Understanding the variation in response to methotrexate

Abstract

ORIGINAL ARTICLE, p 165 Methotrexate (MTX) has been used in the management of psoriasis since the 1960s and despite the increasing use and success of newer biologic agents, it remains a first‐line treatment in patients with moderate to severe psoriasis, due to its efficacy and cost‐effectiveness.1 It is used as a standard comparator in randomized controlled trials of biologic agents in psoriasis. However, a significant number of patients on MTX do not experience benefit and up to 30% of patients are unable to tolerate the drug because of toxicity including nausea, myelosuppression or hepatotoxicity.2 Reasons for this inter‐individual variability in both toxicity and response are partially unknown but may include demographic factors (such as patient age and weight), external or environmental influences (for instance adherence to treatment, drug dosage), and genetic variation in pharmacokinetics (for instance, drug metabolizing enzymes) or pharmacodynamics (drug targets). Pharmacogenetics is the study of those inherited factors that influence the inter‐individual variability in response to drugs and is a rapidly developing field. The pharmacokinetics and pharmacodynamics of MTX, as have recently been unravelled, have proved to be complicated, and early attempts at pharmacogenetic studies in both rheumatology and dermatology using a candidate gene approach have not been definitive. MTX is a pro‐drug which is actively transported into the cell via a transmembrane reduced folate carrier protein (SLC19A1) and actively exported from the cell by ATP‐binding cassette transporters ABCC1 and ABCG2. Polymorphisms in ABCC1 and ABCG2 have been found to correlate with a better response to MTX (with odds ratios of about 2) and polymorphisms in SLC19A1 and ABCC1 have been associated with MTX toxicity. Within the cell, MTX is activated by the sequential addition of between two and seven glutamic acid residues under the action of the enzyme folylpolyglutamate synthetase, thus converting the parent drug to the active and more stable polyglutamated form. MTX polyglutamates (MTXPGs) persist intracellularly, exerting a sustained effect which allows for its once‐weekly administration.3 Some studies of patients with rheumatoid arthritis have shown a correlation between intracellular MTXPG levels and MTX treatment efficacy.4, 5