Thalia Hummel

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.

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

Abstract 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.

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.

The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity

A large proportion (25–46%) of adults with inflammatory bowel disease in remission has symptoms of irritable bowel syndrome (IBS), which are thought to reflect ongoing inflammation. Data on paediatric inflammatory bowel disease patients are lacking.

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.

Adalimumab therapy in children with Crohn disease previously treated with infliximab

Objectives: Adalimumab, a humanised anti-tumour necrosis factor antibody, is an effective treatment in adult patients with refractory Crohn disease (CD). The available literature on its efficacy in children remains limited. We aimed to evaluate the real-world efficacy in paediatric patients with CD and compare the efficacy between infliximab (IFX) nonresponders and patients who lost response to IFX. Methods: All Dutch patients with CD receiving adalimumab before the age of 18 years after previous IFX therapy were identified. We analysed longitudinal disease activity, assessed by the mathematically weighted Pediatric Crohns Disease Activity Index (wPCDAI) or the physician global assessment (PGA), and adverse events (AEs). Results: Fifty-three patients with CD were included. Twelve patients received monotherapy and the others received combination treatment with thiopurines (n = 21), methotrexate (n = 11), steroids (n = 7), or exclusive enteral nutrition (n = 2). Median follow-up was 12 months (interquartile range 5–23). Remission was reached in 34 patients (64%, wPCDAI < 12.5 or PGA = 0) after a median of 3.3 months, and maintained by 50% for 2 years. Eleven patients (21%) reached response but not remission (decrease in wPCDAI ≥ 17.5 or decrease in PGA). Eighteen patients (34%) failed adalimumab treatment because of nonresponse (n = 4), lost response (n = 11), or AEs (n = 3). More IFX nonresponders failed adalimumab treatment than patients who lost response to IFX (2/3 vs 8/34, hazard ratio 18.8, 95% confidence interval 1.1–303.6). Only 1 patient encountered a serious AE, a severe but nonfatal infection. Conclusions: In clinical practice, adalimumab induces remission in two-thirds of children with IFX refractory CD.

Methotrexate for maintaining remission in paediatric Crohn's patients with prior failure or intolerance to thiopurines: a multicenter cohort study.

BACKGROUND AND AIMS Methotrexate [MTX] is an immunomodulating drug that can be used to maintain remission in patients with Crohns disease [CD], but data on efficacy and tolerability in children and teenagers are scarce. We evaluated the long-term efficacy and tolerability of MTX monotherapy after thiopurine therapy in paediatric CD patients. METHODS A multicenter cohort of paediatric MTX users who stopped thiopurines due to ineffectiveness or intolerance between 2002 and 2012 were included and followed for at least 12 months. Relapse-free use was defined as steroid and biologics-free clinical remission after the introduction of MTX, and included intentional discontinuation of successful therapy before the end of the observation period. RESULTS A total of 113 patients with CD in remission were followed while on MTX monotherapy, of whom 75 [66%] had failed on thiopurines and 38 [34%] had stopped thiopurines due to side effects. Median age at the introduction of MTX was 14 years [range 7 to 17], and 93% used the subcutaneous route. Kaplan-Meier analysis showed that 52% of the study cohort were still in steroid- and biologics-free remission after 12 months of MTX monotherapy, with a difference that did not reach significance between thiopurine-intolerant and thiopurine-failing patients [p = 0.21, log-rank test]. CONCLUSIONS The findings of this cohort study suggest that MTX is an effective immunomodulator to maintain remission after stopping thiopurines. MTX maintenance should be considered before stepping up to anti-tumor necrosis factor alpha therapy. MTX is probably somewhat more effective in patients who stopped thiopurines due to side effects than in those who failed on thiopurines.

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.

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 patients 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 &mgr;g/mL of actual measured concentrations for 88% of measurements. The median prediction error (ie, measure of bias) was −0.15 &mgr;g/mL (95% confidence interval −0.37 to −0.05 &mgr;g/mL) and absolute prediction error (ie, measure of precision) was 0.26 &mgr;g/mL (95% confidence interval 0.15 to 0.40 &mgr;g/mL). At standard maintenance dosing of 5 mg/kg every 8 weeks, a trough >3 &mgr;g/mL was predicted to be achieved in 32% of patients. To achieve a trough >3 &mgr;g/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.

Raised faecal calprotectin is associated with subsequent symptomatic relapse, in children and adolescents with inflammatory bowel disease in clinical remission

Reliable data on inflammatory biomarkers for predicting relapse of paediatric inflammatory bowel disease (IBD) are lacking.