Objective:To explore the efficacy and safety of dual targeted therapy（DTT）in the treatment of refractory inflammatory bowel disease（IBD）in children.Methods:The diagnosis and treatment processes of refractory IBD children treated with DTT in the Department of Gastroenterology,Beijing Children's Hospital Affiliated to Capital Medical University from April 2022 to May 2024 were analyzed retrospectively,and their clinical characteristics were summarized.Results:A total of ten children with refractory IBD were included,including five males and five females,with a median onset age of 12.58 (5.25,13.33) years old,and seven cases of Crohn's disease (CD) and three cases of ulcerative colitis (UC),with a median disease course of 1.25 (0.91,4.00) years，were treated with DTT for a median time of 6.08 (6.00,13.40)months.Two (2/7) cases of CD patients were partially effective with infliximab(IFX) treatment,while five (5/7) cases were partially effective with a combination of IFX and azathioprine treatment.These patients received DTT with UST in addition to continuous using of IFX.When the seven CD patients were treated with DTT for four weeks,12 weeks and 24 weeks,and the clinical remission rates were 42.9%(3/7),71.4%(5/7) and 100%(7/7)，respectively.The pediatric Crohn's disease activity index gradually decreased,which were significantly lower than those before treatment( P<0.05).Fecal calprotectin,C-reactive protein,erythrocyte sedimentation rate,and blood white blood cells all gradually decreased,which were lower than those before treatment,while hemoglobin and serum albumin were higher than those before treatment.Three children with UC were all resistant to glucocorticoids.One case was partially effective with adalimumab treatment,one case was partially effective with IFX combined with immunosuppressive agents,and one case was partially effective with vedolizumab.All the three UC patients received DTT treatment with UST in addition to continuous using of the original biological preparation.When the three UC patients were treated with DTT for four weeks and 12 weeks,one case showed clinical remission,one case showed clinical response,and one case showed no clinical response.After 24 weeks of DTT treatment,two cases achieved clinical remission and one case had no clinical response.Re-examination of colonoscopy showed that one case of clinical remission had mucosal healing and one case had mild disease activity.However,there was a slight improvement in disease activity under endoscopy compared with that before DTT in patient who had no clinical response.During DTT treatment,no adverse events occurred in all patients. Conclusion:DTT is effective and relatively safe for children with refractory IBD,and can be one of the attempts for children with IBD when they are partially effective with one biological agent.

Objective:To analyze the etiology of chronic pancreatitis(CP) and evaluate the impact of different intervention methods on the prognosis.Methods:This is a retrospective analysis conducted on clinical data of pediatric patients with CP admitted to Beijing Children's Hospital between January 2010 and December 2023,including etiology,clinical manifestations,imaging data and treatments.Follow-up assessments included height,weight,complications occurrence,and long-term nutritional status evaluated by using Z scores.Results:A total of 98 patients with CP were included in the study,containing 51 males and 47 females,with an age range of 1.95 to 15.96 years (median 8.49 years).The etiological contained the gene mutation (39.8%,39/98) (involving PRSS1, SPINK1, CFTR),the anatomical abnormality (26/98,26.5%),idiopathic pancreatitis (33.7%,33/98).Predominant clinical manifestations included abdominal pain (79/98,79.6%),nausea/vomit(48/98,49.0%),chest tightness/chest pain (10/98,10.2%),with malnutrition (44/98,44.9%) and the serum amylase increased in some patients.Imaging findings revealed heterogeneous pancreatic echoes,dilated pancreatic ducts and pancreatic stones via abdominal ultrasound,and a full or atrophic pancreas with irregular margins,tortuous or dilated pancreatic ducts through abdominal magnetic resonance imaging.Compared with CP caused by other reasons,hereditdry CP had a higher rate of pancreatic morphological changes(100.0% vs.88.1%, P<0.05).By March 2024,follow-up showed all 98 patients underwent initial medical treatment,followed by surgical intervention in 13 cases,endoscopic retrograde cholangiopancreatography intervention in 51 cases,and no surgical or endoscopic intervention in 34 cases.Six children developed diabetes,six had reduced fecal pancreatic elastase-1 but without fat diarrhea.Long-term follow-up indicated improved nutritional status among children who underwent endoscopic retrograde cholangiopancreatography intervention(Z score,-1.22 vs.0.74, P<0.001). Conclusion:Gene mutations and anatomical abnormalities is the main etiological factors in pediatric patients with CP.Early endoscopic intervention can significantly improve the long-term prognosis of the children.

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disease that affects the intestines.Drug therapy includes 5-aminosalicylic acid (5-ASA) drugs, glucocorticoids, immunomodulators, and biological agents, which can effectively induce and maintain remission and prevent complications.5-ASA is the first-line drug for inducing and maintaining remission in children with mild to moderate UC.Glucocorticoids are the first-line therapy for moderate to severe UC and the second-line remission inducing therapy for patients with mild to moderate UC who do not respond to 5-ASA.Immunomodulators(purine preparations)are suitable for maintenance remission therapy after steroid dependence, 5-ASA intolerance, frequent recurrence, and acute severe UC response to hormone-induced therapy.Calcineurin inhibitors and the biological agent infliximab can be used as second-line treatment for patients with acute severe UC who do not respond to glucocorticoids therapy.Vedolizumab and ustekinumab can be used as second-line biotherapy after failure of anti-tumor necrosis factor-α, but data are lacking in studies of pediatric UC.The purpose of this article is to review the progress of drug therapy for children with UC, and provide reference for clinical practice.

Objective:To investigate the clinical features and risk factors of the extraintestinal manifestations(EIM)in children with ulcerative colitis(UC).Methods:A retrospective case-control study was conducted.The clinical data of 99 children with UC diagnosed in Department of Gastroenterology, Beijing Children′s Hospital, Capital Medical University from January 2016 to December 2021 were analyzed.According to whether the patients had EIM or not, they were divided into EIM-positive group and EIM-negative group.Rank sum test, χ2test or Fisher′s exact test were used to compare the variables between the 2 groups, including the clinical features, laboratory examination results and treatments.The Logistic regression was used to analyze the risk factors of EIM in children with UC. Results:A total of 99 children with UC were enrolled, including 57 males and 42 females; the age of onset was 10.3(6.4, 12.6)years, and the course of disease was 4.2(1.6, 10.1)months.The patients were mainly characterized by extensive disease(E3)and pancolitis(E4)(69/99, 69.7%), moderate to severe activity(63/99, 63.6%)and moderate to severe inflammation of colonic mucosa(89/99, 89.9%). There were 77 patients(77.8%)in the EIM-negative group and 22 patients(22.2%)in the EIM-positive group, of which 5 patients had two types of EIMs; the most common EIMs were oral ulcers(9 cases), joint lesions(7 cases), and skin lesions(6 cases). Compared with the EIM-negative group, those in the EIM-positive group, such as the E4 type(77.3% vs 44.2%, χ2=7.513, P=0.006), moderate to severe activity(81.8% vs 58.4%, χ2=4.041, P=0.044), pediatric ulcerative colitis activity index score[47.5(35.0, 57.5)score vs 35.0(25.0, 50.0)score, Z=-2.260, P=0.024], the proportion of C-reactive protein≥8mg/L at diagnosis(54.5% vs 19.5%, χ2=10.607, P=0.001), erythrocyte sedimentation rate[30.0(13.8, 47.8)mm/h vs 10.0(4.0, 19.5)mm/h, Z=-3.918, P<0.001], the proportion of glucocorticoid treatment within one year after diagnosis(77.3% vs 49.4%, χ2=5.403, P=0.020)and the proportion of biological agents treatment(45.5% vs 23.4%, χ2=4.112, P=0.043)were significantly higher; the E3 type were significantly lower than those in the EIM-negative group(0 vs 23.4%, χ2=4.813, P=0.028), and the differences were statistically significant.Multivariate Logistic regression analysis showed that erythrocyte sedimentation rate at diagnosis was an independent risk factor of EIM in children with UC( OR=1.063, 95% CI: 1.025~1.103, P=0.001). Conclusion:The UC patients with EIM had more extensive lesions, more severe disease activity, significantly increased inflammatory indicators, and more commom glucocorticoid and biologic therapy.Increased erythrocyte sedimentation rate was an high risk factor of EIM in children with UC.

Objective:To compare the efficacy of combination therapy on cyclic vomiting syndrome(CVS)in children, and improve the efficacy of CVS treatment in the future.Methods:This study retrospectively analyzed patients′ medical records of CVS, which were admitted to Digestive Department of Beijing Children′s Hospital from 2012 to 2019.The treatment regimen was A(Cyproheptadine+ Doxepin+ Valproate), B(Propranolol+ Cyproheptadine), or C(Propranolol+ Amitriptyline). Meanwhile, the patients should take drugs more than three months.The clinical data of 42 cases were analyzed retrospectively, and the treatment effect after discharge was followed up by telephone until October, 2020.Results:Among the 42 cases, 17 were male and 25 were female, whose mean age of onset was (4.65±3.23) years, and the age of diagnosis was (6.79±3.58) years.The main accompanied symptoms were abdominal pain and upper gastrointestinal bleeding.Forty-two patients were moderate/severe CVS.The regimens A, B and C were observed in 7, 11, and 24 patients, respectively.The age at improvement was(8.17±4.12)years.The course of treatment was(1.37±0.96)years.The age at follow-up was(10.32±4.03)years.During the 1-year follow-up, 35 cases were effective, and the efficiency was 83.3%.Among them, 23 cases had no paroxysmal vomiting and 7 cases had no effect.There was no significant difference in therapy effects among group A, B and C. Between the effective group and non-effective group, there were statistical differences in the personal history of hiatus hernia( P=0.024), the weight at follow-up ( P=0.042), and the course of medication( P=0.020). Conclusion:The combination regimen has a higher effective rate in the treatment of CVS.There was no significant difference among the three regimens in the treatment of CVS.For children with refractory CVS, who can not be treated with combination therapy, individualized therapy should be further developed.

Objective:To evaluate the efficacy and safety of Adalimumab(ADA) in the treatment of pediatric Crohn′s disease (CD).Methods:The clinical data of 20 CD patients treated with ADA at Beijing Children′s Hospital, Capital Medical University from September 2016 to September 2021 were retrospectively analyzed.The disease activity status and mucosal inflammation in CD patients were evaluated using the Pediatric Crohn′s Disease Activity Index (PCDAI) and Crohn′s Disease Endoscopic Severity Index(CDEIS). Data were compared between groups using the rank sum test or Fisher′ s exact test. Results:A total of 20 CD patients were recruited, including 12 males and 8 females.The mean age at diagnosis of CD was (9.5 ± 4.9) years old, ranging from 0.9-15.1 years old.The mean age of the first use of ADA was (10.4 ± 4.8) years old, ranging from 1.2-16.7 years old.The median duration of CD symptoms before ADA treatment was 0.9 (0.4, 1.7) years.The mean PCDAI score of 20 CD patients before ADA treatment was (28.5±19.8) points (range: 0-65.0 points). Of the 20 cases, 8 cases (40.0%) had severe disease activity, and 4 cases (20.0%) were in remission.A total of 15 CD patients underwent CDEIS assessment.The results showed that 9 patients had moderate to severe disease activity, and the symptoms were improved in 1 case under endoscopy.Ten patients (10/20 cases, 50.0%) received Infliximab (IFX) treatment preceding ADA treatment.IFX discontinuation was due to the loss of response(8/10 cases, 80.0%) and allergic reactions (2/10 patients, 20.0%). After 6 weeks of ADA treatment, the median PCDAI score of the 20 CD patients was 5.0 (0, 10.0) points, which was significantly lower than that before ADA treatment ( P<0.001). The clinical remission rate and clinical response rate of 16 patients with active CD treated with ADA for 6 weeks were 62.5% (10/16 cases) and 87.5% (14/16 cases), respectively.There were no significant differences in the clinical remission rate and clinical response rate between the patients who did not receive IFX and those who had previously received IFX(all P> 0.05). The median ADA treatment period was 5.5 (2.6, 17.8) months.During the follow-up period, 6 patients (6/20 cases, 30.0%) suffered from clinical recurrence of CD.At the end of the follow-up visit, seventeen patients(17/20 cases, 85.0%) maintained clinical remission, one had primary non-response and two experienced secondary non-response.Adverse events were reported in 7 patients, mainly including pneumonia (4 cases) or upper respiratory tract infection (2 cases). No tumor or other serious adverse events were recorded. Conclusions:ADA has good efficacy in inducing and maintaining clinical remission in pediatric CD patients, and does not cause serious adverse events.

Objective:To evaluate the efficacy and safety of infliximab(IFX)in pediatric patients with ulcerative colitis(UC).Methods:The clinical data of 17 UC patients who received IFX treatment at Beijing Children′s Hospital, Capital Medical University from January 2017 to December 2021 were retrospectively analyzed, and the pediatric ulcerative colitis activity index(PUCAI)and laboratory data were compared before and after treatment to evaluate the efficacy and safety of IFX.Results:A total of 17 UC patients were included, and among them there were 9 boys and 8 girls.The age of onset was 12.1(10.7, 12.8)years old, and median age at IFX initiation was 12.5(11.8, 13.6)years old.The duration of IFX medication was 46.1(17.4, 56.9)weeks, and the times of IFX injections was 8.0(4.5, 10.5). The mean PUCAI score of the 17 UC patients at start of IFX treatment was (50.6±21.2) points, and the Mayo endoscopic score showed: ten severe activity, six moderate activity, and one mild activity.IFX efficacy analysis: the clinical response rate was 87.5%(14/16), and the clinical remission rate was 56.3%(9/16) at the 14th week.The sustained response rate was 81.8%(9/11), and the sustained remission rate was 36.4%(4/11) at the 30th week.At the 14th week of IFX treatment, PUCAI score[2.5(0, 10.0)points vs.50.0(41.3, 70.0)points] and white blood cell count[5.7(4.8, 8.6)×10 9/L vs.8.7(6.4, 13.5)×10 9/L] significantly decreased(all P<0.05), hemoglobin[(113.8±20.4)g/L vs.(99.3 ± 19.4)g/L] and albumin level[42.2(40.0, 44.4)g/L vs.36.6(28.6, 40.2)g/L] significantly increased compared with those before IFX treatment, and the differences were statistically significant(all P<0.05). The Mayo endoscopic scores at 14 weeks of IFX treatment in 12 active UC patients showed: only 2 patients achieved mucosal healing, 5 patients had reduced from severe to moderate mucosal inflammation, and 5 patients had no improvement.Seven patients had 10 adverse events, 2 cases had 4 times acute infusion reactions, and 5 cases had 6 times infections. Conclusion:IFX is effective and relatively safe in inducing and maintaining clinical remission in pediatric UC patients.

Objective:To investigate the clinical features of pediatric ulcerative colitis (UC) and analyze the risk factors of disease relapse.Methods:The clinical data of 79 children with UC diagnosed in Beijing Children′s Hospital, Capital Medical University from January 2016 to February 2021 were retrospectively analyzed. They were divided into early relapse group and non-early relapse group according to the clinical relapse within 12 months after diagnosis. T-test, rank sum test, χ 2 test or Fisher′s exact test were used to compare the variables between the 2 groups, including the clinical features, laboratory examination results and treatments. The Logistic regression was used to analyze the risk factors of early relapse. The cumulative relapse rate during follow-up was calculated by Kaplan-Meier method. Results:Among the 79 UC children, 46 were males and 33 were females, and the age of onset was 10.6 (6.4, 12.7) years. The children were mainly characterized by extensive disease (E3) and pancolitis (E4) (51/79, 65%), moderate to severe activity (48/79, 61%) and moderate to severe inflammation of colonic mucosa (71/79, 90%). Thirty-eight (48%) patients had atypical phenotype and 17 (22%) had extraintestinal manifestations. The follow-up period was 43.9 (22.8, 61.3) months, and of the 41 patients rechecked with colonoscopy, 7 (17%) had disease progression. According to Kaplan-Meier analysis, the cumulative relapse rate of the 79 cases at 3 months, 6 months, 1 year and 2 years after diagnosis were 27% (21/79), 47% (37/79), 57% (45/79) and 73% (53/73), respectively. There were 45 children (57%) in early relapse group and 34 (43%) in non-early relapse group. In early relapse group, hemoglobin and mucosal healing rate were both significantly lower (105 (87, 122) vs. 120 (104, 131) g/L, 28% (7/25) vs. 7/9, Z=-2.38, χ2=4.87, both P<0.05). The rate of steroid-dependent, E3 and step-up therapy during the induction period were all significantly higher than those in non-early relapse group (11/19 vs. 1/12, 24% (11/45) vs. 6% (2/34), 29% (13/45) vs. 6% (2/34), χ2=5.67, 4.85, 6.66, all P<0.05). Multivariate Logistic regression analysis showed that extraintestinal manifestations ( OR=4.33, 95% CI 1.05-17.83), E3 ( OR=8.27, 95% CI 1.47-46.46) and step-up therapy during the induction period ( OR=5.58, 95% CI 1.01-30.77) were independent risk factors for early relapse. Conclusions:Pediatric UC is usually extensive and severe, with atypical phenotype, a high rate of relapse and a risk of disease progression. Extraintestinal manifestations, E3 and step-up therapy during the induction period are independent risk factors for early relapse.

Objective:To summarize clinical and genetic features of infantile-onset inflammatory bowel disease(IO-IBD) patients.Methods:The clinical data of 48 IO-IBD patients from Beijing Children′s Hospital, Capital Medical University, including age of onset, family history, clinical manifestations and drug efficacy were retrospectively analyzed.Based on target gene panel, next generation sequencing (NGS) was performed for 43 patients, and further compared clinical features between gene mutation and non-gene mutation IO-IBD groups.Results:Among the 48 IO-IBD patients, 41 cases suffered from Crohn′s disease (CD) and 7 cases were ulcerative colitis (UC). The median age of onset was 2.00(0.24-6.00) months, and 45.8%(22/48 cases) of patients′ onset age was within 1 month.Diarrhea (48/48 cases, 100%), fever (45/48 cases, 93.8%) and hematochezia (37/48 cases, 77.1%) were the main clinical symptoms.Perianal lesions and rashes were common extraintestinal manifestations, accounting for 43.8%(21/48 cases) each.Among 41 CD patients, 73.2%(30/41 cases) had predominantly colonic disease (L2 type), and disease behavior was mainly nonstricturing and nonpenetrating (B1 type) (33/41 cases, 80.5%). Among 7 UC patients, 57.1%(4/7 cases) had predominantly pancolonic (E4 type). The surgical rate of the 48 IO-IBD patients was 12.5%(6/48 cases), the clinical remission rate was 50.0%(24/48 cases), and the mortality rate was 25.0%(12/48 cases). Among the 43 IO-IBD patients, 23 (23/43 cases, 53.5%) had meaningful gene mutations, of which 22 cases had mutations in interleukin-10 receptor A ( IL-10 RA) and 1 case with mutation in TTC37.A total of 11 mutation sites were detected in 22 patients with IL-10 RA mutations, including one novel mutation site c. 635G>C (p.R212P); 19 cases c. 301C>T (p.R101W) and 8 cases c. 537G>A (p.T179T) that were common mutation sites.Compared with non-gene mutation IO-IBD group, patients in gene mutation IO-IBD group had earlier onset age [0.3 (0.1-1.0) months vs.(6.27±5.64) months, P<0.001], higher proportion of malnutrition [14 cases(60.9%) vs.5 cases(25.0%), P=0.018], oral ulcers [14 cases(60.9%) vs. 30 cases(15.0%), P=0.006] and perianal lesions [17 cases(73.9%) vs.3 cases(15.0%), P<0.001], and the lower rate of clinical remission[7 cases(30.4%) vs.15 cases(75.0%), P=0.004]. Conclusions:IO-IBD patients had a high rate of monogenic mutation, and IL-10 RA gene mutation was the common mutation.IO-IBD patients developing with gene mutation were characterized by early age of onset, higher incidence of malnutrition, oral ulcers, perianal lesions, and the lower clinical remission rate.

Objective:To explore the infection rate and clinical characteristics of toxigenic Clostridium difficile in children with inflammatory bowel disease (IBD). Methods:From July 2015 to October 2016, the fecal samples and clinical data of 30 IBD children admitted to Department of Gastroenterology, Beijing Children′s Hospital, Capital Medical University, as well as the specimens and data of 30 healthy children were collected in the meantime. The toxin gene of Clostridium difficile was detected and clinical characteristics of children with positive toxin gene were analyzed retrospectively. χ 2 test was used to compare the variables between groups. Results:Among the 30 IBD patients, 15 were in ulcerative colitis (UC) group and 15 in Crohn′s disease (CD) group. In the IBD group, 6 (3 in UC and 3 in CD group) had positive result of toxigenic Clostridium difficile (20%), among whom 5 were toxin Clostridium difficile A (tcdA) +toxin Clostridium difficile B (tcdB) -, and 1 was tcdA+tcdB+. In the healthy group, only one had positive result of toxigenic Clostridium difficile (3%), which was tcdA+tcdB-. Binary toxin gene was negative in both groups. The infection rate of toxigenic Clostridium difficile in IBD group was significantly higher than that in healthy control group (χ 2=4.043, P=0.044). In UC group, no Clostridium difficile toxin gene was detected during the remission period (0/1), one case was positive for toxin gene (1/11) during mild active period, and 2 cases were (2/3) during moderately active period. There were significant differences in the infection rate of toxigenic Clostridium difficile between patients in different active period (χ 2=4.000, P=0.046). The main manifestations of the 6 cases were diarrhea, abdominal pain and bloody stool, and the relapsed case was characterized by sudden aggravation. TcdA was detected in all toxin gene positive samples, and 1 case combined with tcdB had more serious bloody mucopurulent stool. Five cases had colonoscopy, but there was no obvious characteristics of toxigenic Clostridium difficile colitis such as yellow white plaques or pseudomembranous spot. Three cases had antibiotic exposure history. All 6 cases were sensitive to metronidazole treatment, and stable without relapse during the 3-month follow-up. Conclusions:The infection rate of toxigenic Clostridium difficile in children with IBD is higher than that in healthy children. The patients with both tcdA and tcdB could have more serious clinical symptoms, although there may not be specific pathological changes of toxigenic Clostridium difficile colitis. The recognition of toxigenic Clostridium difficile infection in IBD children should be strengthened in clinical work.