Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an anti-inflammatory molecule that negatively regulates the non-canonical nuclear factor-κB pathway. Although TRAF3 haploinsufficiency (TRAF3 HI) can influence innate and adaptive immune cells, its effect on inflammatory bowel disease (IBD) development remains unclear. Here, we report the first case of severe early-onset IBD with a novel TRAF3 variant leading to HI, successfully treated with ustekinumab. A 6-year-old girl with a recurrent parotitis, otitis media, tonsilitis, and atopic dermatitis developed IBD involving the stomach, small intestine, and colon. At diagnosis, the immunoglobulin (Ig)G and IgA levels were relatively high, and lymphocyte subsets showed increased counts of plasmablasts, class-switch recombination B cells, and circulating T-follicular helper cells. Treatment with azathioprine and infliximab failed to maintain remission marked by several relapses accompanied by erythema nodosum and arthritis; however, ustekinumab, an anti-interleukin (IL)-12/23p40 antibody, led to long-term clinical remission, normalizing the Ig level and reducing abnormal lymphocyte counts. Whole-exome sequencing revealed a novel heterozygous mutation in TRAF3 [p.(Pro487Leufs*8)], resulting in TRAF3 under-expression. Our case may highlight the contribution of TRAF3 HI to the development of IBD and provide insights into IBD pathophysiology, suggesting the involvement of the IL-12/23-T-follicular helper cell pathway affected by genetic mutations.

Background/Aims: The incidence of perianal lesions (PL) in children with Crohn’s disease (CD) is higher in East Asia than in Western countries. Early intervention for PL is essential to prevent sphincter dysfunction and ostomy placement. In this study, we aimed to investigate the clinical features, treatment, and consequences of pediatric CD with PL. Methods: We retrospectively reviewed a cohort of children diagnosed with CD from 2010 to 2020 at a Japanese children’s hospital. Demographics, treatments, and outcomes were evaluated and compared among subgroups. Results: Among 112 pediatric patients with CD, 36 (32.1%) had experienced PL during the observational period. The median ages at diagnosis and follow-up periods were 131 and 70 months, respectively. Six (85.7%) patients in the very early-onset (VEO) group (CD diagnosed before 6 years old) and 24 (82.8%) in the older age group had PL upon diagnosis of CD (P= 0.851). Biologics were given to 94.4% of patients: infliximab (67.7%), adalimumab (58.8%), ustekinumab (44.1%), risankizumab (11.8%), and vedolizumab (5.9%). Biologics were introduced within 1 year in 89.5% and 40.0% of patients diagnosed in 2016–2020 and 2010–2016, respectively (P= 0.002). Seton was frequently used in the older age group (87.5 vs. 42.9%, P= 0.190). Ostomy was frequently required in the VEO group (42.9% vs. 0.0%, P= 0.006). Conclusions Patients with VEO-CD and PL had a notably high risk of ostomy placement. The earlier introduction of biologics and surgical interventions reduced corticosteroids use and ostomy placement in pediatric CD patients with PL.

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.

Purpose: A change in diagnosis from ulcerative colitis (UC) to Crohn's disease (CD) has been reported in pediatric inflammatory bowel disease; however, only a few clinical characteristics and predictors of this diagnostic change have been reported. We aimed to describe the clinical characteristics of patients with UC who underwent a change in diagnosis to CD and identify variables associated with the change. Methods: The medical records of pediatric patients with UC who were followed up at the National Center for Child Health and Development between 2006 and 2019 were retrospectively reviewed. Clinical data on disease phenotype, laboratory parameters, endoscopic findings, and treatment of patients whose diagnosis changed to CD (cCD) were compared to those of patients whose diagnosis remained UC (rUC). Results: Among the 111 patients initially diagnosed with UC, 11 (9.9%) patients were subsequently diagnosed with CD during follow-up. There was no significant difference between the cCD and rUC groups in terms of sex, age at initial diagnosis, and the extent and severity of disease at initial diagnosis. Albumin and hemoglobin levels were significantly lower in the cCD group than in the rUC group. The proportion of patients who required biologics was significantly higher in the cCD group than in the rUC group (p<0.05). Conclusion Approximately 10% children initially diagnosed with UC were subsequently diagnosed with CD. Hypoalbuminemia and anemia at initial diagnosis and use of biologics could be predictors of this diagnostic change.

Purpose: A change in diagnosis from ulcerative colitis (UC) to Crohn's disease (CD) has been reported in pediatric inflammatory bowel disease; however, only a few clinical characteristics and predictors of this diagnostic change have been reported. We aimed to describe the clinical characteristics of patients with UC who underwent a change in diagnosis to CD and identify variables associated with the change. Methods: The medical records of pediatric patients with UC who were followed up at the National Center for Child Health and Development between 2006 and 2019 were retrospectively reviewed. Clinical data on disease phenotype, laboratory parameters, endoscopic findings, and treatment of patients whose diagnosis changed to CD (cCD) were compared to those of patients whose diagnosis remained UC (rUC). Results: Among the 111 patients initially diagnosed with UC, 11 (9.9%) patients were subsequently diagnosed with CD during follow-up. There was no significant difference between the cCD and rUC groups in terms of sex, age at initial diagnosis, and the extent and severity of disease at initial diagnosis. Albumin and hemoglobin levels were significantly lower in the cCD group than in the rUC group. The proportion of patients who required biologics was significantly higher in the cCD group than in the rUC group (p<0.05). Conclusion Approximately 10% children initially diagnosed with UC were subsequently diagnosed with CD. Hypoalbuminemia and anemia at initial diagnosis and use of biologics could be predictors of this diagnostic change.