Abstract
Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterized by chronic inflammation of multiple peripheral joints, which leads to destruction of cartilage and bone, progressive deformity and severe disability [1]
This work aims to evaluate the influence of single nucleotide polymorphism (SNPs) in genes encoding for MTX membrane transport proteins on the occurrence of non-response to MTX in Portuguese rheumatoid arthritis (RA) patients
disease modifying antirheumatic drug (DMARD), while 59 patients (25.3%) were treated with MTX combined with other classic DMARDs and 28 patients (12.0%) were treated with MTX combined with biological DMARDs
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterized by chronic inflammation of multiple peripheral joints, which leads to destruction of cartilage and bone, progressive deformity and severe disability [1]. In Portugal, the prevalence of RA is 0.36% and the incidence is between 20 and 40 cases per 100.000 inhabitants [3,4]. Several studies from controlled and uncontrolled clinical trials have established that methotrexate (MTX), an antifolate, is an effective disease modifying antirheumatic drug (DMARD) [10,11,12]. MTX is metabolized into methotrexate polyglutamates (MTXPGs) by a sequential addition of glutamic acid residues via the enzyme folylpolyglutamate synthetase (FPGS) [13,14]. Gamma-glutamyl hydrolase (GGH) enzyme removes the glutamic acid residues of MTXPGs and, MTX can be transported out of the cells [13]. 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G
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