SAT0693 Genetic polymorphisms and efficacy of metothrexate in rheumatoid arthritis
Authors: E. Chamizo, E. González, C. Carrasco, S. Rojas, J.J. Aznar, P. Dorado, A. Llerena
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Methotrexate (MTX) is the DMARD of choice in the treatment of rheumatoid arthritis (RA). There is important variability in its therapeutic response. The identification of genetic factors related to the absorption, metabolism and action of MTX may facilitate a more efficient use. <h3>Objectives</h3> To study the effect of clinical characteristics and different single nucleotide polymorphisms (SNPs), related to the transport and metabolic pathways of MTX, on the therapeutic response of MTX in monotherapy in RA patients. <h3>Methods</h3> Observational study. Outcome variable: response to MTX (DAS-PCR &lt;3.2). Study factors: SNPs of transport (ABCB1 C3435T), glutamation (GGH T16C and FPG G2782A), transmetylation(MTHFR C677T and MTHFR A1298C) and adenosine (AMPD1 C34T, ADA A534G, ITPA C94A). The association between SNPs and therapeutic response was analysed by logistic regression, assessing the allele independence (Hardy-Weinberg equilibrium) and interaction by sex. Different models of SNPs inheritance were analysed. Models were adjusted by the characteristics of the patient, of disease and of treatment. The haplotypes of the MTHFR SNPs (C677T and A1298C) were also analysed. <h3>Results</h3> Bivariate analysis showed lower probability of response with smoking (OR=0.37), erosions (OR=0.26), Mantoux (OR=0.20), disease activity (OR=0,08), previous DMARDs (OR=0.46) and doses of folic acid (OR=0.97), MTX (OR=0.87) and prednisone (OR=0.93), with higher response at a higher age at diagnosis (OR=1.05). In relation to the SNPs, the C/A genotype of the ITPA_C94A decreases the probability of response (OR=0.48) according to an overdominant inheritance model, and the C/C genotype of MTHFR_A1298C is also associated with a lower response according to a model of recessive inheritance (OR=0.18). An interaction between the GGH_T16C SNP and sex was observed, so that the C/C genotype increases the possibility of response in women (OR=2.95), but not in men. In the adjusted models, only the effect of genotype C/C of MTHFR_A1298C is mantained (OR=0,14), irrespective of age, sex, smoking, alcohol, RF, anti-CCP, erosions, extra-articular manifestations, Mantoux, DAS28-CRP, previous DMARDs, time to MTX, doses of folic acid, prednisone, MTX and route of administration. On the contrary, the association between the ITPA-C94A polymorphism and the response was not maintained nor the interaction effect of the C/C genotype of GGH_T16C observed in bivariate analysis. Finally, the CC haplotype of the combination MTHFR C677T and MTHFR A1298C is associated with a decrease in the response (OR=0.55) in the adjusted models, so it is an effect independent of the control variables. No interaction effects were observed by sex. <h3>Conclusions</h3> Genetic polymorphisms related to the transport and metabolism of MTX have little effect on the therapeutic response, or at least much lower than other patient (smoking), disease (activity, erosions), or treatment (number of previous DMARDs) characteristics. <h3>Disclosure of Interest</h3> None declared