Background Methotrexate is the cornerstone of treatment of RA1. However, major drawbacks of MTX therapy are the large interpatient variability in clinical response and unpredictable appearance of a large spectrum of side effects1. Several studies have been conducted to evaluate the role of potential biomarkers in predicting MTX-related toxic effects2,3. Nevertheless, there is no information regarding Portuguese population.
Objectives To determine possible MTX-related toxicity with clinical and genetic variables in Portuguese patients with RA.
Methods 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 P<0.05) were performed according variables using Student’s t test, Mann-Whitney U test or Χ2 test. Differences in genotype distribution groups were tested by 2x2 cross-tabulations for carriers vs noncarriers with analyses by 2-sided χ2 test.
Results Clinical variables: both female and male patients presented the same significant profile for n-MTX-Tox (P<0.001 and 0.005, respectively); postmenopausal females and patients with comorbidities had less probability to develop MTX-Tox (P=0.037 and P=0.001, respectively); patients positive for RF, anti-CCP and/or ANA´s had a higher probability to nMTX-Tox (P<0.001, <0.001 and 0.014, respectively); higher CRP levels were found in MTX-Tox patients (P=0.045); patients taking NSAIDs and/or corticotherapy and/or folic acid had less probability to develop MTX-Tox (P<0.001). Genetic variables: homozygous CC for MTHFRC677T were associated with MTX-Tox and T carriers were associated with nMTX-Tox (P=0.037); patients carrying the 6bp+ allele for TYMS 1494del6 were associated with MTX-Tox and homozygous 6bp-6bp- associated with nMTX-Tox (P=0.046). No statistical differences were found between MTX-Tox/nMTX-Tox for all other variables studied, both clinical and genetic.
Conclusions These findings indicate that genotyping of MTHFR and TYMS, combined with CPR, may help clinicians to identify patients whom will not benefit from MTX treatment due to potential occurrence of ADEs.
Hider, S.L. et al. The pharmacogenetics of methotrexate. Rheumatology,2007;46(10):1520-1524.
Maillefert, J.F. et al. Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis. Joint Bone Spine,2010;77(6):558-563.
Dervieux, T. et al. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum,2006;54(10):3095-3103.
Disclosure of Interest None Declared