Background:Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA) (1).Objectives:This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate’s kinetics and efficiency profile.Methods:A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analysed.Results:Genetic variants of four main proteins, with different functions, have been consistently described.Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most commonly studied variant of the gene is the 80G > A variant (rs1051266), mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission (2).ABC transporters are involved in the eflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T (rs1045642) is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment (3).Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors (1). The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat (rs34743033), with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity (4).The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T (rs1801133) and A1298C (rs1801131). Both are associated with a decreased efficacy and an increased toxicity of MTX (5).Conclusion:MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction, enhancing the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.References:[1]Song, G. et al. Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol33, 1715–1724 (2014).[2]Hayashi H. et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet. 2013;28(2):164-8.[3]Zhu H. et al. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014 Mar;15(4):551-66.[4]Owen SA. et al. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharm J. 2013;13:227–34.[5]Hughes LB. et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2006;65:1213–8.Disclosure of Interests:None declared
METHYLENETETRAHYDROFOLATE REDUCTASE AND REDUCED FOLATE CARRIER-1 GENOTYPES AND METHOTREXATE SERUM CONCENTRATIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS
