AB0338 EVALUATION OF THE ASSOCIATION OF ALLELES OF INTOLERANCE RISK TO METOTREXATE IN RHEUMATOID ARTHRITIS PATIENTS UNDER TREATMENT WITH BIOLOGIC THERAPIES
Authors: A. Escudero Contreras, R. Ortega Castro, J. Calvo Gutierrez, N. Mena-Vázquez, R. Cáliz Cáliz, E. Collantes Estevez, A. Fernandez-Nebro, M. D. C. Abalos-Aguilera, C. Lopez-Pedrera, M. T. Ruiz Jimenez, F. U. Pilar
Journal: Annals of the Rheumatic Diseases (2020)

Background: Metotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA) both in monotherapy and in combination with biologic disease-modifying antirheumatic drugs (bDMARDs), it usually well tolerated but AEs may appear that causing toxicity that requires suspension of the treatment Objectives: Determine the prevalence of certain polymorphisms among patients that receive bDMARD in monotherapy or in combination with MTX to confirm its relevance as biomarkers of intolerance. Evaluate the influence of certain polymorphisms in the effectiveness of monotherapy or combined treatment in patients, through “Disease Activity Score 28” (DAS28), SDAI Simple disease activity index (SDAI), Clinical disease activity index (CDAI) and each one of its components Methods: Retrospective observational multicentric study (University Hospital Complex, Granada, Carlos de Haya Hospital, Malaga and University Hospital Reina Sofia, Cordoba), of cases-control of 227 patients with RA (criteria ACR/EULAR), of which 120 received MTX and bDMARD combined therapy (cases) and other with only bDMARD (controls). All of them had been or were currently treated with MTX, remained with stable doses of bDMARD, and had a DNA sample stored before the inclusion in the study DNA was isolated from total peripheral blood and by fluorescent probe HybProbe and/ or Taqman, 10 polymorphisms of 10 protein coding genes were determined involved in the metabolism and toxicity of MTX according to current evidence Besides the type of polymorphism, data on the activity of the disease were analysed (DAS28VSG, DAS28PCR, SDAI, CDAI, at the start of the MTX income, of the BT, and in the inclusion visit A descriptive and comparative study was carried out on all that and afterwards an assessment was made through a multiple logistic regression analysis (MLR) on the risk of intolerance to MTX Results: An analysis was carried out on 227 patients (120 cases and 107 controls) with an average age of 60 (12,1) being women 78,4%, with a time of evolution since diagnosis of 14,84 (7,78) years 48,9% registered adverse events (AE) MTX related, mainly gastrointestinal, hepatobiliary and skin-subcutaneous tissue. The percentage of AE appearance was superior in the monotherapy group than in the group with combined therapy The most prevalent polymorphism (84,6% (IC95%: 84,09%-85,11%) and in cases (86,0% (IC95%: 79,43%-92,57%) was homozygous CC (ITPase-c94a ); in controls homozygous GG (GGH-T401C ) (87,5% (IC95%:81,58%-93,42%) There were no significant differences in the parameters of activity between groups, in both, patients were best basally controlled than at the start of the MTX income and/or bDMARD Being homozygous-AA for the DHFR gene was significantly associated (p&lt;0.05) with the appearance of AE (none of the 4 homozygous AA patients for that gene had AE) In MLR, homozygous GG (ref. heterozygous AG) in polymorphism GGH-T401C, being homozygous CC (ref. heterozygous TC) in polymorphism ABCC2-C24T and PCR (mg/dL) at the start of bDMARD resulted independent predictive factors of MTX intolerance Conclusion: Polymorphisms T401C for the GGH gene and C24T for the ABCC2 gene and PCR at the start of the bDMARD resulted independent predictive factors of MTX intolerance . Polymorphism homozygous AA for DHFR gene was related to significant protection against appearance of AE Disclosure of Interests: Alejandro Escudero Contreras: None declared, Rafaela Ortega Castro: None declared, Jerusalem Calvo Gutierrez: None declared, Natalia Mena-Vázquez: None declared, Rafael Cáliz Cáliz: None declared, Eduardo Collantes Estevez Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene, Antonio Fernandez-Nebro: None declared, Maria del Carmen Abalos-Aguilera: None declared, Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Mª Teresa Ruiz Jimenez Employee of: Roche Farma, SPAIN, Font Ugalde Pilar: None declared