BACKGROUND:The etiology of pediatric-onset immune-mediated inflammatory disease (pIMID) is poorly understood, particularly the interplay of early-life adversities. We explored how interrelated early-life adversities affect the pIMID risk in a life-course birth cohort. METHODS:We included all children born in Denmark between 1981 and 2015. Adversities encountered during the first 1000 days of life were obtained from the Danish registries and categorized into three dimensions: biological, material, and familial. The outcome was developing pIMID (autoimmune liver disease, inflammatory bowel disease, juvenile idiopathic arthritis, vasculitis, and systemic lupus erythematosus) between ages 2 and 18. Cox proportional hazards and additive hazard model assessed the effect of the cumulative adversity load on developing pIMID. A machine learning model identified exposure patterns associated with increased absolute risk estimates. RESULTS:Of 2,123,827 children, 9070 developed pIMID. The cumulative burden of biological adversities was associated with higher risks of developing pIMID; aHR of two adversities was 1.23 (95 %CI: 1.07 to 1.41), aHR of ≥4 adversities was 1.8 (95 %CI: 1.4 to 2.2). Conversely, >2 familial adversities were associated with a reduced risk (0.66 [95 %CI: 0.41 to 1.1]). No associations were found in the material dimension. The machine learning model identified a pattern of adversities associated with a five-fold higher pIMID risk in a population subgroup. CONCLUSION:Early-life biological adversities are important risk factors for developing pIMID. The lower risk observed in the familial dimension was unexpected but may reflect delayed diagnosis in socially vulnerable families. This potential inequality in healthcare needs further exploration.

Abstract Background Children diagnosed with inflammatory bowel disease (IBD) often experience a more severe disease course than adults, and up to 50% develop extra-intestinal manifestations (EIMs).1 The most common EIM is juvenile idiopathic arthritis (JIA), affecting approximately 16–33% of paediatric patients with IBD, increasing risks of long-term complications such as uveitis, joint destruction, reduced physical activity, and psychological challenges.2 MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression and play key roles in immune and inflammatory processes. They hold potential as biomarkers and therapeutic targets in IBD, offering opportunities for advancements in early diagnosis and treatment.3 The aim of this study was to investigate whether miRNA expressed in intestinal biopsies can identify paediatric patients with IBD at risk of developing JIA. Methods Paediatric patients under 18 years of age diagnosed with IBD between 1 May 2021 and 1 May 2024, along with healthy controls from the Copenhagen IBD Inception Cohort, were enrolled.4 One mucosal biopsy from either the ileum or colon was collected from each patient during their index endoscopy. Additionally, biopsies from paediatric patients diagnosed with both IBD and JIA (IBD-JIA) prior to 1 May 2021 were retreived from the Department of Pathology at Copenhagen University Hospital, Hvidovre. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue, and miRNA expression was analysed using the GeneChip™ microarray platform. Results The study included 62 biopsies from 62 patients (27 with IBD, 25 with both IBD and JIA (IBD-JIA), and 10 HC). Patient characteristics are shown in table 1. Analysis identified 532 significantly differentially expressed probe sets (adjusted p<0.05) among IBD, IBD-JIA, and HC (Figure 1). Among these, 123 probe sets, including miR-486-2, let-7b-5p, and miR-92a-3p, exhibited a more than two-fold change (adjusted p<0.001) between IBD and IBD-JIA, with 120 miRNAs upregulated and 3 downregulated in IBD-JIA compared to IBD. Conclusion This study provides the first evidence of differential miRNA expression in paediatric patients with IBD and co-occurring JIA. These miRNAs may serve as novel biomarkers for the early detection, aiding in timely diagnosis and better management of paediatric IBD patients. References 1.Gordon H, Burisch J, Ellul P, et al. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis. 2024;18(1):1-37. doi:10.1093/ecco-jcc/jjad108 2.Cardile S, Romano C. Current issues in pediatric inflammatory bowel disease-associated arthropathies. World J Gastroenterol. 2014;20(1):45-52. doi:10.3748/wjg.v20.i1.45 3.Alfaifi J, Germain A, Heba AC, et al. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2023;29(6):986-999. doi:10.1093/ibd/izac250 4.Attauabi M, Madsen GR, Bendtsen F, et al. Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study): the protocol for a Copenhagen IBD Inception Cohort Study. BMJ Open. 2022;12(6). doi:10.1136/bmjopen-2021-055779

Abstract Background Perianal Crohn's disease (CD) is characterised by fistulae and/or abscesses in the anal region and leads to significant morbidity. We aimed to estimate the incidence and describe the disease course of perianal disease in paediatric-onset CD patients (<18 years at CD diagnosis). Methods In a nationwide registry-based cohort study, we identified all incident patients with paediatric-onset CD in Denmark from 1980 to 2018. We followed the patients until emigration, death, or December 31, 2022, and recorded the cumulative incidence of perianal disease based on data from the National Patient Registry. Using perianal disease as an exposure, we further assessed the risks of major abdominal surgeries, colorectal and anal cancer, and mortality. We used multivariate Cox regression analysis with biological age as the timescale to estimate hazard ratios adjusted (aHR) for sex, family income, and calendar year of CD diagnosis. Results We identified 2,356 paediatric-onset CD patients, of whom 769 (32.6%) were diagnosed with perianal CD. Total follow-up time was 38,584 person-years. The cohort is described in detail in Table 1. The cumulative incidence of perianal CD was 14.0%, 21.1%, and 28.1% after 1, 5, and 10 years after CD diagnosis, respectively. The incidence density during the study period was 29 (95% confidence interval [CI]: 26.8–30.9) per 1,000 person-years, corresponding to 45.2% after 30 years of follow-up. Among the 769 patients with perianal CD, 460 (59.8%) had perianal abscesses, 399 (51.9%) perianal fistula, and 627 (81.5%) patients underwent perianal surgery. Of CD patients with perianal disease, 308 (40.1%) required a stoma compared to 147 (9.3%) of patients without, corresponding to an aHR of 2.8 (95% CI: 2.3-3.4). When comparing CD patients with perianal disease to those without, the aHRs for major abdominal surgery, cancer, and mortality were 1.5 (95%CI: 1.3–1.8), 0.8 (95% CI: 0.2–2.7), and 1.5 (95%CI: 0.9–2.7), respectively. Of the 68 patients that died, 35 (2.2/1,000 person-years) had perianal disease, whereas 33 (1.4/1,000 person-years) had not. Further risk analysis is presented in Figure 1. Conclusion In this nationwide cohort of patients with paediatric-onset CD (<18 years at CD diagnosis), 29 patients per 1,000 person-years developed perianal disease between 1980-2022. Patients with perianal CD were more likely to require major abdominal surgery, including stoma surgery, and had a higher risk of mortality compared to patients without perianal CD. Our study underlines the severity of perianal disease in paediatric-onset CD.

Abstract Background Cytokines play a central role in the aetiology, disease severity and treatment of adult-onset inflammatory bowel disease (IBD)1. However, despite the aggressive phenotype reported in paediatric-onset IBD, little is known about the cytokine levels in paediatric-onset IBD. This systematic review and meta-analysis aimed to summarize findings of cytokine levels in peripheral blood in patients with paediatric-onset IBD compared to healthy controls. Methods This systematic review followed the PRISMA guidelines2 and was registered at Prospero [CRD42024579684]. A literature search was performed on the 1st of August 2024 in PubMed, EMBASE, Web of Science and Scopus. We included studies that reported levels of cytokines in plasma or serum, in patients with paediatric-onset IBD and healthy controls. To ensure a complete overview, we did not exclude studies based on patients’ treatment status. Pooled effect sizes of mean values were calculated using Hedges’ g for any cytokine reported by two or more studies. The Newcastle-Ottawa scale was used for quality assessment. Results The literature search revealed 10,110 papers (4,582 duplicates), and 5,528 articles were independently screened by two authors. Twenty-one articles met the inclusion criteria including a total of 950 patients with paediatric-onset IBD, and 481 healthy controls. Studies reported on 57 different cytokines. Meta-analysis was performed for interleukin-6 (IL-6) (12 studies, of which 7 provided mean values) and tumour necrosis factor-α (TNF-α) (7 studies, of which 2 provided mean values). Mean values of other cytokines were not provided by two or more studies, and meta-analysis could therefore not be performed. Pooled effect sizes showed increased levels of IL-6 (standardized mean difference: 1.99, 95% confidence interval: 1.15-3.26). However, the heterogeneity between studies was high (Figure 1). Levels of TNF-α did not differ between patients and controls (standardized mean difference: 0.36 95% confidence interval: -0.08-0.79). Overall, the included studies had moderate-good quality. Conclusion IL-6 was increased in the peripheral blood of patients with paediatric-onset IBD. Data on other cytokines were scarce. References 1)Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-342. doi:10.1038/nri3661 2)Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Published 2021 Mar 29. doi:10.1136/bmj.n71

Abstract Background Psychological and emotional stress can cause inflammation, leading to immune-mediated inflammatory diseases (IMID) and impact the disease course in adults with IBD but the relationship in children remains understudied. [1,2] In a population-based cohort study, we aimed to estimate the effect of childhood adversities on developing a severe disease course in paediatric-onset IBD (pIBD) and IMID (pIMID) Methods Using the Danish registries, we identified all individuals born between 1981 and 2001 who were diagnosed with pIMID before age 18 (defined as IBD [most common pIMID], autoimmune liver disease, juvenile idiopathic arthritis, systemic lupus erythematosus, or vasculitis). We used nationwide health and socioeconomic registries to model childhood adversity from ages 0 to 15. We divided it into 5 trajectories: low adversity, early-life material deprivation, persistent material deprivation, loss or threat of loss, and high adversity.[3] The trajectories were modelled based on poverty, unemployment, death or severe illness, parental drug or alcohol abuse, maternal separation, or foster care. The outcome was developing a severe disease course as defined by requiring biologics, steroid dependency, surgery (disease-specific), hospitalisation (>5 days), and complications indicative of disease progression. We used Cox regression to estimate sex-adjusted hazard ratios (aHR) with age as the underlying timescale. Person time started at pIMID diagnosis and ended at the earliest of the outcome, emigration, death, or 31 DEC 2021. The low adversity trajectory was used as comparator for all analyses. Results Of 5,847 incident pIMID patients (3,014 [52%] pIBD), 3,829 (65%) developed a severe pIMID disease course. Table 1 presents patient characteristics. Patients with persistent material deprivation were more likely to develop steroid dependency (aHR 1.15 [95%CI:1.01-1.30]), require surgery (1.30 [95%CI: 1.07-1.58)] and prolonged hospitalisation (aHR 1.67 [95%CI: 1.42-1.96]), and develop complications (aHR 1.32 [95%CI: 1.03-1.70]). Patients with persistent material deprivation and high adversity were less likely to receive biologics (aHR 0.86 [95%CI: 0.75-0.99] and aHR 0.65 [95%CI: 0.48-0.87], respectively). Figure 1 presents the cumulative risks of developing a severe disease course. Conclusion Childhood adversity, especially persistent material deprivation, is associated with developing a severe disease course in pIBD and pIMID, indicating substantial social inequality despite the universal free healthcare setting. It should be investigated whether this effect represents physiological changes or is mediated through socioeconomic factors such as poor family support. References 1:Schneider KM, Blank N, Alvarez Y, et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell. 2023;186(13):2823-2838.e20. doi:10.1016/j.cell.2023.05.001 2:Zhao J, Xue E, Zhou S, et al. Allostatic load increases the incidence and risk of adverse prognosis in inflammatory bowel disease. Aliment Pharmacol Ther. 2024;60(8):1062-1074. doi:10.1111/apt.18217 3:Rod NH, Bengtsson J, Budtz-Jørgensen E, et al. Trajectories of childhood adversity and mortality in early adulthood: a population-based cohort study. The Lancet. 2020;396(10249):489-497. doi:10.1016/S0140-6736(20)30621-8

BACKGROUND & AIMS:Perianal Crohn's disease (CD) is characterized by fistulae and/or abscesses in the anal region and leads to significant morbidity. We aimed to estimate the incidence and describe the disease course of perianal disease in pediatric-onset CD. METHODS:In a nationwide registry-based study, we included patients diagnosed with pediatric-onset CD (<18 years) between 1980 and 2018. Cumulative incidence of perianal disease was calculated. Cox regression was used to assess the risks of major abdominal surgeries, colorectal cancer, and mortality. Hazard ratios were adjusted (aHR) for sex, family income, and year of CD diagnosis. RESULTS:We identified 2356 patients with pediatric-onset CD, of whom 769 (32.6%) developed perianal CD. The cumulative incidence of perianal CD was 14.0%, 21.1%, and 28.1% after 1, 5, and 10 years. The incidence rate was 28.8 per 1000 person-years (95% confidence interval [CI], 26.8-30.9), corresponding to 45.2% after 30 years. Perianal abscesses developed in 460 patients (59.8%) and fistulas in 399 (51.9%). When comparing patients with/without perianal disease, the aHR for major abdominal surgery, cancer, and mortality were 1.5 (95% CI, 1.3-1.8), 0.8 (95% CI, 0.2-2.7), and 1.5 (95% CI, 0.9-2.7). A stoma was required in 308 (40.1%) and 147 (9.3%) patients with and without perianal disease, respectively (aHR, 2.8; 95% CI, 2.3‒3.4). Of mortalities, 35 had perianal disease (4.6%; mortality rate, 2.2/1000 person-years) and 33 did not (2.1%; mortality rate, 1.4/1000 person-years). CONCLUSIONS:We report a high incidence of perianal disease in pediatric-onset CD. Patients with perianal disease had higher risks of major abdominal surgery and requiring stomas than patients without perianal CD.

Background: Pediatric-onset ulcerative colitis (pUC) represents a more aggressive disease phenotype compared with adult-onset UC. We hypothesized that this difference can, in part, be explained by the composition of the microbiota. Methods: In a prospective, longitudinal study, we included pediatric (N = 30) and adult (N = 30) patients with newly or previously (>1 year) diagnosed UC. We analyzed the microbiota composition in the mucosa-adherent microbiota at baseline, using 16S rRNA gene sequencing, and the fecal microbiota at baseline and at 3-month intervals, using shotgun metagenomics. Results: For fecal samples, the bacterial composition differed between pUC and aUC in newly diagnosed patients (beta-diversity, Bray Curtis: R2 = 0.08, P = .02). In colon biopsies, microbial diversity was higher in aUC compared with pUC (alpha-diversity, Shannon: estimated difference 0.54, P = .006). In the mucosa-adherent microbiota, Alistipes finegoldii was negatively associated with disease activity in pUC while being positively associated in aUC (estimate: -0.255 and 0.098, P = .003 and P = .02 in pUC and aUC, respectively). Finally, we showed reduced stability of the fecal microbiota in pediatric patients, evidenced by a different composition of the fecal microbiota in newly and previously diagnosed pUC, a pattern not found in adults. Conclusions: Our results indicate that pediatric UC patients have a more unstable fecal microbiota and a lower alpha diversity than adult patients and that the microbiota composition differs between aUC and pUC patients. These findings offer some explanation for the observed differences between pUC and aUC and indicate that individualized approaches are needed if microbiota modifications are to be used in the future treatment of UC.

BACKGROUND:The gut microbiome plays a crucial role in the pathogenesis and progression of inflammatory bowel disease (IBD). Understanding the dynamics of the gut microbiome in relation to treatment can provide valuable insights into disease management and therapy strategies. The aim of this study is to investigate if diversity and composition of the gut microbiome correlate with time since treatment and disease activity during maintenance infliximab (IFX) therapy among children with IBD. METHODS:Data was collected from IBD patients aged 10-17 participating in an IFX-eHealth study. IFX infusions were administered in 4-12-week intervals based on weekly faecal calprotectin (FC) combined with symptom scores. Excess stool samples underwent microbiome profiling using 16S rRNA gene sequencing. Microbiome features, including alpha diversity and single taxa, were analysed for three key variables: 1) weeks-since-treatment, 2) FC, and 3) symptom score. RESULTS:From 25 patients (median age 14.4 years) diagnosed with Crohn´s Disease (n = 16) or ulcerative colitis (n = 9), microbiota were analysed in 671 faecal samples collected across 15 treatment intervals. A significant decrease over time in Shannon diversity, following the initial increase within four weeks of treatment, was found across patients. FC levels showed no association with alpha diversity (p>0.1), while symptom scores showed a negative association with Shannon and observed diversity in patients with UC. At the genus level, a lower abundance of the genera Anaerostipes and Fusicatenibacter (Firmicutes), and a greater abundance of the genus Parasutterella (Proteobacteria), were associated (p.adj<0.05) with the time elapsed since last infusion in UC specifically, while only Parasutterella was associated across the full cohort (p.adj = 1e-10). CONCLUSIONS:We found a recurring reduction over time in alpha diversity following the initial increase in diversity after an IFX infusion. Changes in an individual's microbiome may be an early sign of increasing disease activity that precedes clinical symptoms and increased FC.

Abstract Background Thiopurines are frequently used in patients with inflammatory bowel disease (IBD). The aim of this study was to assess the cancer risk of thiopurine monotherapy and thiopurine in combination with biologics compared to unexposed IBD patients. Methods Incident Danish IBD patients from 1996 to 2018 were identified in the national registers. Time at risk started at the date of IBD diagnosis and exposure status was time-dependent. Exposure was defined as registration of thiopurine and/or biologics. A lag period of 6 months was introduced at the first thiopurine registration as it was unlikely to have caused an effect on any immediate cancer case. If no new registration of thiopurines occurred 6 months from the last registration, the patient was assigned to the discontinued group. Non-melanoma skin cancer was analysed separately to avoid masking severe cancer forms and excluded from the overall cancer analyses. Cox regressions were performed to assess the risk of first cancer and risk estimates were presented as hazard ratios (HR) with 95% confidence intervals (CI). Only the incidence bar plot included non-IBD controls, matched on age, sex and municipality. Controls were unexposed to thiopurines. Results In total, 43,404 IBD patients were followed for a median of 8.2 years (IQR:3.7-14.2) from diagnosis. During follow-up, 7,736 Crohn’s disease (CD) (50.6%) and 6,632 ulcerative colitis (UC) patients (23.6%) were exposed to thiopurines. Cancer occurred in 1,292 (8.4%) CD and 1,840 (6.5%) UC patients. Both monotherapy and combination therapy were associated with developing any cancer (HR: 1.61 (95%CI:1.42-1.84) and (HR: 3.15 (95%CI:2.10-4.73), respectively) compared to unexposed IBD patients. In the elderly (>65 years), this was particularly apparent (Figure 1). The association between cancer and thiopurines was observed in non-melanoma skin-, melanoma-, urinary tract-, female genital organ-, lymphoid tissue-, colorectal- and digestive organ cancers. In patients who discontinued thiopurines, the HR returned to the level of unexposed HR: 1.01 (95%CI:0.91-1.13). The association with different cancer forms were higher in patients with >4 years and 1-4 years of thiopurine exposure, HR 1.58 (95%CI:1.37-1.82) and HR 1.24 (95%CI:1.07-1.44), compared to unexposed. Conclusion Thiopurines were associated with an increased risk of cancer in both mono- and combination therapy, especially in the elderly. This was noticeable in patients with 1-4 and >4 years of exposure, with 24% and 58% increased risk compared to unexposed. Reassuringly, discontinuation of thiopurines returned the risk to baseline and the absolute number of cancers was low. This warrants closer monitoring of all IBD patients, especially the elderly in combination therapy.

Background and Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

BACKGROUND & AIMS: Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age. METHODS: Danish national registers were used to identify incident IBD patients, exposure to drugs, and status of cancers, in 1996 to 2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer. RESULTS: We followed 43,419 patients with IBD for a median of 8.2 years (interquartile range, 3.7-14.2 years) after IBD diagnosis. Cancer was reported in 3128 (7.2%) patients with IBD. The risk of cancer was increased in patients with IBD in all age categories compared with non-IBD individuals (<50 years: adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.43-1.77; 50-65 years: aHR, 1.31; 95% CI, 1.19-1.44; and >65 years: aHR, 1.14; 95% CI, 1.05-1.24). Monotherapy (aHR, 1.36; 95% CI, 1.17-1.57) and combination therapy (aHR, 2.49; 95% CI, 1.64-3.78) were associated with an increased risk of cancer compared to unexposed patients with IBD. Among elderly patients (>65 years), the aHR was 2.79 (95% CI, 1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR, 0.89; 95% CI, 0.78-1.01). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching an aHR of 1.36 (95% CI, 1.15-1.61). CONCLUSIONS: Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than 5 years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines.

Abstract Background Approximately 20% of patients with Crohn's disease (CD) are diagnosed during childhood (pCD). At diagnosis, the vast majority (87%) of patients with pCD demonstrate severe disease activity.(1) Severe disease activity necessitates intensive treatment followed by frequent blood tests, faecal calprotectin tests, and endoscopic procedures. Ileocolonoscopy is burdensome for the patient, as bowel preparation and general anaesthesia are needed, and furthermore, the procedure is costly. In recent European guidelines for pCD management, Intestinal Ultrasound (IUS) is recommended for clinical follow-up. Our objective was to investigate the extent to which patients with pCD underwent subsequent endoscopy after having IUS performed during their follow-up regimen. Methods We conducted a retrospective descriptive cohort study, encompassing all patients with pCD at a referral center (Department of Paediatric and Adolescence Medicine, Copenhagen University Hospital, Amager and Hvidovre) who had undergone a minimum of one ultrasound examination over a 2.5-year period (May 1, 2021, to November 1, 2023). Results A total of 29 patients with pCD were enrolled in the study. Demographic data can be found in Table 1. The median follow-up since time of diagnosis was 40 months (interquartile range (IQR) 30-57). Time to the first IUS examination after diagnosis was median 28 months (IQR 13-49). The indications for IUS were as follows: Clinical suspicion of disease activity and/or elevated faecal calprotectin levels (66% of cases), evaluation of disease activity after initiating biologic therapy (10%), assessment of disease activity status (14%), suspicion of treatment failure (7%) and other indications (3%). Following the IUS procedure, 10% of patients subsequently underwent ileocolonoscopy, which was performed within 11, 14, or 53 days after IUS. Among the remaining 90% of patients, 14% underwent ileocolonoscopy 8-16 months after the IUS procedure, while 76% never had a repeat ileocolonoscopy performed after a median follow-up of 342 days (IQR 247-441) after IUS. Conclusion In 90% of patients with pCD IUS can be used to evaluate disease activity without the necessity for an ileocolonscopy in the subsequent 12 moths of follow up. References: (1) Wewer MD, Langholz E, Munkholm P, Bendtsen F, Benedict Seidelin J, Burisch J. Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018. J Crohns Colitis. 2023 Apr 3;17(3):329-337. doi: 10.1093/ecco-jcc/jjac140. PMID: 36124895.

BACKGROUND:Paediatric-onset and elderly-onset inflammatory bowel disease (IBD) present unique treatment challenges. AIMS:We investigated treatment patterns following a first and second course of systemic steroids in paediatric- and elderly-onset IBD and compared them to adult-onset IBD. METHODS:All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 2000 and 2018 were identified through the Danish healthcare registries. Patients were divided into groups based on their age at diagnosis. Kaplan-Meier plots were prepared for medications and surgeries after diagnosis and after the first and second courses of systemic steroids. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariate Cox regression analysis for steroid-sparing medications. RESULTS:1851 CD (13%) and 1687 (6%) UC patients were paediatric-onset, while 2952 (20%) CD and 5812 (23%) UC patients were elderly-onset. Paediatric-onset more frequently received immunomodulators [CD: HR: 1.64, CI: 1.52-1.77, UC: HR: 2.29, CI: 2.02-2.61] and biologics [CD: HR: 1.43, CI: 1.25-1.65, UC: HR: 1.27, CI: 0.99-1.64], while elderly-onset less frequently received immunomodulators [CD: HR: 0.39, CI: 0.35-0.44, UC: HR: 0.58, CI: 0.50-0.67] and biologics [CD: HR: 0.19, CI: 0.14-0.25, UC: HR: 0.36, CI: 0.27-0.48] compared to adult-onset age groups. After two courses of systemic steroids, elderly-onset still received less steroid-sparing medications. High frailty was associated with lower usage of medications for elderly-onset. CONCLUSION:There are significant differences in the use of steroid-sparing medication between age of onset, even after two courses with systemic steroids. High frailty could account for some of these differences in elderly-onset IBD.

Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.

LINKED CONTENTThis article is linked to Malham et al papers. To view these articles, visithttps://doi.org/10.1111/apt.17994andhttps://doi.org/10.1111/apt.18012.

Background and objectives: 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. Methods: 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-alpha antagonists (anti-TNF alpha). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR). Results: 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-TNF alpha treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1-22.6]). Conclusions: We found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNF alpha were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.

BACKGROUND:Paediatric-onset immune-mediated inflammatory diseases (pIMID) show more aggressive phenotypes than when diagnosed in adults. However, data on mortality are often extrapolated from adult studies. AIM:To estimate the effect of pIMID on mortality. METHODS:In a population-based cohort study using the nationwide Danish healthcare registers, we included all patients diagnosed with pIMID in Denmark from 1980 to 2018. PIMID were defined as ICD codes indicative of autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, lupus erythematosus, or vasculitis registered before age 18 years. All-cause mortality was the primary outcome; cause-specific mortality was the secondary outcome. We used Cox survival analysis to estimate hazard ratios (HR), and Aalen survival analysis to estimate rate differences. RESULTS:We included 11,581 individuals diagnosed with pIMID and 99,665 reference individuals, accounting for 1,371,994 person-years of follow-up. Median and interquartile (IQR) age at diagnosis was 12.6 (7.9-15.9) years. During follow-up, 152 patients with pIMID and 316 reference individuals died; adjusted HR (aHR) was 3.8 (95% confidence interval [CI] 3.1-4.7). This corresponded to 6.9 (95% CI: 5.3-8.5) additional deaths per 10,000 person-years. The strongest associations were found for gastrointestinal diseases (aHR 22.8; 95% CI 9.6-64.1), gastrointestinal cancers (aHR 19.2; 95% CI 5.0-74.2) and lymphoproliferative disorders (aHR 6.8; 95% CI 2.8-16.8). CONCLUSION:Patients diagnosed with pIMID have a fourfold higher risk of mortality when followed into early adulthood compared with reference individuals. This underlines the severe disease course of pIMID and highlights the need for multidisciplinary care.

Abstract Background Early–life antibiotic exposure has been associated with a decreased richness of the microbiome, which is associated with the development of inflammatory bowel disease (IBD). The aim of this study was to assess the risk of developing paediatric-onset IBD (pIBD) after being exposed to systemic antibiotics during the first five years of life. Methods We identified all patients < 18 years old diagnosed with pIBD in Denmark between 1995-2018 in the National Patient Registry. Data on antibiotic prescriptions during first five years of life were retrieved from the National Prescription Register. PIBD patients were matched with up to ten healthy controls. Risk estimates were presented by Hazard ratios (HR). Results We identified 1,808 patients with pIBD (989 Crohn’s disease [CD]/819 ulcerative colitis [UC]) and 17,234 matched controls. An increased risk of developing pIBD was associated with prescription of antibiotics during first five years (HR = 1.32 [95%CI: 1.2-1.5], p= <0.0001), and risk was further increased if the patient had ≥ 4 antibiotic prescriptions compared to no antibiotic prescription (HR = 1.43 [95%CI: 1.2-1.6], p= <0.0001). Prescription of broad-spectrum antibiotics increased the risk of pIBD compared to prescription of only narrow-spectrum antibiotics (HR: 1.19, [95%CI 1.0-1.4], p=0.04). When stratified by IBD subtypes, only CD was significantly associated with exposure to antibiotics (HR = 1.43 [95%CI: 1.2-1.7], p=0.0003). Conclusion In this nationwide registry-based study, we found that antibiotic exposure during first five years of life, was associated with an increased risk of pIBD. Repeated antibiotic exposures increased risk estimates.