Ustekinumab in paediatric patients with moderately to severely active Crohn's disease: UniStar study long-term extension results.

OBJECTIVES: To assess the efficacy, safety, immunogenicity, and pharmacokinetics through 240 weeks of ustekinumab treatment in paediatric patients from the long-term extension (LTE) of the phase 1, double-blind UniStar trial. METHODS: Paediatric patients with moderately to severely active Crohn's disease (CD) were randomised 1:1 and stratified by body weight (<40 or ≥40 kg) to low- or high-dose intravenous ustekinumab followed by a subcutaneous maintenance dose at Week 8. At Week 16, patients were eligible to enter the LTE at the discretion of the investigator and continued maintenance dosing every 8 weeks up to Week 240. RESULTS: Of the 34 patients who entered the LTE, 25 patients with evaluable data completed Week 48, and 41.2% (14/34) achieved clinical remission at Week 48. Among the 24 patients with Week-0 C-reactive protein (CRP) levels ≥3 mg/L, 29.2% (7/24) achieved normalisation of CRP at Week 48, while imputing missing data as failures. Through Week 240, the most common adverse events were infections (n = 28) and gastrointestinal disorders (n = 26). The most common serious adverse event was worsening of CD (n = 6). Only one patient had detectable antibodies to ustekinumab. Median serum ustekinumab concentrations remained consistent through Week 48, were detectable through Week 224, and trended lower in patients <40 kg. CONCLUSIONS: Efficacy and pharmacokinetics through 1 year and safety and immunogenicity through 4 years of ustekinumab treatment in paediatric patients with CD were generally comparable to those previously reported in adults.

A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients With Crohn's Disease.

BACKGROUND & AIMS: Pan-enteric capsule endoscopy (PCE) is effective for assessment of small intestinal and colonic Crohn's disease (CD) in pediatric patients. We aimed to determine whether PCE can be used to monitor mucosal healing and deep remission, in a treat to target strategy for pediatric patients with CD. METHODS: We performed a prospective study of 48 children with a diagnosis of CD at a tertiary care pediatric gastroenterology unit; 46 patients were included in the final analysis. Biomarker, imaging, and PCE analyses were performed at baseline and after 24 and 52 weeks. Small bowel and colonic mucosal healing were defined by Lewis scores <135 and simple endoscopic score for CD ≤1, respectively. Clinical remission was defined as defined as a pediatric CD activity index score <10 and biomarker-based remission based on normal levels of biomarkers; deep remission was defined as a combination of clinical remission, biomarker-based remission, and mucosal healing. Treatments were adjusted based on findings from PCE (imaging was considered only for patients with negative findings from PCE). Therapies were introduced, optimized, switched, or combined at the discretion of treating clinicians. The primary outcome was the ability of PCE to assess mucosal healing and deep remission at 3 timepoints and to guide a treat to target strategy. RESULTS: PCE detected inflammation in 34 patients (71%) at baseline, 22 patients (46%) at week 24, and 18 patients (39%) at week 52 (P for comparison among timepoints <.05). Findings from PCE led to a change in therapy for 34 patients (71%) at baseline and 11 patients (23%) at 24 weeks, whereas only 2 patients with negative results from PCE (4%) changed therapies based on findings from imaging. When the treat to target strategy was applied, proportions of patients with mucosal healing and deep remission increased from 21% at baseline, to 54% at week 24, to 58% at week 52 (P for comparison among timepoints <.05); 2 patients (4%) did not respond to treatment. CONCLUSION: In a prospective study of 48 children with CD, we found a treat to target strategy, based on findings from PCE, to significantly increase the proportions of patients with mucosal healing and deep remission. CLINICAL TRIAL: gov no: NCT03161886.

Clinical and Fecal Microbial Changes With Diet Therapy in Active Inflammatory Bowel Disease.

GOAL: To determine the effect of the specific carbohydrate diet (SCD) on active inflammatory bowel disease (IBD). BACKGROUND: IBD is a chronic idiopathic inflammatory intestinal disorder associated with fecal dysbiosis. Diet is a potential therapeutic option for IBD based on the hypothesis that changing the fecal dysbiosis could decrease intestinal inflammation. STUDY: Pediatric patients with mild to moderate IBD defined by pediatric Crohn's disease activity index (PCDAI 10-45) or pediatric ulcerative colitis activity index (PUCAI 10-65) were enrolled into a prospective study of the SCD. Patients started SCD with follow-up evaluations at 2, 4, 8, and 12 weeks. PCDAI/PUCAI, laboratory studies were assessed. RESULTS: Twelve patients, ages 10 to 17 years, were enrolled. Mean PCDAI decreased from 28.1±8.8 to 4.6±10.3 at 12 weeks. Mean PUCAI decreased from 28.3±23.1 to 6.7±11.6 at 12 weeks. Dietary therapy was ineffective for 2 patients while 2 individuals were unable to maintain the diet. Mean C-reactive protein decreased from 24.1±22.3 to 7.1±0.4 mg/L at 12 weeks in Seattle Cohort (nL<8.0 mg/L) and decreased from 20.7±10.9 to 4.8±4.5 mg/L at 12 weeks in Atlanta Cohort (nL<4.9 mg/L). Stool microbiome analysis showed a distinctive dysbiosis for each individual in most prediet microbiomes with significant changes in microbial composition after dietary change. CONCLUSIONS: SCD therapy in IBD is associated with clinical and laboratory improvements as well as concomitant changes in the fecal microbiome. Further prospective studies are required to fully assess the safety and efficacy of dietary therapy in patients with IBD.

Clinical Characteristics of Disaccharidase Deficiencies Among Children Undergoing Upper Endoscopy.

OBJECTIVES: The epidemiology and clinical significance of disaccharidase deficiencies have not been thoroughly characterized. Recent work suggests at least genetic sucrase-isomaltase deficiency is more prevalent than previously believed. Because lactase deficiency (LD) is well described, the present study focuses on the clinical characteristics of children with disaccharidase deficiencies determined by esophagogastroduodenoscopy. METHODS: Endoscopic records were reviewed from patients undergoing esophagogastroduodenoscopies with biopsies assayed for disaccharidase activity performed by 13 pediatric gastroenterologists during 5 years (2010-2014). Presenting symptoms, clinical and histological diagnosis, treatment, disaccharidase results, and demographic variables were obtained from medical and endoscopic records of those with maltase and sucrase deficiency (SD). RESULTS: Among 963 patients undergoing intestinal disaccharidase testing, 73 (7.6%) had SD on biopsy (enzyme activity <25 µmol ·â€Šmin ·â€Šg). Thirty-four (34/73; 47%) had normal duodenal histology and are the focus of this report. Four patients had SD without LD. Pan-disaccharidase deficiency was observed in 24 patients when maltase and palatinase assays were obtained (n = 646), and 11 had SD + LD when just those 2 enzymes were analyzed (n = 317). Those with SD without LD were younger 4.6 ±â€Š6.1 versus 14.1 ±â€Š3.6 years and uniformly presented with diarrhea. Patients with pan-disaccharidase deficiency or SD + LD primarily reported abdominal pain (33/35; 94%), diarrhea (16/35; 46%), nausea (14/35; 40%); and poor weight gain/weight loss (10/35; 29%); constipation, flatulence, and bloating were also noted. Maltase deficiency is less common (8/963; 0.8%), presenting with similar symptoms. CONCLUSIONS: Genetic sucrase-isomaltase deficiency often occurs together with lactase or pan-disaccharide deficiency. Disaccharidase deficiency should be considered a potential cause of abdominal pain and/or diarrhea in children and adolescents.

Colon capsule endoscopy compared with other modalities in the evaluation of pediatric Crohn's disease of the small bowel and colon.

BACKGROUND AND AIMS: Data on colon capsule endoscopy (CCE) in evaluating the small bowel and colon concurrently are rare. This study aimed to evaluate the accuracy of CCE in assessing disease activity of the small bowel and colon in pediatric Crohn's disease (CD) by comparison with magnetic resonance enterography (MRE), small-intestine contrast US (SICUS), and ileocolonoscopy. METHODS: We prospectively enrolled 40 consecutive patients (22 male, 18 female, mean age 13.1 ± 3.1 years) with CD of the small bowel and colon. All underwent SICUS, MRE, CCE, and ileocolonoscopy sequentially over 5 days. All investigators were blinded to patient history and test results. Patients were classified as active or inactive for the small bowel and the colon according to specific criteria for each tool (simple endoscopic score for CD, Lewis score, US and magnetic resonance parameters of activity). For colon mucosa evaluation, ileocolonoscopy was the comparator. For the small bowel, a consensus panel was convened. RESULTS: Sensitivity of CCE to detect colon inflammation was 89%, and specificity was 100%. The positive predictive value (PPV) and negative predictive value (NPV) of CCE for colon inflammation were 100% and 91%, respectively. In the small bowel, CCE showed 90% sensitivity, 94% specificity, with PPV and NPV of 95% and 90%, respectively. Accuracy parameters for SICUS (sensitivity 90%, specificity 83%) and MRE (sensitivity 85%, specificity 89%) were lower than those for CCE. No serious adverse events related to the CCE procedure or preparation were reported. CONCLUSIONS: CCE is of great usefulness in evaluating both small bowel and colon mucosa in pediatric CD. This single, noninvasive tool makes it possible to evaluate the small-bowel and the colon concurrently with high diagnostic accuracy. Future multicenter studies need to define the role of CCE in the routine management of pediatric patients with CD. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02199626.).

Patients Perceive Clinical Benefit with the Specific Carbohydrate Diet for Inflammatory Bowel Disease.

BACKGROUND: Recent studies suggest that dietary therapy may be effective for patients with inflammatory bowel disease (IBD), but limited published data exist on the usage and efficacy of dietary therapy. AIM: To evaluate the perspective of IBD patients using the specific carbohydrate diet (SCD). METHODS: An anonymous online survey was conducted using REDCap, a Web-based survey tool. Survey links were sent to known Web sites as well as support groups in an attempt to characterize patient utilization of the SCD and perception of efficacy of the SCD. RESULTS: There were 417 respondents of the online survey on the SCD with IBD. Mean age for individuals on the SCD was 34.9 ± 16.4 years. Seventy percent were female. Forty-seven percent had Crohn's disease, 43 % had ulcerative colitis, and 10 % had indeterminate colitis. Individuals perceived clinical improvement on the SCD. Four percent reported clinical remission prior to the SCD, while 33 % reported remission at 2 months after initiation of the SCD, and 42 % at both 6 and 12 months. For those reporting clinical remission, 13 % reported time to achieve remission of less than 2 weeks, 17 % reported 2 weeks to a month, 36 % reported 1-3 months, and 34 % reported greater than 3 months. For individuals who reported reaching remission, 47 % of individuals reported associated improvement in abnormal laboratory values. CONCLUSIONS: The SCD is utilized by many patients as a primary and adjunct therapy for IBD. Most patients perceive clinical benefit to use of the SCD.

Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease.

BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.

Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease.

OBJECTIVE: The aim of the study was to prospectively evaluate clinical and mucosal responses to the specific carbohydrate diet (SCD) in children with Crohn disease (CD). METHODS: Eligible patients with active CD (Pediatric Crohn's Disease Activity Index [PCDAI] ≥ 15) underwent a patency capsule and, if passed intact, capsule endoscopy (CE) was performed. Patients taking SCD were monitored for 52 weeks while maintaining all prescribed medications. Demographic, dietary, and clinical information, PCDAI, Harvey-Bradshaw Index (HBI), and Lewis score (LS) were collected at 0, 12, and 52 weeks. CEs were evaluated by an experienced reader blinded to patient clinical information and timing. RESULTS: Sixteen patients were screened; 10 enrolled; and 9 completed the initial 12-week trial-receiving 85% of estimated caloric needs before, and 101% on the SCD. HB significantly decreased from 3.3 ± 2.0 to 0.6 ± 1.3 (P = 0.007) as did PCDAI (21.1 ± 5.9 to 7.8 ± 7.1, P = 0.011). LS declined significantly from 2153 ± 732 to 960  ± 433 (P = 0.012). Seven patients continued the SCD up to 52 weeks; HB (0.1 ± 0.4) and PCDAI (5.4 ± 5.5) remained improved (P = 0.016 and 0.027 compared to baseline), with mean LS at 1046 ± 372 and 2 patients showed sustained mucosal healing. CONCLUSIONS: Clinical and mucosal improvements were seen in children with CD, who used SCD for 12 and 52 weeks. In addition, CE can monitor mucosal improvement in treatment trials for pediatric CD. Further studies are critically needed to understand the mechanisms underlying SCD's effectiveness in children with CD.

Outcomes in Adult Inflammatory Bowel Disease Clinical Trials: Assessment of Similarity Among Participants with Adolescent-Onset and Adult-Onset Disease.

BACKGROUND AND AIMS: Most pediatric IBD studies are performed after medications are approved in adults and the majority of participants in these studies are adolescents. We hypothesized that adolescent-onset IBD is not fundamentally different than adult-onset IBD. If this is correct, the value of delaying access to novel drugs in adolescents becomes questioned. METHODS: Data from 11 randomized, double-blind, placebo-controlled adult phase 2 and 3 trials of 4 biologics were analyzed. Participants were categorized as having adolescent- or adult-onset disease (diagnosed 12 to <18, or ≥18 years). Multivariable modelling explored the association between age at diagnosis and response to treatment after adjustment for disease duration, extent, and severity at baseline. Data from dose arms were pooled to evaluate similarity of therapeutic response between adolescent- and adult-onset IBD within the same trial (not between doses or across trials). Ratios of odds ratios between the two groups were evaluated. RESULTS: Data from 6,283 study participants (2,575 with Crohn's disease [CD], 3,708 with ulcerative colitis [UC]) were evaluated. Of 2,575 study participants with CD, 325 were 12-<18 years old at diagnosis; 836 participants (32.4%) received placebo. Of 3,708 participants with UC, 221 were 12-<18 years old at diagnosis; 1,212 (33%) were receiving placebo. The majority of the ratios of ORs were within two-fold, suggesting that responses in adolescent and adult-onset participants are generally similar. CONCLUSION: Data presented lend support for extrapolating efficacy of biologics from adults to adolescents with IBD, which would facilitate earlier labeling and patient access.

Pediatric capsule endoscopy: review of the small bowel and patency capsules.

BACKGROUND AND OBJECTIVE: Because capsule endoscopy (CE) avoids ionizing radiation, deep sedation, and general anesthesia, CE may be valuable in pediatrics. We report a single pediatric center's experience with the use and safety of CE. METHODS: In a retrospective review of consecutive CE studies, 284 CE studies were performed in 277 patients with a mean age of 15 (±3.7) years during a 5-year period. The youngest to swallow the capsule was 4.6 years old. Twenty capsules were placed. Overall, 245 (86%) patients underwent CE for suspected (184, 65%) or confirmed (61, 21%) Crohn disease (CD); 27 (9.5%) anemia or gastrointestinal bleeding; 6 (2%) polyposis; and 4 (1.4%) celiac disease. RESULTS: Positive findings were observed in 205 (72%) of the studies, with 152 (54%) having small bowel findings. Of these, 72 (47%) were diagnostic. Gastric (95, 33%) and colonic (31, 11%) abnormalities were also identified. Five CE studies (1.8%) resulted in retention of the capsule in nonsurgical patients. A patency capsule before CE in 23 patients allowed 19 CE to proceed with only 1 retained capsule. In 65 (21%) patients, the video capsule did not enter the colon before the video's end. Of these, 36 (65%) had significant findings, including 27 (49%) documenting small bowel (SB) CD. CONCLUSIONS: CE is useful to diagnose SB disease in children. Even in a study population with a high prevalence of confirmed and suspected CD, the risk of retention remains small. The patency capsule may lessen that risk. CE may identify gastric or colonic disease even when SB lesions are not present.

Predictors of proctocolectomy in children with ulcerative colitis.

OBJECTIVES: Few clinical predictors are associated with definitive proctocolectomy in children with ulcerative colitis (UC). The purpose of the present study was to identify clinical predictors associated with surgery in children with UC using a disease-specific database. METHODS: Children diagnosed with UC at age <18 years were identified using the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) database. Demographic and clinical variables from January 1999 to November 2003 were extracted alongside incidence and surgical staging. RESULTS: Review of the PediIBDC database identified 406 children with UC. Approximately half were girls (51%) with an average age at diagnosis of 10.6 ±â€Š4.4 years in both boys and girls. Average follow-up was 6.8 (±4.0) years. Of the 57 (14%) who underwent surgery, median time to surgery was 3.8 (interquartile range 4.9) years after initial diagnosis. Children presenting with weight loss (hazard ratio [HR] 2.55, 99% confidence interval [CI] 1.21-5.35) or serum albumin <3.5 g/dL (HR 6.05, 99% CI 2.15-17.04) at time of diagnosis and children with a first-degree relative with UC (HR 1.81, 99% CI 1.25-2.61) required earlier surgical intervention. Furthermore, children treated with cyclosporine (HR 6.11, 99% CI 3.90-9.57) or tacrolimus (HR 3.66, 99% CI 1.60-8.39) also required earlier surgical management. Other symptoms, laboratory tests, and medical therapies were not predictive for need of surgery. CONCLUSION: Children with UC presenting with hypoalbuminemia, weight loss, a family history of UC, and those treated with calcineurin inhibitors frequently require restorative proctocolectomy for definitive treatment. Early identification and recognition of these factors should be used to shape treatment goals and initiate multidisciplinary care at the time of diagnosis.

Small bowel capsule endoscopy impacts diagnosis and management of pediatric inflammatory bowel disease: a prospective study.

PURPOSE: Accurately classifying inflammatory bowel disease (IBD) type in pediatric patients may impact medical decision-making, direct therapy, and improve outcomes. METHODS: This was a prospective cohort study evaluating classification of IBD and patient management with use of capsule endoscopy in pediatric patients with suspected or known IBD. Treating physicians completed a questionnaire before and after capsule endoscopy (CE) assessing clinical suspicion of Crohn's disease (CD) diagnosis, patient management decisions, and perceived impact of CE findings. RESULTS: Eighteen subjects [11F/7M, mean age 13.8 (± 2.5) years], 4 previously diagnosed with CD, 4 with ulcerative or indeterminate colitis (UC/IC), and 10 "suspected" to have IBD were included. Following CE, 2 of 4 (50%) UC/IC patients were reclassified as having small bowel CD. In the 4 subjects with known CD, 2 (50%) had CE evidence of more proximal small bowel mucosal disease than previously recognized. In the 10 subjects with "suspected" IBD, 8 (80%) had SB ulcerations leading to a definitive diagnosis of CD. Treating physicians reported CE helped diagnosing CD in 15 of 18 (83.3%) subjects and impacted medical decision-making in 13 of 18 (72.2%), leading to a change in medical management in 14 of 18 (77.8%). CONCLUSIONS: In "suspected" pediatric IBD, CE often leads to a definitive diagnosis of CD. CE can lead to reclassification of IBD from UC/IC to CD and previously diagnosed CD patients may have a more significant burden of small bowel disease. These data may help integrate CE in evaluating IBD patients, lead to more targeted medical management changes and improve outcomes.

Pharmacokinetics, Safety and Efficacy of Intravenous Vedolizumab in Paediatric Patients with Ulcerative Colitis or Crohn's Disease: Results from the Phase 2 HUBBLE Study.

BACKGROUND AND AIMS: To date, there are no systematic pharmacokinetic [PK] data on vedolizumab in paediatric inflammatory bowel disease [IBD]. We report results from HUBBLE, a dose-ranging, phase 2 trial evaluating the PK, safety and efficacy of intravenous vedolizumab for paediatric IBD. METHODS: Enrolled patients [aged 2-17 years] with moderate to severe ulcerative colitis [UC] or Crohn's disease [CD] and body weight ≥10 kg were randomized by weight to receive low- or high-dose vedolizumab [≥30 kg, 150 or 300 mg; <30 kg, 100 or 200 mg] on Day 1 and Weeks 2, 6 and 14. Week 14 assessments included PK, clinical response and exposure-response relationship. Safety and immunogenicity were assessed. RESULTS: Randomized patients weighing ≥30 kg [UC, n = 25; CD, n = 24] and <30 kg [UC, n = 19; CD, n = 21] had a baseline mean [standard deviation] age of 13.5 [2.5] and 7.6 [3.2] years, respectively. In almost all indication and weight groups, area under the concentration curve and average concentration increased ~2-fold from low to high dose; the trough concentration was higher in each high-dose arm compared with the low-dose arms. At Week 14, clinical response occurred in 40.0-69.2% of patients with UC and 33.3-63.6% with CD in both weight groups. Clinical responders with UC generally had higher trough concentration vs non-responders, while this trend was not observed in CD. Fourteen per cent [12/88] of patients had treatment-related adverse events and 6.8% [6/88] had anti-drug antibodies. CONCLUSIONS: Vedolizumab exposure increased in an approximate dose-proportional manner. No clear dose-response relationship was observed in this limited cohort. No new safety signals were identified.

Use of capsule endoscopy in diagnosis and management of pediatric patients, based on meta-analysis.

BACKGROUND & AIMS: To further our understanding of capsule endoscopy (CE) in children, we systematically compiled data on indications and outcomes and evaluated the effectiveness of CE on patient management using meta-analyses. METHODS: We searched the Medline and PubMed databases (January 2001-May 2010) for English language citations of use of CE in patients ≤18 years old. Duplicate reports and those that included 5 patients or fewer were removed. We analyzed data from 15 source documents with 740 CE procedures in 723 patients. RESULTS: Suspicion or evaluation of inflammatory bowel diseases was the most common indication for CE (54%: 34% for patients suspected to have Crohn's disease [CD], 16% for patients known to have CD, 1% for patients with ulcerative colitis, and 3% for patients with indeterminate colitis). Completion and retention rates were 86.2% (95% confidence interval [CI], 81.5-90.3) and 2.6% (95% CI, 1.5-4.0), respectively. Retention rates for children that underwent gastric (0.5%) or small bowel (1.9%) CE were similar to those of adults, by indication. For CE, 65.4% of procedures resulted in positive findings (95% CI, 54.8-75.2). Where reported, 69.4% of CE examinations (95% CI, 46.9-87.9) resulted in a new diagnosis and 68.3% (95% CI, 43.6-88.5) led to change in therapy. CONCLUSIONS: The relative frequency of CE indications varies among pediatric and adult patients. In pediatric patients, CE is used primarily to evaluate patients with CD - to aid in diagnosis, monitor disease severity, and assist patient management. Retention rates appear to be related to indication, rather than patient age; capsule retention is relatively infrequent for adults and children.

The use of a patency capsule in pediatric Crohn's disease: a prospective evaluation.

BACKGROUND: Capsule endoscopy (CE) retention remains a concern in patients with suspected or known Crohn's Disease (CD). AIM: The aim of this study was to evaluate the ability of a patency capsule (PC) to establish functional patency in pediatric patients with suspected or known, symptomatic IBD. METHODS: A prospective, single center study evaluating the impact of CE on CD management used PC to qualify patients for CE. Patients excreting an intact PC, usually within 40 h of ingestion, were able to undergo standard video CE. Excretion time, structural integrity and patient safety were evaluated. RESULTS: Eighteen patients (10-16 years of age; 9 male; 5 known CD, 3 indeterminate colitis, 1 ulcerative colitis, 9 suspected CD) ingested the PC. Fifteen patients excreted intact PC (mean 34.5 h), 12 patients within 40 h (range 9-60 h). Sixteen (89%) underwent subsequent CE successfully. CD was eventually diagnosed in all patients having PC transit ≥40 h, whereas CD was the diagnosis in 9/12 (75%) in those patients who passed the PC within 40 h. The mean time of passage for an intact PC was 34.7 h, the longest 60 h. There were no capsule retentions or adverse events. CONCLUSIONS: The PC appears to be a useful screening tool for functional patency of the small bowel in suspected or known pediatric CD. Delayed passage of an intact PC requires careful interpretation.

Capsule Endoscopy in Children.

Since its clearance for use throughout the world, capsule endoscopy (CE) has become an important diagnostic tool, helping us to understand and document both normal and abnormal findings in the small intestine, especially in children, since CE usually can be employed without sedation or radiation. The indications in children and adults are similar, though their relative frequencies are different, with evaluation of potential and known inflammatory bowel disease the most common in the pediatric population, with CE also yielding increased diagnostic certainty compared to radiographic studies and surrogate biomarkers. Newer capsules now create opportunities to expand that understanding and our practices so that we can learn when and how to employ CE and pan-enteric CE to better monitor and guide therapy. It will take further studies to determine the best uses for CE and how to select the appropriate candidates, especially with ongoing concern about capsule ingestion vs. placement, the potential for capsule retention (particularly in known Crohn's disease), still elusive optimal methods for bowel cleansing, and the most meaningful scoring for research and clinical use.

Ustekinumab in Paediatric Patients with Moderately to Severely Active Crohn's Disease: Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study.

BACKGROUND AND AIMS: The objective was to evaluate the pharmacokinetics, safety/tolerability, and efficacy of ustekinumab in children with moderately to severely active Crohn's disease. METHODS: In this Phase 1, multicentre, 16-week, double-blind, induction dose-ranging study [NCT02968108], patients aged 2-<18 years [body weight ≥10 kg] were randomised [1:1] to one of two weight range-based intravenous induction doses: 130 mg vs 390 mg in patients ≥40kg and 3 mg/kg vs 9 mg/kg in patients <40kg. At Week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90 mg in patients ≥40kg or 2 mg/kg in patients <40kg. RESULTS: A total of 44 patients were randomised and treated with ustekinumab [n = 23 lower dose; n = 21 higher dose]; median [interquartile range] age was 13.0 [12-16] years. Pharmacokinetics were similar to those in adults with Crohn's disease. However, serum ustekinumab concentrations were lower among those with body weight <40 kg compared with patients ≥40 kg and the reference Phase 3 adult population. Through Week 16, 73% of patients reported ≥1 adverse event [82.6% lower vs 62% higher dose]; two discontinued due to adverse events [one in each group]. Serious adverse events occurred in 16% [26% lower, 5% higher dose], with Crohn's disease exacerbation being the most frequent. At Week 16, 22%/29% [lower/higher dose] achieved clinical remission [Paediatric Crohn's Disease Activity Index ≤10]. CONCLUSIONS: The pharmacokinetics/safety profiles were generally consistent with those observed in adults with Crohn's disease. These results suggest a different dosing regimen may be required for patients <40 kg from that employed in this study; additional pharmacokinetic analyses may be needed in this population.

Capsule Retention in Crohn's Disease: A Meta-analysis.

BACKGROUND: The main factor that limits wider utilization of capsule endoscopy (CE) in Crohn's disease (CD) is the potential risk of retention. The aim of this systematic review was to evaluate capsule retention rates in adult and pediatric CD and determine if retention risk is reduced in established CD (ECD) with patency capsule (PC) or magnetic resonance/computed tomography (MR/CT) enterography. METHODS: Studies of CD patients undergoing CE that reported retention were identified. Pooled estimates for retention rates and relative risk in ECD to suspected CD (SCD) were calculated. All hypothesis tests were 2-sided; statistical significance was set at a P value of <0.05. RESULTS: In the overall CD cohort, retention rates were 3.32% (95% confidence interval [CI], 2.62%-4.2%): 4.63% (95% CI, 3.42%-6.25%) and 2.35% (95% CI, 1.31%-4.19%) in ECD and SCD, respectively. Retention rates were 3.49% (95% CI, 2.73%-4.46%) and 1.64% (95% CI, 0.68%-3.89%) in adult and pediatric CD, respectively. Retention risk in adult ECD was 3.4 times higher than SCD, but there was no difference in retention risk in pediatric ECD compared with SCD. Retention rates in ECD were decreased after patency capsule (2.88%; 95% CI, 1.74%-4.74%) and MR/CT enterography (2.32%; 95% CI, 0.87%-6.03%). CONCLUSIONS: In comparison with older literature, this meta-analysis demonstrates lower CE retention rates in SCD and ECD. Retention rates in pediatric CD were lower than in adult CD. Retention rates in adult ECD were higher than SCD, but there were no differences between pediatric ECD and SCD. Retention rates in ECD were lower after negative PC or MR/CT enterography.

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.