RESUMEN
Anti-tumor necrosis factor (anti-TNF) drugs are effective against psoriasis, although 20-30% of patients are nonresponders. Few pharmacogenomic studies have been performed to predict the response to anti-TNF drugs in psoriasis. We studied 173 polymorphisms to establish an association with the response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis (N=144). We evaluated the response using PASI75 at 3, 6 and 12 months. The results of the multivariate analysis showed an association between polymorphisms in PGLYR4, ZNF816A, CTNNA2, IL12B, MAP3K1 and HLA-C genes and the response at 3 months. Besides, the results for polymorphisms in IL12B and MAP3K1 were replicated at 6 months. We also obtained significant results for IL12B polymorphism at 1 year. Moreover, polymorphisms in FCGR2A, HTR2A and CDKAL1 were significant at 6 months. This is the first study to show an association with these polymorphisms. However, these biomarkers should be validated in large-scale studies before implementation in clinical practice.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Biomarcadores/metabolismo , Femenino , Genotipo , Humanos , Masculino , Farmacogenética/métodos , Psoriasis/metabolismoRESUMEN
Polymorphisms at genes encoding proteins involved in the pathogenesis of psoriasis (Psor) or in the mechanism of action of biological drugs could influence the treatment response. Because the interleukin (IL)-17 family has a central role in the pathogenesis of Psor, we hypothesized that IL17RA variants could influence the response to anti-TNF drugs among Psor patients. To address this issue we performed a cross-sectional study of Psor patients who received the biological treatments for the first time, with a follow-up of at least 6 months. All of the patients were Caucasian, older than 18 years old, with chronic plaque Psor, and had completed at least 24 weeks of anti-TNF therapy (adalimumab, etanercept or infliximab). The treatment response to anti-TNF agents was evaluated according to the achievement of PASI50 and PASI75 at weeks 12 and 24. Those who achieved PASI75 at week 24 were considered good responders. All patients were genotyped for the selected single-nucleotide polymorphisms (SNPs) at IL17RA gene. A total of 238 patients were included (57% male, mean age 46 years). One hundred and five patients received adalimumab, 91 patients etanercept and 42 infliximab. The rs4819554 promoter SNP allele A was significantly more common among responders at weeks 12 (P=0.01) and 24 (P=0.04). We found a higher frequency of AA versus AG+GG among responders, but the difference was only significant at week 12 (P=0.03, odd ratio=1.86, 95% confidence of interval=1.05-3.27). Thus, in the study population, the SNP rs4819554 in the promoter region of IL17RA significantly influences the response to anti-TNF drugs at week 12.
Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Psoriasis/genética , Receptores de Interleucina-17/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/uso terapéutico , Alelos , Estudios Transversales , Etanercept/uso terapéutico , Femenino , Genotipo , Humanos , Infliximab/uso terapéutico , Interleucina-17/genética , Masculino , Persona de Mediana Edad , Psoriasis/tratamiento farmacológicoRESUMEN
Paradoxical psoriasiform reactions to anti-tumor necrosis factor α (TNFα) agents have been described. We aimed to study the association between these reactions and polymorphisms in genes previously associated with psoriasis or other autoimmune diseases. A total of 161 patients with plaque-type psoriasis treated with anti-TNFα drugs were genotyped for 173 single-nucleotide polymorphisms (SNPs) using the Illumina Veracode genotyping platform. Among the 161 patients, 25 patients developed a paradoxical psoriasiform reaction consisting of a change in morphology, mostly to guttate psoriasis (88%). These lesions developed 9.20±13.52 months after initiating treatment, mainly with etanercept (72%). Psoriasis type and a Psoriasis Area and Severity Index (PASI) 75 response to treatment were not associated with lesions. Multivariate logistic regression revealed that five SNPs (rs11209026 in IL23R, rs10782001 in FBXL19, rs3087243 in CTLA4, rs651630 in SLC12A8 and rs1800453 in TAP1) were associated with paradoxical reactions. This is the first study to show an association between genetic polymorphisms and paradoxical reactions in patients with psoriasis treated with anti-TNFα drugs.The Pharmacogenomics Journal advance online publication, 21 July 2015; doi:10.1038/tpj.2015.53.
Asunto(s)
Fármacos Dermatológicos/efectos adversos , Erupciones por Medicamentos/genética , Variantes Farmacogenómicas/genética , Polimorfismo de Nucleótido Simple , Psoriasis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2/genética , Adulto , Anciano , Antígeno CTLA-4/genética , Proteínas de Unión al ADN/genética , Erupciones por Medicamentos/diagnóstico , Proteínas F-Box/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Pruebas de Farmacogenómica , Fenotipo , Valor Predictivo de las Pruebas , Psoriasis/inmunología , Receptores de Interleucina/genética , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunologíaAsunto(s)
Artritis Psoriásica/tratamiento farmacológico , Variantes Farmacogenómicas , Factor de Necrosis Tumoral alfa/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Proteínas de Unión al ADN/genética , Resistencia a Medicamentos/efectos de los fármacos , Humanos , Persona de Mediana Edad , Dimensión del Dolor , Pruebas de Farmacogenómica , Polimorfismo de Nucleótido Simple , Calidad de Vida , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Índice de Severidad de la Enfermedad , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Psoriasis (Ps) is a chronic inflammatory disease with an important genetic component. It shares pathophysiological mechanisms with other autoimmune diseases such as psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn's disease (CD). These conditions can be treated using biological drugs such as infliximab, adalimumab and etanercept, which selectively block the proinflammatory cytokine tumor necrosis factor (TNF)-α. Although these agents have greatly improved the prognosis of Ps, PsA, RA and CD, they do not cure the disease and are expensive; in addition, significant proportions of patients do not respond or develop serious adverse effects. Therefore, it is important to investigate biomarkers, such as gene polymorphisms, that can predict which patients will respond best to a specific drug. Some polymorphisms in genes TNF, TNF receptor superfamily 1B (TNFR1B) and TNFα-induced protein 3 gene (TNFAIP3) have been associated with response to anti-TNF therapy in patients with Ps. The present article reviews other polymorphisms that could also play a role in prediction of response to these treatments.