Safety of Thioguanine in Pediatric Inflammatory Bowel Disease:A Multi-Center Case Series

Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS: A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS: Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS: In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed

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

Psychosocial developmental trajectory of adolescents with inflammatory bowel disease

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. A total of 62 adolescents (response rate 74%, boys 51.6%, mean age 18.6 years) completed the course of life questionnaire. 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. 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 adult

Exogenous pigment in Peyer patches of children suspected of having IBD

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. 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 +++). 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). 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 autophag

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

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. 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. 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). IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IB

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

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 6-17years, 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 mu g/g, calprotectin: 50 mu g/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 (Cl) 94% to 99%) vs 71% (95% Cl 63% to 79%), respectively). When ROC-based thresholds were used (calgranulin-C: 0.75 mu g/g, calprotectin: 400 mu g/g), both tests performed equally well (specificity: 97% (95% Cl 94% to 99%) vs 98% (95% Cl 95% to 100%)). Conclusions: Both calgranulin-C and calprotectin have excellent test characteristics to predict IBD and justify endoscopy

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

Endoscopy is currently the primary diagnostic technique for inflammatory bowel disease (IBD) in children. 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. 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. 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. 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 coliti