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Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers
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Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers
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Journal Article
Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers
2016
Overview
Key Points
Methotrexate shows good efficacy in a proportion of patients: 40% of treated patients with rheumatoid arthritis achieve an ACR50 response
The mechanism of action of methotrexate has not fully been defined, however potentiation of adenosine signalling carries the most robust data
Pharmacokinetic parameters, particularly intracellular methotrexate polyglutamation, show some association with disease activity, although they cannot yet be used to predict treatment response
An exploration of the expression and polymorphisms of genes encoding molecules linked to proposed mechanisms of methotrexate action is underway to identify methotrexate-responsive signatures
At present, no robust markers or predictive models exist for methotrexate responsiveness in RA
Methotrexate remains the first-line therapy for rheumatoid arthritis (RA). However, not all treated patients respond, and its mechanism of action remains incompletely understood. This Review describes putative mechanisms of action of methotrexate at the low doses used in RA and discusses potential biomarkers of treatment response, which could ultimately inform precision use of this therapy.
The treatment and outcomes of patients with rheumatoid arthritis (RA) have been transformed over the past two decades. Low disease activity and remission are now frequently achieved, and this success is largely the result of the evolution of treatment paradigms and the introduction of new therapeutic agents. Despite the rapid pace of change, the most commonly used drug in RA remains methotrexate, which is considered the anchor drug for this condition. In this Review, we describe the known pharmacokinetic properties and putative mechanisms of action of methotrexate. Consideration of the pharmacodynamic perspective could inform the development of biomarkers of responsiveness to methotrexate, enabling therapy to be targeted to specific groups of patients. Such biomarkers could revolutionize the management of RA.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Antirheumatic Agents - pharmacology
/ Antirheumatic Agents - therapeutic use
/ Arthritis, Rheumatoid - drug therapy
/ Cell Adhesion Molecules - drug effects
/ Cell Adhesion Molecules - metabolism
/ Folic Acid Antagonists - pharmacology
/ Humans
/ Identification and classification
/ Metalloproteases - drug effects
/ Metalloproteases - metabolism
/ Methotrexate - therapeutic use
/ Pharmacogenomic Variants - genetics
/ Polymorphism, Single Nucleotide
/ Reactive Oxygen Species - metabolism
/ Signal Transduction - drug effects
/ Toxicity
