RESUMEN
BACKGROUND: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. METHODS: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR. RESULTS: Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). CONCLUSION: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.
RESUMEN
Around a 20-30% of inflammatory bowel disease (IBD) patients are diagnosed before they are 18 years old. Anti-TNF drugs can induce and maintain remission in IBD, however, up to 30% of patients do not respond. The aim of the work was to identify markers that would predict an early response to anti-TNF drugs in pediatric patients with IBD. The study population included 43 patients aged <18 years with IBD who started treatment with infliximab or adalimumab. Patients were classified into primary responders (n = 27) and non-responders to anti-TNF therapy (n = 6). Response to treatment could not be analyzed in 10 patients. Response was defined as a decrease in over 15 points in the disease activity indexes from week 0 to week 10 of infliximab treatment or from week 0 to week 26 of adalimumab treatment. The expression profiles of nine genes in total RNA isolated from the whole-blood of pediatric IBD patients taken before biologic administration and after 2 weeks were analyzed using qPCR and the 2-∆∆Ct method. Before initiation and after 2 weeks of treatment the expression of SMAD7 was decreased in patients who were considered as non-responders (p value < 0.05). Changes in expression were also observed for TLR2 at T0 and T2, although that did not reach the level of statistical significance. In addition, the expression of DEFA5 decreased 1.75-fold during the first 2 weeks of anti-TNF treatment in responders, whereas no changes were observed in non-responders. Expression of the SMAD7 gene is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD. TLR2 and DEFA5 need to be validated in larger studies.
Asunto(s)
Adalimumab/farmacología , Antiinflamatorios/farmacología , Antirreumáticos/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/farmacología , Transcriptoma/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/uso terapéutico , Adolescente , Antiinflamatorios/uso terapéutico , Antirreumáticos/uso terapéutico , Niño , Preescolar , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/genética , Infliximab/uso terapéutico , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/sangre , ARN Mensajero/genética , Receptores Tipo II del Factor de Necrosis Tumoral/biosíntesis , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Proteína smad7/biosíntesis , Proteína smad7/genética , Receptor Toll-Like 2/biosíntesis , Receptor Toll-Like 2/genética , Resultado del Tratamiento , Receptor Activador Expresado en Células Mieloides 1/biosíntesis , Receptor Activador Expresado en Células Mieloides 1/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , alfa-Defensinas/biosíntesis , alfa-Defensinas/genéticaRESUMEN
Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014-2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6-8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn's Disease activity index [wPCDAI] < 12.5). Faecal calprotectin (FC) levels (µg/g) decreased significantly after EEN (830 [IQR 500-1800] to 256 [IQR 120-585] p < 0.0001). Patients with wPCDAI ≤ 57.5, FC < 500 µg/g, CRP >15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6-8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn's disease regardless of the location of disease and disease activity.
