Aims: Clinical response to methotrexate (MTX) treatment differs among rheumatoid arthritis patients. Genetic variation can partly account for this phenomenon. In this study, functional... Show moreAims: Clinical response to methotrexate (MTX) treatment differs among rheumatoid arthritis patients. Genetic variation can partly account for this phenomenon. In this study, functional polymorphisms in genes related to the mechanism of action of MTX or immunopathogenesis of rheumatoid arthritis were studied for association with treatment outcome in a Dutch cohort of patients with early rheumatoid arthritis. Furthermore, tests for replication of previous research on these genetic variants were performed according to reported end points. Materials & methods: Seven polymorphisms in seven genes were analyzed in 205 genotyped patients with active rheumatoid arthritis. All patients received standardized MTX treatment (<= 25 mg per week orally) combined with folic acid. MTX treatment outcome was evaluated by disease activity score criteria and adverse drug events. The following genetic variants were analyzed and correlated: ABCB1 3435C > T, ITPA IVS2 +21A > C, HLA-G (-14 bp >+14 bp), TGFB1 +869T > C and TLR4 +896A > G. In case of significant differences, regression analyses were applied. Since carriers of the minor alleles of the SNPs DHFR 829C > T and IMPDH2 +787C > T were not observed, no statistical analyses could be performed. Results: No significant associations or replications of these genetic variants with MTX efficacy were demonstrated. Regarding toxicity, patients carrying the ABCB1 3435T-allele and TLR4 +896G-allele were 2.5-times more likely to develop adverse drug events at 6 months (odds ratio: 2.6; 95% CI: 1.1-6.2, and odds ratio: 2.5; 95% CI: 1.1-6.1, respectively). Additionally, this chance increased almost fourfold in patients with the two unfavorable genotypes (odds ratio: 3.9; 95% CI: 1.5-10.3). However, none of these associations remained significant after correction for multiple testing (p < 0.004). Conclusion: Our data indicate that MTX toxicity was potentially associated with ABCB1 3435C > T and TLR4 +896A > G. However, after correction, none of these associations remained significant. Furthermore, no significant associations or replications of these functional variants with efficacy were found. Show less
Over the last decades important progress is being made regarding disease modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Nevertheless, a substantial part of... Show moreOver the last decades important progress is being made regarding disease modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Nevertheless, a substantial part of the patients fail to achieve a good response and/or experience toxicity, which limits further treatment leading to progression of inflammation and destruction of joints. These high interindividual differences in drug response gave rise to the need for prognostic markers in order to individualize and optimize therapy with these antirheumatic agents. Besides demographic and clinical factors, studies in the research field of pharmacogenetics have reported potential markers associated with clinical response on treatment with methotrexate and TNF inhibitors. However, publicized conflicting results and underlying interpretation difficulties inhibit drawing definitive conclusions. Presently, clinical implementation of pharmacogenetics as an important step for individualizing drug therapy in RA is not feasible yet. Replication and prospective validation in large patient cohorts are required before pharmacogenetics can be used in clinical practice. This review provides the current state of art in genotyping RA patients as a potential guide for clinical decision making. Show less
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
