Daniël R. Hoekman

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.

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.

Functional constipation in childhood: current pharmacotherapy and future perspectives

Introduction: Childhood constipation is a common problem, varying from mild and short-lived to severe and chronic. In the majority of children, no organic cause can be identified and complaints are, thus, referred to as functional constipation. Infrequent painful defecation in combination with fecal incontinence has a significant impact on a childs quality of life. Pharmacological treatment often consists of fecal disimpaction and maintenance therapy. With current treatment options, results are often disappointing. Areas covered: The aim of this review is to provide an overview of current and future pharmacological therapies for functional constipation in childhood. Expert opinion: Despite the widespread use of laxatives, there is a paucity of evidence to support this practice. No strong conclusions can be drawn on which laxative to prefer over the other. However, polyethylene glycol appears to be a reasonable first choice for maintenance therapy. Due to advances in our understanding of intestinal (patho)physiology, new classes of drugs have been developed. Data from adult studies are promising; however, pediatric data are lacking. Ongoing and future studies have to determine the efficacy and safety of these new drugs in the treatment of functional constipation in children.

The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

Objective To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain‐related functional gastrointestinal disorders. Study design The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo‐controlled trials concerning children 4‐18 years of age with an abdominal pain‐related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta‐regression analysis. Results Twenty‐one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%‐49%; 17 studies) and with no pain was 17% (95% CI, 8%‐32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was −0.73 (95% CI, −1.04 to −0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). Conclusions Approximately 41% of children with abdominal pain‐related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies.

Inter- and intrarater reliability of the Chicago Classification in pediatric high-resolution esophageal manometry recordings

The Chicago Classification (CC) facilitates interpretation of high‐resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software‐based CC diagnosis in a pediatric cohort.

The prevalence of irritable bowel syndrome-type symptoms in inflammatory bowel disease patients in remission

Objective Symptoms of irritable bowel syndrome (IBS) are common in inflammatory bowel disease (IBD) and are believed to reflect ongoing inflammation. Consequently, a low prevalence of IBS-type symptoms in IBD patients with normal inflammatory markers is expected. We aimed to investigate the prevalence of IBS-type symptoms in IBD patients in biochemical remission (evidenced by low fecal calprotectin levels) and the relationship of these symptoms with fecal calprotectin levels. Patients and methods In this observational, cross-sectional study, we included all adults with a history of IBD who had calprotectin levels less than 200 µg/g during routine follow-up between August 2014 and May 2015 at our hospital. Patients were excluded if calprotectin was measured because of gastrointestinal complaints. All patients were approached by telephone to evaluate the presence of IBS-type symptoms using Rome III questionnaires. Patients fulfilling IBS criteria were subclassified according to bowel habits. Results In total, 74 patients were included; 33 (45%, 95% confidence interval: 34–56%) fulfilled the IBS criteria. A larger proportion of Crohn’s disease patients with IBS-type symptoms had ileal disease compared with Crohn’s disease patients without IBS symptoms (55 vs. 24%; P=0.03). Other characteristics were similar between groups. No difference was found in calprotectin levels between patients with and without IBS-type symptoms (P=0.91). The majority of patients with IBS-type symptoms had diarrhea-predominant or mixed-type IBS (64 and 27% of patients with IBS-type symptoms, respectively). Conclusion The prevalence of IBS-type symptoms in IBD patients in biochemical remission is high. A significant proportion of IBS-type symptoms is unrelated to ongoing inflammation and probably reflects ‘true IBS’.

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.

536 Non-Trough IFX Concentrations Reliably Predict Trough Levels and Accelerate Dose-Adjustment in Crohn's Disease

0.018); however, higher TNFa concentrations at baseline correlated with lower vedolizumab concentrations at week 6 (Adjusted R2= 0.87, p-value 0.01). Conclusions: While traditional markers of inflammation did not correlate with response to therapy with vedolizumab, sMAdCAM-1 appears to be a possible marker of response to therapy. Further investigations into the etiology underlying the presence of sMAdCAM-1 may help further elucidate the pharmacodynamics and mechanism of action of vedolizumab. Validation in a larger cohort of patients is ongoing.

924 Long-Term Outcomes of Top-Down Versus Step-up Treatment in Newly Diagnosed Crohn's Disease: Final Data

G A A b st ra ct s variables, healthcare utilization, comorbidities and baseline immunosuppressive medication use, to assess the relative effectiveness and safety of IFX and ADA. Results: Our cohort comprised 1869 biologic-naive UC pts (age, 42.3±16.0y; 50.8% males) who were prescribed IFX (n=1470) or ADA (n=399) as first-line anti-TNF agents, and followed over median of 1.7 years (IQR, 0.9-3.0). Baseline demographics, healthcare utilization (outpatient, inpatient or emergency room visits; imaging and endoscopic procedures), comorbidities and prior medication exposure was comparable between the two groups (Table 1). As compared to ADA, pts treated with IFX were significantly less likely to require IBD-related hospitalization and new steroid prescription, after adjusting for baseline demographic variables, healthcare utilization, comorbidities and baseline immunosuppressive medication use (Table 2). There was no significant difference in the risk of abdominal surgery, though the number of events was small. Persistence on therapy at 6 months was significantly higher for IFX (61.4%) compared to ADA (14.8%). The incidence of serious infections was comparable between IFXand ADA-treated pts (incidence rate per 100 patient years: IFX vs. ADA, 1.49 vs. 2.25). Conclusion: In a large cohort of biologic-naive UC pts, IFX appears superior to ADA as first-line anti-TNF agent for important clinically relevant outcomes, without increased risk of serious infections. This requires further validation in randomized trials. Baseline characteristics of biologic-naive patients with ulcerative colitis.