Objective:To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD).Methods:A retrospective cohort study was conducted on 181 children with IBD who were scheduled for azathioprine or 6-mercaptopurine therapy at the Department of Gastroenterology, Children′s Hospital, Zhejiang University School of Medicine between January 2010 and January 2023. Among them, 168 children who received treatment were divided into a genotyped group and non-genotyped group based on pre-treatment TPMT and NUDT15 genotyping. The incidence of drug-related adverse reactions was compared between the two groups. The impact of genotyping on medication selection and discontinuation rates was analyzed. Chi-square test or Fisher exact test were used for intergroup comparisons. Logistic regression analysis was used to control the confounding factors. Firth Logistic regression analysis was applied for data with complete separation. The probability of discontinuation was assessed using survival analysis with Cox proportional hazards modeling.Results:Among the 181 children with IBD, 13 did not receive azathioprine or 6-mercaptopurine due to genetic variants, while the remaining 168 underwent the therapy (154 cases of Crohn′s disease and 14 cases ulcerative colitis; 108 males and 60 females). Excluding the 13 untreated cases, 77 children underwent TPMT and NUDT15 genotyping were assigned to the genotyped group, and the remaining 91 to the non-genotyped group. Adverse reactions included myelosupression (26 cases,15.5%), hepatotoxicity (18 cases,10.7%), gastrointestinal disturbance (25 cases,14.9%), alopecia (12 cases,7.1%), fever (3 cases,1.8%), rash (2 cases,1.2%), and pancreatitis (1 case,0.6%). The incidence of overall adverse reactions was significantly higher in the non-genotyped group compared to that of the genotyped group (40.7% (37/91) vs. 26.0% (20/77), P<0.05). Specifically, the non-genotyped group had a higher rate of gastrointestinal reactions compared to the genotyped group (24.2% (22/91) vs. 3.3% (3/77), P<0.01). Cox regression analysis revealed that non-genotyped group had a higher risk of treatment discontinuation due to the adverse reactions ( HR=1.47, 95% CI 0.65-3.30). Conclusion:Pre-treatment genotyping of TPMT and NUDT15 variants can help guide the selection of clinical drugs, reduce the incidence of drug-related adverse reactions and enhance tolerability of azathioprine or 6-mercaptopurine therapy in IBD children.

Objective:To analyze the clinical and genetic features of four children with pediatric acute liver failure (PALF) caused by neuroblastoma-amplified sequence ( NBAS) gene variant, as well as the correlation between clinical phenotype and genotype. Methods:The clinical data and genetic test results of four children with NBAS gene variants admitted to the Department of Gastroenterology, Children's Hospital Affiliated to Zhejiang University School of Medicine from August 2015 to June 2023 mainly presenting with pediatric acute liver failure (PALF) were retrospectively analyzed. The relevant literature from January 2015 to May 2024 was retrieved using the Chinese and English keywords " NBAS," "neuroblastoma amplified sequence," "SOPH," "short stature with optic nerve atrophy and Pelger Hu?t anomaly," "liver failure," and "neuroblastoma amplified sequence" indexed in the CNKI database, Wanfang Data Knowledge Service Platform, and PubMed database. The clinical features and gene mutation characteristics of domestic patients were summarized. Results:The age at which the initial PALF attack occurred in the four children varied from eight months to three years and seven months. All patients developed PALF within 1-2 days after the onset of fever, with symptoms such as vomiting, convulsions, and mental depression or confusion, accompanied by a sharp increase in transaminases, elevated bilirubin and blood ammonia, hyperlactatemia, and hepatomegaly. The PALF gradually improved, and three pediatric patients showed extrahepatic manifestations following antipyretic, fluid replacement, and other symptomatic supportive treatment. Long-term follow-up showed that active temperature control and symptomatic therapy reduced the recurrence of PALF. Genetic testing identified eight kinds of NBAS gene variants sites. Family testing validated compound heterozygous variants, which included four missense variants, one nonsense variants, and three frameshift mutations. A literature study revealed that out of 51 Chinese patients with NBAS gene variants, 98.0% (50/51) had liver involvement, and 37 cases showed PALF. A total of 61 mutation sites were identified, with c.3596G>A (45.1%, 23/51) as a hotspot variants. Conclusions:PALF caused by NBAS gene variant has obvious clinical and genetic characteristics, and there is a correlation between genotype and clinical phenotype. The c.3596G>A variant site is a hotspot mutation in China and is strongly correlated with the liver failure phenotype.

Objective:To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD).Methods:A retrospective cohort study was conducted on 181 children with IBD who were scheduled for azathioprine or 6-mercaptopurine therapy at the Department of Gastroenterology, Children′s Hospital, Zhejiang University School of Medicine between January 2010 and January 2023. Among them, 168 children who received treatment were divided into a genotyped group and non-genotyped group based on pre-treatment TPMT and NUDT15 genotyping. The incidence of drug-related adverse reactions was compared between the two groups. The impact of genotyping on medication selection and discontinuation rates was analyzed. Chi-square test or Fisher exact test were used for intergroup comparisons. Logistic regression analysis was used to control the confounding factors. Firth Logistic regression analysis was applied for data with complete separation. The probability of discontinuation was assessed using survival analysis with Cox proportional hazards modeling.Results:Among the 181 children with IBD, 13 did not receive azathioprine or 6-mercaptopurine due to genetic variants, while the remaining 168 underwent the therapy (154 cases of Crohn′s disease and 14 cases ulcerative colitis; 108 males and 60 females). Excluding the 13 untreated cases, 77 children underwent TPMT and NUDT15 genotyping were assigned to the genotyped group, and the remaining 91 to the non-genotyped group. Adverse reactions included myelosupression (26 cases,15.5%), hepatotoxicity (18 cases,10.7%), gastrointestinal disturbance (25 cases,14.9%), alopecia (12 cases,7.1%), fever (3 cases,1.8%), rash (2 cases,1.2%), and pancreatitis (1 case,0.6%). The incidence of overall adverse reactions was significantly higher in the non-genotyped group compared to that of the genotyped group (40.7% (37/91) vs. 26.0% (20/77), P<0.05). Specifically, the non-genotyped group had a higher rate of gastrointestinal reactions compared to the genotyped group (24.2% (22/91) vs. 3.3% (3/77), P<0.01). Cox regression analysis revealed that non-genotyped group had a higher risk of treatment discontinuation due to the adverse reactions ( HR=1.47, 95% CI 0.65-3.30). Conclusion:Pre-treatment genotyping of TPMT and NUDT15 variants can help guide the selection of clinical drugs, reduce the incidence of drug-related adverse reactions and enhance tolerability of azathioprine or 6-mercaptopurine therapy in IBD children.

Objective:To analyze the clinical and genetic features of four children with pediatric acute liver failure (PALF) caused by neuroblastoma-amplified sequence ( NBAS) gene variant, as well as the correlation between clinical phenotype and genotype. Methods:The clinical data and genetic test results of four children with NBAS gene variants admitted to the Department of Gastroenterology, Children's Hospital Affiliated to Zhejiang University School of Medicine from August 2015 to June 2023 mainly presenting with pediatric acute liver failure (PALF) were retrospectively analyzed. The relevant literature from January 2015 to May 2024 was retrieved using the Chinese and English keywords " NBAS," "neuroblastoma amplified sequence," "SOPH," "short stature with optic nerve atrophy and Pelger Hu?t anomaly," "liver failure," and "neuroblastoma amplified sequence" indexed in the CNKI database, Wanfang Data Knowledge Service Platform, and PubMed database. The clinical features and gene mutation characteristics of domestic patients were summarized. Results:The age at which the initial PALF attack occurred in the four children varied from eight months to three years and seven months. All patients developed PALF within 1-2 days after the onset of fever, with symptoms such as vomiting, convulsions, and mental depression or confusion, accompanied by a sharp increase in transaminases, elevated bilirubin and blood ammonia, hyperlactatemia, and hepatomegaly. The PALF gradually improved, and three pediatric patients showed extrahepatic manifestations following antipyretic, fluid replacement, and other symptomatic supportive treatment. Long-term follow-up showed that active temperature control and symptomatic therapy reduced the recurrence of PALF. Genetic testing identified eight kinds of NBAS gene variants sites. Family testing validated compound heterozygous variants, which included four missense variants, one nonsense variants, and three frameshift mutations. A literature study revealed that out of 51 Chinese patients with NBAS gene variants, 98.0% (50/51) had liver involvement, and 37 cases showed PALF. A total of 61 mutation sites were identified, with c.3596G>A (45.1%, 23/51) as a hotspot variants. Conclusions:PALF caused by NBAS gene variant has obvious clinical and genetic characteristics, and there is a correlation between genotype and clinical phenotype. The c.3596G>A variant site is a hotspot mutation in China and is strongly correlated with the liver failure phenotype.

Objective:To analyze the efficacy of switching to adalimumab (ADA) treatment in pediatric with inflammatory bowel disease (IBD) after failure of infliximab (IFX) treatment.Methods:Clinical data of children with IBD who were treated at the Children's Hospital of Zhejiang University School of Medicine from January 2019 to May 2023 and switched to ADA treatment after IFX treatment failure were retrospectively included. The clinical symptoms, laboratory results, disease activity index of pediatrics, and endoscopic severity scores under colonoscopy were compared between baseline, treatment after 3 months and 12 months.Results:A total of 47 IBD patients were enrolled, including 36 cases of Crohn's disease, 4 cases of ulcerative colitis, and 7 cases of IBD unclassified. There were 28 male and 19 female patients. Among patients who were converted to ADA treatment, 31/47 (66.0%) had low trough concentration and high anti-IFX antibodies, 12/47 (25.5%) had allergic reactions to IFX, and 4/47 (8.5%) had low IFX trough concentration and no anti-IFX antibody. The overall 12 month retention rate of IBD patients who converted to ADA treatment after IFX treatment was 76.6% (36/47). After 3 months of ADA treatment, compared to the baseline, in body mass index for age, height for age, and serum albumin levels increased, while inflammatory markers such as high sensitivity C reactive protein, erythrocyte sedimentation rate, and pediatric Crohn's disease activity index scores decreased. Compared to 3 months of treatment, nutritional and inflammatory markers after 12 months of treatment were stable. No serious adverse reactions or severe infections were found. Six (13%) patients who had pain and swelling at the injection site. Two patients were detected to have high titers of antibodies.Conclusions:Pediatric IBD patients switched to ADA treatment after failure of IFX treatment with ADA for 3 months improves nutrition status and serum albumin levels, while reducing inflammatory markers and disease activity. No serious adverse reactions are found. Application of ADA after failure of IFX treatment provides a practical basis for converting biological agents for pediatric IBD.

Diacylglycerol o-acyltransferase 1（DGAT1）is the key enzyme in fat metabolism.When DGAT1 gene who encodes this enzyme is mutated，it can affect the intracellular fat metabolism in organism with various clinical manifestations.DGAT1 gene deficiency is one of the causes of congenital diarrhea and enteropathies.The onset age in patients with DGAT1 deficiency is early.The main clinical manifestations of such patients include protein-losing enteropathy，malnutrition and other nutritional disorders.There is no specific drug for such disease so far.Early identification of DGAT1 deficiency and nutritional therapy in early infancy can treat this disease effectively and improve the prognosis.

Objective:To analyze the efficacy of switching to adalimumab (ADA) treatment in pediatric with inflammatory bowel disease (IBD) after failure of infliximab (IFX) treatment.Methods:Clinical data of children with IBD who were treated at the Children's Hospital of Zhejiang University School of Medicine from January 2019 to May 2023 and switched to ADA treatment after IFX treatment failure were retrospectively included. The clinical symptoms, laboratory results, disease activity index of pediatrics, and endoscopic severity scores under colonoscopy were compared between baseline, treatment after 3 months and 12 months.Results:A total of 47 IBD patients were enrolled, including 36 cases of Crohn's disease, 4 cases of ulcerative colitis, and 7 cases of IBD unclassified. There were 28 male and 19 female patients. Among patients who were converted to ADA treatment, 31/47 (66.0%) had low trough concentration and high anti-IFX antibodies, 12/47 (25.5%) had allergic reactions to IFX, and 4/47 (8.5%) had low IFX trough concentration and no anti-IFX antibody. The overall 12 month retention rate of IBD patients who converted to ADA treatment after IFX treatment was 76.6% (36/47). After 3 months of ADA treatment, compared to the baseline, in body mass index for age, height for age, and serum albumin levels increased, while inflammatory markers such as high sensitivity C reactive protein, erythrocyte sedimentation rate, and pediatric Crohn's disease activity index scores decreased. Compared to 3 months of treatment, nutritional and inflammatory markers after 12 months of treatment were stable. No serious adverse reactions or severe infections were found. Six (13%) patients who had pain and swelling at the injection site. Two patients were detected to have high titers of antibodies.Conclusions:Pediatric IBD patients switched to ADA treatment after failure of IFX treatment with ADA for 3 months improves nutrition status and serum albumin levels, while reducing inflammatory markers and disease activity. No serious adverse reactions are found. Application of ADA after failure of IFX treatment provides a practical basis for converting biological agents for pediatric IBD.

Abstract OBJECTIVE To explore the reliability and validity of the Chinese version of the Morisky scale(including guardian version and minor version) applied in assessing medication adherence of children with inflammatory bowel disease, and to clarify the current status and features of medication adherence in children. METHODS The 141 children with inflammatory bowel disease were studied, and collect data through on-site distribution and collection of questionnaires using the Chinese version of the Morisky scale as an evaluation tool. Cronbach's a and factor analysis were used to evaluate the internal consistency and construct validity of scales, respectively, and Spearman test was used to evaluate the correlation between medication adherence and disease severity in children. RESULTS The internal consistency of guardian and minor version of Morisky scale determined by Cronbach's a were 0.701 and 0.738, respectively, while factor analysis indicated that the two scales were all composed of three factors which could explain 67.94% and 72.24% of total variance contribution rate, respectively. The adherence score of the 141 children was 6.75(4.75, 8.0). Among them, 58(41.1%), 39(27.7%) and 44(31.2%) children had poor, moderate and good medication adherence respectively; significant negative correlation was found between children's medication adherence and their disease severity(Rs=-0.286, P=0.001). CONCLUSION Both the guardian and minor version of the Chinese-version Morisky scale exhibit good reliability and validity in evaluating medication adherence in children with inflammatory bowel disease, thus can be applied to evaluate medication adherence in children. Nearly half of the children with inflammatory bowel disease have poor medication adherence, while forgetting to take medicine is the main barrier, and significant negative correlation is found between children's medication adherence and their disease severity, high attention should be given to clinical practice.

Abstract OBJECTIVE To investigate the effect of infliximab through concentration and antibody monitoring on the clinical outcome of children with Crohn's disease after 54 weeks of treatment. METHODS A retrospective analysis was conducted with clinical data of pediatric patients aged 6-17 years who were diagnosed with Crohn's disease at Children's Hospital, Zhejiang University School of Medicine from August 2017 to March 2023. They were divided into a reactive and a proactive monitoring group according to the monitoring method. The mucosal healing rate, disease activity, and laboratory indicators were compared after 54 weeks of treatment. RESULTS There were 77 pediatric patients with Crohn's disease included, with 34 patients from the reactive therapeutic drug monitoring group and 43 from the proactive therapeutic drug monitoring group, including 48 males and 29 females. At 54 weeks, the mucosal healing rate in the proactive therapeutic drug monitoring group was higher than that in the reactive therapeutic drug monitoring group, which was 80%(24/30) and 46.43%(13/28), respectively. The two groups had a statistical difference(P=0.01). The total clinical remission rate at 54 weeks was 84.42%(65/77), while the clinical remission rates at 54 weeks were 76.47%(26/34) in the reactive therapeutic drug monitoring group and 90.70%(39/43) in the proactive therapeutic drug monitoring group, respectively. The two groups had no statistical difference. The improvement of hypersensitive C-reactive protein, erythrocyte sedimentation rate, and serum albumin level in the proactive monitoring group was greater than in the reactive monitoring group. There was no statistical difference in the production rate of antibodies to infliximab between the two groups. CONCLUSION Proactive therapeutic drug monitoring in detecting through concentration of infliximab and antibodies may improve the mucosal healing rate compared with reactive therapeutic drug monitoring after 54 weeks of infliximab treatment.

Objective:To observe the efficacy of maintenance treatment of thiopurines after exclusive enteral nutrition (EEN) therapy for Crohn′s disease (CD) children, and explore the influencing factors of recurrence.Methods:A retrospective case-control study was conducted. CD children treated in the Children′s Hospital of Zhejiang University School of Medicine from March 2013 to March 2021 were included retrospectively. Data before EEN were collected including general demographics, Paris classification, the pediatric Crohn′s disease activity index (PCDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and serum albumin levels. According to the recurrence at 1 year of follow-up, patients were divided into remission group and recurrence group. The differences in clinical data before EEN between the 2 groups were analyzed. The factors influencing the recurrence were analyzed.Results:Thirty-five children were enrolled, including 25 (71.4%) males and 10 (28.6%) females. The age at diagnose was (11.2 ± 3.1) years old and the disease duration was 3.5 (2.2, 6.9) months. After 1 year of follow-up, 15 children had recurrence at least for one time and were divided into the recurrence group. Twenty (57.1%) children continued to maintain 6-mercaptopurine (6-MP) monotherapy and were divided into the remission group. There was no significant differences in gender, diagnostic age, and CRP, ESR, serum albumin and PCDAI before EEN between the two groups (all P>0.05). There was significant difference in the percentage of patients with disease duration of longer than 1 year before EEN between the two groups ( P = 0.026) . Conclusions:The children with the disease duration of longer than 1 year before EEN may be in high risk of recurrence on the regimen of maintenance treatment of thiopurines after EEN.