Paediatric-onset immune-mediated inflammatory disease is associated with an increased mortality risk-A nationwide study.

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.

Short noncoding RNAs as predictive biomarkers for the development from inflammatory bowel disease unclassified to Crohn's disease or ulcerative colitis.

Numerous pathogenic processes are mediated by short noncoding RNAs (sncRNA). Twenty percent of inflammatory bowel disease (IBD) patients are labelled as IBD unclassified (IBDU) at disease onset. Most IBDU patients are reclassified as Crohn's disease (CD) or ulcerative colitis (UC) within few years. Since the therapeutic methods for CD and UC differ, biomarkers that can forecast the categorization of IBDU into CD or UC are highly desired. Here, we investigated whether sncRNAs can predict CD or UC among IBDU patients. 35 IBDU patients who were initially diagnosed with IBDU were included in this retrospective investigation; of them, 12, 15, and 8 were reclassified into CD (IBDU-CD), UC (IBDU-UC), or remained as IBDU (IBDU-IBDU), respectively. Eight IBD patients, were included as references. SncRNA profiling on RNA from mucosal biopsies were performed using Affymetrix miRNA 4.0 array. Selected probe sets were validated using RT-qPCR. Among all patients and only adults, 306 and 499 probe sets respectively were differentially expressed between IBDU-CD and IBDU-UC. Six of the probe sets were evaluated by RT-qPCR, of which miR-182-5p, miR-451a and ENSG00000239080 (snoU13) together with age and sex resulted in an AUC of 78.6% (95% CI: 60-97) in discriminating IBDU-CD from IBDU-UC. Based on the three sncRNAs profile it is possible to predict if IBDU patients within 3 years will be reclassified as CD or UC. We showed that the expression profile of IBDU patients differ from that of definite CD or UC, suggesting that a subgroup of IBDU patients may compose a third unique IBD subtype.

Disease Activity Patterns of Paediatric Inflammatory Bowel Disease: A Danish Nationwide Cohort Study (1996-2018).

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.

Mucosal expression of PI3, ANXA1, and VDR discriminates Crohn's disease from ulcerative colitis.

Differential diagnosis of inflammatory bowel disease (IBD) to Crohn's disease (CD) or ulcerative colitis (UC) is crucial for treatment decision making. With the aim of generating a clinically applicable molecular-based tool to classify IBD patients, we assessed whole transcriptome analysis on endoscopy samples. A total of 408 patient samples were included covering both internal and external samples cohorts. Whole transcriptome analysis was performed on an internal cohort of FFPE IBD samples (CD, n = 16 and UC, n = 17). The 100 most significantly differentially expressed genes (DEG) were tested in two external cohorts. Ten of the DEG were further processed by functional enrichment analysis from which seven were found to show consistent significant performance in discriminating CD from UC: PI3, ANXA1, VDR, MTCL1, SH3PXD2A-AS1, CLCF1, and CD180. Differential expression of PI3, ANXA1, and VDR was reproduced by RT-qPCR, which was performed on an independent sample cohort of 97 patient samples (CD, n = 44 and UC, n = 53). Gene expression levels of the three-gene profile, resulted in an area under the curve of 0.84 (P = 0.02) in discriminating CD from UC, and therefore appear as an attractive molecular-based diagnostic tool for clinicians to distinguish CD from UC.

Psychiatric disorders in paediatric-onset immune-mediated inflammatory diseases: a nationwide Danish study.

OBJECTIVES: To investigate the frequency of psychiatric disorders before and after onset of paediatric-onset immune-mediated inflammatory diseases (pIMID). STUDY DESIGN: In a nationwide study from 1996 to 2018, we investigated psychiatric disorders in patients with paediatric-onset inflammatory bowel diseases, autoimmune liver diseases and rheumatic diseases, using Danish national healthcare and population registers. Each case was matched with up to 10 controls from the background population. The cumulative incidence for psychiatric disorders prior to pIMID onset in patients was compared with controls. Cox proportional regression was used to estimate adjusted HRs (aHR) with a 95% CI between cases and controls after the index date. RESULTS: We included 11 208 cases (57% female) and 98 387 controls. The median age at disease onset was 12.5 years (IQR 8-15) and follow-up time 9.8 years (IQR 5-15). We found an association between psychiatric disorders before index date and a diagnosis of subsequent pIMID (OR 1.3, 95% CI 1.2 to 1.4). Notably, after index date, cases also had an increased risk (aHR 1.6, 95% CI 1.5 to 1.7) of psychiatric disorders compared with controls. This risk was increased for all groups of psychiatric disorders. Female patients had an increased risk of suicide attempt after index date (aHR 1.4, 95% CI 1.1 to 1.8). CONCLUSION: Patients with pIMID are at increased risk for a broad spectrum of psychiatric disorders both before and after onset of pIMID. The results support the need for awareness of psychiatric morbidity in this young patient group and the need for coordinated healthcare for those with comorbid states.

Early Life Oral Antibiotics Are Associated With Pediatric-Onset Inflammatory Bowel Disease-A Nationwide Study.

OBJECTIVES: Early-life environmental triggers are thought to play a larger role in pediatric-onset inflammatory bowel disease (pIBD) compared to adult-onset IBD. We aimed to assess the risk of developing pIBD after exposure to oral antibiotics during the first 5 years of life. METHODS: In a nation-wide cohort study, we identified all patients diagnosed with pIBD (<18 years at diagnosis) in Denmark between 1995 and 2018 from the National Patient Registry and matched them with up to 10 reference individuals. Antibiotic exposure was defined as being prescribed antibiotics during first 5 years of life. Data were retrieved from the National Prescription Register. Outcome was developing pIBD. Risk estimates are presented by hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: We identified 1927 pIBD patients and 18,318 reference individuals. Oral antibiotic exposure during the first 5 years of life was associated with a higher risk of developing pIBD (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). The risk was also increased if patients had ≥4 antibiotic prescriptions compared to no antibiotics (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). Broad-spectrum antibiotics increased the risk of pIBD compared to narrow-spectrum antibiotics (HR = 1.29 [95% CI: 1.2-1.4], P < 0.0001). When stratified by IBD subtypes, only Crohn disease was significantly associated with exposure to antibiotics (HR = 1.37 [95% CI: 1.1-1.7], P = 0.002). CONCLUSIONS: In this nationwide registry-based study, we found that oral antibiotic exposure during first 5 years of life was associated with an increased risk of pIBD. Repeated antibiotic exposures increased risk estimates.

Age-Related Prevalence of Open Ductus Arteriosus in Full-Term Newborns.

BACKGROUND: The ductus arteriosus is part of the fetal circulation. Normally, the vessel closes during the cardiac transition. Delayed closure is associated with complications. The aim of this study was to evaluate the age-related prevalence of open ductus arteriosus in full-term neonates. METHODS: Echocardiograms were collected in the population study, the Copenhagen Baby Heart Study. The present study included full-term neonates with an echocardiogram performed within 28 days after birth. All echocardiograms were reviewed to assess ductus arteriosus patency. RESULTS: A total of 21,649 neonates were included. In neonates examined at day zero and day seven, an open ductus arteriosus was found in 36% and 0.6%, respectively. Beyond day seven, the prevalence remained stable at 0.6%. CONCLUSION: More than one-third of full-term neonates had an open ductus arteriosus on the first day of life, declining rapidly within the first week and stabilizing below 1% after day seven.

Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients.

BACKGROUND AND AIMS: Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. METHODS: Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. RESULTS: The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). CONCLUSION: Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.

Pre- and perinatal exposures associated with developing pediatric-onset immune-mediated inflammatory disease: A Danish nation-wide cohort study.

OBJECTIVES: We aimed to identify pre- and perinatal risk factors for developing pediatric-onset immune-mediated inflammatory (pIMID). METHODS: This nation-wide, cohort study included all children born in Denmark from 1994 to 2014 identified from the Danish Medical Birth registry. Individuals were followed through 2014 and cross-linked to the continuously updated national socioeconomic and healthcare registers to obtain data on pre- and perinatal exposures (maternal age, educational level, smoking, maternal IMID, parity, mode of conception and delivery, plurality, child's sex, and birth season). The primary outcome was a pIMID diagnosis (inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, juvenile idiopathic arthritis, or systemic lupus erythematosus) before 18 years of age. Risk estimates were calculated using Cox proportional hazards model and presented by hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: We included 1,350,353 children with a follow-up time of 14,158,433 person-years. Among these, 2,728 were diagnosed with a pIMID. We found a higher risk of pIMID in children born to women with a preconception IMID diagnosis (HR: 3.5 [95%CI: 2.7-4.6]), children born by Caesarean section (HR: 1.2 [95%CI: 1.0-1.3]), and among females (1.5 [95%CI: 1.4-1.6]) than among children without these characteristics. Plural pregnancies were associated with a lower risk of pIMID than single pregnancies (HR: 0.7 [95%CI: 0.6-0.9]). CONCLUSIONS: Our results indicate a high genetic burden in pIMID but also identifies intervenable risk factors, such as Cesarean section. Physicians should, keep this in mind when caring for high-risk populations and pregnant women previously diagnosed with an IMID.

Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland.

OBJECTIVES: Pediatric-onset inflammatory bowel disease (pIBD) increases the risk of developing several different cancer forms. In this case-control study, we aimed to assess the impact of medical treatment and disease activity on the risk of developing disease-associated cancer (DAC) and treatment-associated cancer (TAC). METHODS: In a previous study, we identified 27 cases of DAC (colorectal cancer, small bowel cancer, and cholangiocarcinoma) and 28 TAC (lymphoma and skin cancer) in 6689 patients with pIBD in Denmark and Finland during the period 1992-2015. In this study, the patient charts were reviewed manually. Cancer-free patients from another population-based pIBD cohort were included as controls. We recorded data on phenotype, medical treatment, surgery, and relapses. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) to estimate the relative risk. RESULTS: We included 16 cases with DAC, 21 with TAC, and 331 controls. For DAC, lower frequencies of IBD-relapses were associated with an increased risk of cancer (OR 0.2 [95% CI: 0.04-0.8]). For TAC, we found an increased risk in patients receiving thiopurines at any point during the follow-up period (aOR: 11.7 [95% CI: 2.1-116.2]) and an association with proportion of follow-up time being exposed to thiopurines (aOR 5.6 [95% CI: 1.1-31.5]). CONCLUSIONS: In this nation-wide study, covering all pIBD patients from Denmark and Finland, we found that pIBD patients treated with thiopurines had an increased risk of TAC.

The Incidence and Prevalence of Paediatric- and Adult-Onset Inflammatory Bowel Disease in Denmark During a 37-Year Period: A Nationwide Cohort Study (1980-2017).

BACKGROUND: Incidence rates of inflammatory bowel disease [IBD] reported from developed countries are rising, with some levelling out. The aim of this study was to assess the disease burden of IBD by estimating the incidence and prevalence across age groups and projecting these to 2030 in a high-incidence country. METHODS: Using an algorithm [incorporating ICD codes, medications and histopathology], patients [n = 69 862] diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] between 1980 and 2017 were identified in the Danish National Patient Registry and included in a nationwide cohort. RESULTS: From 1980 to 2017 the overall incidence of CD increased from 5.1 [95% CI: 4.5-5.8] to 15.6 [95% CI: 14.6-16.6] per 100 000, while the incidence of UC increased from 6.2 [95% CI: 5.5-6.9] to 27.2 [95% CI: 25.9-28.6] per 100 000. For paediatric-onset CD [pCD], the incidence increased from 1.9 [95% CI: 1.2-2.8] to 9.9 [95% CI: 8.1-11.8] per 100 000 and from 1.8 [95% CI: 1.2-2.8] to 8.7 [95% CI: 7.1- 10.5] per 100 000 for paediatric-onset UC [pUC]. In 2017, the prevalence of CD and UC was 293 [95% CI: 288-297] and 523 [95% CI: 517-528] per 100 000. For pCD and pUC, the prevalence was 35 [95% CI: 31-38] and 28 [95% CI: 26-32] per 100 000. CONCLUSIONS: The incidence of paediatric- and adult-onset IBD in Denmark continues to increase and is among the highest in the world.

Psychiatric comorbidity in childhood onset immune-mediated diseases-A systematic review and meta-analysis.

AIM: To estimate psychiatric comorbidity in childhood onset immune-mediated inflammatory diseases (IMID). METHODS: The PRISMA guidelines were followed, and the protocol was registered at Prospero (ID: CRD42021233890). Literature was searched in PubMed, PsycINFO and Embase. Original papers on prevalence rates of diagnosed psychiatric disorders and/or suicide in paediatric onset inflammatory bowel disease (pIBD), rheumatic diseases (RD) and autoimmune liver diseases were selected. Pooled prevalence rates of psychiatric disorders (grouped according to ICD-10 criteria) within the various IMID were calculated using random-effects meta-analysis. Risk of bias was evaluated by the Newcastle-Ottawa scale. RESULTS: Twenty-three studies were included; 13 describing psychiatric disorders in pIBD and 10 in RD. Anxiety and mood disorders were mostly investigated with pooled prevalence rates in pIBD of 6% (95% confidence interval (CI): 4%-9%) and 4% (95%CI: 2%-8%), respectively, in register-based studies, and 33% (95%CI: 25%-41%) and 18% (95%CI: 12%-26%), respectively, in studies using psychiatric assessment. In RD, rates were 13% (95%CI: 12%-15%) for anxiety disorders and 20% (95%CI: 15%-26%) for mood disorders based on psychiatric assessment. CONCLUSION: Anxiety and depression are commonly reported in childhood onset IMID. Physicians should be attentive to mental health problems in these patients as they seem overlooked.

Clinical Features and Outcomes of Paediatric Patients With Isolated Colonic Crohn Disease.

OBJECTIVES: Adult studies suggest that patients with isolated colonic Crohn disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-caecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2. METHODS: Retrospective data was collected through the Porto Inflammatory Bowel Disease group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) on Paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to first flare, hospital admissions, initiation of anti-tumor necrosis factor-alpha (TNFα) drug, stricture and surgery. RESULTS: Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P < 0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic (pANCA) positivity significantly differed between the three groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to first flare and admission were similar between groups, patients with L1 were commenced on anti-TNFα earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2. CONCLUSIONS: Significant differences are observed in the clinical presentation and outcomes of Paediatric patients with L2, compared to patients with L1 and UC.

Mucosal microRNAs relate to age and severity of disease in ulcerative colitis.

Despite significant evidence that the expression of several microRNAs (miRNAs) impacts disease activity in patients with ulcerative colitis (UC), it remains unknown if the more severe disease phenotype seen in pediatric onset UC can be explained by an altered miRNA expression. In this study, we assessed the relationship between miRNA expression, age, and disease severity in pediatric and adult patients with UC. Using RT-qPCR, we analyzed the expression of miR-21, miR-31, miR-126, miR-142 and miR-155 in paraffin embedded rectum biopsies from 30 pediatric and 30 adult-onset UC patients. We found that lesions from adult patients had significantly higher expression levels of miR-21 compared to pediatric patients and that the expression levels of miR-31 (all patients) and miR-155 (pediatric patients only) correlated inversely with histological assessed disease severity. Using in situ hybridization followed by image analysis, the expression level estimates of miR-21 and miR-126 correlated with histological assessed disease severity. In conclusion, we found that the expression of miRNAs depends on the age of the patient and/or the severity of the disease, suggesting that miRNAs may contribute to the regulation of inflammation in UC and could be useful biomarkers in the surveillance of disease severity.

P002 Psychiatric Comorbidity and Suicide in Childhood Onset Immune-Mediated Diseases -A Systematic Review and Meta-Analysis.

BACKGROUND: The course of paediatric onset immune mediated inflammatory diseases (IMID) is both physically and mentally challenging. Emotional distress with anxiety and depressive symptoms is commonly reported, however, data on diagnosed comorbid psychiatric disorders is scarce. The aim of this study was to provide a literature overview of psychiatric comorbidity, suicide rates, and their potential risk factors, in childhood onset IMID. METHODS: This was a systematic review following the PRISMA guidelines. The protocol was registered at Prospero (ID: CRD42021233890). A literature search was made in the databases Pubmed, PsychINFO, and Embase. We included the following IMID: paediatric onset inflammatory bowel disease (pIBD), rheumatic diseases (RD) and autoimmune liver diseases. Studies that provided prevalence rates of diagnosed psychiatric disorders and/or suicide, were included. Pooled prevalence rates of psychiatric disorders (grouped according to ICD-10 criteria) reported by three or more studies, within the same IMID, were calculated using random-effects meta-analysis. Two authors independently evaluated risk of bias using the New-Castle Ottawa scale. RESULTS: Twenty-three studies met the inclusion criteria; 13 describing psychiatric disorders in pIBD and 10 in RD. No study reported on psychiatric disorders in autoimmune liver diseases. Compared to controls without somatic disease, IMID patients had an increased risk of psychiatric disorders, with anxiety and mood disorders being the most common. Prevalence rates for anxiety and mood disorders in pIBD were 6% (95% confidence interval (CI): 4%-9%) and 4% (95%CI: 2%-8%), respectively, in register-based studies, and 33% (95%CI: 25%-41%) and 18% (95%CI:12%-26%), respectively, in studies using psychiatric assessment. In RD pooled estimates were 13% (95%CI: 12%-15%) for anxiety disorders and 20% (95%CI: 15%-26%) for mood disorders. Based on single studies, risk of suicide was increased in pIBD, but not in juvenile idiopathic arthritis, the most common RD. CONCLUSION: In this systematic review, patients with childhood onset IMID had increased prevalence of psychiatric disorders compared to controls. However, only pooled estimates on emotional disorders were possible and studies investigating broad spectrum of psychiatric disorders are needed.

MicroRNA Biomarkers in IBD-Differential Diagnosis and Prediction of Colitis-Associated Cancer.

Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). These are chronic autoimmune diseases of unknown etiology affecting the gastrointestinal tract. The IBD population includes a heterogeneous group of patients with varying disease courses requiring personalized treatment protocols. The complexity of the disease often delays the diagnosis and the initiation of appropriate treatments. In a subset of patients, IBD leads to colitis-associated cancer (CAC). MicroRNAs are single-stranded regulatory noncoding RNAs of 18 to 22 nucleotides with putative roles in the pathogenesis of IBD and colorectal cancer. They have been explored as biomarkers and therapeutic targets. Both tissue-derived and circulating microRNAs have emerged as promising biomarkers in the differential diagnosis and in the prognosis of disease severity of IBD as well as predictive biomarkers in drug resistance. In addition, knowledge of the cellular localization of differentially expressed microRNAs is a prerequisite for deciphering the biological role of these important epigenetic regulators and the cellular localization may even contribute to an alternative repertoire of biomarkers. In this review, we discuss findings based on RT-qPCR, microarray profiling, next generation sequencing and in situ hybridization of microRNA biomarkers identified in the circulation and in tissue biopsies.

Paediatric hepatitis B and hepatitis C virus infections: An observational study of a Danish cohort.

AIM: The aim of this study was to describe the epidemiological and clinical characteristics in children with either chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in Denmark. METHODS: In this observational study, children and adolescents with either chronic HBV or HCV infection followed at the largest paediatric departments in Denmark between 2001 and 2013 were included. Data collection included as well epidemiological data as clinical data like virus genotype, viral load, serological markers, liver biochemistry, liver elastography and histology if available. RESULTS: The study included 131 children. None of the patients had decreased liver function or end-stage liver disease during follow-up. Ten of the 18 children who underwent liver biopsy had signs of fibrosis. Thirteen (11%) children with HBV and one (7%) child with HCV received treatment. Different indications and different treatment regimens were used. CONCLUSION: This study confirms that chronic HBV and HCV infections are often mild diseases during childhood. Nevertheless, children are at higher risk of serious liver disease early in life because of the early time of infection and probably also because of the high viral loads.

Extraintestinal Manifestations Are Associated With Disease Severity in Pediatric Onset Inflammatory Bowel Disease.

OBJECTIVES: The aim of this study was to investigate a possible association between extraintestinal manifestations (EIM) and a more severe disease course in pediatric onset inflammatory bowel disease (pIBD). METHODS: This study compares the disease course of pIBD patients (IBD diagnosis <15 years of age) with and without EIM in a population-based cohort from Denmark. Patients diagnosed with pIBD between 1998 and 2008 were included in the study and followed until December 31, 2014. Data on phenotype, treatment, relapses, and the temporal relationship between IBD relapses and activity of EIM were collected at end of follow-up by manual revision of patient charts. RESULTS: Of 333 pIBD patients, 14 (4.2%) had EIM at time of diagnosis and 47 (14.1%) developed EIM during follow-up. Median follow-up time was 9.6 years for patients with EIM and 8.8 years for patients without. In ulcerative colitis, EIM were associated with an increased risk of biological treatment and surgery (hazard ratio: 2.6; 95% confidence interval [CI]: 1.3-5.5, P = 0.008 and 2.9 [95% CI: 1.1-7.7, P = 0.03], respectively). In Crohn disease, EIM were associated with an increased relapse rate (1.3 [95% CI: 1.1-1.5], P = 0.001). Lastly, we found a positive temporal relationship between relapse of IBD and EIM activity. CONCLUSION: The presence of EIM is associated with a more severe disease course in pIBD. This should be considered when deciding treatment options, as a more aggressive treatment approach could be warranted in patients with EIM. However, prospective studies are needed to fully evaluate this.