Abstract
Objectives Methotrexate (MTX) is used as an anchor drug in the treatment of rheumatoid arthritis (RA), although more than a half of the patients with RA require additional treatments. We designed a prospective study involving two medical centers in Japan to examine the association between the expression of MTX-related genes including a drug transporter ATP-binding cassette sub-family G member 2 (ABCG2) gene and the clinical response to MTX in MTX-naive patients with RA. Methods The primary endpoint of this study was good response based on the European League Against Rheumatism (EULAR) response criteria by Disease Activity Score using 28-joint count (DAS28). We evaluated the association between the baseline expression of six genes involved in the intracellular pharmacokinetics of MTX, including ABCG2, as well as their temporal changes, and the clinical response at week 12 from the initiation of MTX. Results Based on the clinical response at 12 weeks after the initiation of MTX, 24 patients were classified into good responders (n = 9) and non-good responders (n = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of the baseline gene expression levels to predict the EULAR good response at week 12 showed a significant association with ABCG2 expression alone. Furthermore, the rate of baseline expression of ABCG2 mRNA above the cut-off value determined using a receiver operating characteristic curve was higher in good responders than in non-good responders (p = .012). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median −76% vs. +41% from baseline, respectively; p = .011). The ABCG2 expression level did not correlate with DAS28 at baseline or week 12. Conclusions Our study revealed that good response to MTX is associated with a decrease in the expression of ABCG2 in patients with RA.
Highlights
Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA)
A univariate logistic regression analysis of baseline gene expression levels for the prediction of the European League Against Rheumatism (EULAR) good response at week 12 showed a significant association with ATP-binding cassette sub-family G member 2 (ABCG2) alone, and the rate of baseline expression of ABCG2 mRNA above the cut-off value determined by a receiver operating characteristic curve was higher in good responders than in non-good responders (p = 0.012)
ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks
Summary
Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). We previously performed a cross-sectional, observational study and reported an association between the gene expression level of the drug transporter ABCG2/BCRP (breast cancer resistance protein) and RA disease control in patients receiving MTX. Methotrexate (MTX) is a first-line therapeutic drug for the treatment of rheumatoid arthritis (RA), it is the anchor drug for disease-modifying anti-rheumatic drugs (DMARDs), and it is used throughout the world for treatment-naïve, active RA patients [1,2,3]. In addition to lower disease activity, male sex, lack of seropositivity, lower serum tumor necrosis factor (TNF), and levels of TNF-producing cells in the peripheral blood were all previously associated with clinical effectiveness [7,8,9,10]. The gene expression profiles of biomolecules involved in the intracellular pharmacokinetics of MTX are likely to play a crucial role in the prediction of clinical response [11, 14], as are the development of dose-dependent adverse events such as liver dysfunction and cytopenia
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