Genetic polymorphisms in psoriasis: investigating genetic variations for precise profiling of response to brodalumab in real-life clinical practice

Abstract

Background: Numerous studies have investigated the association that exists between genetic variants and the efficacy profile of biologic therapies for the management of psoriasis. However, as far as we know, data on this association for brodalumab are lacking in the currently available scientific literature. Objectives: To analyze the association of 180 polymorphisms with an optimal response to brodalumab in real-world clinical practice. Methods: A total of 119 patients with plaque psoriasis on a 24-regimen of brodalumab recruited from 11 Spanish hospitals were genotyped for 180 polymorphisms. Optimal response was evaluated as absolute (PASI) 1 at 6 and 12 months. Polymorphisms with false discovery rates < 0.25 were included in a multiple regression model. Results: A total of 68% and 62% of patients achieved PASI 1 at 6 and 12 months, respectively. Patient weight, history of biological therapy, disease-modifying anti-rheumatic drugs, and psoriatic arthritis were identified as risk factors for failing to achieve PASI 1. At 12 months, polymorphisms rs495337 (SPATA2), rs6311 (HTR2A), and rs4085613 (LCE3D) were associated with achieving a PASI 1 regardless of previous use of biologics and DMARDs, psoriatic arthritis, or weight. The genotypes CT-TT for rs6311 (HTR2A) and GT for rs4085613 (LCE3D) were identified as risk factors for lack of optimal response at 12 months, while genotypes AG-AA for rs495337 (SPATA2) increase the probability of response. No polymorphism was associated to brodalumab response at 6 months. Conclusions: This study identified genetic variations associated with the ability to achieve an optimal response to brodalumab, providing potential insights into its efficacy profile for treating plaque psoriasis.

Antecedentes: No existen estudios sobre el uso de polimorfismos en psoriasis para predecir la respuesta a brodalumab. Objetivos: Analizar la relación de 180 polimorfismos con una respuesta óptima a brodalumab en práctica clínica real. Métodos: Se incluyeron pacientes con psoriasis en placas tratados con brodalumab durante al menos 24 semanas. Se genotiparon 180 polimorfismos de genes relacionados con la inmunopatogenia de la psoriasis. La respuesta óptima (PASI absoluto 1) al tratamiento se evaluó a los 6 y 12 meses. En el análisis multivariante se incluyeron los polimorfismos con False Discovery Rate 0,25. Resultados: El estudio incluyó 119 pacientes; el 68% y el 62% alcanzaron un PASI 1 a los 6 y a los 12 meses, respectivamente. Se identificaron como factores de riesgo para no lograr un PASI 1: el uso previo de biológicos y fármacos antirreumáticos modificadores de la enfermedad, diagnóstico de artritis psoriásica y el peso. El análisis de asociación a los 12 meses reveló que los polimorfismos rs495337 (SPATA), rs6311 (HTR2A) y rs4085613 (LCE3D) se asocian con alcanzar un PASI 1 independientemente del uso previo de biológicos, artritis psoriásica o el peso. Los genotipos CT-TT para rs6311 y GT para rs4085613 fueron identificados como factores de riesgo para alcanzar PASI 1, mientras que AG-AA para rs495337 aumentaron la probabilidad de lograr respuesta óptima. Ningún polimorfismo se asoció con la respuesta a los 6 meses. Conclusiones: Este estudio identificó variaciones genéticas que podrían predecir la respuesta a brodalumab, permitiendo optimizar su uso en el tratamiento de la psoriasis.