Genetic Predictors of Long-term Response to Antitumor Necrosis Factor Agents in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value  < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.

Gene Signatures of Early Response to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

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.

Helicobacter pylori Infection in Children. Antimicrobial Resistance and Treatment Response.

BACKGROUND: The aim of this study was to determine the appropriateness of the recent recommendations for managing Helicobacter pylori infection in children in a university hospital in Southern Europe. Antimicrobial resistance and response to eradication therapy were also determined. MATERIALS AND METHODS: The presence of H. pylori was studied in 143 children: by gastric biopsy culture (GBC), (13)C-urea breath test (UBT) and stool antigen immunochromatography test (SAIT) in 56 children; by GBC and UBT in 20, by GBC and SAIT in 18, and by GBC alone in 49. Antimicrobial susceptibility was determined by E-test. Infection was defined as a positive culture or positivity in both UBT and SAIT. Disease progression was studied in 118 patients. First evaluation of symptoms was carried out at 3-6 months after diagnosis and/or after treatment of the infection. RESULTS: H. pylori was detected in 74 from the 143 children analyzed (100% GBC positive, 98.1% UBT positive, and 58.1% SAIT positive). The main symptom was chronic abdominal pain (n = 121). Macroscopic antral nodularity was observed in 29.7% of infected patients and in 5.8% of uninfected patients, respectively. Resistance to clarithromycin and metronidazole was found in 34.7 and 16.7%, respectively. Eradication when susceptible antimicrobials were used occurred in 78.7% (48/61) versus 37.5% (3/8) when the treatment included a drug with resistance (p = .024). In patients with recurrent abdominal pain, symptoms resolved in 92.9% (39/42) patients with HP eradication versus 42.9% (6/14) without HP eradication (p < .001). CONCLUSION: Treated patients often failed to meet the criteria established in the guidelines for H. pylori diagnostic screening and treatment because most of them had only recurrent abdominal pain, but remission of their symptoms was associated with H. pylori eradication.

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

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.