Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterised by inflammation of multiple joints, leading to destruction of cartilage and juxta articular bone. It eventually leads to deformity, disability, and impaired quality of life. Methotrexate (MTX), has a reported response rate of 33 to 65%, and this variability may be explained by genetic variations (polymorphisms) in the metabolic pathway of this drug.

To evaluate possible relationships between polymorphisms in the metabolic pathway and response to MTX in patients with RA.

Methodology A systematic search and review of the literature was conducted. A total of 29 studies that evaluated polymorphisms in the metabolic pathway of MTX were included, due to their full text and methodological quality.

Results Of the 29 studies, five were systematic reviews and/or meta-analyses, three of which clinical trials none was triple blind and only one was double-blind, six were cohort, seven were case-control, and eight cross sectional. The polymorphism identified were: methylene tetrahydrofolate reductase, dihydrofolate reductase, thymidylate synthase, 5-amino-imidazole-4- carboxamide ribonucleotide formyl transferase (AICAR formyltransferase), 5-aminoimidazole-4- carboxamide polymorphisms formyltransferase/IMP cyclohydrolase ribonucleotide (ATIC) identified conveyors attached to ATP cassette (ABC ATP-binding cassette), folylpoly-glutamate, glutamyl hydrolase, reduced folate carrier (RFC-SLC10A1). The dihydrofolate reductase and methylene tetrahydrofolate reductase polymorphism were shown to be associated with increased MTX toxicity. RFC and C677 T polymorphisms are associated with better efficacy of MTX.

Conclusions The polymorphisms of methylene tetrahydrofolate reductase, C677 T and RFC1 - G80A generate increased efficacy and toxicity in patients treated with MTX. However, for the other polymorphisms, although studies show statistically significant associations, they are not conclusive and some are contradictory. This justifies conducting multicentre studies to assess the presence and association with the effectiveness or toxicity in patients with RA treated with MTX.

Antecedentes La artritis reumatoide (AR) es una enfermedad inflamatoria de origen autoinmune, caracterizada por inflamación de múltiples articulaciones que lleva a destrucción del cartílago y del hueso yuxta articular, con el tiempo genera deformidad, discapacidad y deterioro de la calidad de vida. El metotrexato (MTX), reporta un índice de respuesta del 33 al 65%, esta variabilidad puede ser explicada por las variaciones genéticas (polimorfismos) en la ruta metabólica de este fármaco.

Objetivo Evaluar las posibles asociaciones entre los polimorfismos de la ruta metabólica del MTX y su respuesta en pacientes con AR.

Metodología Revisión sistemática de la literatura cualitativa (integrative review). Se realizó una búsqueda sistemática de la literatura, 29 estudios fueron incluidos por texto completo y por calidad metodológica para alcanzar el objetivo del estudio, estos estudios evaluaron polimorfismos en la ruta metabólica del MTX.

Resultados De los 29 estudios, cinco fueron revisiones sistemáticas o metaanálisis, tres ensayos clínicos de los cuales ninguno fue triple ciego y solo uno fue doble ciego, seis fueron cohortes, siete fueron casos y controles y ocho de corte transversal. Se identificaron los polimorfismos de metiltetrahidofolato reductasa, dihidrofolato reductasa, timidilato sintetasa, 5-aminoimidazol-4- carboxamida ribonucleótido formiltransferasa (AICAR formiltransferasa), 5-aminoimidazol-4- carboxamida ribonucleótido formiltransferasa/IMP ciclohidrolasa (ATIC), transportadores de casete unidos a ATP (ABC ATP-binding cassette), folilglutamato sintetasa, glutamil hidrolasa, transportador de folato reducido (RFC-SLC10A1). Los polimorfismos metiltetrahidofolato reductasa y dihidrofolato reductasa demostraron estar asociados con un aumento en la toxicidad del MTX; los polimorfismos RFC y C677 T están asociados a una mejor eficacia del MTX.