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.

Changes in Incidence and Management of Acute Appendicitis in Children-A Population-Based Study in the Period 2000-2015.

INTRODUCTION: Recent studies suggest that the epidemiology and management of appendicitis have changed during the last decades. The purpose of this population-based study was to examine this in the pediatric population in Denmark. MATERIALS AND METHODS: Data were retrieved from the Danish National Patient Registry, the Danish Civil Registration System, and the Statbank Denmark. Patients aged 0 to 17 years diagnosed with appendicitis and appendectomized during the period 2000 to 2015 were included. The primary outcome was the annual incidences of appendicitis. Secondary outcomes were the annual percent of patients with appendicitis having a laparoscopic appendectomy, delay from admission to surgery, length of postoperative hospital stay, and 30-day postoperative mortality. RESULTS: A total of 24,046 pediatric cases of appendicitis were identified. The annual incidence steadily declined until 2008 (-29%, all ages) and then remained stable. The surgical approach of choice changed from being open appendectomy in 2000 (97%) to laparoscopic appendectomy in 2015 (94%). Simultaneously, the duration of postoperative hospital stay declined from 41 hours (median) to 17 hours. Delay from admission until surgery did not change during the period. Only one child died within the 30-day postoperative period. CONCLUSION: In accordance with other recent studies from Western countries, we found significant changes in the incidence of acute appendicitis including a decline in all age groups except those below 5 years of age, a shift toward laparoscopic appendectomy, and decreasing time spent in the hospital during the years 2000 to 2015.

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.

Complicated Disease and Response to Initial Therapy Predicts Early Surgery in Paediatric Crohn's Disease: Results From the Porto Group GROWTH Study.

INTRODUCTION: The ability to predict risk for poor outcomes in Crohn's disease [CD] would enable early treatment intensification. We aimed to identify children with CD with complications at baseline and throughout the study period who are at risk for surgery 2 years from diagnosis. METHODS: Newly diagnosed children with CD were enrolled into a prospective, multicentre inception cohort. Disease characteristics and serological markers were obtained at baseline and week 12 thereafter. Outcome data including disease activity, therapies, complications and need for surgery were collected until the end of 104 weeks. A chi-square automatic interaction detection [CHAID] algorithm was used to develop a prediction model for early surgery. RESULTS: Of 285 children enrolled, 31 [10.9%] required surgery within 2 years. Multivariate analysis identified stricturing disease at baseline (odds ratio [OR] 5.26, 95% confidence interval [CI] 2.02-13.67 [p = 0.001]), and Paediatric Crohn's Disease Activity Index [PCDAI] >10 at week 12 (OR 1.06, 95% CI 1.02-1.10 [p = 0.005]) as key predictors for early surgery. CHAID demonstrated that absence of strictures at diagnosis [7.6%], corticosteroid-free remission at week 12 [4.1%] and early immunomodulator therapy [0.8%] were associated with the lowest risk of surgery, while stricturing disease at diagnosis [27.1%, p < 0.001] or elevated PCDAI at week 12 [16.7%, p = 0.014] had an increased risk of surgery at follow-up. Anti-OmpC status further stratified high-risk patients. DISCUSSION: A risk algorithm using clinical and serological variables at diagnosis and week 12 can categorize patients into high- and low-risk groups from diagnosis.

Plasma calprotectin is superior to serum calprotectin as a biomarker of intestinal inflammation in ulcerative Colitis.

Background and aims: Despite promising results, only a few studies have been published on serum calprotectin as a biomarker in IBD. Recently, plasma measurements of calprotectin have been shown to be more reliable than serum measurements. In this study, we aim to assess plasma and serum calprotectin measurements as biomarkers of disease activity in paediatric and adult ulcerative colitis.Methods: Paediatric (5-18 years) and adult (>18 years) patients scheduled for colonoscopy due to suspected or confirmed ulcerative colitis were included prospectively. Stool and blood samples were collected at time of colonoscopy and patient symptom scores were recorded. At colonoscopy the Ulcerative Colitis Endoscopic Index of Severity was recorded. Histology was graded according to the Geboes score.Results: 84 patients where included; 30 paediatric and 54 adult patients. Plasma calprotectin had a stronger correlation to all outcome variables than serum calprotectin. Plasma calprotectin correlated positively to disease extent (Rho = 0.53, p < .0001), symptoms scores (Rho = 0.54, p = .002, only in the paediatric cohort), endoscopic scores (Rho = 0.39, p = .0003), histological scores (Rho 0.28, p = .01) and, when using endoscopic assessment of severity as reference, could discriminate active disease from patients in remission (p = .03).Conclusions: While more studies are needed to assess if plasma calprotectin can discriminate healthy individuals from ulcerative colitis, this study indicates that plasma calprotectin can be used as a biomarker of disease activity, especially in cases where faecal calprotectin measurements are cumbersome either due to patient compliance or logistical requirements.

The incidence of cancer and mortality in paediatric onset inflammatory bowel disease in Denmark and Finland during a 23-year period: a population-based study.

BACKGROUND: Recent studies report increased risks of both cancer and mortality in paediatric onset inflammatory bowel disease (pIBD) but the reproducibility of this is unknown. AIM: To estimate the risk of cancer and mortality in the Danish and Finnish pIBD population in a 23-year period compared to the general population. METHODS: The pIBD population was defined as individuals registered in the national patient registries with a diagnosis of Crohn's disease (CD), ulcerative colitis (UC) or IBD-unclassified before their 18th birthday from 1992 to 2014. This cohort was cross referenced with the national cancer and mortality registries identifying all pIBD patients who subsequently developed cancer and/ or died and followed up to the end of 2014. Risk estimates are presented as standardised incidence ratios calculated based on incidence figures from the populations. RESULTS: Six thousand six hundred and eight-nine patients with pIBD were identified (median age at follow-up 22.3 years; median follow-up: 9.6 years [interquartile range: 4.8-16.0]). Seventy-two subsequently developed cancer and 65 died. The standardised incidence ratio of cancer in general was 2.6 (95% CI: 1.8-3.7) and 2.5 (95% CI: 1.8-3.4) in CD and UC, respectively. The standardised mortality ratios were 2.2 (95% CI: 1.4-3.4) and 3.7 (95% CI: 2.7-5.0) in CD and UC, respectively. The leading causes for mortality were cancer, suicide and infections. CONCLUSIONS: We found an increased risk of cancer and mortality in pIBD. This underlines the importance of cancer surveillance programs and assessment of mental health in the standard of care in adolescent pIBD patients.

Serum Calprotectin in Adolescents With Inflammatory Bowel Disease-A Pilot Investigation.

OBJECTIVES: Fecal calprotectin (FC) is a well-integrated parameter in the monitoring of adolescent patients with inflammatory bowel disease (IBD). However, measurement of FC is limited by day-to-day-variation and by the feces consistency. Furthermore, adolescents are often noncompliant to deliver fecal sampling leading to suboptimal monitoring. Consequently, we see the need of a substitute biomarker whenever measurement of FC fails and aimed to investigate serum calprotectin (SC) in adolescents with IBD. METHODS: In cross sectional data from 19 ulcerative colitis (UC) patients <18 years old, a Spearman correlation was used to analyze the correlation between SC, FC, C-reactive protein (CRP) and endoscopic and symptom scores. In longitudinal data collected from 20 UC and Crohn disease (CD) patients (10-17 years old), Mixed Effect Models (MEM) were used to analyze the association between SC, FC, CRP, and symptom scores. RESULTS: We found positive correlations between SC (19 samples) and the endoscopic score, symptom score, and CRP (r = 0.56, P = 0.01; r = 0.64, P = 0.003; r = 0.97, P < 0.0001). We found no significant correlation between SC and FC. In 27 samples from UC patients, the association of SC with FC and CRP were positive and significant (P = 0.004, estimate = 0.32; P = 0.0001, estimate = 0.002). The association between SC and symptom score was insignificant. In 49 samples from CD patients, the association between SC and CRP was significant (P = 0.02, estimate = 0.002) whereas associations between SC and FC and symptom score were insignificant. CONCLUSIONS: In the current pilot study, we found a correlation between SC and the endoscopically assessed inflammation in UC. SC may have the potential to improve disease monitoring of adolescent patients.

Biochemical Markers, Genotype, and Inflammation in Pediatric Inflammatory Bowel Disease: A Danish Population-Based Study.

BACKGROUND: Our aim was to characterize the biochemical markers at diagnosis in patients with inflammatory bowel disease (IBD), to assess the utility of these to predict disease course and investigate if genotype influences biochemical markers of inflammation. SUMMARY: Patients were included from a population-based pediatric IBD cohort from Eastern Denmark. Data on biochemical markers and medical as well as surgical treatment were registered at diagnosis, 30 days, 6 and 12 months after diagnosis. Fifty-two single nucleotide polymorphisms (SNPs) known to be associated with IBD were selected for genotyping based on previous genetic studies. Key messages: A total of 190 IBD patients (97 ulcerative colitis [UC], 87 Crohn's disease [CD], and 6 IBD unclassified) were included. UC patients with extensive disease had higher C-reactive protein, erythrocyte sedimentation rate, and platelet count at diagnosis compared to UC patients with less extensive disease. No similar differences between disease extent groups were found in CD. Low albumin at diagnosis was associated with an increased risk of surgery in both UC (OR 1.35; 95% CI: 1.05-1.75) and CD patients (OR 1.23; 95% CI: 1.01-1.48) and increased use of azathioprine and anti-tumor necrosis factor alpha use in the total IBD cohort (OR 1.15; 95% CI: 1.04-1.27 and OR 1.19 [1.08-1.34]). One SNP (rs4986791 in the TLR-4 locus) and 2 SNPs (rs6785049 in the Pregnane-x-receptor gene and rs10500264 in the SLCA10 gene) were associated with a change in albumin and hemoglobin over time respectively in our IBD cohort. Our study confirms albumin to be a marker of severe disease course. Furthermore, the patient's genotype possibly affects the inflammatory response. Future studies in larger pediatric cohorts are needed to confirm our findings.

Response to treatment is more important than disease severity at diagnosis for prediction of early relapse in new-onset paediatric Crohn's disease.

BACKGROUND: Paediatric Crohn's disease is characteried by frequently relapsing disease which may lead to hospitalisations and complications. AIM: To develop predictive models for early relapse following first remission. METHODS: The GROWTH CD prospective inception cohort was designed to predict risk for early disease relapse and poor outcomes. Newly diagnosed children underwent endoscopies and imaging. They were phenotyped and followed at scheduled visits through 78 weeks for relapses. Twenty-eight dichotomous and continuous variables were assessed at baseline and week 12, including phenotype, inflammatory markers, disease activity (PCDAI) and other markers. Clinical relapses defined as PCDAI >10 after remission were recorded using a relapse form. Logistic regression & risk modelling was performed. RESULTS: We enrolled 282 eligible patients of whom 178 (63.6%) patients achieved steroid free remission by week 12. Disease complications developed in 22/76(29%) of patients with relapse compared to 20/206 (9.7%) without relapse (P = 0.01). Multivariable analysis demonstrated that while variables from age/gender at diagnosis were not predictive, week 12 variables including PCDAI >5 (P = 0.02), CRP >20 mg/L (P = 0.02), and faecal calprotectin >400 µg/g (P = 0.03) as optimal cut-offs were associated with increased risk of relapse. A prediction model for patients in remission including gender, age, week 12 PCDAI, calprotectin and CRP had sensitivity 43%, specificity 92%, PPV 78%, NPV 71% for relapse. CONCLUSIONS: Early relapses were associated with a higher risk for disease complications at followup. Relapse prediction based on week 12 disease activity or inflammation is superior to prediction using data from diagnosis.

A new mutation in the C-terminal end of TTC37 leading to a mild form of syndromic diarrhea/tricho-hepato-enteric syndrome in seven patients from two families.

Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital enteropathy with seven main clinical features: intractable diarrhea of infancy, hair abnormalities, intrauterine growth restriction (IUGR), facial dysmorphism, immune dysfunction, and liver and skin abnormalities. SD/THE is caused by mutations in TTC37 or SKIV2L, two genes encoding components of the human SKI complex. To date, approximately 50 SD/THE patients have been described with a wide spectrum of mutations, and only one recurrent mutation has been identified in independent families. We present a detailed description of seven patients of Turkish origin with the same new mutation in TTC37: c.4572 G>A p.(Trp1524X). All seven patients were homozygous for this mutation and presented the typical clinical features of SD/THE, but with a milder presentation than usual. All seven patients were alive at the last follow-up. Four out of seven patients had no IUGR, and four patients never required parenteral nutrition. All patients presented a better growth rate than previously described in patients with SD/THE, with 4/7 above the 3rd percentile. The mutation is localized only forty amino acids from the end of TTC37, and as TTC37 is longer than the yeast SKI3, it is possible that a truncated protein is expressed and plays a reduced role in the SKI complex.

Differences in Outcomes Over Time With Exclusive Enteral Nutrition Compared With Steroids in Children With Mild to Moderate Crohn's Disease: Results From the GROWTH CD Study.

BACKGROUND: Exclusive enteral nutrition [EEN] and corticosteroids [CS] induce similar rates of remission in mild to moderate paediatric Crohn's disease [CD], but differ with regard to mucosal healing. Our goal was to evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes. METHODS: We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications [fibrostenotic disease, penetrating disease, and active perianal disease] and growth were recorded throughout the study. A propensity score analysis was performed. RESULTS: A total of 147 children [mean age 12.9 ± 3.2 years], treated by EEN [n = 60] or CS [n = 87] were included. New complications developed in 13.7% of CS [12/87] versus 11.6% of EEN [7/60], p = 0.29. Remission was achieved in 41/87 [47%] in CS and 38/60 [63%] EEN, p = 0.036. Median time to relapse did not differ [14.4 ± 1 months with CS, 16.05 ± 1.1 EEN, p = 0.28]. Mean height Z scores decreased from Week 0 to Week 78 with CS [-0.34 ± 1.1 to -0.51 ± 1.2, p = 0.01], but not with EEN [-0.32 ± 1.1 to -0.22 ± 0.9, p = 0.56]. In a propensity score analysis, EEN was superior to CS for inducing remission [p = 0.05] and trended to superiority for height Z score [p = 0.055]. CONCLUSIONS: Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD.

Individualized Infliximab Treatment Guided by Patient-managed eHealth in Children and Adolescents with Inflammatory Bowel Disease.

BACKGROUND: To individualize timing of infliximab (IFX) treatment in children and adolescents with inflammatory bowel disease (IBD) using a patient-managed eHealth program. METHODS: Patients with IBD, 10 to 17 years old, treated with IFX were prospectively included. Starting 4 weeks after their last infusion, patients reported a weekly symptom score and provided a stool sample for fecal calprotectin analysis. Based on symptom scores and fecal calprotectin results, the eHealth program calculated a total inflammation burden score that determined the timing of the next IFX infusion (4-12 wk after the previous infusion). Quality of Life was scored by IMPACT III. A control group was included to compare trough levels of IFX antibodies and concentrations and treatment intervals. Patients and their parents evaluated the eHealth program. RESULTS: There were 29 patients with IBD in the eHealth group and 21 patients with IBD in the control group. During the control period, 94 infusions were provided in the eHealth group (mean interval 9.5 wk; SD 2.3) versus 105 infusions in the control group (mean interval 6.9 wk; SD 1.4). Treatment intervals were longer in the eHealth group (P < 0.001). Quality of Life did not change during the study. Appearance of IFX antibodies did not differ between the 2 groups. Eighty percent of patients reported increased disease control and 63% (86% of parents) reported an improved knowledge of the disease. CONCLUSIONS: Self-managed, eHealth-individualized timing of IFX treatments, with treatment intervals of 4 to 12 weeks, was accompanied by no significant development of IFX antibodies. Patients reported better control and improved knowledge of their IBD.

[Gluten-free diet is for some a necessity, for others a lifestyle].

This review provides a brief overview of the gluten-related conditions coeliac disease (CD), wheat allergy (WA), and non-coeliac gluten sensitivity (NCGS). NCGS is a new entity which includes individuals who report symptoms when exposed to gluten and benefit from gluten-free diet, but do not have CD or WA. The concept NCGS is still controversial and a subject of considerable overdiagnosis, and consensus regarding diagnostic criteria is lacking. Furthermore, the overlap with irritable bowel syndrome is unsettled.

Development and Validation of Diagnostic Criteria for IBD Subtypes Including IBD-unclassified in Children: a Multicentre Study From the Pediatric IBD Porto Group of ESPGHAN.

BACKGROUND: The revised Porto criteria identify subtypes of paediatric inflammatory bowel diseases: ulcerative colitis [UC], atypical UC, inflammatory bowel disease unclassified [IBDU], and Crohn's disease [CD]. Others have proposed another subclassifiction of Crohn's colitis. In continuation of the Porto criteria, we aimed to derive and validate criteria, termed "PIBD-classes," for standardising the classification of the different IBD subtypes. METHODS: This was a multicentre retrospective longitudinal study from 23 centres affiliated with the Port -group of ESPGHAN. Both a hypothesis-driven judgmental approach and mathematical classification and regression tree [CART] modelling were used for creating a diagnostic algorithm. Since small bowel inflammation is easily recognised as CD, we focused here primarily on the phenotype of colitis. RESULTS: In all, 749 IBD children were enrolled: 236 [32%] Crohn's colitis, 272 [36%] UC and 241 [32%] IBDU [age 10.9 ± 3.6 years] with a median follow-up of 2.8 years (interquartile range [IQR] 1.7-4.3). A total of 23 features were clustered in three classes according to their prevalence in UC: six class-1 features [0% prevalence in UC], 12 class-2 features [< 5% prevalence], and five class-3 features [5-10% prevalence]. According to the algorithm, the disease should be classified as UC if no features exist in any of the classes. When at least one feature exists, different combinations classify the disease into atypical UC, IBDU or CD. The algorithm differentiated UC from CD and IBDU with 80% sensitivity (95% confidence interval [CI] 71-88%) and 84% specificity [77-89%], and CD from IBDU and UC with 78% sensitivity [67-87%] and 94% specificity [89-97%]. CONCLUSIONS: The validated PIBD-classes algorithm can adequately classify children with IBD into small bowel CD, colonic CD, IBDU, atypical UC, and UC.

[Lactose malabsorption and -intolerance - who will benefit from a lactose-reduced diet?]

During the last decade, lactose-free diets have become increasingly popular in the general population, either isolated or as a part of a cow's milk-free diet. However, health-related benefits from a lactose-free diet are only documented for individuals with clinical lactose intolerance due to decreased intestinal lactase activity and subsequent lactose malabsorption. In this paper we summarize the current knowledge of lactose intolerance regarding diagnostic procedures and treatment.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

F-calprotectin and Blood Markers Correlate to Quality of Life in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Our aim was to investigate predictors of health-related quality of life (HRQoL) with respect to changes in disease parameters over time in children with inflammatory bowel disease. METHODS: This was a prospective longitudinal study examining the association between HRQoL (IMPACT III) and symptom scores (Pediatric Crohn Disease Activity Index, abbreviated Pediatric Ulcerative Colitis Activity Index), fecal calprotectin measures and blood analyses (C-reactive protein, erythrocyte sedimentation rate, orosomucoid, albumin, hemoglobin, and vitamin-D) in a cohort of 10- to 17-year-old patients with inflammatory bowel disease. Data were collected prospectively at 3-month intervals during a 2-year period. Associations were analyzed using linear mixed-effect models. Patients were divided into 2 groups, which received nonbiological oral treatment or biological parenteral treatment. RESULTS: From 79 patients (39 Crohn disease/40 ulcerative colitis), representing a total of 43,132 days of observation, 572 IMPACT measurements were paired with variables. A decrease in the IMPACT III score was significantly associated with increased ulcerative colitis-symptom score in the biological group (P = 0.005), and a similar inverse tendency was found in the nonbiological group and for Crohn disease symptoms in both groups. We found in both treatment groups overall a significant (P < 0.05) inverse association between the IMPACT III and the levels of fecal calprotectin, erythrocyte sedimentation rate, and orosomucoid, whereas albumin, hemoglobin, and vitamin-D were directly significantly associated. CONCLUSIONS: The IMPACT score, already known to correlate with disease activity, has now been shown to be associated with disease markers in feces and blood. This emphasizes that objective markers of disease activity indirectly can predict the patient's HRQoL.