Intestinal Research

Original Article

Orofacial granulomatosis in pediatric Crohn’s disease: clinical outcomes and genetic background in the era of biologics: a retrospective study in Japan: Ryusuke Nambu, Takeo Naito, Mei Haruyama, Junichi Hosokawa, Hirotaka Shimizu, Ichiro Takeuchi, Shin-ichiro Hagiwara, Tatsuki Mizuochi, Yugo Takaki, Takashi Ishige, Takuya Nishizawa, Takahiro Kudo, Natsuki Ito, Yosuke Kawai, Yoichi Kakuta, Masao Nagasaki, Toshiaki Shimizu, Itaru Iwama, Katsuhiro Arai; Received June 18, 2025 Accepted September 1, 2025 Published online January 2, 2026; DOI: https://doi.org/10.5217/ir.2025.00109 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Background/Aims
Occasionally, pediatric Crohn’s disease (CD) may develop after diagnosis of orofacial granulomatosis (OFG), which is characterized by chronic granulomatous lesions of the oral mucosa, lips, and perioral area. This study aimed to clarify clinical characteristics, treatment responses, and potential genetic contributors in pediatric patients with CD complicating OFG.
Methods
We studied pediatric patients with CD complicating OFG who were treated from 2013 to 2022 at 7 Japanese institutions specializing in pediatric inflammatory bowel disease. Their clinical courses were analyzed retrospectively, and analyses of 71 genes associated with monogenic inflammatory bowel disease were performed.
Results
Among 13 patients, 8 were girls. Median ages at diagnosis of OFG and CD were 9.2 (3.8–15.3) and 10.3 (6.4–15.3) years old, respectively. Upper gastrointestinal lesions were frequent in 8 cases (62%), while perianal lesions were present in 7 (54%). OFG failed to improve or relapsed despite remission of intestinal lesions in about half of the patients (n = 7, 54%). During follow-up, OFG went into remission in 7 patients, including 6 of the 9 who were treated with biologics (66%) and 1 of the 4 who were not (25%). In 8 patients, the NCF1 p.Arg90His allele was detected by genetic analysis; 7 were heterozygous and 1 homozygous, a higher prevalence than in the general Japanese population.
Conclusions
Clinical features of OFG associated with pediatric CD are diverse, and biologic agents were beneficial for OFG patients. NCF1 p.Arg90His mutation may contribute to the pathogenesis of pediatric CD complicating OFG.

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Review

IBD

Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease: Ichiro Takeuchi, Katsuhiro Arai, Pornthep Tanpowpong, Ming-Wei Lai, Andrew S Day, Way Seah Lee, James Guoxian Huang, Karen Sophia Calixto-Mercado, Rosanna Ming Sum Wong, Muhammad Arshad Alvi, Zubin Grover, Jung Ok Shim, Ujjal Poddar; Intest Res 2025;23(4):405-429. Published online October 28, 2025; DOI: https://doi.org/10.5217/ir.2025.00082

Abstract PDF PubReader ePub: Children diagnosed with inflammatory bowel disease (IBD) before the age of 6 years are considered to have “very early-onset IBD (VEO-IBD),” which is challenging to diagnose and treat. Notably, many children with VEO-IBD have monogenic forms of the disease, meaning that early genetic testing is useful. However, because the prevalence of genetic variants causing VEO-IBD differs globally, the diagnosis and treatment of this disease should be tailored to each region. In the present review paper, the IBD Subcommittee of the Scientific Committee of the Asia-Pacific Society of Pediatric Gastroenterology, Hepatology and Nutrition (APSPGHAN) has summarized the epidemiology, presenting features, diagnosis, and treatment of VEO-IBD in the Asia– Pacific region, with an aim to guide clinicians and researchers who work with VEO-IBD in this area. Our 3 main messages are as follows: endoscopy is essential for VEO-IBD diagnosis; all children diagnosed with VEO-IBD should be suspected of having a monogenic form; and children with suspected monogenic IBD should undergo early genetic testing. Our messages aim to improve the early diagnosis and treatment of VEO-IBD in the Asia–Pacific region, including the early detection of monogenic IBD in this area.

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Case Report

IBD

Inflammatory bowel disease in a young female patient with a novel de novo TRAF3 frameshift variant responsive to ustekinumab: a case report: Ichiro Takeuchi, Kosuke Taniguchi, Katsuhiro Arai, Toru Uchiyama, Miho Terao, Asuka Hori, Toshinao Kawai, Takako Yoshioka, Reiko Kyodo, Hirotaka Shimizu, Satoshi Fujita, Kenichiro Motomura, Yuka Okazaki, Takashi Ishikawa, Masao Ogura, Kentaro Hayashi, Kenji Matsumoto, Shuji Takada, Masafumi Onodera, Hideaki Morita, Kenichiro Hata; Intest Res 2026;24(1):182-188. Published online April 4, 2025; DOI: https://doi.org/10.5217/ir.2024.00190

Abstract PDF Supplementary Material PubReader ePub: 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.

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Original Articles

IBD

Characteristics and long-term outcomes of children with perianal Crohn’s disease: Ching-Chun Lin, Ichiro Takeuchi, Hirotaka Shimizu, Reiko Kyodo, Mitsuru Kubota, Akira Ishiguro, Katsuhiro Arai; Intest Res 2026;24(1):164-173. Published online March 5, 2025; DOI: https://doi.org/10.5217/ir.2024.00154

Abstract PDF PubReader ePub

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.

Citations

Citations to this article as recorded by

Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
Ichiro Takeuchi, Katsuhiro Arai, Pornthep Tanpowpong, Ming-Wei Lai, Andrew S Day, Way Seah Lee, James Guoxian Huang, Karen Sophia Calixto-Mercado, Rosanna Ming Sum Wong, Muhammad Arshad Alvi, Zubin Grover, Jung Ok Shim, Ujjal Poddar
Intestinal Research.2025; 23(4): 405. CrossRef

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IBD

Process of empowerment in mothers of children with very-early-onset inflammatory bowel disease: a qualitative study: Mikako Yokoo, Satomi Nomura, Satoe Fukui, Ichiro Takeuchi, Hirotaka Shimizu, Katsuhiro Arai; Intest Res 2026;24(1):151-163. Published online February 24, 2025; DOI: https://doi.org/10.5217/ir.2024.00048

Abstract PDF PubReader ePub: Background/Aims
Mothers of children with very-early-onset inflammatory bowel disease (VEO-IBD) face unique challenges; however, these challenges and their consequences have not been well described. This study clarified the experiences and processes of empowerment of mothers of children with VEO-IBD.
Methods
This study performed a qualitative inductive analysis using semi-structured interviews. The interview content was transcribed, generating core categories, categories, and subcategories with a focus on mothers raising children with VEO-IBD. A modified grounded theory approach was employed to inductively construct a theory from the qualitative data.
Results
Fifteen mothers of children with VEO-IBD were interviewed (mean age, 43.9 ± 6.2 years). The modified grounded theory approach revealed the processes experienced by the mothers. The mothers faced various difficulties when their children developed VEO-IBD; however, their efforts to cope with these difficulties changed their situation. Furthermore, they were supported by various individuals, including family members, medical personnel, and, occasionally, families of other children with VEO-IBD. These processes strengthened and empowered the mothers.
Conclusions
Mothers of children with VEO-IBD who faced various difficulties were empowered through their efforts and support from family and others who understood their challenges. This process of empowerment continues throughout the development of children with VEO-IBD.

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IBD

Clinical features of very early-onset inflammatory bowel disease in Japan: a retrospective single-center study: Masaaki Usami, Ichiro Takeuchi, Reiko Kyodo, Yuri Hirano, Kosuke Kashiwagi, Hiroki Fujikawa, Hirotaka Shimizu, Toshinao Kawai, Katsuhiro Arai; Intest Res 2022;20(4):475-481. Published online June 13, 2022; DOI: https://doi.org/10.5217/ir.2021.00142

Abstract PDF PubReader ePub

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.

Citations

Citations to this article as recorded by

Process of empowerment in mothers of children with very-early-onset inflammatory bowel disease: a qualitative study
Mikako Yokoo, Satomi Nomura, Satoe Fukui, Ichiro Takeuchi, Hirotaka Shimizu, Katsuhiro Arai
Intestinal Research.2026; 24(1): 151. CrossRef
Long‐term clinical and endoscopic outcomes of ustekinumab in pediatric Crohn's disease with anti‐tumor necrosis factor failure
Yoko Yamamoto, Ichiro Takeuchi, Hirotaka Shimizu, Hiroki Fujikawa, Masanori Toda, Eri Miyata, Hiroaki To, Satoru Nagata, Katsuhiro Arai
Journal of Gastroenterology and Hepatology.2025; 40(1): 123. CrossRef
Disease phenotypic and outcome of very-early onset inflammatory bowel disease in Asian children: an understudied population
Way-Seah Lee, Kee-Seang Chew, James-Guoxian Huang, Pornthep Tanpowpong, Karen S. C. Mercado, Almida Reodica, Veena Logarajah, K. L. W. Hathagoda, Shaman Rajindrajith, Yoko Kin-Yoke Wong, Suporn Treepongkaruna, Marion Margaret Aw
Frontiers in Pediatrics.2025;[Epub] CrossRef
Curing inflammatory bowel diseases: breaking the barriers of current therapies– emerging strategies for a definitive treatment
Daniele Noviello, Chiara Amoroso, Maurizio Vecchi, Federica Facciotti, Flavio Caprioli
Current Opinion in Immunology.2025; 95: 102593. CrossRef
Feasibility and Safety of Small Bowel Capsule Endoscopy in Very Early-Onset Inflammatory Bowel Disease: A Multi-Institutional Study
Shin-ichiro Hagiwara, Hirotaka Shimizu, Ryusuke Nambu, Keisuke Jimbo, Emiri Kaji, Takuya Nishizawa, Fumihiko Kakuta, Itaru Iwama, Takashi Ishige, Takahiro Kudo, Katsuhiro Arai
Inflammatory Bowel Diseases.2025; 31(12): 3279. CrossRef
Asian–Pacific perspectives on the management of very early-onset inflammatory bowel disease
Ichiro Takeuchi, Katsuhiro Arai, Pornthep Tanpowpong, Ming-Wei Lai, Andrew S Day, Way Seah Lee, James Guoxian Huang, Karen Sophia Calixto-Mercado, Rosanna Ming Sum Wong, Muhammad Arshad Alvi, Zubin Grover, Jung Ok Shim, Ujjal Poddar
Intestinal Research.2025; 23(4): 405. CrossRef
Impact of age at diagnosis on long‐term prognosis in patients with intestinal Behçet's disease
Ji Young Chang, Soo Jung Park, Jae Jun Park, Tae Il Kim, Jae Hee Cheon, Jihye Park
Journal of Gastroenterology and Hepatology.2024; 39(3): 519. CrossRef
Neither hepatic steatosis nor fibrosis is associated with clinical outcomes in patients with intestinal Behçet’s disease
Hye Kyung Hyun, Jihye Park, Soo Jung Park, Jae Jun Park, Tae Il Kim, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Seung Up Kim, Jae Hee Cheon
European Journal of Gastroenterology & Hepatology.2024; 36(4): 445. CrossRef
Surgical outcomes of very-early-onset ulcerative colitis: retrospective comparative study with older pediatric patients
Takashi Fumita, Keita Terui, Ryohei Shibata, Ayako Takenouchi, Shugo Komatsu, Satoru Oita, Hiroko Yoshizawa, Yuichi Hirano, Yusaku Yoshino, Takeshi Saito, Tomoro Hishiki
Pediatric Surgery International.2024;[Epub] CrossRef
Fecal Calprotectin at Postinduction Is Capable of Predicting Persistent Remission and Endoscopic Healing after 1 Year of Treatment with Infliximab in Pediatric Patients with Crohn’s Disease
Yoo Min Lee, Eun Sil Kim, Sujin Choi, Hyo-Jeong Jang, Yu Bin Kim, So Yoon Choi, Byung-Ho Choe, Ben Kang
Gut and Liver.2024; 18(3): 498. CrossRef
Genomic testing identifies monogenic causes in patients with very early-onset inflammatory bowel disease: a multicenter survey in an Iranian cohort
Golnaz Eslamian, Mahnaz Jamee, Tooba Momen, Pejman Rohani, Sarehossadat Ebrahimi, Mehrnaz Mesdaghi, Soodeh Ghadimi, Mahboubeh Mansouri, Seyed Alireza Mahdaviani, Mahnaz Sadeghi-shabestari, Morteza Fallahpour, Bibi Shahin Shamsian, Narges Eslami, Samin Sha
Clinical and Experimental Immunology.2024; 217(1): 1. CrossRef

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