title: The use of low dose methotrexate in rheumatoid arthritis - are we entering a new era of therapeutic drug monitoring and pharmacogenomics?
abstract: Methotrexate (MTX) is one of the most commonly used medications in the treatment of rheumatoid arthritis (RA). It has proven efficacy as a sole agent as well as in combination with other disease modifying anti-rheumatic agents (DMARDs) including the newer biological agents. MTX is generally well tolerated although there are a number of potentially serious adverse effects. Of these, haematopoietic suppression, hepatotoxicity and pulmonary toxicity are the more severe and patients are therefore required to have appropriate monitoring while they remain on MTX. In the past, attempts at therapeutic drug monitoring using serum MTX concentrations have been unsuccessful. However, MTX is taken into red blood cells (RBC) where up to four glutamates are added to form MTX polyglutamates (MTXPG(n)). More recently it has been suggested that higher RBC MTXPG(3-5) concentrations may be associated with improved disease control. Genetic variations in enzymes involved in the uptake of MTX into cells and its metabolism are also being examined for their ability to predict drug response and potential for adverse events. While it is unlikely that a single genetic variant will predict efficacy or toxicity there is preliminary evidence that a "pharmacogenetic index" that takes into account the effects of multiple genetic variants maybe useful. Although in their infancy at present, both therapeutic drug monitoring using MTXPG concentrations and pharmacogenomics of MTX may prove useful in the future and are worthy of further investigation.
authors.affiliation: Department of Medicine, Christchurch School of Medicine and Health Sciences, University of Otago, P. O. Box 4345, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz
authors.forename: Lisa
authors.initials: L
authors.lastname: Stamp
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roberts
authors.forename: Martin
authors.initials: M
authors.lastname: Kennedy
authors.forename: Murray
authors.initials: M
authors.lastname: Barclay
authors.forename: John
authors.initials: J
authors.lastname: O'Donnell
authors.forename: Peter
authors.initials: P
authors.lastname: Chapman
mesh_terms: D018501:Antirheumatic Agents / Q000378:metabolism / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods / Q000639:trends; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000378:metabolism / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods / Q000639:trends; D011099:Polyglutamic Acid / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D018501:Antirheumatic Agents; D004798:Enzymes; D011099:Polyglutamic Acid; D008727:Methotrexate