Comparison of two different folic acid doses with methotrexate – a randomized controlled trial (FOLVARI Study)

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

Influence of High-Dose Folic Acid on Methotrexate Efficacies and Safety in Japanese Rheumatoid Arthritis Patients

“…Dhir V et al reported that additional folic acid use at doses more than 10 mg/week for the treatment of adverse effects caused by high dose methotrexate had little advantage over the therapy with usual dose of folic acid [6]. These observations are consistent with our present findings.…”

“…Major conclusion Folic acid dose was dependent on the hospitals, while efficacies and hepatotoxicity of methotrexate was not basically different between patients taking less and more than 5 mg/week of folic acid. of folic acid 24-48 h after the methotrexate administration [6]. However, the dose of folic acid may be independently determined among the hospitals or physicians, while folic acid at doses more than 5 mg/week may influence the efficacies of methotrexate.…”

Disease modifying anti-rheumatic drugs in juvenile idiopathic arthritis: striving for individualized therapy

“…5mTHF) [59]. However, it is interesting to note that associations between higher baseline erythrocyte folate levels and lower disease activity scores after 3 months of MTX therapy was observed in one of the studies [57] and reduced serum folates levels at baseline were associated with 'undesirable symptoms' related to MTX therapy in the other [58]. These findings require further study to determine the potential role of monitoring circulating folate levels in the treatment of JIA, in particular, studies are needed to see if variation in folate levels can account for the observed variations in drug efficacy and toxicity.…”

“…Interestingly, folic acid supplementation was documented in 47% of patients receiving MTX, but was not found to be associated with any difference in circulating 5mTHF levels. In contrast to these findings, two recent studies in RA patients that utilized competitive folate binding protein immunoassays to measure serum and erythrocyte folate found that initiation of MTX therapy along with folic acid supplementation at levels of 10-30 mg/week resulted in no significant reduction in serum or erythrocyte folate levels [57,58]. The origin of this discrepancy may reflect differences in the level of folate supplementation in the studies, innate differences in systemic folate regulation in pediatric versus adult patients, or more than likely, differences in the analytical methodologies marked by the inability of competitive folate binding protein assays to distinguish between individual folate species with a higher affinity of these proteins for the inactive supplemental form of folate (i.e.…”

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology

“…To avoid side effects, split doses of MTX administration and folate supplementation are gradually being used in ophthalmic clinic. Prescription of 5 to 10 mg of folate supplementation has a significant role in MTX safety [ 128 ], but the higher dosage is less applied, even with higher dose of MTX [ 129 ]. Prophylactic folate supplementation is not necessary in most patients [ 130 ].…”