Prognosis of pediatric ulcerative colitis after infliximab failure: A multicenter registry-based cohort study.

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.

Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1.

DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.

Anxiety, Depression, and Quality of Life in Parents of Adolescents with Inflammatory Bowel Disease: A Longitudinal Study.

Purpose: The parents of adolescents with inflammatory bowel disease may experience impaired mental health and quality of life. This longitudinal study aimed to verify whether the mental health and quality of life of the parents of adolescents with inflammatory bowel disease declined when their children had active disease. Methods: Sociodemographic data, parental anxiety, depression, and quality of life were analyzed using validated questionnaires for each variable. After the baseline survey, the second and follow-up surveys were conducted at 3 and 12 months, respectively. The active disease group comprised eight parents whose children had active disease during the baseline and second surveys. The remission group comprised 14 parents whose children remained in remission during both surveys. The improved group comprised nine parents whose children experienced active disease at baseline and remission during the second survey. Parental mental health and quality of life were compared among the groups. Results: Significantly higher levels of anxiety were observed in the active disease group in all surveys (p<0.050). Although depression levels and quality of life did not differ significantly among the three groups, pairing the active disease group with other groups showed some large effect sizes. Conclusion: Parents tended to experience decreased mental health and quality of life when their adolescents experienced active inflammatory bowel disease. Consequently, our hypothesis was partially verified. Therefore, parents need support when their children have active disease; this finding highlights the need for parental support systems.

Predictors of Small Bowel Transit Time for Capsule Endoscopy in Children with Inflammatory Bowel Disease.

Purpose: The development of assistive devices has allowed for the performance of capsule endoscopy in children. Anticipating the capsule's transit time could affect the efficacy of the investigation and potentially minimize the fasting period. This study determined the predictors of small bowel transit time for small-bowel capsule endoscopy in children and adolescents with inflammatory bowel disease. Methods: We retrospectively examined children and adolescents with inflammatory bowel disease who underwent capsule endoscopy by the age 18 at a Japanese tertiary care children's hospital. Small bowel transit time predictors were analyzed using multiple regression with explanatory variables. Results: Overall, 92 patients, aged 1-17 years, with inflammatory bowel disease (63 Crohn's disease and 29 ulcerative colitis cases) were examined for factors affecting small bowel transit time. In the simple regression analysis, diagnosis, age, height, weight, serum albumin, general anesthesia, and small intestine lesions were significantly associated with small bowel transit time. In the multiple regression analyses, serum albumin (partial regression coefficient: -58.9, p=0.008), general anesthesia (partial regression coefficient: 127, p<0.001), and small intestine lesions (partial regression coefficient: 30.1, p=0.037) showed significant associations with small bowel transit time. Conclusion: Hypoalbuminemia, the use of general anesthesia for endoscopic delivery of the capsule, and small intestine lesions appeared to be predictors of prolonged small bowel transit time in children and adolescents with inflammatory bowel disease. Expecting the finishing time may improve examination with a fasting period reduction, which benefits both patients and caregivers.

Utility of a rapid assay for prostaglandin E-major urinary metabolite as a biomarker in pediatric ulcerative colitis.

Prostaglandin E-major urinary metabolite (PGE-MUM) is a urinary biomarker reflecting ulcerative colitis (UC) activity. This prospective observational study aimed to evaluate the usefulness of PGE-MUM via rapid chemiluminescent enzyme immunoassay in detecting endoscopic remission (ER) and histologic remission (HR) in pediatric UC (6-16 years) in comparison with fecal calprotectin (FCP). ER and HR were defined as Mayo endoscopic score (MES) of 0 and Matts' histological grades (Matts) of 1 or 2, respectively. A total of 104 UC and 39 functional gastrointestinal disorder (FGID) were analyzed. PGE-MUM levels were significantly higher in the UC group than in the FGID group (P < 0.001). FCP levels were significantly elevated in the group without ER and HR than in the group with ER and HR (P < 0.001 and P = 0.001), whereas PGE-MUM levels were significantly higher in the group without ER compared to the group with ER (P < 0.001). No significant differences were noted in the AUCs for PGE-MUM and FCP in detecting ER and HR. Although PGE-MUM was inferior to FCP for the detection of HR, it might have the potential for application as a biomarker of endoscopic activity in pediatric UC owing to its noninvasive and rapid method.

Clinical outcome of ulcerative colitis with severe onset in children: a multicenter prospective cohort study.

BACKGROUND: As best practices for treating children with severe-onset ulcerative colitis remain controversial in the era of biologic agents, we prospectively investigated treatments and outcomes in a multicenter cohort. METHODS: Using a Web-based data registry maintained in Japan between October 2012 and March 2020, we compared management and treatment outcomes in an S1 group defined by a Pediatric Ulcerative Colitis Activity Index of 65 or more points at diagnosis with those in an S0 group defined by an index value below 65. RESULTS: Three hundred one children with ulcerative colitis treated at 21 institutions were included, with follow-up for 3.6 ± 1.9 years. Among them, 75 (25.0%) were in S1; their age at diagnosis was 12.3 ± 2.9 years, and 93% had pancolitis. Colectomy free rates in S1 were 89% after 1 year, 79% after 2, and 74% after 5, significantly lower than for S0 (P = 0.0003). Calcineurin inhibitors and biologic agents, respectively, were given to 53% and 56% of S1 patients, significantly more than for S0 patients (P < 0.0001). Among S1 patients treated with calcineurin inhibitors when steroids failed, 23% required neither biologic agents nor colectomy, similarly to the S0 group (P = 0.46). CONCLUSIONS: Children with severe ulcerative colitis are likely to require powerful agents such as calcineurin inhibitors and biologic agents; sometimes colectomy ultimately proves necessary. Need for biologic agents in steroid-resistant patients might be reduced to an extent by interposing a therapeutic trial of CI rather than turning to biologic agents or colectomy immediately.

Expert consensus on vaccination in patients with inflammatory bowel disease in Japan.

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.

Monogenic inflammatory bowel disease with STXBP2 mutations is not resolved by hematopoietic stem cell transplantation but can be alleviated via immunosuppressive drug therapy.

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.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

Long-Term Efficacy and Safety of Golimumab for Ulcerative Colitis in a Pediatric Inflammatory Bowel Disease Center in Japan.

Purpose: Golimumab (GLM) is an anti-tumor necrosis factor (TNF)-α antibody preparation known to be less immunogenic than infliximab (IFX) or adalimumab. Few reports on GLM in pediatric patients with ulcerative colitis (UC) are available. This study aimed to review the long-term durability and safety of GLM in a pediatric center. Methods: The medical records of 17 pediatric patients (eight boys and nine girls) who received GLM at the National Center for Child Health and Development were retrospectively reviewed. Results: The median age at GLM initiation was 13.9 (interquartile range 12.0-16.3) years. Fourteen patients had pancolitis, and 11 had severe disease (pediatric ulcerative colitis activity index ≥65). Ten patients were biologic-naïve, and 50% achieved corticosteroid-free remission at week 54. Two patients discontinued prior anti-TNF-α agents because of adverse events during remission. Both showed responses to GLM without unfavorable events through week 54. However, the efficacy of GLM in patients who showed primary nonresponse or loss of response to IFX was limited. Four of the five patients showed non-response at week 54. Patients with severe disease had significantly lower corticosteroid-free remission rate at week 54 than those without severe disease. No severe adverse events were observed during the study period. Conclusion: GLM appears to be safe and useful for pediatric patients with UC. Patients with mild to moderate disease who responded to but had some adverse events with prior biologics may be good candidates for GLM. Its safety and low immunogenicity profile serve as favorable options for selected children with UC.

Qing-Dai for pediatric ulcerative colitis multicenter survey and systematic review.

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.

Clinical features of very early-onset inflammatory bowel disease in Japan: a retrospective single-center study.

BACKGROUND/AIMS: Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed in patients younger than 6 years, is a challenge for pediatric gastroenterologists. Although there have been reports regarding VEO-IBD in Western countries, those in Asia are still lacking. This study aimed to investigate the clinical features of Japanese VEO-IBD patients. METHODS: Patients with VEO-IBD diagnosed between 2006 and 2019 were evaluated retrospectively. The disease phenotypes were classified into ulcerative colitis type (UC-type) and Crohn's disease type (CD-type), and the clinical features and courses were compared between the phenotypes. RESULTS: Overall, 54 VEO-IBD patients (19 patients with UC-type and 35 patients with CD-type) were evaluated. The median age at onset was 18 months. One patient had severe combined immunodeficiency (SCID), and 9 patients had monogenic IBD. Monogenic IBD was more prevalent in the CD-type patients with perianal disease (CD-type (PD)). The age at onset was significantly lower in the CD-type group (P<0.05). The most common initial symptom was bloody stools (70%), followed by diarrhea (63%), weight loss (24%), fever (20%), and perianal disease (20%). Excluding patients with SCID and monogenic IBD, 23 out of 44 patients (52%) required biologics. The biologics were switched in 11 out of 44 patients (25%), and the majority of these patients (82%) were in the CD-type group. Overall, 9 patients (20%) required intestinal resection or ostomy placement. CONCLUSIONS: CD-type tends to occur at an earlier age, and monogenic IBD occurs significantly more frequently in CD-type (PD). Disease severity and treatment should be individualized, owing to the disease heterogeneity.

Novel biallelic mutations in the DUOX2 gene underlying very early-onset inflammatory bowel disease: A case report.

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.

A review on the current status and definitions of activity indices in inflammatory bowel disease: how to use indices for precise evaluation.

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.

Both fecal calprotectin and fecal immunochemical tests are useful in children with inflammatory bowel disease.

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.

Safety and efficacy of the endoscopic delivery of capsule endoscopes in adult and pediatric patients: Multicenter Japanese study (AdvanCE-J study).

BACKGROUND AND AIM: We retrospectively determined the safety and efficacy of the endoscopic delivery (ED) of capsule endoscopes. METHODS: We enrolled 10,156 patients who underwent small bowel capsule endoscopy (SBCE), 3182 who underwent patency capsule (PC), and 1367 who underwent colon capsule endoscopy (CCE), at 11 gastroenterological and nine pediatric centers. RESULTS: Small bowel capsule endoscopies, PCs, and CCEs were endoscopically delivered to 546 (5.4%), 214 (6.7%), and 14 (1.0%) patients, respectively. Only mild complications occurred for 21.6% (167/774), including uneventful mucosal damage, bleeding, and abdominal pain. Successful ED of SBCE to the duodenum or jejunum occurred in 91.8% and 90.7% of patients aged <16 years and ≥16 years, respectively (P = 0.6661), but the total enteroscopy rate was higher in the first group (91.7%) than in the second (76.2%, P < 0.0001), for whom impossible ingestion (87.3%) was significantly more common than prolonged lodging in the stomach (64.2%, P = 0.0010). Successful PC and CCE delivery to the duodenum occurred in 84.1% and 28.6%, thereafter the patency confirmation rate and total colonoscopy rate was 100% and 61.5%, respectively. The height, weight, and age cutoff points in predicting spontaneous ingestion were 132 cm, 24.8 kg, and 9 years 2 months, respectively, in patients aged <16 years. Patients aged ≥16 years could not swallow the SBCEs mainly due to dysphagia (75.0%); those who retained it in the esophagus due to cardiac disease (28.6%), etc. and in the stomach due to diabetes mellitus (15.7%), etc. CONCLUSIONS: This large-scale study supports the safety and efficacy of ED in adult and pediatric patients. UMIN000042020.

Intestinal outcome of bone marrow transplantation for monogenic inflammatory bowel disease.

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.