Folates and antifolates in rheumatoid arthritis

Abstract

Almost all current standard treatment of care for patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) includes the folate antagonist methotrexate (MTX). Despite the proven efficacy of MTX in RA treatment, it is anticipated that further improvement of antifolate-based therapies can be achieved by integrating the continuously extending knowledge of parameters underlying drug efficacy. Herein, an overview will be presented of strategies that may assist in the future design of rationalized and personalized targeted therapies with a folate antagonist. Issues that will be discussed include (i) early detection of arthritis, (ii) genomic studies of folate/MTX pathway genes for MTX response predictions, (iii) identification of MTX resistance modalities, (iv) exploration of second/third generation of antifolates which may substitute for MTX, and (v) folate (food) supplementation.

Keywords

• antifolates
• folates
• rheumatoid arthritis
• abbreviations and enzyme codes: atic/aicartf, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (ec 2.1.2.3); dhfr, dihydrofolate reductase (ec 1.5.1.3); fpgs, folylpolyglutamate synthetase (ec 6.3.2.17); frα/β, folate receptor alpha/beta; gart, glycinamideribonucleotide formyltransferase (ec 2.1.2.2); ggh/fpgh, gamma-glutamyl hydrolase/folylpolyglutamate hydrolyse (ec 3.4.19.9); mthfr, methylenetetrahydrofolate reductase (ec 1.5.1.20); mtx, methotrexate; pb, peripheral blood; pcft/slc46a1, proton-coupled folate transporter; pg, polyglutamates; rfc/slc19a1, reduced folate carrier; tyms, thymidylate synthase (ec 2.1.1.45).