Good response to methotrexate is associated with a decrease in the gene expression of ABCG2, a drug transporter, in patients with rheumatoid arthritis

Abstract

Background 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.Methods We designed a prospective study in two medical centers in Japan to con rm the association of ABCG2 gene expression level with the clinical response to MTX in MTX-naive patients with RA. 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, a total of 24 patients were classi ed into the good responders (n = 9) and non-good responders (n = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of baseline gene expression levels for the prediction of the EULAR good response at week 12 showed a signi cant association with 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). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median -76% versus +41% from baseline, respectively; p = 0.011). The ABCG2 gene expression level did not correlate with DAS28 at baseline or at week 12, and neither did the rate of change in ABCG2 gene expression level.Conclusions We have con rmed the association between the gene expression level of the drug transporter ABCG2 and the clinical response to MTX in patients with RA.

Biomarkers (mRNAs and non-coding RNAs) for the diagnosis and prognosis of rheumatoid arthritis

“…They are essential for developing the immune system and regulation ( 96 ). In addition, miRNAs have high tissue specificity and are expressed differentially in various tissues ( 97 ). An analysis of circulatory miRNAs comprising 50 RA patients showed that miR-126-3p, miR-221-3p, let-7d-5p, miR-431-3p, miR-24-3p, and miR-130a-3p were significantly elevated in the serum of RA patients and “at-risk individuals,” as well as miR-130a-3p combined with the remaining five to yield a higher AUC.…”

Toward Overcoming Treatment Failure in Rheumatoid Arthritis

“…BCRP transported both methotrexate and polyglutamylated methotrexate and participated in methotrexate resistance ( 44 ). Good response to methotrexate was associated with a decrease in expression of BCRP in RA patients ( 45 ), while the association of BCRP polymorphisms with the effectiveness of methotrexate was not observed ( 46 ), suggesting that BCRP expression was not genetically determined, but might be associated with environmental factors ( 45 ). BCRP inhibition could be a strategy for overcoming nonresponse to methotrexate.…”

Is Pharmacogenetic Panel Testing Applicable to Low-Dose Methotrexate in Rheumatoid Arthritis? – A Case Report

“…While SLC19A1 and SLC46A1 are facilitating cellular entry, there are members of the ATP-binding cassette transporter family, namely ABCB1 , 15 ABCC2 and ABCG2 , that are assumed to limit methotrexate bioavailability by active efflux of the molecule. 16 MTX response depends on the expression of ABCG2 (breast cancer resistance protein, BCRP) 17 and it has been shown that genetic variants influenced MTX plasma levels in pediatric patients. 18 Moreover, ABCG2 was associated with MTX discontinuation in a clinical PGx model.…”

“…Studies on C3435T polymorphism had diverging results. The 3435C allele was associated with increased toxicity, 17 while the 3435T allele has been associated with high disease activity and increased ADRs, 20 non-response, 21 and with a low disease activity score 22 and PharmGKB 44 cites that carriers of the 3435T allele might have an increased risk of toxicity. With these inconclusive findings reported in the literature, it is difficult to decide on the impact the variants in ABCB1 would have on MTX transport, thereby making a predictive decision impossible.…”