RESUMO
INTRODUCTION: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment. OBJECTIVE: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease. PATIENTS AND METHODS: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7⯵g/mL) or infratherapeutic (<3⯵g/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test. RESULTS: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], pâ¯<â¯0.05; HR, 0.39 [95%CI, 0.18-0.88], pâ¯<â¯0.05; and HR, 0.04 [95%CI, 0.18-0.92] pâ¯>â¯0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505â¯T was associated with infratherapeutic levels (pâ¯<â¯0.05). CONCLUSION: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab.
Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Feminino , Humanos , Interleucina-10/genética , Interleucina-6/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptor 2 Toll-Like/genética , Resultado do Tratamento , Adulto JovemAssuntos
Doença de Addison/induzido quimicamente , Insuficiência Adrenal/complicações , Antimetabólitos/efeitos adversos , Imunossupressores/efeitos adversos , Tacrolimo/efeitos adversos , Trimetoprima/efeitos adversos , Insuficiência Adrenal/tratamento farmacológico , Antimetabólitos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Tacrolimo/uso terapêutico , Trimetoprima/uso terapêuticoRESUMO
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