Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication ofMTHFRrs1801133 andATICrs4673993 Polymorphisms

Abstract

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.

Impact of methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism on the outcome of methotrexate treatment in a sample of Egyptian rheumatoid arthritis patients

“…In concordance with our results, Lima et al 9 studied the role of MTHFR C677T and ATIC T675C polymorphisms and clinicopathological variables in clinical response to MTX in RA patients. It was found that MTX dose and concomitant use of NSAIDs were significantly associated with MTX drug response.…”

“…8 Factors influencing disease course and therapeutic outcome include clinicopathological variables such as patient-related variables, disease-related variables and treatment-related variables in addition to genetic factors such as genetic polymorphisms in the key MTX pathway genes. 9 The study of the associations between genetic variations such as polymorphisms and drug efficacy and toxicity is known as pharmacogenetics. Thus, pharmacogenetic studies can predict the therapeutic outcomes of MTX and this in turn may help clinicians to individualize appropriate treatment for each patient.…”

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

“…A number of investigations of genetic predictors of response to MTX in RA patients have been published, but these have largely been candidate gene studies based on genes involved in MTX metabolism, including the folate pathway, and almost all have had small sample sizes [7][8][9][10] . A few genetic variants have been nominally associated with response in more than one study (rs2372536 in ATIC, reviewed in Plant et al 11 ) or in a meta-analysis (rs1051266 in SLC19A1 (RFC1) 12 ), but results are inconsistent across studies and not close to reaching genome-wide significance levels.…”

Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

“…Earlier detection of RA and the prompt institution of effective and aggressive therapeutic are key factors to achieve the disease remission and improve survival rates [ 7 , 8 , 9 ]. 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 ].…”