Very Early Onset Inflammatory Bowel Disease Patients Research Articles

P570 Efficacy and safety of Adalimumab in Very Early-onset IBD- A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN

Abstract Background Patients with very early onset inflammatory bowel disease (VEOIBD) often present with severe disease course and require escalation to biologics. Exclusion of pediatric patients from clinical trials lead to scarcity of efficacy and safety data on TNFa antagonists therapy in VEOIBD. We aimed to assess safety and efficacy of adalimumab (ADM) induction and maintenance therapy in patients with VEOIBD. Methods This was a retrospective study involving 31 sites affiliated with the IBD Porto Group and IBD Interest Group of ESPGHAN, as well as centers in North America. Demographic, clinical and laboratory data were collected from patients diagnosed with VEOIBD who commenced ADM therapy before 6 years of age between 2014 to 2023. Results We identified 77 VEOIBD patients with a median age at diagnosis of 2.6 years (interquartile range [IQR] 1.3–4.1), of whom 29 (38%) were diagnosed at age <2 years (infantile-onset IBD). Thirty-seven (48%) patients were diagnosed with Crohn’s disease, 25 (32%) with ulcerative colitis and 15 (20%) with IBD-unclassified. Five (9%) from those genetically tested were diagnosed with monogenic disease. Median age at initiation of ADM was 4.2 (IQR 2.8-5.1) years. Forty-four patients (57%) were Infliximab experienced, discontinued mainly due to pharmacokinetic (20 [45%]) and pharmacodynamic (13 [30%]) failures. At initiation of ADM, concomitant corticosteroids and immunomodulators were given in 37 (48%) and 29 (37%) patients, respectively. The median wPCDAI and PUCAI scores at baseline were 45 [37.5-60] and 45 [27.5-57.5], respectively. Median follow-up time was 85.4 (IQR 40.4-139.2) weeks. While patients with CD showed significant clinical improvement after 26 and 52 weeks (PCDAI decreased to 10 [0-33.4], p<0.001, and 10 [0-25], p<0.05, respectively), No significant improvement in PUCAI score was observed among patients with UC (Figure 1). Inflammatory markers and calprotectin showed a gradual decrease over time (Figure 1). Weight and Height Z scores did not differ significantly throughout the follow-up period. ADM discontinuation rates after 1 and 3 years were 40% and 65%, respectively, mainly due to primary non-response (14, 29.8%) and loss of response (19, 40.4%). Drug discontinuation rates were not dependent on concomitant immunomodulator treatment or ADM initiation or on age (less or above 3 years). Four patients (5.2%) developed severe infections, including a patient with TTC7A mutation who died following septic shock. Conclusion Adalimumab therapy was relatively safe and seemed more effective in young patients with Crohn’s disease, but not in those with ulcerative colitis. Durability was relatively low due to high rates of primary non-response and secondary loss of response.

Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.

Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD. Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression. In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed. Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.

NOD2 Polymorphisms May Direct a Crohn Disease Phenotype in Patients With Very Early-Onset Inflammatory Bowel Disease.

NOD2/CARD15 was the first susceptibility gene recognized for adult-onset Crohn's (or Crohn) disease (CD). Recessive inheritance of NOD2 polymorphisms has been implicated as a mechanistic driver of pediatric-onset CD. In patients with very early-onset inflammatory bowel disease (VEO-IBD), however, the clinical relevance of NOD2 polymorphisms has not been fully established. Ten VEO-IBD patients with NOD2 polymorphisms ( NOD2 +) were compared to 16 VEO-IBD patients without genetic variants in NOD2 or any other VEO-IBD susceptibility genes ( NOD2 -). The majority of NOD2 + patients exhibited a CD-like phenotype (90%), linear growth impairment (90%), and arthropathy (60%), all of which were significantly more common than in the NOD2 - group ( P = 0.037, P = 0.004, P = 0.026, respectively). We propose that the presence of NOD2 polymorphisms in patients with VEO-IBD might confer a CD-like phenotype, linear growth impairment, and arthropathy. These findings should be validated in larger cohorts and may guide precision medicine for patients with VEO-IBD in the future.

Efficacy and Tolerance of Thalidomide in Patients With Very Early Onset Inflammatory Bowel Disease.

Few drugs have been studied for patients with very early onset inflammatory bowel disease (VEOIBD). This study aimed to evaluate the efficacy and tolerance of thalidomide in children with VEOIBD compared with children with pediatric-onset IBD (pIBD). A retrospective cohort study with a control group was conducted. Propensity score 1:1 matching was used to identify control subjects. The treatment persistence; the causes of drug withdrawal; the rate of clinical remission and mucosal healing at 1, 2, and 3 years; and adverse events (AEs) were evaluated in children with VEOIBD treated with thalidomide and compared with children with pIBD. Thirty-nine courses of treatment with thalidomide in VEOIBD and pIBD patients were compared. The treatment persistence at 1, 2, and 3 years was 68.2% (95% confidence interval [CI], 50.8%-80.6%), 57.0% (95% CI, 39.6%-71.1%), and 50.9% (95% CI, 33.7%-65.8%) for VEOIBD patients and 81.7% (95% CI, 65.3%-90.9%), 60.0% (95% CI, 41.7%-74.3%) and 33.0% (95% CI, 17.4%-49.5%) for pIBD patients, respectively (P = .12). A significantly higher proportion of VEOIBD patients discontinued therapy due to lack of efficacy (48.2% vs 17.2%; P = .03), while AEs were the main reason for discontinuation in pIBD patients. Clinical remission and mucosal healing rates did not significantly differ between VEOIBD and pIBD patients. A significatively lower number of VEOIBD patients experienced AEs compared with pIBD patients (14 [35.9%] vs 30 [76.9%]; P = .0005). Thalidomide is an effective and tolerated treatment in children with VEOIBD. Discontinuation due to lack of efficacy is more frequent, but AEs are less common than in children with pIBD.

Clinical Course of Very Early-Onset Inflammatory Bowel Disease.

Data on the phenotypes and disease outcomes of very early-onset inflammatory bowel disease (VEO-IBD) are limited. The aims of this study were to describe the clinical features, outcomes, and treatment response of VEO-IBD patients and to compare them with later-onset pediatric inflammatory bowel disease (P-IBD) patients. All consecutive patients aged 0-6 years who were diagnosed with Crohn disease (CD), ulcerative colitis, or IBD unclassified (IBD-U) at 2 academic hospitals from 2010 to March 2021 were included. They were compared to sex-matched IBD patients aged 6-17 years. Two hundred thirty-two patients were included, 78 (34%) with VEO-IBD and 154 (66%) with P-IBD. IBD-U was the most common diagnosis in the VEO-IBD group compared to P-IBD (28% vs 3%, P < 0.001), while CD was predominant in older children (27% vs 52%, P < 0.001). The VEO-IBD group showed lower rates of clinical remission after induction with steroids compared to older children (82% vs 93%, P = 0.01), higher rates of steroid resistance (14% vs 5%, P = 0.02), and steroid dependence (27% vs 8%, P < 0.001). The number of patients who started anti-tumor necrosis factor (TNF)-α agents was similar between the groups. Anti-TNF-α retention was lower in the VEO-IBD group at 1 and 2 years (59% vs 85%, P = 0.003; 16% vs 55%, P < 0.001, respectively). Surgical risk appeared to be higher for VEO-IBD (32% vs 14%, P < 0.001). When compared to P-IBD patients, patients with VEO-IBD may have a more severe disease course, a poorer response to steroids and anti-TNF-α agents, and require more frequent surgical procedures.

DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease

BackgroundThiopurine methyltransferase (TPMT) is a crucial enzyme for azathioprine biotransformation and its activity is higher in very early onset inflammatory bowel disease (VEO-IBD) patients than in adolescents with IBD (aIBD). AimsThe aims of this pharmacoepigenetic study were to evaluate differences in peripheral blood DNA methylation of the TPMT gene and in azathioprine pharmacokinetics in patients with VEO-IBD compared to aIBD. MethodsThe association of age with whole genome DNA methylation profile was evaluated in a pilot group of patients and confirmed by a meta-analysis on 3 cohorts of patients available on the public functional genomics data repository. Effects of candidate CpG sites in the TPMT gene were validated in a larger cohort using pyrosequencing. TPMT activity and azathioprine metabolites (TGN) were measured in patients’ erythrocytes by HPLC and associated with patients’ age group and TPMT DNA methylation. ResultsWhole genome DNA methylation pilot analysis, combined with the meta-analysis revealed cg22736354, located on TPMT downstream neighboring region, as the only statistically significant CpG whose methylation increases with age, resulting lower in VEO-IBD patients compared to aIBD (median 9.6% vs 12%, p = 0.029). Pyrosequencing confirmed lower cg22736354 methylation in VEO-IBD patients (median 4.0% vs 6.0%, p = 4.6 ×10−5). No differences in TPMT promoter methylation were found. Reduced cg22736354 methylation was associated with lower TGN concentrations (rho = 0.31, p = 0.01) in patients with VEO-IBD and aIBD. ConclusionMethylation of cg22736354 in TPMT gene neighborhood is lower in patients with VEO-IBD and is associated with reduced azathioprine inactivation and increased TGN concentrations.

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

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. 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. 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. 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.

Pattern-based Histologic Approach in Very Early Onset IBD: Main Features and Differential Diagnosis.

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella classification composed of IBD-like diseases encompassing both classic IBD (Crohn's disease and ulcerative colitis) and monogenic disorder, both arising before 6 years of age. VEO-IBD patients present significant clinical differences from IBD occurring in older children and in adults, including more severe disease, often unresponsive to conventional IBD therapy and a greater proportion of cases featuring an underlying genetic alteration. Histologic findings of gastrointestinal biopsies can show an IBD-like pattern (both Crohn's disease-like and ulcerative colitis-like pattern), an apoptotic-like and enterocolitis-like pattern. Findings of specific morphologic alterations, such as villous blunting, apoptosis, dense eosinophilic infiltrates, lack of plasma cells and severe glandular atrophy, can suggest a monogenic disorder. Moreover, individuals with monogenic disorders may develop significant problems such as primary immunodeficiency, impacting treatment options. Finally, IBD histology in childhood can differ from that in older patients and adults. This complexity makes a differential diagnosis between IBD and other pediatric diseases involving the gastrointestinal tract difficult, especially considering that histologic features can be similar between different diseases. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery and more intensive medical therapies rather than specific therapy directed toward the underlying defect. For these reasons, a pattern-based histologic approach correlated with clinical and laboratory findings with a multidisciplinary approach is fundamental to reach a correct diagnosis in an adequate clinical context.

Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases

BackgroundDefects in interleukin 10 (IL10) and its receptors are particularly involved in very early onset inflammatory bowel disease (VEOIBD). However, large fragment deletions of IL10 receptor A (IL10RA) are rare.MethodsVEOIBD patients with confirmed mutations in the IL10RA gene were enrolled from January 1, 2019 to June 30, 2020. The clinical features and endoscopic-radiological findings of the patients with large fragment deletions of the IL10RA gene were determined and followed up.ResultsThirty-five patients with IL10RA gene mutations, namely, 28 compound heterozygous mutations and 7 homozygote mutations, were enrolled in this study. Six patients carried the reported point mutation c.301C > T (p. R101RW) or c.537 G > A (p. T179T) in one locus and a large fragment deletion in exon 1 in another locus, which were novel mutations in this gene. A 333-bp deletion of exon 1 (117857034–11857366 del) was the main mutation in this locus in 85.7% of the patients with large fragment deletions. The time of disease onset ranged from birth to 4 years, and diarrhea was the main initial symptom. In total, 6/7 patients had perianal complications, including perianal abscess, fistula and skin tags. Six patients accepted thalidomide treatment, 5/7 accepted mesalamine, 3/7 accepted hematopoietic stem cell transplantation (HSCT), and 3/7 were waiting for HSCT.ConclusionsWe identified a novel large deletion of exon 1 involving the IL10RA gene for the first time and showed the characteristics of VEOIBD patients. This study expands the spectrum of Chinese VEOIBD patients with IL0RA gene mutations.

Trichohepatoenterický syndrom u pacienta s mutacemi genu TTC37 – kazuistika

We report a patient with somatic retardation and woolly hair appearance who suffered from recurring episodes of watery mucous diarrhea, impaired liver functions, and failure to thrive. He manifested with severe infection courses, including hepatitis of unknown origin complicated by liver failure at 4 months, bronchopneumonia at 4 years, and life-threatening sepsis with septic shock at 8 years of age. Esophagogastroduodenoscopy and colonoscopy were performed at 4 years to rule out inflammatory bowel disease (IBD), and only signs of nonspecific colitis were evident. Immunology workup revealed slight reduction in CD4+ naive subsets and impaired T cell response to mitogens. Massive parallel sequencing (also termed next-generation sequencing – NGS) targeting a panel of primary immunodeficiency-related genes was used to examine the patient’s DNA. NGS analysis revealed two heterozygous variants in the TTC37 gene. Nonsense p.Arg1201* and missense p.Leu1505Ser variants in exons 34 and 42, respectively, were evaluated as pathogenic based on in silico predictions, their rare occurrence in the general population, and the fact that both mutations had already been described in patients with trichohepatoenteric syndrome (THES). As clinical features in our patient were in accordance with this diagnosis, we consider our findings as causative. THES could be a life-threatening condition, particularly in children who develop liver disease or severe infection courses. THES can have a similar clinical presentation as does very early-onset inflammatory bowel disease (VEO-IBD) and is often assigned to this group. Although IBD is generally regarded as a polygenic disease, some children with VEO-IBD are known also to have diseases with monogenic etiologies, as in THES. Targeted NGS is an efficient tool for establishing an accurate dia gnosis in VEO-IBD patients.

The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.

A251 VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN: A SINGLE CENTER EXPERIENCE OVER 15 YEARS

Abstract Background Very-early-onset inflammatory bowel disease (VEOIBD) refers to an IBD diagnosis established before the 6th year of life, including a subset of patients with disease onset before the age of 2 years, known as infantile-onset IBD (IO-IBD) (1). VEO-IBD accounts for 15% of pediatric IBD and infantile IBD in approximately 1% (2,3). VEOIBD is considered to be a unique entity, and compared to adults with IBD, VEO-IBD children are more likely to present with extensive and treatment-resistant disease (4). Aims To analyze the clinical characteristics and management of patients diagnosed with very early onset inflammatory bowel disease (VEO-IBD). Methods A retrospective analysis of children diagnosed with VEO-IBD (age &amp;lt;6 years) at the Montreal Children’s Hospital from 2003–2018 was performed. Clinical data for VEO-IBD patients was collected to identify the clinical, biochemical, endoscopic and histological features of these patients and their clinical course until 2018. Results A total of 28 VEO-IBD patients (71% male) were included in this study. The median age of disease onset was 52 months. A diagnosis of Crohn’s disease (CD) or CD-like intestinal manifestations accounted for 89% of the VEO-IBD cases. Most patients had Crohn’s colitis (36%) of whom 50% had evidence of granulomatous Crohn’s disease; 11 patients[NAD1] [AQAB2] (39%) had upper gastrointestinal involvement. Over their progress of the disease, 4 patients (14%) required surgical intervention, while 11 patients (39%) required biologic therapy for maintenance therapy. Genetic[NAD3] [AQAB4] results were available for 5 patients out of 28 (18%) and 3 of them were identified to have monogenic IBD. Conclusions In our center, the majority of patients with VEO-IBD had typical Crohn’s disease presentation. Most of the VEO-IBD patients responded well to the standard IBD treatment. Genetic studies were not done regularly for all of our patients, however, among those who had this testing performed 3/5 had an identifiable cause, suggesting that these patients should be investigated for an underlying genetic abnormality. Funding Agencies None

A171 MAGNETIC RESONANCE IMAGING IN CHILDREN WITH EARLY ONSET INFLAMMATORY BOWEL DISEASE- A RETROSPECTIVE COHORT STUDY

Abstract Background Magnetic Resonance (MR) Imaging is the preferred imaging method in Inflammatory Bowel Disease (IBD) patients to investigate for small bowel disease. There are challenges in performing MR imaging in Early Onset IBD (EO-IBD) patients, and in particular in children with Very Early Onset IBD (VEO-IBD). These children often need a general anaesthetic which exposes them to adverse effects and preclude conventional luminal distention influencing the quality of the test. Therefore, the utility of MR imaging in this age group is questionable. Aims To assess the quality of MRI studies in VEO-IBD and EO-IBD patients and to compare the utility of this test between the two groups. Methods We retrospectively identified and reviewed IBD patients diagnosed under 10 years of age, between January 1999 and December 2011, from the British Columbia Children’s Hospital (BCCH) GI Division IBD database. Patients’ first diagnostic MRI results were recorded. Disease location and severity were documented according to the Paris classification. Results 124 patients were included in the cohort, 54 VEO-IBD and 70 EO-IBD patients (See Table 1). Median age at diagnosis was 6.46 (IQR 3.94–8.71), 65.32% males and 43.54% were diagnosed with Crohn’s disease. Overall, 52 patients underwent MRI, 17 (31.48%) in the VEO-IBD group and 35 (50%) in the EO-IBD group; median time from diagnosis to MRI was 3.02 years (IQR 1.08–5.83) for VEO-IBD and 0.44 years (IQR 0.07–1.58) for EO-IBD (p&amp;lt;0.001). In the EO-IBD group there was a significantly higher percentage of patients with MRI findings than in the VEO-IBD group, 23 (67.31%) and 5 (29.41%) respectively (p=0.014). Only one patient in the VEO-IBD group had a disease characteristic identified by MR imaging that could not be diagnosed by endoscopy (small bowel disease). Conclusions The diagnostic yield of MRI in children with VEO-IBD appears to be quite limited but requires further study. Funding Agencies None

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

P173 Very–Early-Onset inflammatory bowel disease: Russian single centre experience

Abstract Background The incidence of very early-onset inflammatory bowel disease (VEOIBD) is on the rise in Russia but the clinical data is lacking. We aim to study the disease phenotype, clinical course and the presence of primary immunodeficiency (PID) patients in this group. Methods Clinical records of VEOIBD patients treated in Russian State Pediatric Hospital between 2000 and 2018 were revised. In 60 patients admitted between 2016 and 2018 targeted sequencing (PID panel) was performed. 10 patients received genetic testing previously. Results 135 VEOIBD patients were identified: 95 (70%)with ulcerative colitis (UC), 31 (23%) with Crohn’s disease, 9 (7%) with PID. In 14 (11%) IBD patients the diagnosis was changed from UC to CD and vice versa. Median time of diagnosis was 7 months in UC, 24 months in CD and 44 months in PID. The most common clinical symptoms were loose stools (UC—98%, CD—84%), bloody stools (UC—93, CD—65%), stomach ache (UC—53%, CD—52%), fever (UC—35%, CD—42%). Common laboratory features included anemia (UC—56%, CD—39%), low serum ferrum level (UC—75%, CD—61%), thrombocytosis (UC—53%, CD—45%). From 103 patients tested for ANCA 26% had positive results (24—UC, 3—CD). Mean calprotectin level (76 patients) was 750 ± 54.4 μg/g. Pancolitis was seen in UC (84%), as well as in CD (61%). Epithelioid granulomas in CD were present in 7 patients, in 5 of them they were detected years after initial diagnosis. Sixty-nine% of UC and 90% of CD patients received steroids as induction therapy, steroid-dependency was common (42% in UC and 55% in CD). Forty-nine% of patients with UC and 23% od CD patients received azathioprine, anti-TNF agents were used in 26% UC patients and 77% CD patients. In 35% of patients receiving anti-TNF biologic therapy was started before the age of 6 years. 23,8% of VEOIBD patients failed to achieve clinical remission. Total colectomy was performed in 11 patients, in 3 of them the diagnosis was subsequently changed to CD. Segmental resection was performed in 9 CD patients, in 3 of them while on therapy. The most common form of PID was XIAP deficiency (3 patients), 2 of them achieved endoscopic remission after allogenic stem cell transplantation. Conclusion In the VEOIBD group CD resembles UC clinically and endoscopically. A substantial number of patients requires immunosuppressive and biologic therapy before the age of 6 years. Colectomy rates are still high regardless the use of biologics. Boys with refractory VEOIBD should be screened for XIAP deficiency.

Infliximab for very early-onset inflammatory bowel disease: A tertiary center experience in Japan.

Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6years 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. 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). 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 54weeks in two patients, and three eventually required surgery. In contrast, all patients in the NUC-PD and NUC-NPD groups followed up over 54weeks 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. 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.

Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study

Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported. We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children. Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events. Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group (p < 0.01). Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

Very early onset inflammatory bowel disease

Very early onset inflammatory bowel disease (VEO-IBD) represents a unique and growing subset of patients with inflammatory bowel disease (IBD). Some VEO-IBD patients present with immunodeficiency and possess loss of function genetic mutations involving immune pathways that cause their IBD. A search for Mendelian causes of IBD is likely most beneficial when the presentation involves extra-intestinal autoimmunity or involves intestinal histopathology that is atypical for IBD. While a subset of these young patients will have highly aggressive courses (and likely present with immunodeficiency), the majority of patients with VEO-IBD appear to have disease courses similar to that of their older counterparts. Most notably, many of these young children will require long courses of immunosuppression simply as a result of the profoundly early presentation—thus increasing their long-term risks of cancer and opportunistic infections.

Nutritional Therapy in Very Early-Onset Inflammatory Bowel Disease: A Case Report

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract caused by a dysregulated immune response to the fecal microbiota. Very early-onset inflammatory bowel disease (VEO-IBD) refers to a subgroup of pediatric patients with IBD diagnosed before 6years of age. This subgroup is often characterized by increased severity, aggressive progression, strong family history of IBD, and often poor response to conventional treatments. Nutritional therapies have been utilized to treat IBD, but their role in VEO-IBD is unclear. Disease behavior in VEO-IBD is often different from disease in adolescents and adults, as it is often restricted to the colon and refractory to standard medical therapies. Up to 25% of VEO-IBD patients have an identified underlying immunodeficiency, which may impact response to therapy. While specific mutations in interleukin 10 (IL-10), the IL-10 receptor (IL-10R), and mutations in NCF2, XIAP, LRBA, and TTC7 have been identified in VEO-IBD, polymorphisms in these genes are also associated with increased risk of developing IBD in adolescence or adulthood. We describe two cases in which infants presenting with VEO-IBD achieved clinical remission using exclusive enteral nutrition, a formula-based diet which has been shown to induce remission in older children with active Crohn's disease.

IL-10 and IL-10 Receptor Mutations in Very Early Onset Inflammatory Bowel Disease.

Very early onset inflammatory bowel disease (VEO-IBD) is a unique disease entity with a complex genetic susceptibility in affected patients. Next-generation gene sequencing techniques have revealed various monogenetic mutations contributing to the pathogenesis of VEO-IBD, including interleukin 10 (IL-10) and IL-10 receptor (IL-10R) mutations. In this article, we reviewed the features of and effective therapeutic options for VEO-IBD with IL-10 and/or IL-10R mutations. The IL-10 signal pathway inhibits the release of several key cytokines and thereby has a significant anti-inflammatory effect in the gastrointestinal tract. Mutations of the genes encoding IL-10 and/or IL-10R have been detected in VEO-IBD patients among myriad populations throughout the world. VEO-IBD patients with IL-10 or IL-10R mutations often present with repeated bouts of bloody diarrhea, marked weight loss, growth retardation, and recurrent perianal problems, including abscesses, fistulas, and significant fissures. Moreover, some patients may have folliculitis and present with pulmonary infections. While the therapeutic efficacy of immunosuppressants is typically poor in these patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to improve symptoms significantly. However, the long-term prognosis of VEO-IBD patients with IL-10 or IL-10R gene mutations treated with HSCT requires further exploration to verify the efficacy and safety of this treatment. We concluded that clinicians should recognize the clinical phenotype of VEO-IBD, as mutational analysis of the IL-10 pathway can support the diagnosis and prompt early treatment of this complicated disease.