Inflammatory bowel disease (IBD) encompasses a spectrum of chronic, idiopathic, and progressive inflammatory conditions of the gastrointestinal tract, with Crohn's disease and ulcerative colitis comprising the majority. Both conditions have distinct pathophysiological and clinical characteristics but share common immune-mediated mechanisms. Specific facets of IBD and its management in the pediatric population differ from adult parallels. This article explores the surgical treatments of pediatric IBD, focusing on indications for surgery and perioperative considerations.

Real-world data on ustekinumab for the treatment of pediatric Crohn's disease (CD) are limited. This study sought to evaluate the effectiveness, long-term durability, and safety of ustekinumab in the treatment of children with CD.

A retrospective longitudinal cohort study of children with CD treated with ustekinumab from two large centers between 2015 and 2020 was performed. The primary outcome was frequency of steroid-free clinical remission at 1 year. Secondary outcomes included time to steroid-free clinical remission, frequency of clinical and biochemical remission, drug escalation and discontinuation, serum level data, and adverse events. Standard descriptive and comparative statistics were performed. Logistic regression was used to identify factors associated with steroid-free remission at 1 year. Kaplan-Meier curves were used to visualize time-to-event relationships for outcomes.

A total of 101 patients were included. Median follow-up time on ustekinumab was 16.6 months (interquartile range [IQR]: 8.71-31.2) with drug failure in 28% at 1 year. Fifty-nine patients were in steroid-free clinical remission at 1 year. Higher baseline disease activity (odds ratio [OR]: 0.91 (95% confidence interval [CI]: 0.84-0.97), p = 0.01) and stricturing/penetrating disease phenotype (OR: 0.14 (95% CI: 0.03-0.65), p = 0.02) were associated with decreased likelihood of steroid-free clinical remission at 1-year. Ustekinumab drug escalation occurred in 70% of patients, and after escalation, 50 (70%) achieved clinical remission, and 49 (69%) achieved steroid-free remission at the last follow-up. Adverse events were rare and did not require therapy discontinuation.

Ustekinumab is effective and safe in the treatment of children with CD. Escalation of therapy occurs frequently but results in sustained durability.

Pediatric Crohn's disease (CD) is a chronic inflammatory bowel disorder that poses significant health risks to children. Although the precise etiology of CD remains elusive, further exploration is needed to identify diagnostic biomarkers and therapeutic targets.

This study utilized single-cell and bulk RNA sequencing data derived from ileal and colonic biopsy samples to explore the molecular mechanisms and cell types associated with CD, as well as to pinpoint potential biomarkers and therapeutic targets.

The results revealed a more pronounced alteration in both the quantity and functional state of neutrophils in the CD cohort compared to those with ulcerative colitis and healthy controls. Neutrophils were present in higher proportions in the CD group, primarily in an activated state, potentially correlating with the presence of deep ulcerations and inflammatory histopathological features. Additionally, neutrophil interactions with other cell types were markedly enhanced in the CD group, making neutrophils the dominant participants in cell-to-cell communications. Further analysis indicated a shift in neutrophil phenotype from pro-inflammatory and antimicrobial to tissue-repairing, which may contribute to the progression and exacerbation of CD.

IL1B, ICAM1, CXCL1, and CXCL9, primarily expressed in neutrophils, were potential biomarkers for CD. Neutrophils might be considered a potential target for pediatric CD.

This study demonstrated that patients with CD exhibited a greater proportion of activated neutrophils, with enhanced interactions between neutrophils and all other cell types, resulting in neutrophils contributing the most cell-cell interactions within the CD gut. Neutrophils in the CD gut transition from a pro-inflammatory and antibacterial phenotype to one that promotes tissue healing, potentially influencing the progression and exacerbation of CD. Neutrophils represent a promising therapeutic target in pediatric CD. Hub genes associated with CD, including IL1B, ICAM1, CXCL1, and CXCL9, are predominantly expressed in neutrophils, positioning them as promising diagnostic biomarkers for CD.

Due to its rarity, there is limited information on the clinicopathologic features of dysplasia in pediatric patients with inflammatory bowel disease (IBD). The existing surveillance guidelines for these patients do not include dysplasia as a potential risk factor for colorectal cancer (CRC), and there is no clear guidance on the optimal strategy for detecting dysplasia. As such, we analyzed the clinicopathologic features of 20 IBD patients who developed at least one instance of dysplasia (n = 56) before the age of 21 years. The results were then compared with data from a previously published adult cohort, which included 315 dysplastic lesions from 167 consecutive adult IBD patients. The study group consisted of 11 males and 9 females, with a mean age of 11 years at the time of IBD diagnosis. The mean age at the time of the first dysplasia diagnosis was 18 years for the study group compared to 54 years for the adult group. The study group had a lower incidence of ulcerative colitis (65% vs. 92% in the adult group, p < 0.001), but the proportion of patients with concurrent primary sclerosing cholangitis (PSC) was nearly double that of the adult group (25% vs. 13%, p = 0.129). Dysplasia in the study group was more likely to be nonconventional (38%, p = 0.047) and invisible or flat (50%, p < 0.001) compared to the adult group (25% and 24%, respectively). High-risk nonconventional dysplastic subtypes, including crypt dysplasia (13%, p = 0.016), goblet cell-deficient dysplasia (11%, p = 0.010), and hypermucinous dysplasia (9%, p = 0.009), were more common in the study group compared to the adult group (4%, 3%, and 2%, respectively). The mean duration from IBD diagnosis to the first dysplasia diagnosis was significantly shorter in the study group (8 years) than in the adult group (16 years) (p = 0.005). While dysplastic lesions in the adult group were more likely to present as high-grade dysplasia (HGD) at initial diagnosis (17% vs. 4% in the study group, p = 0.008), the rate of advanced neoplasia (HGD or CRC) on follow-up was similar between the two groups (26% in the adult group vs. 22% in the study group, p = 1.000). In conclusion, dysplasia in pediatric IBD patients is often associated with nonconventional features (including the high-risk subtypes), an invisible/flat appearance, concurrent PSC, and early development (within 8 years of IBD diagnosis).

Inflammatory bowel diseases (IBD) are chronic, incurable pathologies with unknown causes, affecting millions of people. Pediatric-onset IBD, starting before the age of 18 years, are increasing, with more aggressive and extensive features than adult-onset IBD. These differences remain largely unexplained. Intestinal mucosal damage, cell death, DNA release from nuclear, mitochondrial, or microbiota sources, and DNA-sensing activating the cGAS-STING pathway may contribute to disease evolution. Increased colonic cGAS and STING are increasingly reported in experimental and human IBD. However, limited knowledge of the mechanisms involved hinders the development of new therapeutic options. Here, we discuss recent advances and unresolved questions regarding DNA release, DNA sensor activation, and the role and therapeutic potential of the cGAS-STING pathway in inflammatory colitis.

Pediatric-onset Crohn's disease (CD) has a more severe phenotype than adult-onset, and nearly one-third of pediatric CD patients will require surgical therapy. There is limited data on patient/disease characteristics that are associated with earlier surgical management.

All pediatric CD patients (<22 yrs) who underwent ileocolectomy from 2005 to 2021 were included. Unadjusted analyses were performed with Pearson chi-squared tests for categorical dependent variables, and t-tests, or analysis of variance, for numerical dependent variables.

One hundred thirty-five pediatric CD patients underwent ileocolectomy. The median time to surgery was 3.75 yrs. Patients treated with early surgery (<3.75 yrs from diagnosis) were older at diagnosis (16.5 versus 11.6 yrs, P < 0.001) yet had surgery at a younger age (16.8 versus 18.9 yrs, P < 0.001). They also were prescribed fewer CD medications (2.0 versus 4.0, P < 0.001), were less likely to have trialed multiple biologics (25.6% versus 54.2%, P = 0.001), had a shorter time from diagnosis to biologic (0.3 versus 3.5 yrs, P < 0.001), and had a shorter interval from biologic to surgery (0.4 versus 2.5 yrs, P < 0.001). Abscess formation was a more common indication for early surgery (39.4% versus 14.7%, P = 0.002), whereas failure to thrive/refractory pain was more common for later surgery (27.3% versus 55.9%, P = 0.001).

Surgical therapy remains an important component of the overall management of pediatric CD. In our cohort, earlier surgical management was associated with earlier use of biologics, a shorter duration between biologic and surgery, and decreased number of overall medications and biologic agents prior to surgery, suggesting a severe disease phenotype refractory to medical management.

Data on biosimilar use in pediatric inflammatory bowel diseases (IBD) are scarce compared to the status of studies in adults, resulting in limitations in its treatment. We compared effectiveness and safety of biosimilars versus originators in this population.

We used data from the French National Health Data System to identify children (less than 18 years old at treatment initiation) initiating treatment with a biosimilar or the originator infliximab or adalimumab for Crohn's disease (CD) or ulcerative colitis (UC), from first biosimilar launch (January 2015 and October 2018, respectively) to 31 December 2022. Patients' follow-up went until 30 June 2023. We compared the risks of treatment failure and overnight hospitalization in biosimilar versus originator new users using inverse harzard ratio (HR) of probability of treatment weighted Cox regressions (IPTW).

We included 5870 patients (infliximab: n = 3491; adalimumab: n = 2379) in the study. Biosimilars represented, respectively, 76.0% (n = 2652) and 29.0% (n = 691) of infliximab and adalimumab initiations. CD represented 70.9% (n = 2476) and 69.0% (n = 1642) of infliximab and adalimumab initiations. Biosimilar use was not associated with increased risks of treatment failure [IPTW HR (95% confidence interval, CI): infliximab 0.92 (0.78-1.09) in CD, 0.98 (0.76-1.27) in UC; adalimumab 0.98 (0.85-1.14) in CD, 1.01 (0.82-1.24) in UC]. Occurrence of all-cause hospitalization was not different between exposure groups [IPTW HR (95% CI): infliximab 0.96 (0.78-1.18); adalimumab 1.03 (0.80-1.33)]. No difference in occurrence of serious infections, mainly gastro-intestinal or dermatological, was found.

We provide reassuring results on the use, effectiveness and safety of biosimilars in a large unselected pediatric population suffering from IBD.

Pediatric Crohn's disease (CD) easily progresses to an active disease compared with adult CD, making it important to predict and minimize CD relapses. However, prediction of relapse at various time points (TPs) during pediatric CD remains understudied. We aimed to develop a real-time aggregated model to predict pediatric CD relapse in different TPs and time windows (TWs).

This retrospective study was conducted on children diagnosed with CD between 2015 and 2022 at Severance Hospital. Laboratory test results and demographic data were collected starting at 3 months after diagnosis, and cohorts were formed using data from 6 different TPs at 1-month intervals. Relapse-defined as a pediatric CD activity index ≥ 30 points-was predicted, and TWs were 3-7 months with 1-month intervals. The feature importance of the variables in each setting was determined.

Data from 180 patients were used to construct cohorts corresponding to the TPs. We identified the optimal TP and TW to reliably predict pediatric CD relapse with an area under the receiver operating characteristic curve score of 0.89 when predicting with a 3-month TW at a 3-month TP. Variables such as C-reactive protein levels and lymphocyte fraction were found to be important factors.

We developed a time-aggregated model to predict pediatric CD relapse in multiple TPs and TWs. This model identified important variables that predicted relapse in pediatric CD to support real-time clinical decision making.

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.

Crohn's disease (CD) varies by location, potentially affecting therapy efficacy and surgery risk, although research on this topic is conflicting. This study aims to investigate the independent association between CD location and therapeutic patterns.

We analyzed patients with CD diagnosed from January 2005 to May 2023 registered in the nationwide ENEIDA registry. A univariate Cox regression analysis assessed the association of disease location with biologic use and persistence (with treatment discontinuation as a failure event), as well as the use of intestinal resections. A multivariate model was constructed to evaluate the independent association of disease location with therapeutic patterns, controlling for potential confounders such as sex, age at inclusion and diagnosis, disease duration and behavior, previous surgery or biological therapy, extraintestinal manifestations, and perianal disease.

The study included 17,292 patients with a median follow-up period of 6 years (interquartile range 2-10 years). Ileocolonic location was associated with a higher biologic use than colonic location (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.22-1.38) and ileal disease (HR 1.21, 95% CI 1.16-1.27), independently predicting biologic use (P < 0.001). Ileal location was associated with a lower biologic persistence than ileocolonic location (HR 1.14, 95% CI 1.07-1.21) and colonic disease (HR 1.10, 95% CI 1.01-1.20), independently predicting biologic persistence (P = 0.019). Ileal disease was associated with a higher likelihood of intestinal resections than colonic (HR 2.82, 95% CI 2.45-3.25) and ileocolonic location (HR 1.13, 95% CI 1.05-1.22), independently predicting the use of surgery (P < 0.001).

CD location with ileal predominance is associated with a distinct therapeutic pattern, including higher biologic use, lower treatment persistence, and increased rates of intestinal resections.

Adult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers.

We used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR).

We included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4-17.7) years for patients and 10.2 (interquartile range: 5.2-17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8-2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2-16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4-15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1-22.6]).

We found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.

The natural history of Crohn's disease (CD) can result in complications requiring surgery. Pediatric data are scarce about major abdominal surgery. The IBD Registry from the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition has been active since 2008 and collects data from major pediatric IBD centers in Italy. The aim of the present report was to explore the prevalence of major abdominal surgery among children affected by CD in an era when antitumor necrosis factor (anti-TNF-α) agents were already used so that we might appraise the incidence of surgical-related complications and identify the factors associated with postoperative disease recurrence.

We retrospectively analyzed data from patients enrolled in the registry from January 2009 to December 2018. Patients with monogenic IBD and patients undergoing surgery for perianal disease were excluded.

In total, 135 of 1245 patients were identified. We report the prevalence of major abdominal surgery of 10.8%. Pediatric surgeons performed the procedure in 54.1% of cases, and a laparoscopic approach was used in 47.4% of surgical procedures. Seventeen patients (12.6%) experienced a total of 21 early postoperative complications, none of which was severe. A laparoscopic approach was the only factor negatively associated with the occurrence of postoperative complications (odds ratio, 0.22; 95% confidence interval, 0.06-0.8; P = .02). Fifty-four (40%) patients experienced postoperative endoscopic recurrence, and 33 (24.4%) of them experienced postoperative clinical recurrence. The postoperative treatment with anti-TNF-α drugs was significantly associated with a reduced risk of endoscopic recurrence (odds ratio, 0.19; 95% confidence interval, 0.05-0.79; P = .02).

In our cohort, the overall prevalence of major abdominal surgery was low, as well as the rate of surgical-related complications. Postoperative anti-TNF-α therapy seems be protective against endoscopic recurrence.

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.

The aim of this study was to compare the diagnostic value of 18 F-FDG PET or PET/CT with FDG PET/MR in patients with inflammatory bowel disease (IBD).

A comprehensive search was performed in PubMed for studies reporting the diagnostic performance of FDG PET (PET/CT) and FDG PET/MR in IBD from the inception of the database to March 14, 2024, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Fourteen studies were included in this systematic review and meta-analysis. Pooled estimates of segment-based sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio for FDG PET (PET/CT) and FDG PET/MR were calculated alongside 95% confidence intervals. Summary receiver operating characteristic (SROC) curves were plotted, and the area under the SROC curve was determined alongside the Q * index.

The segment-based pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the SROC curve of FDG PET (PET/CT) for diagnosing IBD (9 studies) were 0.81, 0.86, 5.76, 0.22, 31.92, and 0.92, respectively. Those of FDG PET/MR (5 studies) were 0.78, 0.92, 10.97, 0.25, 51.79, and 0.95. There was no significant difference in the abilities of detecting or excluding IBD between FDG PET (PET/CT) and FDG PET/MR.

For diagnostic value in patients with IBD, there was no significant difference between FDG PET (PET/CT) and FDG PET/MR. Both FDG PET (PET/CT) and FDG PET/MR have demonstrated high diagnostic performance for accurate diagnosing in patients with IBD.

We summarize the global, regional, and national burden of inflammatory bowel disease (IBD) in children and adolescents from 1990 to 2019.

Based on the Global Burden of Disease Study 2019, the data of IBD in children and adolescents were analyzed by sex, age, year, and location. Joinpoint analysis was applied to assess the temporal trend of the disease burden.

From 1990 to 2019, the incidence of IBD in children and adolescents increased by 22.8%, from 20,897.42 to 25,658.55 cases, especially in high SDI region. During the same period, the DALY numbers decreased by 53.5%, from 243,081.06 to 113,119.86, with all SDI regions experiencing a clear drop in DALYs except high SDI regions. In 2019, early-onset IBD incidence and DALY numbers were reported at 2,053.52 (95% UI: 1,575.62 to 2,677.49) and 73,797.46 (95% UI: 43,655.86 to 105,998.63), respectively.

Early-onset IBD in children and adolescents remains a significant global health concern. The disease burden has not improved in developed countries over the past 30 years, highlighting the need for targeted interventions.

Despite the rising prevalence of Inflammatory Bowel Disease (IBD), age and sex differences in its outcomes remain understudied. We investigated age and sex differences in IBD patients using a nationwide study in Iran, the Iranian Registry of Crohn's and Colitis (IRCC).

The IRCC is a national registry that gathered information on adult IBD patients since 2017. The collected data included demographic information, medication history, disease activity, comorbidities, diagnosis age, prognosis, the extent of ulcerative colitis (UC), Crohn's disease (CD) location, and extraintestinal manifestations. The statistical methods included the independent Student's t-test, Chi-square test, and binary logistic regression, using R version 4.2.2.

Among the 9,392 IBD patients, 7,496 (3,600 females) and 1,896 (808 females) had UC and CD, respectively. Sex difference showed higher odds of active disease in the past six months in male CD patients (OR 1.24 [95%CI 1.03, 1.49]) vs. females, but in male UC patients, the OR was 0.85 [0.78, 0.93]. Severe disease was less likely in CD patients aged 19-59 and >60 vs. <18. Similarly, UC patients <18 had lower odds of severe disease vs. those aged 19-59 and >60.

This study emphasizes the importance of understanding age and sex differences in IBD outcomes. These findings contribute to the ongoing global discussion on IBD management and facilitate the development of targeted interventions and personalized care.

 The aim of this retrospective study was to describe the risk of postoperative recurrence (POR) after ileocecal resection, the occurrence of surgical complications, and identify predictors of these adverse postoperative outcomes in pediatric Crohn's disease (CD).

 All the children less than 18 years of age with a diagnosis of CD, who underwent primary ileocecal resection for CD between January 2006 and December 2016 in our tertiary center, were considered for inclusion. Factors related to POR were investigated.

 A total of 377 children were followed for CD between 2006 and 2016. During this period, 45 (12%) children needed an ileocecal resection. POR was diagnosed in 16% (n = 7) at 1 year and 35% (n = 15) at the end of the follow-up, with a median follow-up of 2.3 years (Q1-Q3 1.8-3.3). Median duration of the postoperative clinical remission was 1.5 years (range 0.5-2). Multivariate Cox regression analysis identified only young age at diagnosis as a risk factor for POR.In total, 7 of the 43 patients (16%) developed severe postoperative complications, defined as requiring surgical, endoscopic, or radiological intervention. The only risk factor was intraoperative abscess.

 Only young age at diagnosis was associated with POR. This information could be useful to develop targeted therapeutic strategies for young CD children. At the end of follow-up with a median follow-up of 2.3 years (Q1-Q3 1.8-3.3), there was no surgical POR: endoscopic dilatation for POR should be considered in order to delay or prevent surgery.

Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall.

For this analysis, we used data from the Paediatric Inflammatory Bowel Disease Network for Safety, Efficacy and Treatment and Quality improvement of care (PIBD-SETQuality) Safety Registry, which collects data on multiple rare and severe adverse events in children younger than 19 years with IBD. Overall, the registry collected data on ten prespecified rare and severe adverse events in children with IBD, as established by a panel of paediatric IBD experts, via reports from paediatric gastroenterologists at participating hospitals between Nov 1, 2016, and March 31, 2023. Reporting physicians, who could only be paediatric gastroenterologists or IBD nurses reporting on behalf of paediatric gastroenterologists, were recruited through invitations sent to both national and international IBD networks and at conferences. Once per month, participating paediatric gastroenterologists received an email with an anonymous and unique link to an online survey asking them to report whether any of ten rare and severe adverse events had occurred in a patient in their paediatric-IBD population in the previous month. Prevalent or retrospective rare and severe adverse events were excluded, as were events occurring in children with an unconfirmed diagnosis of IBD or for whom inflammatory colitis was part of a monogenic immunodeficiency disorder. Duplicates and events that did not meet the definitions and criteria were excluded. Physicians could also report other, non-categorised adverse events if they considered them rare and severe. In case of no response, up to two reminders were sent for each per-month survey. Annual denominator data surveys were sent to obtain the total number of person-years for the estimation of incidence rates, which were calculated via Poisson regression models.

Responses were gathered from 220 paediatric gastroenterologists from 167 centres. 121 centres were in Europe, 23 centres were in North America, 17 centres were in Asia, and six centres were in Oceania. Combined, the total population with paediatric IBD consisted of an estimated 30 193 children with 114 528 person-years of follow-up. 451 adverse events were initially reported. After excluding and reorganising adverse events, 402 were eligible; 261 (65%) were categorised and 141 (35%) were non-categorised. The most frequently reported adverse events were venous-thromboembolic events (n=66), renal failure (n=43), opportunistic infections (n=42), and cancer (n=33). Haemophagocytic lymphohistiocytosis (n=4) and liver failure (n=3) were the least frequently reported adverse events. Incidence rates per 10 000 person-years were 5·50 (95% CI 4·25-6·97) for venous-thromboembolic events, 3·75 (2·74-4·99) for renal failure, 3·67 (2·67-4·89) for opportunistic infection, and 2·88 (2·01-3·98) for cancer. Of 66 venous-thromboembolic events, 31 (47%) involved cerebral venous sinus thrombosis at an incidence rate of 2·71 (95% CI 1·86-3·77).

The PIBD-SETQuality Safety Registry enabled us to identify incidence rates of rare and severe adverse events in children with IBD. Our findings can guide physicians and enhance awareness of the incidence of adverse events in children with IBD that are considered to be rare.

EU Horizon 2020 Research and Innovation Programme.

Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed.

To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease.

We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks.

We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036).

First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease.

NCT02517684.

This study reports the complication and disease recurrence rates for ileocecal resection for pediatric and adult Crohn's disease (CD) and identifies perioperative risk factors for these adverse outcomes in the two groups. Patients who underwent ileocecal resection for CD in a tertiary hospital in Italy (2010-2021) were included. Risk factors for postoperative complications and clinical and surgical disease recurrences were investigated with multivariate models. A total of 96 patients were included (children, 25%). There were no intraoperative complications. Thirty-one (32.3%) patients experienced 35 (36.5%) postoperative complications, and five (5.2%) were severe (Clavien-Dindo III-IV-V), with no intergroup difference for either overall postoperative complication rate (p = 0.257) or severe postoperative complication rate (p = 0.097). Most of these (77.1%) occurred within 30 days after surgery, especially in adults (p = 0.013). The multivariate analysis did not show risk factors for postoperative complications. Clinical and surgical recurrence rates after 5 years were 46.8% and 14.6%, respectively, with no intergroup rate differences. Clinical disease recurrence was positively correlated with previous abdominal surgery (p = 0.047) and negatively correlated with preoperative Hb levels (p = 0.046). A positive correlation was found between perianal disease and both clinical (p = 0.045) and surgical disease recurrences (p = 0.045). Urgent surgery was positively associated with surgical disease recurrence (p = 0.045). Notably, no children underwent urgent surgery in this study. In conclusion, the risk of postoperative complications among CD patients receiving ileocecal resection remains high, but most of them are nonserious. Some factors, such as urgent surgery, may increase the risk of disease recurrences.

Surgical management of pediatric Crohn's disease is fundamentally palliative, aiming to treat the sequalae of complicated disease while preserving intestinal length. Multidisciplinary discussion of risk factors and quality of life should take place prior to operative intervention. Though the surgical management of pediatric Crohn's disease is largely based on the adult literature, there are considerations specific to the pediatric population - notably disease and treatment effects on growth and development. Intrabdominal abscess is approached with percutaneous drainage when feasible, reserving surgical intervention for the patient who is unstable or failing medical therapy. Pediatric patients with fibrostenotic disease should be considered for strictureplasty when possible, for maximum preservation of bowel length. Patients with medically refractory Crohn's proctocolitis should be treated initially with fecal diversion without proctocolectomy.

Management of pediatric-onset Crohn's disease uniquely necessitates consideration of growth, pubertal development, psychosocial function and an increased risk for multiple future surgical interventions. Both medical and surgical management are rapidly advancing; therefore, it is increasingly important to define the role of surgery and the breadth of surgical options available for this complex patient population. Particularly, the introduction of biologics has altered the disease course; however, the ultimate need for surgical intervention has remained unchanged. This review defines and evaluates the surgical techniques available for management of the most common phenotypes of pediatric-onset Crohn's disease as well as identifies critical perioperative considerations for optimizing post-surgical outcomes.

Although surgical management of the ileocolic segment in pediatric Crohn's disease is not curative, the main goal of therapy is to allow for growth, adequate nutrition, and age-appropriate development. Recurrent disease at the site of anastomosis presents as a major morbidity. Several factors have been implicated in the development of surgical recurrence though data in the literature is scarce. This review explores the epidemiology of recurrent ileocolic disease following primary surgery, indications for surgical intervention, and techniques reported in the literature. Pediatric data is scarce, and therefore, much of it is extrapolated from adult literature.

For children with inflammatory bowel disease (IBD), optimal levels of vitamin D are ascribed anti-inflammatory and essential immune system roles that are associated with reduced disease activity, lower postoperative recurrence, and higher quality of life. International guidelines for vitamin D testing and supplementation provide inconsistent recommendations. The aim of this study was to survey Australasian pediatric gastroenterologists to ascertain current practices of vitamin D testing and supplementation for children with IBD.

Members of the Australian Society of Pediatric Gastroenterology, Hepatology and Nutrition were invited to complete an online survey. Respondents were asked to provide information on frequency of vitamin D testing and supplementation, adherence, and benefits of vitamin D to children with IBD.

Thirty-two (54%) pediatric gastroenterologists completed the survey: 27 (84%) from Australia and 5 (16%) from New Zealand. The majority (90%) tested vitamin D levels at diagnosis and follow up, although testing frequency varied (1-3 times/year) and only 8 (28%) tested seasonally. While 28 (88%) recommended supplementation based on serum levels, inconsistent cutoff values were used. Most respondents (n = 27) recommended Stoss (single dose) or vitamin D3 (daily for 8-12 weeks). The majority (84%) rated the overall benefit of optimal vitamin D levels at ≥6/10, although fewer (54%) rated the benefit to disease activity at ≥6/10.

The results indicate that standardized guidelines for vitamin D testing and supplementation for clinicians caring for children with IBD throughout Australasia are required. Consensus statements may optimize the care of children with IBD in this diverse geographical region.

Inflammatory bowel diseases [IBD] are heterogeneous in the frequency and severity of their flare-ups. We aimed to describe disease activity patterns in a Danish nationwide paediatric IBD cohort.

Paediatric patients [<18 years at diagnosis] with Crohn's disease [pCD] or ulcerative colitis [pUC] in the study period from 1996 to 2018 were identified in national registers. Disease activity [severe, moderate-to-mild, remission] was assessed at diagnosis according to medications prescribed, hospitalizations, and surgeries.

In total, 1965 pCD and 1838 pUC incident patients were included in the cohort. At diagnosis, severe disease activity was found in 87%/80% of pCD/pUC and in addition 6.1% of pUC patients had undergone a colectomy during the first year after diagnosis. Five years after diagnosis, the annual proportions of pCD/pUC with no disease activity were 70%/61%, and 10 years after diagnosis the proportions were 72%/64%. Colectomy was required in 6.1, 12, and 16% of pUC patients after 1, 5 and 10 years. No improvement of disease activity was seen in the proportion of prevalent pCD [N = 2515] and pUC [N = 2428] in the study period 2000-2018 concomitant with the introduction of biological treatment. However, decreasing disease activity was the most common pattern in both pCD and pUC [43 and 47%], respectively.

pIBD was characterized by a high proportion of patients with severe activity at diagnosis, followed by an improvement after 5 and 10 years of follow-up. Notably, the proportion of patients with no disease activity was unchanged when biological treatment was introduced and the number of colectomies in pUC remained high.

Pediatric Crohn's disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene expression. Gene expression data was generated from 101 formalin-fixed, paraffin-embedded (FFPE) ileal and colonic biopsies obtained from treatment-naïve CD patients and controls. Clinical outcomes including development of strictures or fistulas and progression to surgery were analyzed using differential expression and modeled using machine learning. Differential expression analysis revealed downregulation of pathways related to inflammation and extra-cellular matrix production in patients with strictures. Machine learning-based models were able to incorporate colonic gene expression and clinical characteristics to predict outcomes with high accuracy. Models showed an area under the receiver operating characteristic curve (AUROC) of 0.84 for strictures, 0.83 for remission, and 0.75 for surgery. Genes with potential prognostic importance for strictures (REG1A, MMP3, and DUOX2) were not identified in single gene differential analysis but were found to have strong contributions to predictive models. Our findings in FFPE tissue support the importance of colonic gene expression and the potential for machine learning-based models in predicting outcomes for pediatric CD.

The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization.

Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes.

Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n = 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26-0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13-0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66-10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation.

aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile.

Anti-TNF agents are the first biologic treatment option in inflammatory bowel disease (IBD). The long-term effectiveness of this strategy at the population level is poorly known, particularly in pediatric-onset IBD.

All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011 in the EPIMAD population-based registry were followed retrospectively until 2013. Among patients treated with anti-TNF, the cumulative probabilities of anti-TNF failure defined by primary failure, loss of response (LOR) or intolerance were evaluated. Factors associated with anti-TNF failure were investigated by a Cox model.

Among a total of 1,007 patients with CD and 337 patients with UC, respectively 481 (48%) and 81 (24%) were treated with anti-TNF. Median age at anti-TNF initiation was 17.4 years (IQR, 15.1-20.9). Median duration of anti-TNF therapy was 20.4 months (IQR, 6.0-59.9). In CD, the probability of failure of 1st line anti-TNF at 1, 3 and 5 years was respectively 30.7%, 51.3% and 61.9% for infliximab and 25.9%, 49.3% and 57.7% for adalimumab (p = 0.740). In UC, the probability of failure of 1st line anti-TNF therapy was respectively 38.4%, 52.3% and 72.7% for infliximab and 12.5% for these 3 timepoints for adalimumab (p = 0.091). The risk of failure was maximal in the first year of treatment and LOR was the main reason for discontinuation. Female gender was associated with LOR (HR, 1.48; 95%CI 1.02-2.14) and with anti-TNF withdrawal for intolerance in CD (HR, 2.31; 95%CI 1.30-4.11) and disease duration (≥ 2 y vs. < 2 y) was associated with LOR in UC (HR, 0.37; 95%CI 0.15-0.94) in multivariate analysis. Sixty-three (13.5%) patients observed adverse events leading to termination of treatment (p = 0.57). No death, cancer or tuberculosis was observed while the patients were under anti-TNF treatment.

In a population-based study of pediatric-onset IBD, about 60% in CD and 70% in UC experienced anti-TNF failure within 5 years. Loss of response account for around two-thirds of failure, both for CD and UC.

Exclusive enteral nutrition (EEN) therapy effectively induces remission in pediatric Crohn's disease (CD). However, this may depend on the type of enteral formula used. Moreover, data on the efficacy of amino acid-based EEN are limited. Thus, we aimed to prospectively evaluate the efficacy of amino acid-based formulas for EEN in pediatric patients with active CD.

Patients with active CD aged between 6 and 17 years were recruited into this prospective study from four hospitals in China between March 2019 and December 2021. Patients received EEN for 8 weeks. Inflammatory and nutrition-associated indices were evaluated at 0, 4, and 8 weeks after treatment. Paired t-tests and Wilcoxon signed-rank tests were used to compare continuous and categorical variables before and after intervention, respectively.

Twenty-four patients were included in the analysis. After an 8-week intervention period, the CD activity index significantly decreased (26.3 ± 12.2 vs 7.1 ± 8.3, P < 0.001). Most patients (66.7%) achieved complete clinical remission. Among the 22 patients who had ulcers and erosions diagnosed endoscopically at baseline, 10 (45.5%) achieved complete mucosal healing. The degree of thickening of the intestinal wall was significantly reduced after EEN intervention, with a transmural healing rate of 42.9%. Furthermore, the serum inflammatory markers decreased and there was a significant improvement in the nutrition-related indices (P < 0.05). There were no severe adverse effects.

Amino acid-based EEN is effective and safe for treating pediatric-onset CD. Studies with larger sample sizes and mechanistic and follow-up studies are required to further validate these findings.

Crohn's disease is a complex, relapsing and remitting inflammatory disorder of the gastrointestinal tract with a variable disease course. While the treatment options for Crohn's disease have dramatically increased over the past two decades, predicting individual patient response to treatment remains a challenge. As a result, patients often cycle through multiple different therapies before finding an effective treatment which can lead to disease complications, increased costs, and decreased quality of life. Recently, there has been increased emphasis on personalized medicine in Crohn's disease to identify individual patients who require early advanced therapy to prevent complications of their disease. In this review, we summarize our current approach to management of Crohn's disease by identifying risk factors for severe or disabling disease and tailoring individual treatments to patient-specific goals. Lastly, we outline our knowledge gaps in implementing personalized Crohn's disease treatment and describe the future directions in precision medicine.

Pediatric Crohn's disease commonly presents with moderate-to-severe intestinal inflammation with a greater risk of complications if remission is not achieved. Anti-tumor necrosis factor therapies have offered the possibility of deep and durable remission; however, many children do not respond or no longer respond over time. Further, some children do not require broader systemic immunosuppression to achieve remission and are better served by an alternative treatment strategy. Proper utilization of advanced biologic and small-molecule therapies, which have become available for adult patients since anti-tumor necrosis factor medications, is paramount for tighter disease control for a large proportion of children. Newer advanced therapies such as anti-integrin and anti-interleukin biologics, and several small-molecule agents capitalize on various mechanisms through narrower immunologic targets and reduced immunogenicity. Given limited regulatory approvals of these agents for use in children with Crohn's disease, clinicians continue to rely on data extrapolated from clinical trials in adult patients, sparse pediatric studies, and a growing real-world experience for treatment selection and optimization. In this article, we discuss currently available treatment options, pipeline drugs, and relevant data as they pertain to some of the most pressing clinical challenges faced in treating pediatric Crohn's disease.

Pediatric inflammatory bowel diseases (IBDs) are chronic, idiopathic illnesses of the digestive tract, which can impact adversely on children's quality of life and burden health systems. International studies have shown these diseases are increasing. The aim was to describe pediatric IBD epidemiology across Oceania by conducting a systematic review and meta-analysis of incidence and prevalence.

Medline, EMBASE and Web of Science databases were searched in October 2022 for studies reporting rates of IBD, Crohn disease (CD), or ulcerative colitis (UC) in children (≤19 years). Several data collection methodologies were included and pooled estimates of incidence and prevalence were calculated using a random effects model with I2 measures of heterogeneity.

Nineteen articles provided 15 incidence and 7 prevalence studies. Fourteen studies were from Australia, 8 studies from New Zealand, and no studies were found from the Pacific Islands. Study dates ranged from 1950 to 2020 with 11 studies using population-based designs. Pooled estimates for annual incidence were IBD 4.1 (3.4-4.8, I2 = 98.7), CD 2.3 (1.9-2.7, I2 = 98.6), and UC 0.9 (0.6-1.1, I2 = 96.8) per 100,000 person-years. Prevalence rates were IBD 36.0 (23.5-48.5, I2 = 98.4), CD 23.2 (6.6-39.8, I2 = 97.8), and UC 7.6 (2.7-12.5, I2 = 99.6) per 100,000 persons.

Pediatric IBD is prevalent in Oceania with high incidence rates, particularly for CD. Low rates of IBD were observed in indigenous Australian, Māori, and New Zealand Pacific children and there were no studies from the Pacific Islands highlighting this as an area in need of further research.

Inflammatory bowel diseases (IBDs) including Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U) are chronic inflammatory disorders which can affect the gastrointestinal tract. Anti-tumor necrosis factors antibodies (anti-TNFα) such as infliximab (IFX) and adalimumab (ADA) are the first line biological therapy for severe or complicated IBDs in pediatric age. Second line therapeutic options as vedolizumab (VDZ) and ustekinumab (UST) are currently used off-label in pediatric age. Furthermore, despite optimization of biologics, a great proportion of patients may fail to respond to biologic agents (up to 30%) or lose response over the time (around 50%) hence these patients may be left without another valid therapeutic option. Consequently, several efforts have been made in the last years in order to develop new drugs and to contrive new therapeutic strategies. Small molecule drugs (SMDs) and combination therapy with either two biologic agents or with a SMD and a biological agent have recently been proposed. Data on safety and efficacy of these new therapeutic options are limited. The objective of the present review is to summarize the most up-to-date available literature in pediatric IBD.

Patients with pediatric inflammatory bowel disease (pIBD) are at an increased risk for complications and comorbidities including infection, nutritional deficiencies, growth delay, bone disease, eye disease, malignancy, and psychologic disorders. Preventative health maintenance and monitoring is an important part to caring for patients with pIBD. Although practice is variable and published study within pIBD is limited, this article summarizes the important field of health-care maintenance in pIBD. A multidisciplinary approach, including the gastroenterologist provider, primary care provider, social worker, psychologist, as well as other subspecialists is necessary.

The application of fecal calprotectin in the relapse of inflammatory bowel disease remains uncertain in children and adolescents. We systematically searched the common databases for eligible studies. Judgment of diagnostic accuracy included pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and pooled area under the receiver operating characteristic curve. Ultimately, a total of 414 participants from six studies were included. The combined sensitivity, specificity, PLR, and NLR with 95% confidence intervals (CIs) were 0.85 (95% CI = 0.65 to 0.79), 0.71 (95% CI = 0.52 to 0.85), 2.95 (95% CI = 1.71 to 5.09), and 0.21 (95% CI = 0.08 to 0.51), respectively. The area under the summary receiver operating characteristic curve was 0.85, and the DOR was 14.14 (95% CI = 4.46 to 44.80). Our study showed that fecal calprotectin as a biomarker to predict the clinical relapse of inflammatory bowel disease during remission in children and adolescents is effective and worth applying. [Pediatr Ann. 2023;52(9):e357-e362.].

Despite the enlarging therapeutic armamentarium, IBD is still plagued by a therapeutic ceiling. Precision medicine, with the selection of the "rights," may present a solution, and this review will discuss the critical process of pairing the right patient with right therapy at the right time. Firstly, the review will discuss the shift to and evidence behind early effective therapy. Then, it delves into promising future strategies of patient profiling to identify a patients' biological pathway(s) and prognosis. Finally, the review lays out practical considerations that drive treatment selection, particularly the impact of the therapeutic sequence.