Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single‐nucleotide polymorphisms in genes coding for folate pathway enzymes

Abstract

Objective. To determine associations of methotrexate (MTX) efficacy and toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for folate pathway enzymes in patients with early rheumatoid arthritis (RA).Methods. Patients (n ‫؍‬ 205) with active RA received MTX at an initial dosage of 7.5 mg/week, which was increased to 15 mg/week and combined with folic acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints (DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy was evaluated at 3 and 6 months and compared for genotypes in 3 analyses: patients with and without good response (DAS44 <2.4), patients with and without good improvement (⌬DAS44 >1.2), and patients with and without moderate improvement (⌬DAS44 >0.6). The association between MTX-related adverse drug events (ADEs) and genotype was evaluated by comparing genotypes between patients with and without ADEs, specifically pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels. The following SNPs were analyzed: methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase (DHFR) ؊473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of significant differences, odds ratios (ORs) were calculated.Results. At 6 months, MTHFR 1298AA was associated with good improvement relative to 1298C (OR 2.3, 95% confidence interval [95% CI] 1.18-4.41), which increased with increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C allele carriers developed more ADEs (OR 2.5, 95% CI 1.32-4.72).Conclusion. Patients with MTHFR 1298AA and MTHFR 677CC showed greater clinical improvement with MTX, whereas only the MTHFR 1298C allele was associated with toxicity. In the future, MTHFR genotypes may help determine which patients will benefit most from MTX treatment.Methotrexate (MTX) is the most widely used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA), and has proven to reduce disease activity and delay or stabilize the development of bone erosions (1,2). However, only ϳ50% of the patients experience good clinical response, and 30% discontinue therapy due to side effects (3,4).

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

“…Genotyping techniques, success rates, and genotype frequencies for 10 of the 17 SNPs in this population, together with their association with MTX response, were previously reported (19,21). These SNPs were in genes coding for adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), inosine triphosphate pyrophosphatase (ITPA), methionine synthase (MTR), methionine synthase reductase (MTRR), dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), and the reduced folate carrier (RFC).…”

“…It must be realized that other studies have shown an association between SHMT 1420CϾT, MTHFR 677CϾT, and MTHFR 1298AϾC with MTX efficacy (19,22). Due to our multiple stepwise backward statistical approach, only those factors contributing most to MTX efficacy at 6 months of treatment were selected.…”

“…Previously, the influences of demographic, clinical, immunologic, and genetic factors on the state of disease in patients with RA have been studied (10)(11)(12)(13)(14)(15)(16)(17)(18). Specifically, polymorphisms in genes coding for methylenetetrahydrofolate reductase (MTHFR), adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC), serine hydroxymethyltransferase 1 (SHMT1), and inosine triphosphate pyrophosphatase (ITPA) demonstrate association with the MTX response (19)(20)(21)(22). Nongenetic factors such as low disease activity at baseline, male sex, treatment with nonsteroidal antiinflammatory drugs (NSAIDs), and lower levels of creatinine clearance are also related to the efficacy of MTX (23).…”

Association of methotrexate effects and single‐nucleotide polymorphisms in the folate pathway in rheumatoid arthritis: Comment on the article by Wessels et al

“…Wessels et al are to be commended for their recent work exploring the effects of single-nucleotide polymorphisms (SNPs) in genes encoding enzymes in the folate pathway on the action of methotrexate (MTX) in rheumatoid arthritis (RA) (1). They examined the influence of SNPs in the reduced folate carrier (RFC), methylenetetrahydrofolate reductase (MTHFR), and dihydrofolate reductase (DHFR) genes on MTX efficacy and toxicity in patients with RA.…”

“…Our approach was based on recommendations for genetic association studies as previously published (1,2). We…”