Pediatric Inflammatory Bowel Disease Research Articles

Tarm1 may affect colitis by regulating macrophage M1 polarization in a mouse colitis model.

In this study, we aimed to explore the role of Tarm1 in juvenile mice with dextran sulfate sodium (DSS)-induced colitis and elucidate the mechanisms that affect intestinal barrier function. A DSS-induced pediatric inflammatory bowel disease mouse model was established using 4-week-old juvenile mice. Disease activity index and histopathological damage scores were determined using hematoxylin and eosin (H&E) staining. Tarm1, F4/80, CD68, and CD86 levels were detected using qPCR, western blotting, and immunofluorescence. Trans epithelial electric resistance (TEER) was detected using the transwell assay. Results revealed that juvenile colitis mice fed 4% DSS drinking water had increased Tarm1 expression in the colon tissue, increased macrophage M1 polarization, higher expression of pro-inflammatory cytokines, and an impaired intestinal mucosal barrier, compared with the control group. Tarm1-knockdown RAW264.7 cells inhibited lipopolysaccharide (LPS)-induced M1 polarization and attenuated barrier damage in co-cultured intestinal epithelial cells. Tarm1 expression was increased in colonic tissues of juvenile mice with colitis, and LPS-induced M1 polarization and intestinal barrier damage were attenuated in Tarm1-knockdown RAW264.7 cells. This suggests that attenuation of Tarm1 expression is a potential target for pediatric inflammatory bowel disease therapy.

Clinical analysis and identification of pediatric patients with colonic ulceration

BackgroundA wide variety of diseases mimic inflammatory bowel disease (IBD). This study aimed to reduce the misdiagnosis among children with colonic ulcers.MethodsEighty-six pediatric patients with colonic ulcers detected by colonoscopy were enrolled in the retrospective study. Children were divided into different groups according to the final diagnosis. The clinical characteristics, laboratory examinations, endoscopic findings, and histopathological results were compared.ResultsIBD (n = 37) was just responsible for 43% of patients with colonic ulceration. Other diagnosis included autoimmune diseases (n = 9), infectious enteritis (n = 13), gastrointestinal allergy (n = 8), and other diseases (n = 19). Comparing IBD and non-IBD groups, children with IBD had a higher frequency of symptoms like weight loss/failure to thrive (P < 0.001), perianal lesions (P = 0.001), and oral ulcers (P = 0.022), and higher expression levels of platelet (P = 0.006), neutrophil-to-lymphocyte ratio (NLR) (P = 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P < 0.001), Immunoglobulin G (P = 0.012), Interleukin-1β (P = 0.003), Interleukin-6 (P = 0.024) and TNF-α (P = 0.026), and a wider ulcer distribution in the lower gastrointestinal tract (LGIT) (P < 0.001). Expression levels of hemoglobin (P < 0.001) and albumin (P = 0.001) were lower in IBD patients. Multivariate analysis showed hemoglobin, NLR, Score of ulceration in LGIT, and pseudopolyps contributing to the diagnosis of pediatric IBD with colonic ulcers.ConclusionsWe displayed potential indicators to help diagnose pediatric IBD differentiating from other disorders with colonic ulcers more prudently.

Considerations in Paediatric and Adolescent Inflammatory Bowel Disease.

The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.

Advancements in the Management of Pediatric and Adult Inflammatory Bowel Disease: A Systematic Review of Treatment Strategies and Long-Term Outcomes

Advancements in the Management of Pediatric and Adult Inflammatory Bowel Disease: A Systematic Review of Treatment Strategies and Long-Term Outcomes

Neutrophil Extracellular Traps in Pediatric Inflammatory Bowel Disease: A Potential Role in Ulcerative Colitis.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls (p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy.

Efficacy of vedolizumab and ustekinumab in pediatric-onset inflammatory bowel disease: A real-world multicenter study.

Vedolizumab and ustekinumab are effective in inducing and maintaining corticosteroid-free clinical remission (CFR) in adult patients with inflammatory bowel disease (IBD). This study describes the efficacy and safety of vedolizumab and ustekinumab in pediatric IBD. All patients ≤18 years of age with Crohn's disease (CD) or ulcerative colitis (UC) treated with vedolizumab or ustekinumab in three centers in Northern France were followed retrospectively. The primary outcome was CFR at Week 14 (W14). Twenty-five patients (9 CD, 16 UC) and 33 patients (28 CD, 5 UC) were started on vedolizumab and ustekinumab respectively between 2016 and 2021. All were previously treated with antitumor necrosis factor (TNF). The median time from diagnosis to treatment initiation was 21.0 (12.0-44.0) and 42.0 (22.0-73.5) months for vedolizumab and ustekinumab respectively. Among vedolizumab-treated patients, 36% were in CFR at W14, including 22% in CD and 44% in UC. At W52, 56% were in CFR, including 33% in CD and 69% in UC. Among ustekinumab-treated patients, 49% were in CFR at W14, including 54% in CD and 20% in UC. At W52, 55% were in CFR, including 57% in CD and 40% in UC. There was a significant increase in median growth velocity between W0 and W52 of +2 SD in vedolizumab-treated patients (p = 0.0002). Four adverse events were reported during vedolizumab treatment, none for ustekinumab-treated patients. Vedolizumab and ustekinumab appear to be effective in inducing and maintaining CFR in pediatric-onset IBD. Randomized controlled trials are needed to confirm these results.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in pediatric Inflammatory Bowel Disease: clinical characteristics and outcomes.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0years (IQR 11.9-16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%)discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%)patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7years (IQR 0.8-4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.

Response from the Canadian Children Inflammatory Bowel Disease Network to the US Food and Drug Administration Draft Guidance for Industry on pediatric inflammatory bowel disease: developing drugs for treatment

Response from the Canadian Children Inflammatory Bowel Disease Network to the US Food and Drug Administration Draft Guidance for Industry on pediatric inflammatory bowel disease: developing drugs for treatment

The circulating methylome in childhood-onset inflammatory bowel disease.

The genetic contribution to inflammatory bowel disease (IBD) encompassing both Crohn's disease (CD) and ulcerative colitis (UC), accounts for around 20% of disease variance, highlighting the need to characterise environmental and epigenetic influences. Recently considerable progress has been made in characterising the adult methylome, in epigenome-wide association studies. We report detailed analysis of the circulating methylome in 86 patients with childhood-onset CD,UC and 30 controls using the Illumina Infinium Human MethylationEPIC platform. We derive and validate a 4-probe methylation biomarker (RPS6KA2, VMP1, CFI and ARHGEF3), with specificity and high diagnostic accuracy for paediatric IBD in UK and North American cohorts (AUC 0.90-0.94). Significant epigenetic age acceleration is present at diagnosis, with the greatest observed in CD patients. Cis-MeQTL analysis identifies genetic determinants underlying epigenetic alterations notably within the HLA 6p22.1-p21.33 region. Passive smoking exposure is associated with the development of UC rather than CD contrary to previous findings. These data provide new insights into epigenetic alterations in IBD and illustrate the reproducibility and translational potential of epigenome-wide association studies in complex diseases.

Biological therapy, surgery, and hospitalization rates for inflammatory bowel disease: An observational Latin American comparative study between adults and pediatric patients

ObjectiveCompare the proportions of use of biological therapy, surgeries, and hospitalizations between adults and pediatric inflammatory bowel disease (IBD)—Crohn's disease (CD) and ulcerative colitis (UC)—patients. Patients and methodsObservational, retrospective, and multicenter study. Data were collected from all consecutive IBD patients seen as outpatients or admitted to hospital, during 2015–2021, in two IBD tertiary centers in a South Brazilian capital. Patients with unclassified colitis diagnosis were excluded from this study. Patients were classified as having CD or UC and sub-categorized as adult or pediatric according to age. Data were analyzed using frequency, proportion, Fisher's exact test, and Chi-square test. ResultsA total of 829 patients were included: 509 with CD (378 adults/131 pediatric) and 320 with UC (225/95). Among patients with CD, no differences were observed for proportions of use of biological therapy (80.2% in pediatric vs. 73.3% in adults; P=0.129), surgery (46.6% vs. 50.8%; P=0.419), or hospitalization (64.9% vs. 56.9%; P=0.122). In UC, significant differences were observed for biological therapy (40.0% vs. 28.0%; P=0.048) and hospitalization (47.4% vs. 24.0%; P<0.001). No significant difference was observed in surgery rates (17.9% vs. 12.4%; P=0.219). ConclusionsBiological therapy and incidence of hospitalization were greater among pediatric patients with UC, compared with adults; no difference was observed in the need for abdominal surgery. In CD, no significant difference was observed in the three main outcomes between the age groups.

C-reactive protein to albumin ratio for diagnosis and predicting behavioral pattern in Crohn’s disease compared to ulcerative colitis in pediatric inflammatory bowel disease

C-reactive protein to albumin ratio for diagnosis and predicting behavioral pattern in Crohn’s disease compared to ulcerative colitis in pediatric inflammatory bowel disease

Very early onset versus pediatric onset inflammatory bowel disease: a prospective cohort analysis

Very early onset versus pediatric onset inflammatory bowel disease: a prospective cohort analysis

Association of paediatric autoimmune cytopenia and inflammatory bowel disease suggests a common genetic origin.

The association of autoimmune cytopenia (AIC) and inflammatory bowel disease (IBD) has been reported in small series, but the incidence of and risk factors for IBD in children with AIC are not known. One thousand six hundred nine children with chronic immune thrombocytopenic purpura, autoimmune haemolytic anaemia or Evans syndrome from the prospective OBS'CEREVANCE cohort are included in this study. Overall, 15 children were diagnosed with IBD, including 14 who developed IBD after AIC diagnosis (median delay: 21 months). The only risk factor for IBD development is age at AIC over 10 years. Out of 10 children genetically tested, germline variants associated with autoimmune disorders were identified in three (CTLA4: two, DOCK11: one). In children and adolescents monitored for AIC or past history of AIC, especially children over 10 years, gastro-intestinal (GI) symptoms (recurrent abdominal pains, GI bleeding, chronic diarrhoea, weight loss) should suggest IBD and deserve specific work-up and genetic studies. Identification of a causal germline variant will allow targeted therapy.

The Interplay of Inflammatory Bowel Disease (IBD) and Diabetes in Pediatrics: A Systematic Review.

The main objective of this study is to provide insights into the clinical problems and considerations in managing pediatric patients with both diabetes and inflammatory bowel disease (IBD) by summarizing the available information.We conducted a comprehensive search across electronic resources, including ScienceDirect, PubMed, Cochrane Library, and Scopus. Two independent reviewers evaluated and retrieved information from qualifying papers. Our data consists of five studies with 79,878 patients, 38225 (47.9%) of whom were female. Three studies included 2432 children diagnosed with IBD, and 17 (0.7%) were found with type 1 diabetes (T1D). Two studies comprised 77,446 children diagnosed with T1D and 83 (0.1%) had IBD. Children with immune-mediated diseases are more likely to have IBD, especially Crohn's disease. The included studies found no connection between T1D and childhood IBD.The important but little-known connection between diabetes and IBD in pediatric populations is brought to light by this comprehensive study. We were unable to discover a connection between pediatric IBD and DM. The review does, however,point out significant gaps in the literature, highlighting the need for more studies to comprehend the intricate interactions between these disorders and to create practical management plans for impacted children.

Pediatric Inflammatory Bowel Disease Type Unclassified: A Nationwide Cohort Study in Scotland With up to 20 Years Follow-up Shows Reclassification in the Majority and Mild Course in Those Whose Diagnosis Is Unchanged.

Given the paucity of long-term longitudinal data for inflammatory bowel disease type unclassified (IBDU), we aimed to clarify IBDU disease course and reclassification rate by presenting nationwide data with up to 20 years of follow-up. We analyzed a prospectively identified 11-year cohort of pediatric patients diagnosed with IBDU between January 1, 2003 and December 31, 2013 at all Scottish pediatric IBD centers and followed up into adult services until December 31, 2022. Data were obtained from electronic medical records at fixed timepoints (5 and 10 years post-diagnosis) and at the final follow-up. Overall, 102 patients were included in the analysis (57/102 [56%] male, median [interquartile range {IQR}] age at diagnosis: 11.5 [9.1-13.2] years) with a median (IQR) follow-up length of 10.5 (8.6-14.0) years. A change of diagnosis was made in 61 of 102 patients (60%); of these, 30 patients (29%) were reclassified to Crohn's disease (CD) and 31 patients (30%) to ulcerative colitis (UC). Patients who remained with IBDU had higher 1- to 5-year remission rates (IBDU 30/39 [77%] vs reclassified 16/57 [28%], P < .05), with lower rates of moderate-to-severe disease (IBDU 3/39 [8%] vs reclassified 31/57 [54%], P < .05) and less need for biologics across all timepoints (IBDU vs reclassified: first timepoint 1/39 [3%] vs 17/57 [30%], second timepoint 1/33 [3%] vs 26/56 [46%], third timepoint 0/18 [0%] vs 16/33 [49%]; all P < .05). Higher rates of surgical resections were observed in reclassified patients (reclassified 11/61 [18%] vs IBDU 1/41 [2%], P = .02). In our nationwide pediatric IBDU cohort, 60% of patients were reclassified to either UC or CD over 10.5 years of median follow-up; those who remained with IBDU had a milder disease course.

PET/MRI in paediatric inflammatory bowel disease – a prospective accuracy study

AbstractCross‐sectional imaging supplements endoscopy in detecting disease manifestations in inflammatory bowel diseases (IBD). This study aimed to evaluate the accuracy of PET/MRI in a paediatric population suspected of IBD. This prospective study consecutively included patients aged 8–17 years under diagnostic evaluation for IBD. Forty‐three patients underwent a PET/MRI scan and subsequent ileocolonoscopy, of whom 26 patients diagnosed with IBD participated in a follow‐up scan, hereof 19 with Crohn's disease (CD), five with Ulcerative colitis and two with unclassified IBD. The results of PET alone, MRI alone, and PET/MRI combined were compared to a reference standard of endoscopy and histopathology. Of the 208 intestinal segments analysed, 109 showed inflammation, and 99 had no inflammation. In the per‐segment analysis PET had a sensitivity of 0.83 (95% CI 0.73–0.93), specificity of 0.59 (95% CI 0.47–0.71), and area under the receiver operating characteristic curve (AUROC) of 0.73 (95% CI 0.67–0.80). MRI had a sensitivity of 0.52 (95% CI 0.41–0.64), specificity 0.89 (95% CI 0.82–0.96), and AUROC of 0.72 (95% CI 0.66–0.77). PET/MRI had a sensitivity of 0.83 (95% CI 0.74–0.94), specificity of 0.57 (95% CI 0.44–0.69), and AUROC of 0.77 (95% CI 0.71–0.84). At follow‐up, PET and MRI scores decreased, and the change in MRI was able to identify patients with a clinical response. The accuracy of the PET/MRI scan in detecting inflammation in the terminal ileum and colon was moderate and not superior to either modality alone. With technological advances and combined reading, PET/MRI may still be valuable in selected cases.

Differences in disease characteristics and treatment exposures between paediatric and adult-onset inflammatory bowel disease using a registry-based cohort.

Previous studies highlighted a more extensive phenotype for paediatric-onset than adult-onset inflammatory bowel disease (IBD). However, most lacked long-term follow-up, and some were conducted before the era of biologics. The aim of this study is to compare disease characteristics and treatment exposures between paediatric-onset and adult-onset IBD. From a registry that periodically and uniformly retrieves demographics, disease characteristics/phenotype, and treatments, we compared the characteristics of paediatric-onset (diagnosed at ≥6 and <18 years) and adult-onset IBD, diagnosed during 2000-2022 and with ≥12 months follow-up. Of the 2837 patients with Crohn's disease and 1332 with ulcerative colitis, 3316 had adult-onset and 853 paediatric-onset IBD. The median follow-up was 6 years. Patients with paediatric-onset presented with more extensive disease and received more intensified therapies, including biologics and JAK inhibitors than those with adult-onset IBD. Paediatric-onset ulcerative colitis showed a higher prevalence of E3 extensive colitis including pancolitis and a greater requirement for systemic steroids, immunomodulators, and biologics than adult-onset ulcerative colitis. Paediatric-onset versus adult-onset Crohn's disease exhibited greater L3 ileocolonic involvement and perianal disease phenotype, and higher exposure to immunomodulators and biologics. Kaplan-Meier curve and Cox proportional hazards analyses showed significantly lower 15-year biologic-free survival from diagnosis among those with paediatric-onset IBD than with adult-onset IBD (p = <0.001), indicating greater and earlier use of biologics in the former. Paediatric-onset presents with more extensive disease with higher exposures to immunomodulators and biologic therapies than adult-onset IBD.

Transabdominal intestinal ultrasound and its parameters used in the assessment of pediatric inflammatory bowel disease.

This article extends on the use of transabdominal intestinal ultrasound in diagnosing pediatric inflammatory bowel disease. Some of the more essential features used in assessing bowel inflammation, such as hyperemia and wall thickness on ultrasound, are expanded upon from the publication on imaging and endoscopic tools in pediatric inflammatory bowel disease.

The association between erythema nodosum and pyoderma gangrenosum and pediatric inflammatory bowel disease.

The objectives of this study is to estimate rates and identify factors associated with erythema nodosum (EN) and pyoderma gangrenosum (PG) in pediatric patients with inflammatory bowel disease (IBD). This cohort study examined longitudinal visits of patients aged ≤ 21 years from the ImproveCareNow (ICN) registry. We evaluated the association of factors at the patient-level (demographics and IBD diagnosis age) and visit-level (IBD severity scores, markers and phenotypes, comorbidities, and treatment) with the presence of EN and PG, using longitudinal logistic regression models adjusted for time and within-patient clustering. A total of 285,913 visits from 32,497 patients aged ≤ 21 years from the ICN registry were analyzed. The occurrence of EN was 1.57% (95% confidence interval [95% CI]: 1.43%-1.71%) and the occurrence of PG was 0.90% (95% CI: 0.80%-1.00%). Co-occurrence of EN and PG was reported in 0.30% (95% CI: 0.25%-0.37%) patients. Both EN and PG were associated (p < 0.0001) with worse intestinal disease, lower remission, higher inflammatory markers, and extraintestinal manifestations (EIMs) arthritis and uveitis. EN and PG were associated with increased disease severity and other noncutaneous EIMs (arthritis and uveitis). A small subset of patients had developed both EN and PG.

Predictors of Unplanned Health Care Utilization Among Children with Inflammatory Bowel Disease in a Rural Region of the Southeastern US.

Pediatric Inflammatory Bowel Disease (IBD) imposes significant healthcare costs and strains emergency services. This study aimed to identify factors associated with unplanned healthcare usage among children with IBD in a rural, medically underserved region in the southeastern United States. In this retrospective cohort study, we analyzed children (<18years) with moderate or severe IBD followed at an academic pediatric gastroenterology clinic between 2016 and 2021. Each planned visit was treated as a separate observation, and patients were followed after each planned visit until the occurrence of the earliest unplanned healthcare event, until the next planned visit, or until censoring. In our analysis of 471 planned visits from 70 children with IBD, we observed 84 (18%) unplanned visits within 12months, with 39 of these visits related to IBD. Unplanned visits occurred at a median interval of 39 days, predominantly to the emergency department (ED). Multivariate Cox proportional hazards analysis revealed a higher hazard of unplanned visits among female patients, individuals with elevated C-reactive protein levels and anemia, those covered by Medicaid insurance, and those residing closer to the clinic. This study elucidates the challenges faced by children with IBD in rural settings. By identifying factors associated with unplanned healthcare utilization, we can better pinpoint patients who may benefit from targeted interventions to reduce such visits.