Abstract
IntroductionThere is reasonable evidence that folic acid 5–10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity.MethodsThis was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18–75 years of age, not be on MTX and have active disease as defined by ‘Modified Disease Activity Score using three variables’ (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed.ResultsAmong 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(±SD) dose of MTX was 22.8 ± 4.4 and 21.4 ± 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non-significantly lower by 7.4 % (95 % confidence interval −27.4 to 12.7 %) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7 %, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7 %, p = 1.0) or cytopenias (4.3, 4.3 %, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3 %, p = 0.5). 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 ‘European League Against Rheumatism’ good or moderate response occurred in 56.9 and 67.4 % (p = 0.3).ConclusionsEven with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week).Trial RegistrationClinicaltrials.gov NCT01583959 Registered 15 March 2012
Highlights
There is reasonable evidence that folic acid 5–10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA)
Will a higher folic acid dose (30 mg per week) reduce the toxicity of MTX compared to a lower dose (10 mg per week) in RA? Second, will a higher folic acid dose lead to blunting of the efficacy of MTX compared to a lower dose?
This study protocol was approved by the Institutional Ethics Committee at the Postgraduate Institute of Medical Education and Research (PGIMER)
Summary
There is reasonable evidence that folic acid 5–10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). This is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity. With the current use of higher MTX doses, such as 25 mg per week, it is unclear whether the dose of folic acid should be increased. Will a higher folic acid dose lead to blunting of the efficacy of MTX compared to a lower dose? Will a higher folic acid dose (30 mg per week) reduce the toxicity of MTX compared to a lower dose (10 mg per week) in RA? Second, will a higher folic acid dose lead to blunting of the efficacy of MTX compared to a lower dose?
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