Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Predicting inflammatory bowel disease in children with abdominal pain and diarrhoea: calgranulin-C versus calprotectin stool tests.

OBJECTIVE: Calgranulin-C (S100A12) is a new faecal marker of inflammation that is potentially more specific for inflammatory bowel disease (IBD) than calprotectin, since it is only released by activated granulocytes. We compared calgranulin-C and calprotectin to see which of the two tests best predicted IBD in children with chronic abdominal pain and diarrhoea. DESIGN: Delayed-type cross-sectional diagnostic study. SETTING AND PATIENTS: Previously undiagnosed patients aged 6-17 years, who were seen in paediatric clinics in the Netherlands and Belgium, sent in a stool sample for analysis. Patients with a high likelihood of IBD underwent upper and lower endoscopy (ie, preferred reference test), while those with a low likelihood were followed for 6 months for latent IBD to become visible (ie, alternative reference test). We used Bayesian modelling to correct for differential verification bias. MAIN OUTCOME MEASURES: Primary outcome was the specificity for IBD using predefined test thresholds (calgranulin-C: 0.75 µg/g, calprotectin: 50 µg/g). Secondary outcome was the test accuracy with thresholds based on receiver operating characteristics (ROC) analysis. RESULTS: IBD was diagnosed in 93 of 337 patients. Calgranulin-C had significantly better specificity than calprotectin when predefined thresholds were used (97% (95% credible interval (CI) 94% to 99%) vs 71% (95% CI 63% to 79%), respectively). When ROC-based thresholds were used (calgranulin-C: 0.75 µg/g, calprotectin: 400 µg/g), both tests performed equally well (specificity: 97% (95% CI 94% to 99%) vs 98% (95% CI 95% to 100%)). CONCLUSIONS: Both calgranulin-C and calprotectin have excellent test characteristics to predict IBD and justify endoscopy. TRIAL REGISTRATION NUMBER: NCT02197780.

Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease.

OBJECTIVES: The pharmacokinetics of infliximab (IFX) is highly variable in children with Crohn disease (CD), and a one-size-fits-all approach to dosing is inadequate. Model-based drug dosing can help individualize dosing strategies. We evaluated the predictive performance and clinical utility of a published population pharmacokinetic model of IFX in children with CD. METHODS: Within a cohort of 34 children with CD who had IFX trough concentrations measured, the pharmacokinetics of each patient was estimated in NONMEM using a published population pharmacokinetic model. Infliximab concentrations were then predicted based on each patient's dosing history and compared with actual measured concentrations (n = 59). In addition, doses 5 to 10 mg/kg and dosing intervals every 4 to 8 weeks were simulated in each patient to examine dose-trough relationships. RESULTS: Predicted concentrations were within ±1.0 µg/mL of actual measured concentrations for 88% of measurements. The median prediction error (ie, measure of bias) was -0.15 µg/mL (95% confidence interval -0.37 to -0.05 µg/mL) and absolute prediction error (ie, measure of precision) was 0.26 µg/mL (95% confidence interval 0.15 to 0.40 µg/mL). At standard maintenance dosing of 5 mg/kg every 8 weeks, a trough >3 µg/mL was predicted to be achieved in 32% of patients. To achieve a trough >3 µg/mL, a dosing interval ≤every 6 weeks was predicted to be required in 29% of patients. CONCLUSIONS: A published IFX population pharmacokinetic model demonstrated accurate predictive performance in a pediatric CD population. Individualized IFX dosing strategies in children with CD will be critical to consistently achieve trough concentrations associated with optimal outcomes.

Adherence to Oral Maintenance Treatment in Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: The aim of this study was to systematically review the rates of nonadherence to oral maintenance treatment in adolescents with inflammatory bowel disease (IBD), and to describe perceived barriers to adherence and psychosocial factors involved. METHODS: The article considered studies published in MEDLINE, Embase, and PsycINFO up to March 2015. Studies that had collected data on adherence to thiopurines or aminosalicylates in a cohort of adolescents with IBD. Case reports and case series were excluded. RESULTS: A total of 25 studies were included. Lack of uniformity of outcome measures made pooling of data impossible. Rates of medication nonadherence ranged from 2% to 93%. The most frequently reported barriers were "just forgot," "wasn't home," and "interferes with activity." Family dysfunction, peer victimization, poor health-related quality of life, poor child-coping strategies, anxiety, and depressive symptoms were associated with medication nonadherence. CONCLUSIONS: Nonadherence to oral maintenance therapy in adolescents with IBD is a significant health care problem and can lead to unnecessary escalation in therapy. Difficulties in family and social interactions, and psychosocial dysfunction can jeopardize IBD treatment outcome and should receive attention early in the course of the disease.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease.

OBJECTIVE: Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. MATERIAL AND METHODS: Children aged <18 years receiving IFX maintenance treatment for Crohn's disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn's Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3-7 µg/ml. RESULTS: Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2-7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = -0.51; p < 0.01] and FC [rs = -0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2-5] and 2.3 µg/ml [IQR 0.3-4.6]; p = 0.2). CONCLUSIONS: IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

Accuracy of abdominal ultrasound and MRI for detection of Crohn disease and ulcerative colitis in children.

BACKGROUND: Endoscopy is currently the primary diagnostic technique for inflammatory bowel disease (IBD) in children. OBJECTIVE: To assess the accuracy of US and dynamic contrast-enhanced MRI for diagnosing inflammatory bowel disease and for distinguishing Crohn disease and ulcerative colitis in comparison to a reference standard. MATERIALS AND METHODS: Consecutive children with suspected IBD underwent diagnostic workup including ileocolonoscopy and upper gastrointestinal endoscopy as the reference standard, abdominal US, and MR enterography and colonography at 3 T. The protocol included a dynamic contrast-enhanced 3-D sequence. Sensitivity, specificity and kappa values were calculated for one ultrasonographer and two MRI observers. RESULTS: We included 28 children (15 boys) with mean age 14 years (range 10-17 years). The diagnosis was IBD in 23 children (72%), including 12 with Crohn disease, 10 with ulcerative colitis and 1 with indeterminate colitis. For the diagnosis of inflammatory bowel disease the sensitivity was 55% for US and 57% (both observers) for MR entero- and colonography, and the specificity was 100% for US and 100% (observer 1) and 75% (observer 2) for MR entero- and colonography. Combined MRI and US had sensitivity and specificity of 70% and 100% (observer 1) and 74% and 80% (observer 2), respectively. With the addition of a dynamic contrast-enhanced MR sequence, the sensitivity increased to 83% and 87%. US and MRI could only distinguish between Crohn disease and ulcerative colitis when terminal ileum lesions were present. CONCLUSION: US and MR entero- and colonography have a high accuracy for diagnosing inflammatory bowel disease in children but cannot be used to distinguish Crohn disease and ulcerative colitis.

Exogenous pigment in Peyer patches of children suspected of having IBD.

OBJECTIVES: The base of human Peyer patches of the terminal ileum has been noted to contain black granular pigment deposits, composed of titanium dioxide and aluminosilicate, which are food additives typically present in a Western diet, and pharmaceuticals. In the present study, we investigated the distribution of exogenous pigment throughout the gastrointestinal tract of children suspected of having inflammatory bowel disease (IBD), the correlation between their age and the presence and amount of pigment in Peyer patches, and its relation to pediatric IBD. METHODS: Biopsies (upper and lower gastrointestinal tract) from children suspected of having IBD who underwent endoscopy, were reassessed by a blinded, expert pathologist. The amount of pigment in biopsies was scored using a semiquantitative scale (range 0 to +++). RESULTS: A total of 151 children were included: 62 with Crohn disease (CD), 26 with ulcerative colitis, and 63 with non-IBD. In 63 children (42%), deposits of black pigment were found only in biopsies from the terminal ileum, located in Peyer patches. A significant correlation was found between increasing age and the amount of pigment (P = 0.004). Pigment deposits were found significantly less in the patients with CD compared with those in patients with ulcerative colitis and those with non-IBD (26% vs 62% and 49%, P = 0.002). CONCLUSIONS: These results provide support for the hypothesis that the amount of pigment, only present in Peyer patches in the terminal ileum, becomes denser with increasing age. Absence of pigment in Peyer patches in a higher number of patients with CD suggests that microparticles may have become involved in the inflammatory process, possibly because of disrupted autophagy.

Psychosocial developmental trajectory of adolescents with inflammatory bowel disease.

BACKGROUND AND OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic, debilitating disorder occurring in young patients in the most productive period of their lives. Little is known about the effect on the developmental trajectory of adolescents growing up with IBD. The purpose of this study was to assess the psychosocial developmental trajectory ("course of life") and sociodemographic outcomes in adolescents with IBD compared with peers from the general population. METHODS: A total of 62 adolescents (response rate 74%, boys 51.6%, mean age 18.6 years) completed the course of life questionnaire. RESULTS: Patients with IBD achieved fewer milestones on the domains of autonomy and social and psychosexual development compared with their healthy peers. They went less frequently on holidays without adults, had fewer jobs during secondary school, were less frequently going out to a bar/disco during secondary school, and were older when falling in love for the first time. After secondary school, patients with IBD were more often unemployed. CONCLUSIONS: Negative consequences in terms of psychosocial development are prevalent in adolescents with IBD. Physicians should be attentive to these consequences and provide additional support if necessary. During transition to adult clinic, these topics are of major importance and should be an integral component of the comprehensive care of chronically ill adolescents and young adults.

Additional value of upper GI tract endoscopy in the diagnostic assessment of childhood IBD.

OBJECTIVES: For the choice of treatment in children with inflammatory bowel disease (IBD), it is important to make a distinction between Crohn disease (CD) and ulcerative colitis (UC). To look for pathognomonic features of CD, upper gastrointestinal tract (UGT) endoscopy has become part of the routine evaluation of children with suspected IBD; however, pathological changes can also be found in the UGT in patients with UC. The aims of the present study were to establish the role of UGT involvement in the diagnostic assessment of suspected IBD in children and to detect histopathological changes in the UGT mucosa, which can distinguish CD from non-CD (UC and non-IBD). METHODS: Biopsies (colon, ileum, duodenum, stomach, esophagus) from children suspected of having IBD who underwent endoscopy between 2003 and 2008 were reassessed by a blinded, expert pathologist. The histological findings of the UGT were compared with the diagnosis based on ileocolonic biopsies and the final diagnosis. RESULTS: In 11% of the children with CD, the diagnosis was based solely on the finding of granulomatous inflammation in the UGT. Focal cryptitis of the duodenum and focally enhanced gastritis were found significantly more frequently in children with CD compared with children with UC and non-IBD, with a specificity and positive predictive value of 99% and 93% and 87.1% and 78.6%, respectively. CONCLUSIONS: Histology on ileocolonic biopsies alone is insufficient for a correct diagnosis of CD or UC in children. UGT endoscopy should, therefore, be performed in the diagnostic assessment of all children suspected of having IBD.