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Background: SLCO2A1 encodes a prostaglandin (PG) transporter, and autosomal recessive pathogenic variants of this gene cause chronic enteropathy associated with SLCO2A1. It is unclear whether a heterozygous pathogenic variant of SLCO2A1 has a role in the pathogenesis of other types of inflammatory bowel disease (IBD). In this study, we investigated the possible involvement of a local epigenetic alteration in SLCO2A1 in patients with a heterozygous pathogenic variant., Methods: We conducted whole-exome sequencing of samples from 2 sisters with suspected monogenic IBD. In addition, we performed bisulfite sequencing using DNA extracted from their small and large intestine samples to explore epigenetic alterations., Results: A heterozygous splicing site variant, SLCO2A1:c.940 + 1G > A, was detected in both patients. To explore the possible involvement of epigenetic alterations, we analyzed protein and messenger RNA expression of SLCO2A1, and observed attenuated SLCO2A1 expression in the inflamed lesions of these patients compared with that in the control individuals. Furthermore, bisulfite sequencing indicated dense methylation in the promoter region of SLCO2A1 only in the inflamed lesions of both patients. The urinary PG metabolite levels in these patients were comparable to those in patients with chronic enteropathy associated with SLCO2A1 and higher than those in the control individuals. We found considerably higher levels of the metabolites in patient 1, who showed more severe symptoms than patient 2., Conclusions: Local DNA methylation attenuated SLCO2A1 expression, which may evoke local inflammation of the mucosa by the unincorporated PG. These findings may improve our understanding of the epigenetic mechanisms underlying IBD development., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Serum leucine-rich alpha-2 glycoprotein (LRG) and calprotectin have been studied as disease activity markers in adults with inflammatory bowel disease (IBD). We evaluated them in pediatric IBD patients., Methods: Subjects under 17 years old undergoing care at 11 Japanese pediatric centers were retrospectively assigned to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illness. Serum LRG and calprotectin were measured using commercial enzyme-linked immunosorbent assay kits., Results: We enrolled 173 subjects, including 74 with CD, 77 with UC, and 22 NC. Serum LRG concentrations in active CD (median, 200 μg/mL) were significantly greater than in remission (81 μg/mL; P < 0.001) or NC (69 μg/mL; P < 0.001). Serum calprotectin concentrations in active CD (2941 ng/mL) also were significantly greater than in remission (962 ng/mL; P < 0.05) or NC (872 ng/mL; P < 0.05). Serum LRG concentrations in active UC (134 μg/mL) were significantly greater than in remission (65 μg/mL; P < 0.01) but not significantly greater than in NC (69 μg/mL); serum calprotectin concentrations in active UC (1058 ng/mL) were not significantly different from those in remission (671 ng/mL) or NC (872 ng/mL). In receiver operating characteristic analyses of LRG, calprotectin, C-reactive protein, and erythrocyte sedimentation rate for ability to distinguish active IBD from remission, CD and UC showed areas under receiver operating characteristic curves for LRG (0.77 and 0.70, respectively), exceeding those for calprotectin, C-reactive protein, or erythrocyte sedimentation rate., Conclusions: In pediatric IBD, serum LRG may better reflect disease activity than serum calprotectin, particularly in CD., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Disease phenotype of pediatric inflammatory bowel disease (PIBD) in children from the Asia-Pacific region differs from that of children from the West. Many parts of Asia are endemic for tuberculosis, making diagnosis and management of pediatric Crohn's disease a challenge. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in Asia due to differences in disease characteristics and regional resource constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) that aims to provide an up-to-date, evidence-based approach to PIBD in the Asia-Pacific region. A group of pediatric gastroenterologists with a special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Attention was paid to publications from the region with special consideration to a resource-limited setting. This current position paper deals with surgical management, disease monitoring, immunization, bone health, and nutritional issues of PIBD in Asia. A special section on differentiating pediatric Crohn's disease from tuberculosis in children is included. This position paper provides a useful guide to clinicians in the surgical management, disease monitoring, and various health issues in children with IBD in Asia-Pacific region., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients' IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice., (© 2023. Japanese Society of Gastroenterology.)

STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Reports of zinc and selenium deficiencies accompanying inflammatory bowel disease (IBD) mostly have originated from Western countries and concerned adult patients. Whether Japanese children with IBD have similar deficiencies remained unclear., Aim: We aimed to elucidate differences in serum zinc and selenium concentrations in Japanese children between types of IBD., Methods: Children under 17 years old undergoing care at 12 Japanese pediatric centers were retrospectively enrolled between November 2016 and February 2018 to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illnesses. Serum zinc and selenium were measured by atomic absorption spectrophotometry. Zinc and selenium deficiencies were defined by serum concentrations < 70 μg/dL and < 9.5 μg/dL, respectively., Results: Subjects included 98 patients with CD (median age, 13 years), 118 with UC (11 years), and 43 NC (11 years). Serum zinc and selenium were significantly lower in CD (median, 64 and 12.6 μg/dL respectively) than in UC (69 and 14.6; P < 0.05 and P < 0.001) or NC (77 and 15.7; P < 0.01 and P < 0.001). Zinc deficiency was significantly more prevalent in CD (60.2%) than in NC (37.2%; P < 0.05), but not than in UC (51.7%; P = 0.22). Selenium deficiency was significantly more prevalent in CD (15.3%) than in UC (5.9%; P < 0.05) or NC (0%; P < 0.01)., Conclusions: In Japanese children under 17 years old, serum zinc and selenium were significantly lower in CD than in UC or NC. Zinc and selenium should be monitored, and supplemented when deficient, in children with IBD, especially CD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Noninvasive biomarkers of intestinal inflammation can reduce the number of endoscopies in children with inflammatory bowel disease (IBD). This study aimed to prospectively investigate the usefulness of fecal calprotectin (FCP) and fecal immunochemical test (FIT) in pediatric IBD., Methods: Patients aged 6-17 years who underwent ileocolonoscopy for established or suspected IBD were eligible for this study. Fecal samples for FCP and FIT were collected before colonoscopy., Results: A total of 251 samples were analyzed: 88 from ulcerative colitis (UC), 74 from Crohn's disease (CD), 75 from healthy controls (HC), and 14 from children with functional gastrointestinal disorders and normal colonoscopy (NC). At IBD diagnosis, both FCP and FIT were significantly higher in the newly diagnosed UC/CD group than in the HC/NC group (P < 0.001). The optimal cutoffs of FCP and FIT to predict IBD diagnosis were 217 mg/kg and 87 ng/mL, respectively. Patients without mucosal healing (MH) showed higher FCP and FIT than those with MH in both UC and CD (P < 0.001). The FCP increased exponentially as the endoscopic activity score increased. The optimal cutoff values of FCP and FIT for predicting MH were 161 mg/kg and 106 ng/mL for UC and 367 mg/kg and 57 ng/mL for CD, respectively. FCP showed better specificity than the FIT. Patients with CD and normal ileocolonoscopy had elevated FCP during active small intestinal inflammation., Conclusions: Both FCP and FIT correlate well with endoscopic activity in pediatric patients with IBD. The FCP is a superior marker for predicting MH., (© 2022. Japanese Society of Gastroenterology.)

Genetic variants affecting the function of dual oxidase 2 (DUOX2), the catalytic subunit of membrane-bound enzymes that produce hydrogen peroxide, are associated with very early-onset inflammatory bowel disease (VEO-IBD). We report the case of a 1-year-old boy diagnosed with VEO-IBD after presenting with bloody diarrhea. He had pancolitis and an extensive small intestinal ulcerative lesion at age 4 years. Infliximab treatment was successful but was discontinued due to delayed reaction. At age 7 years, treatment with ustekinumab was started, and remission has been maintained for more than 2 years. Whole-exome sequencing identified compound heterozygous missense DUOX2 variants of unknown significance (p.[R1212H];[F1490Y]). Protein expression in the whole-cell lysate and plasma membrane was lower in F1490Y-DUOX2 than in wild-type (WT)-DUOX2. Hydrogen peroxide generation upon ionomycin stimulation was lower in cells expressing R1212H-DUOX2 and F1490Y-DUOX2 than in those expressing WT-DUOX2. The novel, inherited, biallelic DUOX2 mutations may be molecular risk factors of VEO-IBD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Many clinical trials have been conducted for inflammatory bowel disease (IBD), so various clinical indices (CIs) and endoscopic indices (EIs) have also been evaluated. However, recently, with the progress of IBD management, review of established indices from previous studies, and establishment of new indices, the landscape of the use of indices in clinical trials have changed. We investigated the number and frequency of the indices adapted in recent clinical trials for ulcerative colitis (CI and EI) and Crohn's disease (CI, EI, index related to magnetic resonance imaging, index for evaluating patient-reported outcomes, and health-related quality of life). Based on the results, we selected representative indices and further reviewed their content and characteristics. Moreover, various definitions, including clinical and endoscopic response or remission, have been described by means of representative indices in clinical trials., (© 2022. The Author(s).)

Background: Pediatric ulcerative colitis (UC) is more challenging to treat than adult UC. Qing-Dai therapy is effective in adults but reports of its efficacy in children are unavailable. We conducted a questionnaire survey on Qing-Dai use among pediatric patients with UC in Japan to determine its efficacy and safety., Methods: Questionnaires were sent to 31 high-volume centers treating pediatric patients with inflammatory bowel disease. The number of patients using Qing-Dai, short-term and long-term effects, and adverse events were assessed. A systematic review of studies on the efficacy and safety of Qing-Dai usage for UC was also performed., Results: Overall, 29/31 facilities (93.5%) responded, Qing-Dai was used in 107 patients with UC, and 84/107 patients (78.5%) initiated treatment. Within 6 months, 81/101 (80.2%) patients had clinical remission, while 59/92 (64.1%) patients had no relapse and 29/92 (31.5%) experienced only one to two relapses yearly. Eighty-seven percent of the patients underwent regular follow ups for adverse events, among whom one patient was diagnosed with pulmonary arterial hypertension (PAH), five with enteritis, and one with headache. In the systematic review, the clinical remission rate was 50-80%, and PAH was observed in 14 of 1,158 patients (1.2%)., Conclusions: Qing-Dai is highly effective in treating pediatric UC. However, Qing-Dai should be administered with caution as it may cause adverse events such as PAH., (© 2021 Japan Pediatric Society.)

Background: Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified., Methods: The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less., Results: Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients., Conclusion: Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing., (© 2021 Japan Pediatric Society.)

Background: The Epstein-Barr virus (EBV) infection status in patients with inflammatory bowel disease (IBD), particularly those using thiopurines, may be associated with the risk of lymphoproliferative disorder and hemophagocytic lymphohistiocytosis. This was the first multicenter survey of EBV infection in Japanese patients with IBD. Factors related to the EBV infection status were also investigated., Methods: Five tertiary institutions in Japan participated in this study to examine pediatric and adult patients with IBD. Serum EBV anti-viral capsid antigen (VCA) IgG, EBV anti-VCA IgM, and anti-EBV nuclear antigen-antibody were measured in 495 patients with IBD. The patients' information was obtained from their medical records. Prior EBV infection was defined as anti-VCA IgM negativity and anti-VCA IgG positivity (UMIN000033004)., Results: The patients' median age was 25 years (range 0-92 years). Of the 495 patients, nine were anti-VCA IgM-positive and 354 were anti-VCA IgG-positive (seroprevalence: 72.8%). The proportion of patients with prior EBV infection was 0% for those aged < 5 years, < 60% for those aged < 30 years, and > 90% for those aged > 30 years. The proportion of EBV-uninfected patients using thiopurines was 28.4% (52/183) for all patients and 51.8% (44/85) for pediatric patients. Age was significantly associated with anti-VCA IgG seropositivity (p < 0.01, odds ratio: 0.902, 95% confidence interval: 0.880-0.925). No cases of lymphoproliferative disorder, hemophagocytic lymphohistiocytosis, or chronic active EBV infection were reported., Conclusions: Approximately 30% of Japanese patients with IBD were EBV-uninfected, including those using thiopurines. Age was a significant factor for anti-VCA IgG seropositivity., (© 2021. Japanese Society of Gastroenterology.)

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment., Objective: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT., Methods: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed., Results: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT., Conclusions: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both interleukin-12 and interleukin-23 with reported efficacy to treat Crohn's disease. However, few studies have reported the use of ustekinumab for pediatric inflammatory bowel disease. This study aimed to assess the clinical efficacy and safety of ustekinumab in children and adolescents with inflammatory bowel disease., Methods: Medical records of patients aged under 20 years with Crohn's disease or Crohn's disease-like inflammatory bowel disease who had received ustekinumab at a Japanese pediatric inflammatory bowel disease center were retrospectively reviewed for efficacy and safety. The primary outcome was the steroid-free clinical remission rate at weeks 26 and 52. The steroid-free remission rate beyond week 52 was also evaluated. Weighted pediatric Crohn's disease activity index and simple endoscopic score for Crohn's disease were used to assess disease activity., Results: Seventeen patients were included (male : female = 8:9, A1a [diagnosed < 10 years old]:A1b [diagnosed ≥ 10 years old] = 8:9). All patients were on ustekinumab at week 26, and 9/10 continued treatment over 1 year. The steroid-free clinical remission rates were 59% at week 26, 50% at week 52, and 70% over 1 year. Three of eight children who underwent endoscopy after ustekinumab introduction achieved endoscopic remission. No serious adverse events were recorded during the study period., Conclusions: Ustekinumab may be an effective and safe treatment option for pediatric and adolescent Crohn's disease and Crohn's disease-like inflammatory bowel disease patients having nonresponse or adverse reactions to anti-tumor necrosis factor agents., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Very early-onset inflammatory bowel disease is defined as inflammatory bowel disease diagnosed before 6 years of age. Very early-onset inflammatory bowel disease has various differential diagnoses, including primary immunodeficiency disorders, and is known to be resistant to conventional treatment. Therefore, global attention is required to manage this challenging condition. We conducted a retrospective epidemiological survey of the number of patients, final diagnosis, and examinations performed to diagnose very early-onset inflammatory bowel disease in Japan., Methods: A primary questionnaire about the number of very early-onset bowel disease cases and its diagnosis was administered to 630 pediatric facilities nationwide in Japan. A secondary survey about the examinations performed to achieve diagnosis was sent to the facilities that responded to the first survey., Results: The answering rate was 92.2% (581/630 facilities); 81 facilities had 225 very early-onset bowel disease patients undergoing their care during the past 68 months. Twenty-six patients (11.6%) were diagnosed with immunodeficiency-associated inflammatory bowel disease. The answering rate of the secondary survey was 70.4% (57/81 facilities). Colonoscopy, esophagogastroduodenoscopy, and small bowel imaging were performed for 99.4%, 67.5%, and 28.8% of patients, respectively. Genetic analysis was performed for 26.9% (43/160 patients) of patients, and 51.2% (22/43) of patients were diagnosed with immunodeficiency-associated inflammatory bowel disease., Conclusions: Approximately 40 patients are diagnosed yearly in Japan. Imaging studies, especially for small bowel lesions, can be challenging for this unique group of patients. However, a comprehensive approach including immunological and genetic analyses appears useful for diagnosing immunodeficiency-associated inflammatory bowel disease., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: In 2019 we reported the results of a Japanese national survey designed to explore the views of adult gastroenterologists regarding transitional care for patients with childhood-onset inflammatory bowel disease (IBD). For the present study, we conducted a similar survey of pediatric gastroenterologists to compare the views of the two sets of specialists., Methods: The survey conducted in 2019 involved 48 representative members of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition. They were contacted by conventional mail and their answers were not anonymized. Respondents who had already referred patients with IBD to adult gastroenterologists were asked in a questionnaire to rank the importance of specific statements on a Likert scale., Results: The response rate was 79% and 29 (60%) of the respondents had experienced transitional care for patients with IBD. Transfer to adult care was considered by 90% of the respondents to be the ideal form of medical care for adolescents/young adults with IBD. However, 59% of the respondents had experienced some degree of difficulty when making referrals for such care. The majority of pediatric gastroenterologists considered that the ideal age for transfer was 18-22 years. Among the respondents, physicians at municipal hospitals considered that the presence of diseases other than IBD and a shortage of manpower were significantly more important issues than other practice settings., Conclusions: The present survey revealed that the general views regarding transitional care for IBD between pediatric and adult gastroenterologists were similar, except for the appropriate time for transfer. The results underline the importance of preparing a transition program appropriate to practice settings., (© 2020 Japan Pediatric Society.)

We encountered a case of Bacillus Calmette-Guérin (BCG) cervical lymphadenitis in a patient undergoing infliximab after 6 years from BCG vaccination. Tumor necrosis factor-α inhibitors may be a risk for reactivation of BCG and serious infection even several years after vaccination.

Background and Aim: Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, tends to be refractory to conventional treatment for IBD. However, there have been a few reports about the usage of infliximab for VEO-IBD. This study aimed to evaluate the efficacy and safety of infliximab for VEO-IBD., Methods: Medical records of a cohort of children with VEO-IBD who had received infliximab in a Japanese tertiary children's hospital were retrospectively reviewed for their disease characteristics and clinical course. Subjects were categorized into three groups for the descriptive comparison: ulcerative colitis type (UCT), non-UCT with perianal disease (NUC-PD), and non-UCT without perianal disease (NUC-NPD)., Results: Seventeen VEO-IBD patients (five UCT, five NUC-PD, and seven NUC-NPD) had received infliximab as their first biologic. In the UCT group, infliximab was continued over 54 weeks in two patients, and three eventually required surgery. In contrast, all patients in the NUC-PD and NUC-NPD groups followed up over 54 weeks remained on infliximab, and two of three patients and three of five patients were in remission at week 54, respectively. Infusion reactions occurred in all five UCT, three of five NUC-PD, and two of seven NUC-NPD patients; however, except for two patients with severe reactions, infliximab was continued with premedication and slow infusions., Conclusions: Infliximab appeared useful for children with VEO-IBD. Children with NUC-PD and NUC-NPD responded better with less infusion reaction compared with that with UCT., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: In 2018, Japanese guidelines for autonomy support of patients with inflammatory bowel disease (IBD) in the transitional period were published. These guidelines, however, were prepared mainly by pediatric gastroenterologists. In order to improve such supportive guidelines, it is necessary for pediatric gastroenterologists to be aware of the attitudes and expectations of adult gastroenterologists. Accordingly, the first Japanese national survey designed to explore the views of adult gastroenterologists regarding successful transitional care was conducted., Methods: The survey involved institutions at which adult gastroenterologists in the Ministry of Health, Labor and Welfare of Japan's Inflammatory Bowel Diseases Study Group, were working. Physicians were contacted by conventional mail, and their answers were not anonymized. A total of 100 eligible adult institutions were identified. Further specific subgroup analysis was conducted., Results: A response rate of 34% was achieved. Seventy-six percent of the respondents had experienced some degree of difficulty when accepting patients with childhood-onset IBD referred from pediatric gastroenterologists. With regard to the ideal form of medical care for adolescent patients with IBD, transfer to adult care was supported by 94% of the respondents. Only 27% of respondents, however, stated they would have no hesitation in accepting patients referred from pediatric care centers. Two crucial areas requiring improvement were identified: inadequate clinical summaries and lack of patient independence from their parents/caregivers., Conclusions: The present survey results reinforce the importance of a transitional program of education for childhood-onset IBD patients and the need to improve communication between adult and pediatric gastroenterologists., (© 2019 Japan Pediatric Society.)

Introduction: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). Methods: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. Results: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 μg/dL vs. 9.3 μg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 μg/mL vs. 12.0 μg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher's ratio (p < 0.01). Conclusion: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers. [ABSTRACT FROM AUTHOR]

Background and Aim: Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC. Methods: A prospective cohort study of pertinent cases enrolled in the Japanese Pediatric Inflammatory Bowel Disease Registry between 2012 and 2020 was conducted to determine outcomes for pediatric UC patients who received IFX but required its discontinuation during follow‐up (IFX failure). Results: Of the 301 pediatric UC patients in the registry, 75 were treated with IFX; in 36 of these, IFX was discontinued during follow‐up. Severity of UC at onset and absence of concomitant immunomodulator therapy were significant risk factors for IFX failure (P = 0.005 and P = 0.02, respectively). The cumulative colectomy rate after IFX failure was 41.3% at 1 year and 47.5% at 2 years. Colectomy was significantly more frequent when IFX was discontinued before June 1, 2018, than when IFX was discontinued later (P = 0.013). This difference likely involves availability of additional biologic agents for treatment of UC beginning in mid‐2018 (P = 0.005). Conclusion: In pediatric UC patients, approximately 50% underwent colectomy during a 2‐year interval following IFX failure. Prognosis after IFX failure appeared to improve with availability of new biologic agents and small‐molecule drugs in mid‐2018. [ABSTRACT FROM AUTHOR]

Pediatric inflammatory bowel disease (PIBD) is rising rapidly in many industrialized and affluent areas in the Asia‐Pacific region. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in this region due to differences in disease characteristics and regional resources constraints. This position paper is an initiative from the Asian Pan‐Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) with the aim of providing an up‐to‐date, evidence‐based approach to PIBD in the Asia‐Pacific region, taking into consideration the unique disease characteristics and financial resources available in this region. A group of pediatric gastroenterologists with special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Gastrointestinal infections, including tuberculosis, need to be excluded before diagnosing IBD. In some populations in Asia, the Nudix Hydrolase 15 (NUD15) gene is a better predictor of leukopenia induced by azathioprine than thiopurine‐S‐methyltransferase (TPMT). The main considerations in the use of biologics in the Asia‐Pacific region are high cost, ease of access, and potential infectious risk, especially tuberculosis. This position paper provides a useful guide to clinicians in the medical management of children with PIBD in the Asia‐Pacific region. [ABSTRACT FROM AUTHOR]

A20 haploinsufficiency (HA20), a disease caused by loss-of-function TNFAIP3 mutations, manifests various autoinflammatory and/or autoimmune symptoms. Some cases of HA20 were initially diagnosed as very early onset inflammatory bowel disease (VEO-IBD). We performed whole-exome sequencing (WES) for a Japanese girl with infantile-onset IBD and a severe perianal lesion and detected a novel de novo 119 kb microdeletion containing only TNFAIP3 (arr[GRCh37] 6q23.3(138125829_138244816) × 1). [ABSTRACT FROM AUTHOR]

Background Although tacrolimus ( TAC) can induce remission in children with refractory inflammatory bowel disease ( IBD) or autoimmune gastroenteropathy ( AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use. Methods This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort. Results Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate ( eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC. Conclusions TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC. [ABSTRACT FROM AUTHOR]

Background and Aim: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported. Methods: This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated. Results: Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 108 red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) ( P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations ( r = 0.275, P < 0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed. Conclusion: The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported. [ABSTRACT FROM AUTHOR]

X-linked inhibitor of apoptosis protein (XIAP) deficiency results in monogenic inflammatory bowel disease. To date, no vasculitis associated with XIAP deficiency has been reported. A 10-year-old boy was diagnosed with Crohn's disease and he responded poorly to conventional treatment for Crohn's disease. He was dependent on corticosteroids and parenteral nutrition. To manage severe colitis, he underwent ileostomy followed by ileocolectomy for an ileo-sigmoid fistula. At the age of 15 years, he developed IgA vasculitis and at the age of 17 years, he developed refractory Takayasu arteritis (TAK), which was resistant to corticosteroid and immunosuppressive therapy. Whole-exome sequencing revealed a novel mutation of the splice acceptor site in XIAP (c.1057-1G > A) at the age of 19 years. Allogeneic hematopoietic stem cell transplantation was successful with subsequent withdrawal of intensive immunosuppressive therapy and clinical remission of both enterocolitis and TAK. This case suggests that patients with XIAP deficiency could develop intractable inflammatory disease involving the intestinal tract and blood vessels. • We report the first case of XIAP deficiency with Crohn's-like enterocolitis and TAK. • A novel single nucleotide variant of XIAP was detected. • Allo-HSCT is effective for enterocolitis and arteritis. [ABSTRACT FROM AUTHOR]