THU0126 The Influence of Clinical and Genetic Variables on Methotrexate-Related Toxicity in Portuguese Rheumatoid Arthritis Patients
Authors: A. Lima, M. Bernardes, J. Monteiro, R. Azevedo, L. Costa, F. Ventura, V. Seabra, R. Medeiros
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Methotrexate is the cornerstone of treatment of RA<sup>1</sup>. However, major drawbacks of MTX therapy are the large interpatient variability in clinical response and unpredictable appearance of a large spectrum of side effects<sup>1</sup>. Several studies have been conducted to evaluate the role of potential biomarkers in predicting MTX-related toxic effects<sup>2,3</sup>. Nevertheless, there is no information regarding Portuguese population. <h3>Objectives</h3> To determine possible MTX-related toxicity with clinical and genetic variables in Portuguese patients with RA. <h3>Methods</h3> Patients (n=233) with active RA treated with MTX as indicated in treatment guidelines were followed from 2009 to date. Twenty-six clinical variables possibly influencing disease state and drug response were analyzed. In addition, six genetic polymorphisms related to the MTX metabolism were determined: rs1801133, rs4673993, rs34743033, rs2853542, rs34489327 and rs1051266. Factors were compared between non-MTX-related toxicity (nMTX-Tox) and MTX-related toxicity (MTX-Tox). MTX-Tox was defined if patients presented any adverse drug event (ADE) particularly, gastrointestinal; skin and subcutaneous tissue; hepatobiliary; respiratory, thoracic and mediastinal ADEs. Statistical analysis (significance at <i>P</i>&lt;0.05) were performed according variables using Student's t test, Mann-Whitney U test or Χ<sup>2</sup> test. Differences in genotype distribution groups were tested by 2x2 cross-tabulations for carriers <i>vs</i> noncarriers with analyses by 2-sided χ<sup>2</sup> test. <h3>Results</h3> Clinical variables: both female and male patients presented the same significant profile for n-MTX-Tox (<i>P</i>&lt;0.001 and 0.005, respectively); postmenopausal females and patients with comorbidities had less probability to develop MTX-Tox (<i>P</i>=0.037 and <i>P</i>=0.001, respectively); patients positive for RF, anti-CCP and/or ANA´s had a higher probability to nMTX-Tox (<i>P</i>&lt;0.001, &lt;0.001 and 0.014, respectively); higher CRP levels were found in MTX-Tox patients (<i>P</i>=0.045); patients taking NSAIDs and/or corticotherapy and/or folic acid had less probability to develop MTX-Tox (<i>P</i>&lt;0.001). Genetic variables: homozygous CC for <i>MTHFR</i>C677T were associated with MTX-Tox and T carriers were associated with nMTX-Tox (<i>P</i>=0.037); patients carrying the 6bp+ allele for <i>TYMS</i> 1494del6 were associated with MTX-Tox and homozygous 6bp-6bp- associated with nMTX-Tox (<i>P</i>=0.046). No statistical differences were found between MTX-Tox/nMTX-Tox for all other variables studied, both clinical and genetic. <h3>Conclusions</h3> These findings indicate that genotyping of <i>MTHFR</i> and <i>TYMS</i>, combined with CPR, may help clinicians to identify patients whom will not benefit from MTX treatment due to potential occurrence of ADEs. <h3>References</h3> Hider, S.L. <i>et al.</i> The pharmacogenetics of methotrexate. <i>Rheumatology</i>,2007;46(10):1520-1524. Maillefert, J.F. <i>et al.</i> Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. <i>Joint Bone Spine</i>,2010;77(6):558-563. Dervieux, T. <i>et al.</i> Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. <i>Arthritis Rheum</i>,2006;54(10):3095-3103. <h3>Disclosure of Interest</h3> None Declared