STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.  Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

A significant increase in anthropometric indices during long-term follow-up of pediatric patients with celiac disease, with no endocrine disorders.

Celiac disease (CeD) is likely to be associated with growth impairment and poor weight gain. However, long-term growth patterns following diagnosis are poorly characterized. We evaluated long-term anthropometric changes in a large cohort of pediatric patients with CeD. A retrospective chart review of patients diagnosed with CeD between 1999 and 2018 was conducted. Demographic and clinical data were collected, and anthropometrics were analyzed from diagnosis and throughout follow-up. The study included 500 patients (59.8% females, median (IQR) age at diagnosis 5.7 (3.7-8.9) years), with a mean follow-up of 5.5 (range 1.5-16.2) years. Weight, height, and BMI Z-score-for-age (WAZ, HAZ, and BMIZ) increased significantly from a mean (± SD) of - 0.82 (± 1.21), - 0.73 (± 1.16), and - 0.32 (± 1.11) at diagnosis to - 0.41 (± 1.23), - 0.45(± 1.16), and - 0.17 (± 1.14) at last follow-up, respectively (p < 0.001 for WAZ and HAZ and p = 0.002 for BMIZ). The largest improvements were observed in patients diagnosed before 3 years of age (p < 0.01). Patients for whom the final adult height was available (n = 86) improved from HAZ mean (± SD) - 0.89 ± 1.37 at diagnosis to - 0.51 ± 1.28 at adulthood measurement, p < 0.05. Wasting was present in 19.7% and stunting in 16.4% of the cohort at diagnosis and normalized in 77.3% and 64.8%, respectively, within a median (IQR) time of 0.79 (0.42-4.24) and 2.3 (0.72-6.02) years, respectively. Gluten-free diet adherence and frequency of visits were not associated with normalization of wasting or stunting in all age groups.  Conclusion: Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. Younger age at diagnosis is associated with greater improvement in weight and linear growth, emphasizing the importance of early diagnosis of CeD. What is Known: • Celiac disease (СeD) is likely to be associated with growth impairment and poor weight gain. • Long-term changes in anthropometric indices after diagnosis of CeD are not well characterized. What is New: • Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. • Young age at diagnosis is associated with larger improvement in weight and linear growth.

Mucosal Genes Encoding Clock, Inflammation and Their Mutual Regulators Are Disrupted in Pediatric Patients with Active Ulcerative Colitis.

Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC.

Adherence to the Mediterranean Diet Is Associated with Decreased Fecal Calprotectin Levels in Children with Crohn's Disease in Clinical Remission under Biological Therapy.

INTRODUCTION: Adherence to the Mediterranean diet (MD) was shown to be associated with decreased disease activity in adult patients with Crohn's disease (CD). Nevertheless, data on its association with fecal calprotectin (FC), particularly in children, remain limited. This study aimed to assess the association between adherence to the MD and FC as an indicator of mucosal healing in patients who are predominantly in remission while undergoing biological therapy. METHODS: This was a cross-sectional study among children with CD. Adherence to MD was evaluated using both the KIDMED questionnaire and a food frequency questionnaire (FFQ). Israeli Mediterranean Diet Adherence Screener (I-MEDAS) score was calculated, and FC samples were obtained. RESULTS: Of 103 eligible patients, 99 were included (mean age 14.3 ± 2.6 years; 38.4% females); 88% were in clinical remission, and 30% presented with elevated FC. The mean KIDMED score was higher among patients who had FC <200 µg/g compared to patients with FC >200 µg/g (5.48 ± 2.58 vs. 4.37 ± 2.47, respectively; p = 0.04). A moderate correlation between the KIDMED score and the I-MEDAS score was observed (r = 0.46; p = 0.001). In a multivariate regression analysis, adherence to MD was associated with decreased calprotectin levels, OR 0.75 [95% CI: 0.6-0.95], p = 0.019. Vegetable consumption was found to be inversely associated with elevated FC (0.9 portion/day [0.3-2.9] in FC >200 µg/g vs. 2.2 portions/day [0.87-3.82] in FC <200 µg/g; p = 0.049). CONCLUSIONS: In children with CD who are mostly in clinical remission under biological therapy, high adherence to MD is associated with decreased FC levels. Encouraging vegetable consumption, especially during remission, may benefit these patients.

Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.

Clinical Features and Natural History of Paediatric Patients with Ulcerative Proctitis: A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN.

BACKGROUND AND AIMS: Ulcerative proctitis [UP] is an uncommon presentation in paediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of UP in children, and to identify predictors of poor outcomes. METHODS: This was a retrospective study involving 37 sites affiliated with the IBD Porto Group of ESPGHAN. Data were collected from patients aged <18 years diagnosed with UP between January 1, 2016 and December 31, 2020. RESULTS: We identified 196 patients with UP (median age at diagnosis 14.6 years [interquartile range, IQR 12.5-16.0]), with a median follow-up of 2.7 years [IQR 1.7-3.8]. The most common presenting symptoms were bloody stools [95%], abdominal pain [61%] and diarrhoea [47%]. At diagnosis, the median paediatric ulcerative colitis activity index [PUCAI] score was 25 [IQR 20-35], but most patients exhibited moderate-severe endoscopic inflammation. By the end of induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 48%, 48%, and 73%, respectively. The rates of treatment escalation to biologics at 1, 3, and 5 years were 10%, 22%, and 43%, respectively. In multivariate analysis, the PUCAI score at diagnosis was significantly associated with initiation of systemic steroids, or biologics, and subsequent acute severe colitis events and inflammatory bowel disease-associated admission, with a score ≥35 providing an increased risk for poor outcomes. By the end of follow-up, 3.1% of patients underwent colectomy. Patients with UP that experienced proximal disease progression during follow-up [48%] had significantly higher rates of a caecal patch at diagnosis and higher PUCAI score by the end of induction, compared to those without progression. CONCLUSION: Paediatric patients with UP exhibit high rates of treatment escalation and proximal disease extension.

Thiopurines Maintenance Therapy in Children With Ulcerative Colitis: A Multicenter Retrospective Study.

BACKGROUND AND AIMS: Thiopurines are an established treatment for pediatric ulcerative colitis (UC). However, data regarding safety and efficacy are lacking. We aimed to determine short and long-term outcome following thiopurines use in children with UC. METHODS: We conducted a retrospective review of children (2-18 years) with UC treated with thiopurines between January 2008 and January 2019 at 7 medical centers in Israel. The primary outcome was corticosteroid (CS)-free clinical remission at week 52 following thiopurines initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). RESULTS: A total of 133 children were included [median age at diagnosis of 12.4 (interquartile range 11.0-15.8) years, 30 (23%) left-sided colitis, 113 (85%) with moderate or severe disease at diagnosis]. At diagnosis 58 patients (44%) were treated with 5-aminosalicylates and 72 (54%) with CS. Sixty patients (45%) received thiopurines as 1st line maintenance therapy. Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy. Predictors of clinical remission were not identified. In a sub-analysis among patients with steroid-responsive moderate to severe UC, 59 (55%) patients achieved this outcome. The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively. CONCLUSION: More than half of children with UC starting thiopurines without previous or concomitant biologic therapy have CS-free clinical remission at 52 weeks later without the need for rescue therapy. Thiopurines are effective in pediatric UC and could be considered prior to biologics.

Comparison of Clinical Outcomes in Pediatric Patients with Ileocolonic Crohn Disease Treated with Infliximab Versus Adalimumab.

OBJECTIVES: Infliximab is considered superior to adalimumab in patients with ulcerative colitis, especially in severe cases. Whether this is true for Crohn disease (CD) patients with colonic involvement is unclear. Our aim was to compare the clinical effectiveness of infliximab versus adalimumab in pediatric ileocolonic (L3) CD. METHODS: This retrospective study included patients <18 years with ileocolonic CD treated with infliximab or adalimumab between 2014 and 2021. Primary outcome was steroid-free clinical remission by week 52. Secondary outcomes were treatment modifications, drug discontinuation, inflammatory bowel disease (IBD)-associated hospitalizations, and surgery during the first year of treatment. RESULTS: We identified 74 patients treated with adalimumab and 41 with infliximab, with comparable demographic features. Concomitant immunomodulator therapy at biologic initiation was significantly lower in the adalimumab group (28% vs 85%, P < 0.001). Rates of drug intensification were higher in the infliximab group at end of induction (EOI) and at 52 weeks (55% vs 32% and 88% vs 46%, P < 0.001). Given significant differences between initial median Pediatric Crohn Disease Activity Index scores (20.0 [interquartile range, IQR 15.0-27.5] vs 11.0 [IQR 7.5-20.0] for infliximab and adalimumab groups, respectively, P < 0.001), propensity score matching was performed. Following matching, the rate of patients in steroid-free clinical remission by EOI was significantly higher in the adalimumab group (93.8% vs 46.9%, P < 0.001), but comparable by 1 year. Moreover, inflammatory markers and fecal calprotectin values were also similar at these time points. Rates of drug discontinuation, IBD-associated admissions, and surgery were similar between groups. CONCLUSIONS: In a retrospective study of patients with ileocolonic CD, adalimumab and infliximab had comparable outcomes by 52 weeks.

A sound mind in a sound body: Stress-induced glucocorticoids exacerbate gut inflammation.

The notion that psychological stress can deteriorate our health is widely accepted. However, the mechanisms at play are poorly understood. In this issue of Cell, Schneider et al. identify the impact of glucocorticoids on enteric glia and neurons and elucidate the underlying mechanisms that link psychological stress to the exacerbation of gut inflammation.

Validation of predictive models for disease outcomes in paediatric ulcerative colitis: A multicentre prospective inception cohort.

BACKGROUND: Several studies have proposed models to predict disease outcomes in paediatric ulcerative colitis (UC), notably PROTECT, Schechter and PIBD-ahead, but none has been validated by external cohorts AIM: To explore these models in a prospective multicentre inception cohort METHODS: Children newly diagnosed with UC in 17 centres were followed at disease onset and 3 and 12 months thereafter, as well as at last visit. Outcomes included steroid-free remission (SFR) and acute severe colitis (ASC). RESULTS: Of the 223 included children, 74 (34%), 97 (43%) and 52 (23%) presented with mild, moderate and severe disease, respectively. SFR rate was 35% at 3 months and 47% at 12 months (62% of those with mild disease at diagnosis vs. 41% in moderate-severe disease; p = 0.01). Thirty-six (16%) children developed ASC during the first month after diagnosis, and 53 (24%) during the first year. The AUC of the PROTECT model for predicting SFR at 3 and 12 months was 0.78 [95% CI 0.65-0.92] and 0.57 [95% CI 0.47-0.66], respectively. The sensitivity/specificity/PPV/NPV of Schechter's criteria to predict sustained SFR at 12 months was 50%/60%/35%/74%. ASC was predicted only by the PUCAI score at diagnosis and at 3 months. CONCLUSIONS: The PROTECT model had a good predictive utility for SFR at 3 months, but not at 12 months. The other predictive models did not achieve sufficient accuracy, which was far from that reported in the original studies. This highlights the necessity for external validation of any prediction model prior to its implementation into clinical practice.

Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a gastrointestinal complication of premature infants with high rates of morbidity and mortality. A comprehensive view of the cellular changes and aberrant interactions that underlie NEC is lacking. This study aimed at filling in this gap. We combine single-cell RNA sequencing (scRNAseq), T-cell receptor beta (TCRß) analysis, bulk transcriptomics, and imaging to characterize cell identities, interactions, and zonal changes in NEC. We find an abundance of proinflammatory macrophages, fibroblasts, endothelial cells as well as T cells that exhibit increased TCRß clonal expansion. Villus tip epithelial cells are reduced in NEC and the remaining epithelial cells up-regulate proinflammatory genes. We establish a detailed map of aberrant epithelial-mesenchymal-immune interactions that are associated with inflammation in NEC mucosa. Our analyses highlight the cellular dysregulations of NEC-associated intestinal tissue and identify potential targets for biomarker discovery and therapeutics.

Immune dysregulation in Glycogen Storage Disease 1b - a CyTOF approach.

Glycogen Storage Disease type 1b (GSD1b) is a rare disease manifesting as hypoglycemia, recurrent infections and neutropenia, resulting from deleterious mutations in the SLC37A4 gene encoding the glucose-6-phosphate transporter. The susceptibility to infections is thought to be attributed not only to the neutrophil defect, though extensive immunophenotyping characterization is currently missing. Here we apply a systems immunology approach utilizing Cytometry by Time Of Flight (CyTOF) to map the peripheral immune landscape of 6 GSD1b patients. When compared to control subjects, those with GSD1b had a significant reduction in anti-inflammatory macrophages, CD16+ macrophages, and Natural Killer cells. Additionally, there was a preference towards a central versus an effector memory phenotype in multiple T cell populations, which may suggest that these changes stem from an inability of activated immune cell populations to undergo the appropriate switch to glycolytic metabolism in the hypoglycemic conditions associated with GSD1b. Furthermore, we identified a global reduction of CD123, CD14, CCR4, CD24 and CD11b across several populations and a multi-cluster upregulation of CXCR3, hinting at a potential role of impaired immune cell trafficking in the context of GSD1b. Taken together, our data indicates that that the immune impairment observed in GSD1b patients extends far beyond neutropenia and encompasses innate and adaptive compartments, which may provide novel insights into the pathogenesis of this disorder.

Infantile-onset inflammatory bowel disease has variable long-term outcomes.

Objective and aim: Infantile-onset inflammatory bowel disease (IO-IBD), defined as IBD diagnosed at age 2 years or younger, tends to be more severe and refractory to conventional treatment than IBD diagnosed at a later age. However, data about IO-IBD and its long-term follow up are limited. We thus aimed to evaluate the presentation and long-term outcomes of patients with IO-IBD in a retrospective multicenter study. Methods: Medical records of patients diagnosed with IO-IBD in eight medical centers during 2000-2017 with at least 1-year follow up were reviewed. Demographics and disease characteristics at diagnosis including age of onset, disease phenotype and location, surgeries, medical therapy, and comorbid conditions were recorded. Results: Twenty-three patients with IO-IBD (16 males, 70%) were identified and followed for a median (range) of 51.2 (26.0-110.3) months. The mean ages at presentation and at the last follow up were 14 ± 9.8 and 101 ± 77 months, respectively. Six (26%) patients needed ileostomy already at the time of diagnosis and 20 (87%) were treated with corticosteroids. During long-term follow up, remission was achieved in 16 (73%) patients; of whom, 3 (14%) were without medications and 7 (32%) were in remission with the use of 5-aminosalicylic acid only. One patient needed hemicolectomy and one developed a severe EBV related infection. Conclusion: The majority of patients with IO-IBD achieved long-term remission, despite a severe disease presentation at diagnosis. Surgery rate however is high, mainly during the first months from diagnosis.

Correlation Between the Nancy Histopathology Index and Markers of Disease Activity in Pediatric Ulcerative Colitis.

The Nancy Histological Index (NHI) was developed to assess histological disease activity in adult ulcerative colitis (UC) patients. However, data in pediatrics is limited. Our aim was to determine whether the NHI correlates with different indices of disease activity in pediatric UC patients. We retrospectively reviewed the NHI in rectal biopsies from 61 pediatric UC patients (median age 14.3 years), of whom 34 (55.7%) were newly diagnosed. The median Pediatric Ulcerative Colitis Activity Index (PUCAI) score among participants was 30 (interquartile range 5-55). Most patients exhibited an NHI of 3 (41/61, 67.2%) or 4 (8/61, 13.1%), reflecting moderate-severe histologic inflammation. A moderate positive correlation was identified between the NHI and PUCAI, fecal calprotectin, and Mayo endoscopic scores ( r = 0.60, 0.54, and 0.56 respectively, P ≤ 0.001), but not with CRP or albumin. These results indicate that the NHI has a modest correlation with clinical, laboratory and endoscopic indices of disease activity in pediatric UC patients.

Recurrence rates following ileo-colic resection in pediatric patients with Crohn's disease.

BACKGROUND: Ileo-colic resection (ICR) is an important therapeutic option for Crohn's disease (CD) patients. There are limited updated data of clinical and endoscopic post-operative recurrence (POR) in pediatric patients with CD for the long run. We aimed to determine recurrence rates following ICR over an extended period of time and asses its risk factors. METHODS: This is a single-center retrospective review of 35 patients with CD between the ages of 6 and 17.9 years who required ICR between 2003 and 2021 at Schneider Children Medical Center of Israel. Medical charts were reviewed at different time-points post-ICR. RESULTS: Clinical recurrence following ICR was demonstrated in only 11.4% and 28.6% (n = 4, n = 10) in the first two and five years-much lower rates than what was reported so far. We found no specific risk factor that correlated with clinical recurrence, although patients that were treated with early prophylaxis of anti-TNF medications following ICR tend to have less recurrence. CONCLUSIONS: We found lower POR following ICR, especially in the first years after surgery-which can be attributed to close surveillance and early medical treatment. Such surveillance seems to improve recurrence rates in the first years following ICR.

A somatic hypermutation-based machine learning model stratifies individuals with Crohn's disease and controls.

Crohn's disease (CD) is a chronic relapsing-remitting inflammatory disorder of the gastrointestinal tract that is characterized by altered innate and adaptive immune function. Although massively parallel sequencing studies of the T cell receptor repertoire identified oligoclonal expansion of unique clones, much less is known about the B cell receptor (BCR) repertoire in CD. Here, we present a novel BCR repertoire sequencing data set from ileal biopsies from pediatric patients with CD and controls, and identify CD-specific somatic hypermutation (SHM) patterns, revealed by a machine learning (ML) algorithm trained on BCR repertoire sequences. Moreover, ML classification of a different data set from blood samples of adults with CD versus controls identified that V gene usage, clusters, or mutation frequencies yielded excellent results in classifying the disease (F1 > 90%). In summary, we show that an ML algorithm enables the classification of CD based on unique BCR repertoire features with high accuracy.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Incidence, Management, and Outcomes of Very Early Onset Inflammatory Bowel Diseases and Infantile-Onset Disease: An Epi-IIRN Study.

BACKGROUND & AIMS: In this nationwide study from the Israeli Inflammatory Bowel Disease Research Nucleus, we aimed to describe the incidence of very early onset inflammatory bowel diseases (VEOIBDs) with a focus on infantile-onset disease and to compare management and disease course with older children. METHODS: Data were retrieved from the 4 Israeli Health Maintenance Organizations covering 98% of the population. Pediatric-onset IBD was categorized as follows: adolescent onset (10 to <18 y), early onset (6 to <10 y), VEOIBD (0 to <6 y), toddler onset (2 to <6 y), and infantile onset (<2 y). RESULTS: A total of 5243 children with 35,469 person-years of follow-up evaluation, were diagnosed with IBD during 2005 to 2020: 4444 (85%) with adolescent onset, 548 (10%) with early onset, and 251 (4.8%) with VEOIBD, of whom 81 (1.5%) had infantile onset. The incidence of pediatric-onset IBD increased from 10.8 per 100,000 in 2005 to 15.3 per 100,000 in 2019 (average annual percentage change, 2.8%; 95% CI, 2.2%-3.4%), but that of VEOIBD remained stable (average annual percentage change, 0%; 95% CI, -2.5% to 2.6%). The infantile-onset and toddler-onset groups were treated less often with biologics (36% and 35%, respectively) vs the early onset (57%) and adolescent-onset groups (53%; P < .001). The time to steroid dependency was shorter in infantile-onset (hazard ratio [HR], 2.1; 95% CI, 1.5-2.9) and toddler-onset disease (HR, 1.6; 95% CI, 1.2-2.0) vs early onset and adolescent-onset disease, but time to hospitalizations, time to surgery, and growth delay were worse only in infantile-onset disease. In a multivariable model, infantile-onset patients had a higher risk for surgery (HR, 1.4; 95% CI, 1.1-1.9) and hospitalization (HR, 1.7; 95% CI, 1.2-2.4) than the toddler-onset group. CONCLUSIONS: The incidence of VEOIBD remained stable. Infantile-onset IBD had worse outcomes than older children, while toddler onset had mostly similar outcomes, despite less frequent use of biologics.