Background Strategies to reduce toxicity of Methotrexate (MTX) have been receiving increasing attention. One strategy backed by good evidence is folic acid supplementation. However, its optimum dose is not known. Although guidelines suggest 5-10mg per week; this is based on weak evidence.1 Indeed, only one clinical trial has compared different doses; but was done 20 yrs ago using low MTX doses.2 Also, effect of folic acid on efficacy of MTX unclear.
Objectives To compare the effect of folic acid at dosages of 10 or 30 mg per week on MTX toxicity and efficacy in patients with rheumatoid arthritis.
Methods Patients included in this double blind randomized controlled trial were started on MTX at 10mg/week which was escalated every two weeks by 2.5 mg till 25 mg per week till 24 weeks. This escalation was based on ongoing disease activity and absence of toxicity evaluated every 8 weeks. They were randomized in a ratio of 1:1 to receive either folic acid 10 mg or 30 mg per week. Patients in the first group recieved two tablets of 5mg folic acid (and four tablets of placebo) and in the second group recieved six tablets of 5 mg folic acid for each week of the study. Patients took one tablet daily except on the day they took MTX. Co-primary endpoints were incidence of toxicity and change in disease activity at 24 weeks. Toxicity included undesirable symptoms (by questionnaire) and laboratory abnormalities including cytopenias (thrombocytopenia or leucopenia) and transaminitis (twice upper limit of normal). Secondary outcomes were change in level of RBC (and serum) folic acid levels at 24 weeks (from baseline) and change in the functional status of patients. Trial # NCT01583959
Results This study included 100 RA patients (F:M=86:14) with mean age 44.3 (±10.9) yrs, disease duration 4.8 (±4.7) yrs, RF+ in 73 and anti-CCP+ in 84. Among these, 51 received folic acid 10 mg per week (FA10) and 49 received 30 mg per week (FA30). By 24 weeks, there were 6 patient withdrawals in either group. Mean methotrexate dose at 24 weeks was 22.8±4.4 and 21.4±4.6mg in FA10 and FA30 respectively (p=0.1). There was no singificant difference in occurrence of undesirable symptoms between groups, although they were numerically higher in the 30 mg folic acid group (Figure 1). There was also no difference in frequency of transaminitis (42.6, 45.7%, p=0.7) or cytopenias (4.3, 4.3%, p=0.9). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1±1.0, -1.3±1.0, p=0.2) and EULAR good or moderate response occurred in 56.9 and 67.4% in FA10 and FA30 (p=0.3). Serum folic acid levels increased in both groups. At 24 weeks serum folic acid levels were higher in the 30mg group (20.4±17.1, 45.1±39.7ng/ml, p<0.001). HAQ declined significantly and similarly in both groups (-0.3±0.5, -0.4±0.4, p=0.27)
Conclusions Our results suggest that supplementation of 5-10 mg folic acid is sufficient when using MTX in RA even at currently used dosages. However, apart from there being no additional benefit of a higher dose of folic acid; it also did not lead to reduction of efficacy of MTX.
Ann Rheum Dis 2009;68(7):1086-93.
Ann Intern Med 1994;121(11):833-41.
Disclosure of Interest None declared