Methotrexate Pharmacogenetics in the Treatment of Rheumatoid Arthritis

Abstract

For many decades, methotrexate (MXT) has remained the drug of choice in the treatment of rheumatoid arthritis (RA). Unfortunately, a considerable number of patients do not achieve an appropriate therapeutic response. Pharmacogenetics studies do not give usable results regarding differences in MTX response among RA patients. The mechanism of MTX action in RA is not completely understood. We present and discuss data regarding the molecular basis of folate and adenosine pathways, the most obvious MTX targets, to explain possible causes of therapy failure. The molecular basis of the disease could also have an impact on therapy outcomes and in this review we explore this. Finally, we make a short review of available pharmacogenetics study results.

Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis

“…RFC1-G80A is one of the most analyzed polymorphisms in studies of MTX in patients with RA, but inconsistent results have been published regarding its role in the prediction of the therapeutic response and toxicity. We did not find an association between this polymorphism and MTX intolerance in our patients, suggesting that its effect on MTX outcomes is mild and may be influenced by a combination with some other genetic factors, as described in previous studies [ 24 ].…”

Association of MTHFR and ABCB1 polymorphisms with MTX‐induced mucositis in Chinese paediatric patients with acute lymphoblastic leukaemia, lymphoma or osteosarcoma—A retrospective cohort study

“…Information on the genetic polymorphisms associated with the toxicity of MTX has been accumulating, but it has not been clearly figured, which also deserve further investigations among various cancers and populations. 3,13 To our best knowledge, the current study was seemed to be the first study to analyse the association between MTHFR and ABCB1 both the efficacy and toxicity of MTX. 26 MTHFR 677C>T (rs1801133) is a common genetic polymorphism that has been extensively studied worldwide.…”

“…As it has been widely reported, diversity in efficacy and toxicities in HDMTX administration, to some extent, be linked with sequence polymorphisms in genes involved in drug absorption, metabolism, excretion, cellular transport, and effector targets or target pathways. 2,3,[13][14][15][16] MTX needs active transport due to its polarity; passive diffusion may also play a part in its cellular influx transport. 17 Once entering the cell, MTX is polyglutamated by folyl-polyglutamyl synthetase (FPGS), then binds dihydrofolate reductase (DHFR) with a greater affinity than that of folate and competitively inhibits the transformation from dihydrofolate to tetrahydrofolate.…”

Clinical efficacy and safety of methotrexate compared with leflunomide in the treatment of rheumatoid arthritis

“…Inhibiting the expression of MMP-1, MMP-2, and other MMPs, so as to inhibit the destruction of joint bone. [ 13 ]…”