Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease.

OBJECTIVES: Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). METHODS: A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 µg/mL at Week 6 and >12 µg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. RESULTS: Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6 and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 µg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR) rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). CONCLUSION: Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

Role of ileal diversion in pediatric inflammatory bowel disease.

Surgical intervention is often indicated in pediatric inflammatory bowel disease (IBD) for medically refractory disease or complications of severe disease. Specifically, surgical intervention via ileal diversion allows for fecal flow to be redirected away from diseased distal bowel and through an ileostomy. It is utilized in patients who have medically refractory colitis, severe perianal disease, or irreversible bowel damage. In patients with ulcerative colitis, it is primarily performed during a restorative proctocolectomy with ileal pouch anal anastomosis to protect the high-risk anastomoses. In the setting of Crohn's disease, ileal diversion reduces the exposure of diseased distal intestine to pro-inflammatory stool. During perioperative planning, it is crucial for the gastroenterologist to partner early with a multidisciplinary team including surgeons, nutritionists, wound ostomy care nurses, psychologists, and social workers. Patients should be assessed for malnutrition and should be optimized nutritionally with enteral or parenteral nutrition. As they are associated with increased risk of postoperative complications, corticosteroids should be significantly reduced or completely discontinued preoperatively. Though ileal diversion may reduce the complications associated with anastomosis, serious postoperative complications can include diversion colitis and high-output fistulae. This review aims to provide an overview of the role of ileal diversion in the treatment of pediatric IBD to pediatric gastroenterologists to inform their medical decision-making and discussions with patients and families.

Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Transcultural adaptation and validation of IMPACT-III and IMPACT-III-P in Spanish families: a multicenter study from SEGHNP.

IMPACT-III and IMPACT-III-P are health-related quality of life (HRQoL) questionnaires for patients with pediatric inflammatory bowel disease (p-IBD) and their parents/caregivers. We aimed to perform a transcultural adaptation and validation for the Spanish context. Translation, back-translation, and evaluation of the questionnaires were performed by an expert committee and 12 p-IBD families. We recruited p-IBD patients aged 10-17 and their parents/caregivers. Utility, content, and face validity were considered. Validation was performed with Cronbach's alpha coefficient and varimax rotation. We confirmed the adequacy of the factor analysis using Kaiser-Meyer-Olkin (KMO) and Bartlett's sphericity tests. A confirmatory factor analysis was performed using the following goodness indexes: chi-square, Normed Fit Index (NFI), Root Mean Square Error of Approximation index (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI). The correlation coefficient between IMPACT-III and IMPACT-III-P was analyzed. We included 370 patients and 356 parents/caregivers (37 hospitals). Both questionnaires had good content and face validity and were considered user-friendly. The KMO measure (0.8998 and 0.9228, respectively) and Bartlett's sphericity test (p-value < 0.001 for both) confirmed the adequacy of the factor analysis. The 4-factor model, complying with Kaiser's criterion, explained 89.19% and 88.87% of the variance. Cronbach's alpha (0.9123 and 0.9383) indicated excellent internal consistency. The CFA showed an adequate fit (NFI 0.941 and 0.918, RMSEA 0.048 and 0.053, SRMR 0.037 and 0.044, and CFI 0.879 and 0.913). The correlation coefficient was excellent (0.92). CONCLUSION: The SEGHNP versions of IMPACT-III and IMPACT-III-P are valid and reliable instruments for Spanish p-IBD families. WHAT IS KNOWN: • IMPACT-III and parent-proxy IMPACT-III (IMPACT-III-P) are useful questionnaires for assessing health-related quality of life (HRQoL) in pediatric inflammatory bowel disease (p-IBD) patients and their parents/caregivers and have been translated and validated in several countries. • To date, no transcultural adaptation and validation of these questionnaires have been published for Spanish patients with p-IBD and their families. WHAT IS NEW: • This is the first transcultural adaptation and validation of IMPACT-III and IMPACT-III-P for Spanish p-IBD families. • These are valid and reliable instruments for assessing HRQoL in Spanish families of patients with p-IBD.

Epidemiology of pediatric inflammatory bowel disease categorized by age subgroups in Korea.

BACKGROUND: Pediatric inflammatory bowel disease (PIBD) affects different age groups and its incidence is increasing worldwide. However, there is a lack of research focusing on age subgroups in Asian countries. In this nationwide population-based study, we investigated the epidemiology of PIBD among different age subgroups in Korea. METHODS: We analyzed Korean health administration data from 2005 to 2016. Data were divided by age at diagnosis as follows: group 1, 0-1 years; group 2, 2-5 years; group 3, 6-9 years; group 4, 10-16 years. We analyzed the overall incidence, temporal changes, and regional differences by age subgroups, using Poisson regression analysis. RESULTS: From 2005 to 2016, 2734 inflammatory bowel disease (IBD) cases were diagnosed among patients under 17 years of age. In the overall population, the incidence rate of PIBD over the entire study period was 2.248/105 person-years (PY), significantly increasing from 1.173/105 PY in 2005-2007 to 3.267/105 PY in 2014-2016. The incidence rates in groups 1 and 2 remained unchanged, whereas those of groups 3 and 4 increased significantly. The same trend was observed when analyzed separately for Crohn's disease (CD) and ulcerative colitis (UC). The incidence rates of CD in groups 3 and 4 showed differences between metropolitan and non-metropolitan areas, whereas those in groups 1 and 2, and UC of all age subgroups showed no difference. CONCLUSIONS: The temporal trend and regional differences of PIBD differed among age subgroups, suggesting that genetic and environmental factors have varying impacts on IBD development across different subgroups.

Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD. METHODS: The candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages. RESULTS: FCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+ macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1ß, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1ß via the NLRP3-caspase-1 axis. CONCLUSIONS: FCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+ macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1ß maturation in macrophages via the NLRP3-caspase-1 axis.

Management and monitoring of pediatric inflammatory bowel disease in the Asia-Pacific region: A position paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group: Surgical management, disease monitoring, and special considerations.

Disease phenotype of pediatric inflammatory bowel disease (PIBD) in children from the Asia-Pacific region differs from that of children from the West. Many parts of Asia are endemic for tuberculosis, making diagnosis and management of pediatric Crohn's disease a challenge. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in Asia due to differences in disease characteristics and regional resource constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) that aims to provide an up-to-date, evidence-based approach to PIBD in the Asia-Pacific region. A group of pediatric gastroenterologists with a special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Attention was paid to publications from the region with special consideration to a resource-limited setting. This current position paper deals with surgical management, disease monitoring, immunization, bone health, and nutritional issues of PIBD in Asia. A special section on differentiating pediatric Crohn's disease from tuberculosis in children is included. This position paper provides a useful guide to clinicians in the surgical management, disease monitoring, and various health issues in children with IBD in Asia-Pacific region.

How can patient registries facilitate guideline-based healthcare? A retrospective analysis of the CEDATA-GPGE registry for pediatric inflammatory bowel disease.

BACKGROUND: Early diagnosis is mandatory for the medical care of children and adolescents with pediatric-onset inflammatory bowel disease (PIBD). International guidelines ('Porto criteria') of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend medical diagnostic procedures in PIBD. Since 2004, German and Austrian pediatric gastroenterologists document diagnostic and treatment data in the patient registry CEDATA-GPGE on a voluntary basis. The aim of this retrospective study was to analyze whether the registry CEDATA-GPGE reflects the Porto criteria and to what extent diagnostic measures of PIBD according to the Porto criteria are documented. METHODS: Data of CEDATA-GPGE were analyzed for the period January 2014 to December 2018. Variables representing the Porto criteria for initial diagnostic were identified and categorized. The average of the number of measures documented in each category was calculated for the diagnoses CD, UC, and IBD-U. Differences between the diagnoses were tested by Chi-square test. Data on possible differences between data documented in the registry and diagnostic procedures that were actually performed were obtained via a sample survey. RESULTS: There were 547 patients included in the analysis. The median age of patients with incident CD (n = 289) was 13.6 years (IQR: 11.2-15.2), of patients with UC (n = 212) 13.1 years (IQR: 10.4-14.8) and of patients with IBD-U (n = 46) 12.2 years (IQR: 8.6-14.7). The variables identified in the registry fully reflect the recommendations by the Porto criteria. Only the disease activity indices PUCAI and PCDAI were not directly provided by participants but calculated from obtained data. The category 'Case history' were documented for the largest part (78.0%), the category 'Imaging of the small bowel' were documented least frequently (39.1%). In patients with CD, the categories 'Imaging of the small bowel' (χ2 = 20.7, Cramer-V = 0.2, p < 0.001) and 'Puberty stage' (χ2 = 9.8, Cramer-V = 0.1, p < 0.05) were documented more often than in patients with UC and IBD-U. CONCLUSION: The registry fully reproduces the guideline's recommendations for the initial diagnosis of PIBD. The proportion of documented diagnostic examinations varied within the diagnostic categories and between the diagnoses. Despite technological innovations, time and personnel capacities at participating centers and study center are necessary to ensure reliable data entry and to enable researchers to derive important insights into guideline-based care.

The Combined Effects of Youth and Parent Illness Intrusiveness on Depressive Symptoms in Adolescents with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) presents physical and emotional challenges for families and imposes significant lifestyle intrusions on both youth and parents. The present study examined the effects of IBD disease activity and youth illness intrusiveness on depressive symptoms in adolescents, and the moderating influence of parent illness intrusiveness on these associations. Adolescents and parents completed measures of illness intrusiveness; youth completed a measure of depressive symptoms. Physicians provided estimates of IBD disease activity. Mediation analysis revealed an IBD disease activity → youth intrusiveness → youth depressive symptoms indirect effect. Moderated mediation analyses revealed this indirect effect to be greater among youth whose parents endorsed more IBD-related intrusions. Youth encountering greater activity disruptions related to IBD are vulnerable to depressive symptoms. When parents also experience IBD-induced intrusions, youth are at even greater risk for depressive symptoms. Clinical implications are discussed within the context of youths' and parents' experiences of IBD.

Medical Management of Pediatric Inflammatory Bowel Disease (PIBD) in the Asia Pacific Region: A Position Paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group.

Pediatric inflammatory bowel disease (PIBD) is rising rapidly in many industrialised and affluent areas in the Asia Pacific region. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in this region due to differences in disease characteristics and regional resources constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) with the aim of providing an up-to-date, evidence-based approach to PIBD in the Asia Pacific region, taking into consideration the unique disease characteristics and financial resources available in this region. A group of pediatric gastroenterologists with special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management and monitoring. Gastrointestinal infections, including tuberculosis, need to be excluded before diagnosing IBD. In some populations in Asia, the Nudix Hydrolase 15 (NUD15) gene is a better predictor of leukopenia induced by azathioprine than thiopurine-S-methyltransferase (TPMT). The main considerations in the use of biologics in the Asia Pacific region are high cost, ease of access, and potential infectious risk, especially tuberculosis. Conclusion: This position paper provides a useful guide to clinicians in the medical management of children with PIBD in the Asia Pacific region.

The child's perception on monitoring inflammatory bowel disease activity.

To determine the perception of children with inflammatory bowel disease (IBD) regarding monitoring tests, we first compared the reported discomfort and patient perspective during gastro-intestinal (GI)-endoscopy, magnetic resonance entrography (MRE), and ultrasound (US) and, in a second comparison, patient preference on non-invasive tests (venipuncture, sampling stool and US). A cross-sectional study in children 8-18 years undergoing an US, MRE, and GI-endoscopy for diagnosis or follow-up of IBD. After each procedure, the children filled out the Discomfort during research procedures questionnaire (DISCO-RC). Items of the DISCO-RC are as follows: nervousness, annoyance, pain, fright, boredom, and tiredness. Answers range from "not" (= 0 points) to "extremely" (= 4 points) (range total score: 0-24). Differences between the procedures were assessed with Friedman test, with subsequent Wilcoxon signed-rank test. The children were also asked which non-invasive test they preferred not to undergo regularly (venipuncture, stool-sampling, or US). Answers were analyzed with χ2-test. Forty-nine patients (27 (55%) female, median age 15 (range 9-17)) were included. The children reported to be most nervous, frightened, and tired after GI-endoscopy (median: 1, 1, 2 points, respectively), equally annoyed by MRE and GI-endoscopy (median 1 point), and equally bored by MRE and US. GI-endoscopy was ranked as most discomfortable, followed by MRE and US (total DISCO-RC scores: 7 vs. 5 vs. 2, p < 0.001). Most of the children preferred not to sample stool or perform venipuncture regularly (n = 20 (41%, both) (p < 0.001)).Conclusion: Our results suggest that the children with IBD report low discomfort after US, MRE, and GI-endoscopy. US is preferred as a monitoring tool, also among non-invasive monitoring tests. GI-endoscopy was most discomfortable. What is Known: • Children with inflammatory bowel disease need to be monitored frequently for disease activity. • Adult studies - including a systematic review - on acceptability of monitoring tools among IBD patients showed mixed results. What is New: • Children in our study ranked gastro-intestinal endoscopy as most discomfortable, followed by MRE and US. • With regard to non-invasive monitoring, most children preferred not to sample stool or perform venipuncture regularly, and preferred US.

Impact of diagnostic delay to the clinical presentation and associated factors in pediatric inflammatory bowel disease: a retrospective study.

BACKGROUND: Undelayed diagnosis is thought to be a major determinant for good prognosis in pediatric inflammatory bowel disease (PIBD). However, factors predicting diagnostic delay and the consequences of this remain poorly defined. We investigated these issues in a well-defined cohort of PIBD patients. METHODS: Comprehensive electronic data were collected from 136 PIBD patients retrospectively. Diagnostic delay was further classified into < 6 and ≥ 6 months, and < 12 and ≥ 12 months. Logistic regression was used to calculate whether the delay was associated with clinical features and/or risk of complications and co-morbidities at diagnosis. RESULTS: The median age of patients was 12.4 years and 43.4% were females. Altogether 35.5% had Crohn´s disease (CD), 59.1% ulcerative colitis (UC) and 6.6% IBD undefined (IBD-U). The median delay before diagnosis was 5.0 months in all, 6.6 months in CD, 4.1 months in UC, and 9.8 months in IBD-U (UC vs. CD, p = 0.010). In all but IBD-U most of the delay occurred before tertiary center referral. Abdominal pain predicted a delay > 6 months in all PIBD (OR 2.07, 95% CI 1.00-4.31) and in UC patients (3.15, 1.14-8.7), while bloody stools predicted a shorter delay in all PIBD (0.28, 0.14-0.59) patients and in CD (0.10, 0.03-0.41) patients. A delay > 6 months was associated with a higher frequency of complications (2.28, 1.01-5.19). CONCLUSIONS: Delay occurred mostly before specialist consultation, was longer in children presenting with abdominal pain and in CD and was associated with risk of complications. These findings emphasize the roles of active case-finding and prompt diagnostic evaluations.

MR enterography grading of pediatric ileocolonic Crohn disease activity based on a single bowel segment.

BACKGROUND: Ileocolonoscopy with histology has been considered the gold standard for Crohn disease (CD) diagnosis and monitoring. Over the last years, magnetic resonance enterography (MRE) has become more and more popular, representing a valid non-invasive technique. OBJECTIVE: To propose a simplified MRE score, the pediatric CD magnetic resonance index (PCDMRI), based only on the most affected bowel segment, to grade active inflammation in children with CD. MATERIALS AND METHODS: Two radiologists retrospectively evaluated MRE images of children with histopathology-proven CD. The PCDMRI was based on six mural and perimural variables assessed for the most affected bowel segment (chosen by visual inspection of the key bowel wall imaging findings associated with active inflammation), and five extramural per-examination features. Correlation analysis was performed between both the PCDMRI and the MRE global score (based on all the affected segments) and the pediatric clinical disease activity index (PCDAI), the simple endoscopic score for CD (SES-CD), serum C-reactive protein (CRP) and fecal calprotectin (fC). Inter-reader reproducibility of the scoring system was estimated. Agreement on disease location between MRE and ileocolonoscopy was evaluated. RESULTS: The study involved 42 children for a total of 80 MRE. PCDMRI and global score positively correlated with PCDAI, SES-CD, CRP and fC. Inter-reader reproducibility was 91%. Agreement on disease location was substantial. CONCLUSION: The PCDMRI and the global score resulted equally correlated with the PCDAI, suggesting a high impact of the most affected segment on symptoms. The PDCMRI may be a useful non-invasive tool for a rapid and reproducible grading of the disease activity in children with ileocolonic CD.

Stigma Moderates the Relation Between Peer Victimization, Thwarted Belongingness, and Depressive Symptoms in Youth with Inflammatory Bowel Disease.

PURPOSE: The stigmatizing nature of IBD symptoms may place youth at risk for being targets of peer victimization, potentially resulting in a decreased sense of social belongingness and poorer emotional adjustment. The present study tested a series of mediation and moderated mediation models examining the associations among peer victimization, thwarted social belongingness, and depressive symptoms, as well as the moderating role of IBD stigma in these associations. We hypothesized peer victimization would have an indirect effect on youth depressive symptoms through thwarted belongingness, and this effect would be amplified for youth endorsing greater IBD stigma. DESIGN AND METHODS: Seventy-five youth (10-18 yrs.) diagnosed with IBD were recruited from a pediatric gastroenterology clinic. Participants completed self-report measures of IBD stigma, peer victimization, thwarted belongingness, and depressive symptoms. RESULTS: As anticipated, mediation analyses revealed a significant peer victimization → thwarted belongingness → depressive symptoms indirect path. Moderated mediation analyses indicated that this indirect effect was moderated by IBD stigma and was significantly greater among youth reporting higher IBD stigma. CONCLUSIONS: Youth who experience higher levels of IBD-related stigma are at increased risk for depressive symptoms as a function of the socially isolating effects of peer victimization. PRACTICE IMPLICATIONS: Our findings highlight the need for routine screening and identification of the socioemotional challenges faced by youth with IBD. Clinical interventions that incorporate coping strategies aimed at minimizing youths' stigmatizing self-perceptions and improving overall social skills and social engagement may lessen the negative impact of peer victimization on youths' social and emotional adjustment.

The Treatment of Pediatric Inflammatory Bowel Disease with Biologic Therapies.

PURPOSE OF REVIEW: Biologics for the treatment of inflammatory bowel disease (IBD) have been transformative to the therapeutic goals in the pediatric population. We review the biologics used to treat IBD, highlighting the importance of patient selection, dosing considerations, and therapeutic drug monitoring in children. RECENT FINDINGS: Infliximab is well-established as a safe and efficacious therapy for Crohn's disease and ulcerative colitis. Both dose escalation strategies and therapeutic drug monitoring increase the likelihood of response to anti-TNFα therapies. Early real-world experience of vedolizumab and ustekinumab in pediatric IBD shows promising results, including clinical response rates comparable to what is seen in adults, but there are limited data using them as first-line therapies. Biologic therapies have improved outcomes in pediatric IBD, including achieving mucosal healing as well as improved growth and pubertal development. Therapeutic drug monitoring improves likelihood of response to anti-TNFα therapies, but further studies for vedolizumab and ustekinumab are necessary.

Premedication with intravenous steroids does not influence the incidence of infusion reactions following infliximab infusions in pediatric inflammatory bowel disease patients-a case-control study.

PURPOSE: Infusion reactions (IR) are commonly described side effects of infliximab (IFX) infusions, often leading to discontinuation of IFX. This study aimed to investigate the influence of steroid premedication (PM) on incidence of IR in pediatric inflammatory bowel disease (PIBD) patients receiving IFX. METHODS: A case-control study in two tertiary centers in Amsterdam, The Netherlands, including PIBD patients receiving IFX. PM with steroids was part of standard care in one center (PM+) but not in the other center (PM-). Acute IR were divided into mild/severe reactions and in grade 1/2/3/4 for detailed exploration. Differences between subgroups were assessed with the T or chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage. RESULTS: We included 226 patients (91 PM+, 50% male, mean age at onset of IBD 12.7 years), receiving 3433 infusions. There was no difference between the PM+ and PM- subgroups in incidence of IR (14.3% vs. 17.0% of patients, p = 0.58) and in percentage of infusions followed by IR (1.4% in both subgroups). The OR of developing IR when using PM was 1.06 (95% CI 0.49-2.27, p = 0.89), and the OR of developing a grade 3 or 4 IR when using PM was 0.90 (95% CI 0.24-3.39, p = 0.88) when correcting for co-medication usage. CONCLUSION: The incidence of IR was low, and premedication with steroids did not decrease the incidence of IR in this cohort of PIBD patients receiving IFX. Our results indicate that PM with steroids is not indicated in PIBD to prevent IR.

The association of autoimmune diseases with pediatric ulcerative colitis does not influence its disease course.

OBJECTIVE: Ulcerative colitis (UC) is a chronic inflammatory condition. Previous reports suggested that UC may have a worse prognosis when associated with auto-immune diseases. We compared characteristics at diagnosis and natural history of the disease between classical ulcerative colitis (CUC) and UC associated with auto-immune diseases (CAI) in children. MATERIAL AND METHODS: In this study, 67 children followed for UC at Nancy University Hospital between 1993 and 2012 were included: 45 patients in the CUC group and 22 in the CAI group. RESULTS: Median follow-up was 4.8 years. Median age at diagnosis was 11.6 years in the CAI group and 9.8 years in the CUC group. Time between symptoms onset and diagnosis was broadly similar in the two groups (<3 months) and there were no significant differences regarding biological and histological findings. At 5 years, the need for corticosteroids and azathioprine did not differ between the CAI and the CUC groups. There was also no significant difference between the two groups regarding infliximab use at 1 and 5 years. CONCLUSIONS: In this pediatric study, CAI had similar characteristics at baseline as CUC. The course of CAI does not seem to be influenced by the presence of concomitant auto-immune diseases.

Bowel Sonography and MR Enterography in Children.

OBJECTIVE: The objective of this study was to assess the diagnostic agreement between bowel sonography and MR enterography in children with suspected or confirmed inflammatory bowel disease (IBD). SUBJECTS AND METHODS: We prospectively studied 33 children undergoing clinically indicated MR enterography. Bowel sonography was performed within 2 hours before MR enterography. The reliability of each modality was assessed by computing the interreader kappa agreement on nine inflammatory markers in eight bowel segments and the interreader intraclass correlation coefficients (ICC) in each bowel segment. The agreement between both modalities in each bowel segment was also calculated using the Kendall coefficient of concordance (KCC) in addition to the sensitivity and specificity of sonography using those of MR enterography as the reference standard. RESULTS: Sonographic readings are substantially reliable in the colon and terminal and distal ileum (ICC = 0.79-0.88) but are highly unreliable in the mid and proximal small bowel. MR enterography has moderate to almost perfect reliability for all bowel segments (ICC = 0.43-0.96). Sonography was in substantial agreement with MR enterography in most of the large bowel (KCC = 0.67-0.83) and terminal and distal ileum (KCC = 0.75) and in moderate agreement in the remaining bowel segments (KCC = 0.45-0.48). Sonographic findings are specific for disease using MR enterography as the reference standard in all bowel segments (0.83-1.00), but sensitivity markedly varies according to disease location. CONCLUSION: Sonography is highly specific and shows substantial agreement with MR enterography in detecting inflammatory and damage changes in the colon and terminal and distal ileum, the segments most likely to be affected by IBD. Therefore, sonography can be a good complement to MR enterography in evaluations of patients with known or suspected IBD, particularly if MR enterography access is limited.

Diffusion-weighted MRI in pediatric inflammatory bowel disease.

OBJECTIVE: Pediatric patients with inflammatory bowel disease (IBD) commonly need repetitive imaging to assess disease activity and complications. Recently, MR enterography has become a first-line radiologic study in children with IBD because of improved image quality, excellent soft-tissue contrast resolution, and lack of ionizing radiation. The purpose of this article is to describe the use of diffusion-weighted imaging (DWI) in MR enterography and the evaluation of pediatric IBD. CONCLUSION: Several contemporary publications have shown that DWI can be useful for assessing both pediatric and adult patients with IBD as an important adjunct pulse sequence. Specifically, DWI can be used to identify abnormal bowel segments, assess disease inflammatory activity, and detect and characterize a variety of extraintestinal IBD-related manifestations and complications.

Neutrophil gelatinase-associated lipocalin in blood in children with inflammatory bowel disease.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa glycoprotein present in the bodily fluids and tissues. It is secreted by neutrophils, epithelial cells, hepatocytes and adipocytes, and its expression is highly increased in response to cellular stress. The role of NGAL in the pathophysiology of inflammatory bowel disease including Crohn's disease and ulcerative colitis in children has thus far not been studied. METHODS: The following groups of children were included: (i) inflammatory bowel disease group, n = 36, aged from 1 to 18 years with Crohn's disease (n = 19) and ulcerative colitis (n = 17); (ii) control group, n = 126; and (iii) disease control group, n = 27, without inflammatory bowel disease, with a food and/or inhalant allergy. RESULTS: Healthy children aged from 1 to 8 years exhibited lower NGAL level than those of 9 to 18 years old (39.0; 18.1-83.7 ng/mL vs 57.6; 28.7-107 ng/mL, P = 0.001). In the younger, but not in the older children, the serum NGAL level correlated with their age, r = 0.334, P = 0.001. In children with inflammatory bowel disease, serum NGAL level was higher (108; 37.3-245 ng/mL) than in healthy (42.0; 18.1-107 ng/mL) and allergic, noninflammatory bowel disease children (49.3; 19.3-107 ng/mL), P = 0.001. Serum NGAL levels in Crohn's disease and ulcerative colitis children did not correlate with age, gender, disease activity, and indices of the inflammation. CONCLUSION: Serum NAGL levels are highly elevated in Crohn's disease and ulcerative colitis in children compared to the healthy control group. Systematic studies are needed to explain the role of this protein in the inflammatory bowel disease.