AB0014 METHOTREXATE - IMPLICATIONS OF PHARMACOGENETICS IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS

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 (DMARD), being widely used for treatment of rheumatoid arthritis (RA) (1). Objectives: This review aims describe main genetic variants identified concerning proteins that play a role in methotrexate’s kinetics efficiency profile. Methods: A literature was conducted since January 2000 until December 2020, by searching PubMed Embase bibliographic databases, employing following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics arthritis. The search limited articles English language. Two independent reviewers screened titles abstracts followed full-text assess papers regarding their eligibility. total 48 matched research criteria were analysed. Results: Genetic four proteins, different functions, have been consistently described. Reduced folate carrier 1 (RFC1), constitutively expressed transport protein has high affinity responsible, almost exclusively, into cell. commonly studied variant gene 80G > (rs1051266), mapped within exon 2, on chromosome 21. It seems improve RA responses MTX, clinical efficacy long remission (2). ABC transporters are involved eflux from cells. An increased expression function these should decrease concentrations target cells, resulting lack therapeutic response. ABCB1 3435 C/T (rs1045642) frequency polymorphism, significantly associated good responses, symptom reduced adverse events, due (3). Thymidylate synthase (TYMS) thymidine synthesis. decreases TYMS activity inhibition decreasing access tetrahydrofolate (THF) cofactors common consists 28 bp tandem repeat (rs34743033), double triple number repeats (2R 3R). 3R allele genotype decreased toxicity (4). 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme indirectly inhibited MTX. SNPs MTHFR C677T (rs1801133) A1298C (rs1801131). Both (5). Conclusion: response affected many variants; effect each separately likely small. Additionally, gene-gene interaction, enhancing potential linkage disequilibrium. shows emerging need better characterization knowledge about distribution according ethnicity, explain at individual level. References: [1]Song, G. et al. Association polymorphisms methotrexate arthritis: meta-analysis. Clin Rheumatol 33, 1715–1724 (2014). [2]Hayashi H. single nucleotide polymorphism predicts Japanese patients Drug Metab Pharmacokinet. 2013;28(2):164-8. [3]Zhu Pharmacogenetics pharmacogenomics responsiveness treatment: 2013 update. Pharmacogenomics. 2014 Mar;15(4):551-66. [4]Owen SA. key pathway genes patients. Pharm J. 2013;13:227–34. [5]Hughes LB. Racial or ethnic differences frequencies single-nucleotide methylenetetrahydrofolate influence Ann Rheum Dis. 2006;65:1213–8. Disclosure Interests: None declared