementary folic acid taken in conjunction with methotrexate (MTX) medication improved disease management and/or exacerbated MTX-related side effects in persons with active rheumatoid arthritis (RA). 

A randomized double-blind randomized controlled experiment comparing 5 mg/wk folic acid to 0.8 mg/wk folic acid was carried out. Patients with rheumatoid arthritis who had been taking MTX for 3 months or more at a steady dosage for 1 month or more were recruited. All individuals had a DAS28 of 3.2 or higher, or the treating doctor recommended a change in treatment. At weeks 0, 4, 8, 16, and 24, disease activity, complete blood count, liver function tests, red blood cell (RBC) folate, and RBC MTX polyglutamates were measured, as well as reports of adverse events.

Forty people were recruited. Between weeks 0 and 24, the mean (SD) change in RBC folate was +87.9 nmol/L in the high-dose group and -113.3 (65.7) nmol/L in the low-dose group (p < 0.05). At 24 weeks, there was no significant difference in DAS28 change between the high- and low-dose groups (−0.13 [95% confidence interval, −0.69 to 0.43] vs −0.25 [−0.87 to 0.37], respectively [p = 0.78]). There was no statistically significant difference in MTX-related side effects between the two groups.

A decrease in RBC folate as a result of folic acid dose reduction was not linked with a change in RA disease activity or MTX-related side effects. The key rationale for co-prescribing folic acid with MTX is the prevention of MTX-related side effects.