Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients. DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (ABCC1), rs1476413 (MTHFR), rs2231142 (ABCG2), rs3740065 (ABCC2), rs4149081 (SLCO1B1), rs4846051 (MTHFR), rs10280623 (ABCB1), rs16853826 (ATIC), rs17421511 (MTHFR) and rs717620 (ABCC2). Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher (p < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher (p < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores. Patients with the rs17421511 SNP AA allele reported significantly lower pain scores (p < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity.
Highlights
Rheumatoid arthritis (RA) is the most common chronic autoimmune inflammatory arthritis, affecting approximately 0.3–1% of the world’s population [1,2]
Conventional synthetic disease-modifying anti-rheumatic drugs such as methotrexate (MTX), hydroxychloroquine (HCQ), cyclosporin, sulfasalazine (SSZ) and leflunomide are commonly used mainstays of the disease; it is widely known that a significant proportion of patients with RA often show poor or inadequate therapeutic response to csDMARDs [5]
This study investigates the influence of ten well-characterised single-nucleotide polymorphism (SNP) in RA and we have tried to correlate this with the appearance and accumulation of metabolites measured in the plasma of patients taking DMARDs such as methotrexate and or sulfasalazine
Summary
Rheumatoid arthritis (RA) is the most common chronic autoimmune inflammatory arthritis, affecting approximately 0.3–1% of the world’s population [1,2]. To prevent irreversible joint damage resulting in substantial disability, it is important to introduce disease-modifying anti-rheumatic drugs (DMARDs) early after onset and failure of non-steroidal anti-inflammatory treatment. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as methotrexate (MTX), hydroxychloroquine (HCQ), cyclosporin, sulfasalazine (SSZ) and leflunomide are commonly used mainstays of the disease; it is widely known that a significant proportion of patients with RA often show poor or inadequate therapeutic response to csDMARDs [5]. MTX is subject to significant metabolic activity in the body; the polyglutamated derivatives of MTX are selectively retained in cells, lengthening the activity of the drug which complicates treatment management, since patients would continue taking their daily drug dosage oblivious to the fact that their circulating drug levels are still high, potentially contributing to undesirable cytotoxic effects [8,9]. The MTX-7-OH metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (only 35 to 50% bound) and contributes to inactivity of the drug or poor response to treatment [11]
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