This review presents recent data supporting the methotrexate (MTX) mechanisms of action, which are likely to account for its anti-proliferative and immunosuppressive effects in rheumatoid arthritis (RA). The effects of MTX in vivo may be mediated by reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine release, altering the expression of cellular adhesion molecules, influencing production of cytokines, humoral responses and bone formation. Several reports indicate that the effects of MTX are influenced by genetic variants, specific dynamic processes and micro-environmental elements such as nucleotide deprivation or glutathione levels. The challenge for the future will be linking biological and genetic markers relevant to the response to MTX in RA.

Objective. To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS <2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.Results. The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of <3.5 had a true positive response rate of 95%. Scores of >6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.Conclusion. This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.

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).

To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.