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

Abstract

Backgrounds Folic acid dose at ≦5 mg/week has been recommended for rheumatoid arthritis (RA) patients to decrease risk of methotrexate adverse effects. However, higher doses of folic acid is used in some cases. We examined the influence of high-dose folic acid on methotrexate efficacies and safety in Japanese RA patients.

Methods 502 RA patients of four hospitals prescribed methotrexate and folic acid were included. These patients were divided into two subgroups according to the threshold of folic acid dose by 5 mg/week. Basic patient characteristics, methotrexate doses, and the efficacies or adverse effects of methotrexate were retrospectively compared between the two patient subgroups.

Results The frequency of folic acid use at doses higher than 5 mg/week was significantly different between the four hospitals (P<0.001). The prevalence of methotrexate adverse effects was not significantly different between the patients taking folic acid less and more than 5 mg/week. However, in the lower dose methotrexate subgroup (≦8 mg/week), the prevalence of patients exhibiting abnormal serum ALT concentrations in the patients using higher (>5 mg/week) dose of folic acid was significantly higher than that in the lower (≦5 mg/week) folic acid-treated subgroup (P=0.029). Folic acid dose between patients taking methotrexate less and more than 8 mg/week was not significantly different.

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.

Key words

methotrexate efficacy and safety - folic acid dose - rheumatoid arthritis therapy

• References

• 1 Tchantchou F, Shea TB. Folate deprivation, the methionine cycle, and Alzheimer’s disease. Folic acid and folates. In: Litwack G. (ed.) Vitamins and Hormones. Elsevier; 2008. 79 83-95
• 2 Schweitzer BI, Dicker AP, Bertino JR. Dihydrofolate reductase as a therapeutic target. FASEB J. 1990; 4: 2441-2452
• 3 Shea B, Swinden MV, Tanjong Ghogomu E. et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013; Issue 5. ArtNo CD000951
• 4 Suzuki Y, Uehara R, Tajima C. et al. Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Scand J Rheumatol 1999; 28: 273-281
• 5 Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: A review. Rheumatology (Oxford) 2004; 43: 267-271
• 6 Dhir V, Sandhu A, Kaur J. et al. Comparison of two different folic acid doses with methotrexate – a randomized controlled trial (FOLVARI Study). Arthritis Research & Therapy 2015; 17: 156
• 7 Shiozawa K, Yamane T, Murata M. et al. MMP-3 as a predictor for structural remission in RA patients treated with MTX monotherapy. Arthritis Research and Therapy 2016; 18: 55
• 8 Sangha O. Epidemiology of rheumatic diseases. Rheumatology 2000; 39 (Suppl. 02) 3-12
• 9 Miyasaka N. Treatment trends of rheumatoid arthritis in Japan: Changes toward globalization and its unique innovation. Inflammation and Regeneration 2011; 31: 25-32
• 10 Tanaka R, Akiyama H. Study of the usefulness of 1 mg/day of folic acid day after day dosage, for side effect of MTX of dose-dependency. Journal of The Central Japan Association of Orthopaedic Surgery & Traumatology 2015; 58: 163
• 11 Miyamoto T, Ohmura S, Ito R. Action to take for the liver damage and digestive organ symptom for MTX remedy patient ~Usefulness of 1 mg/day of folic acid day after day dosage~ General Meeting of Japan College of Rheumatology, Abstract papers Academic Meeting. 2014; 58: 441