Canakinumab for the treatment of autoinflammatory very early onset- inflammatory bowel disease.

Introduction: Therapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1ß monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease. Methods: This is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events. Results: Nineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p<0.01) and length of stay (p<0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period. Conclusion: Canakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD.

A Pattern-based Pathology Approach to Very Early-onset Inflammatory Bowel Disease: Thinking Beyond Crohn Disease and Ulcerative Colitis.

Very early-onset inflammatory bowel disease (VEO-IBD), IBD diagnosed in children younger than 6 years old, is phenotypically and genetically distinct from older onset IBD. Monogenic and digenic causative defects, particularly in primary immunodeficiency and intestinal epithelial barrier genes, have been identified in a subset of patients with VEO-IBD allowing for targeted therapies and improved outcomes. However, these findings are the minority, thus strategies to correctly diagnose patients, including identification of specific histopathologic findings with correlating clinical and laboratory features may provide critical and necessary insight into mechanisms of disease pathogenesis and subsequent therapeutic options. In this article, we review the pathologic findings seen in patients with VEO-IBD and outline a pattern-based approach to diagnosis using examples from primary immunodeficiencies with gastrointestinal manifestations.

Colonoids From Patients With Pediatric Inflammatory Bowel Disease Exhibit Decreased Growth Associated With Inflammation Severity and Durable Upregulation of Antigen Presentation Genes.

BACKGROUND: Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids. METHODS: We measured growth efficiency relative to histopathological and clinical parameters in patient enteroid (ileum) and colonoid (colon) lines. We performed RNA-sequencing on patient colonoids and subsequent flow cytometry after multiple passages to evaluate changes that persisted in culture. RESULTS: Enteroids and colonoids from pediatric patients with IBD exhibited decreased growth associated with histological inflammation compared with non-IBD controls. We observed increased LYZ expression in colonoids from pediatric IBD patients, which has been reported previously in adult patients with IBD. We also observed upregulation of antigen presentation genes HLA-DRB1 and HLA-DRA, which persisted after prolonged passaging in patients with pediatric IBD. CONCLUSIONS: We present the first functional evaluation of enteroids and colonoids from patients with VEO-IBD and older onset pediatric IBD, a subset of which exhibits poor growth. Enhanced, persistent epithelial antigen presentation gene expression in patient colonoids supports the notion that epithelial cell-intrinsic differences may contribute to IBD pathogenesis.

Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease.

The incidence and prevalence of pediatric inflammatory bowel disease (IBD) are rising worldwide, with a steep increase in children under 5 years of age. Compared to adult IBD, pediatric IBD presents with a more severe, aggressive phenotype and unique complications, notably growth impairment. Treatment goals include achieving intestinal healing, reaching growth potential, and optimizing quality of life, all while limiting drug toxicities. In the last 2 decades, the advent of anti-tumor necrosis factor (TNF) α agents has significantly increased the potential to reach these goals. However, nonresponse or loss of response to anti- TNFα agents is still encountered in approximately one-third of patients. Although the development of novel biologic therapies has offered new alternatives in recent years, the use of these therapies in the pediatric setting has been limited due to delayed approval. This article summarizes the key evidence for biologic agents currently used in the treatment of pediatric IBD and discusses challenges and barriers unique to pediatric drug development.

Distinct Histopathological Features at Diagnosis of Very Early Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Children with very early onset inflammatory bowel disease [VEO-IBD] represent a unique cohort, often with a severe phenotype that is refractory to conventional medications, and some cases have underlying primary immunodeficiencies. Previous work has identified distinct histopathological patterns in the gastrointestinal tract in patients with primary immunodeficiencies. The aim of this study is to characterise the diagnostic histological findings in patients with VEO-IBD as compared with older onset paediatric IBD, and determine if there are unique pathological changes that can shed light on the driving forces of the disease, particularly immunodeficiencies. METHODS: Clinical retrospective chart review, including disease characteristics and endoscopic findings, was performed on all included subjects. Two paediatric pathologists reviewed biopsies from diagnostic upper endoscopies and colonoscopies of subjects with very early onset inflammatory bowel disease and older onset inflammatory bowel disease, to evaluate for the presence of 11 histological features previously associated with inflammatory bowel disease and primary immunodeficiencies. RESULTS: The diagnostic gastrointestinal biopsies of subjects with very early onset inflammatory bowel disease differed from those in older onset paediatric IBD, demonstrated by increased frequency of apoptosis, severe chronic architectural changes, small intestine villous blunting, and eosinophils in the crypts, lamina propria, and surface epithelium. CONCLUSIONS: The diagnostic biopsies of children with very early onset inflammatory bowel disease can identify characteristic features that may be important in guiding the diagnostic work-up in this population.

Endoscopic ultrasound with or without fine-needle aspiration has a meaningful impact on clinical care in the pediatric population.

BACKGROUND AND OBJECTIVES: The safety and utility of endoscopic ultrasound (EUS) for the evaluation and management of gastrointestinal (GI) tract disorders among adults has been established. The literature on safety and efficacy in a pediatric referral population (under 21 years of age) is limited. We hypothesized that EUS is safe and useful in the pediatric population. We reviewed the pediatric EUS experience at a single tertiary-care system. We describe the indications, findings, safety, technical success rate, and impact on clinical outcomes. PATIENTS AND METHODS: All patients 21 years of age or younger referred for EUS between 5, 2007 and 11, 2012 were identified from our electronic medical record databases. Retrospective chart review was then conducted to document demographics, procedure indications, procedure type (diagnostic or therapeutic), type of anesthesia used, EUS findings, and the clinical impact of EUS on the subsequent management of the patients. RESULTS: Seventy EUS procedures were attempted in 58 patients during the study. Of these, two EUS procedures were aborted due to inadequate moderate sedation and 68 were successfully completed. The median age at initial endoscopy was 18 years (range 6-21 years), 50% were male and 65% were Caucasian. Four patients underwent EUS-guided pseudocyst drainage. Among the remaining 54 patients, the indications for EUS were the evaluation of GI mucosal/submucosal lesions (n = 14), acute or recurrent pancreatitis (n = 10), localization of suspected insulinoma (n = 8), evaluation of pancreatic abnormalities seen on prior imaging (n = 6), surveillance of tumors or evaluation of luminal lesions in hereditary syndromes (n = 6), abdominal pain of suspected pancreatobiliary origin (n = 5), and other rare indications (n = 5). Fine-needle aspiration was performed in 13 (9 diagnostic, 4 therapeutic) and trans-gastric fine-needle contrast injection of the pancreatic duct was performed in one patient without any complications. Sedation (data available for 66 procedures) included general endotracheal anesthesia in 38 (57%), monitored anesthesia care (MAC) in 19 (29%), and moderate sedation in 9 (14%). There were 4 minor intra-procedural anesthesia-related complications (laryngospasm in 2 and hypoxemia from airway obstruction and secretions in 2) in MAC and general endotracheal anesthesia (GA) cases, and 1 postprocedural complication (fever after pseudocyst drainage). EUS can achieve the diagnostic or therapeutic goal and ruled out suspected pathology in 88% of cases precluding need for additional testing. CONCLUSIONS: (1) EUS in the pediatric population is technically successful and efficacious. (2) Therapeutic and diagnostic EUS impacted clinical care decisions. (3) There is a low risk of immediate significant complications. (4) The overall efficacy and safety support the performance of EUS in a pediatric population by experienced endoscopists.

Pediatric Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), including Crohn disease, ulcerative colitis, and IBD-unspecified, is a chronic immune-mediated condition of the gastrointestinal tract in which the goal of treatment is to induce and maintain durable remission. In pediatrics, there is a wide spectrum of presenting symptoms, but esophagogastroduodenoscopy and colonoscopy are imperative to confirming the diagnosis. Treatment goals include achieving mucosal healing of the gastrointestinal tract, reaching growth potential, limiting medication toxicities, and optimizing quality of life for all patients.

Ultrasound and MRI predictors of surgical bowel resection in pediatric Crohn disease.

BACKGROUND: Imaging predictors for surgery in children with Crohn disease are lacking. OBJECTIVE: To identify imaging features of the terminal ileum on short-interval bowel ultrasound (US) and MR enterography (MRE) in children with Crohn disease requiring surgical bowel resection and those managed by medical therapy alone. MATERIALS AND METHODS: This retrospective study evaluated patients 18 years and younger with Crohn disease undergoing short-interval bowel US and MRE (within 2 months of one another), as well as subsequent ileocecectomy or endoscopy within 3 months of imaging. Appearance of the terminal ileum on both modalities was compared between surgical patients and those managed with medical therapy, with the following parameters assessed: bowel wall thickness, mural stratification, vascularity, fibrofatty proliferation, abscess, fistula and stricture on bowel US; bowel wall thickness, T2 ratio, enhancement pattern, mesenteric edema, fibrofatty proliferation, abscess, fistula and stricture on MRE. A two-sided t-test was used to compare means, a Mann-Whitney U analysis was used for non-parametric parameter scores, and a chi-square or two-sided Fisher exact test compared categorical variables. Imaging findings in surgical patients were correlated with location-matched histopathological scores of inflammation and fibrosis using a scoring system adapted from the Simple Endoscopic Score for Crohn Disease, and a Spearman rank correlation coefficient was used to compare inflammation and fibrosis on histopathology. RESULTS: Twenty-two surgical patients (mean age: 16.5 years; male/female: 13/9) and 20 nonsurgical patients (mean age: 14.8; M/F: 8/12) were included in the final analysis. On US, the surgical group demonstrated significantly increased mean bowel wall thickness (6.1 mm vs. 4.7 mm for the nonsurgical group; P = 0.01), loss of mural stratification (odds ratio [OR] = 6.3; 95% confidence interval [CI]: 1.4-28.4; P = 0.02) and increased fibrofatty proliferation (P = 0.04). On MRE, the surgical group showed increased mean bowel wall thickness (9.1 mm vs. 7.2 mm for the nonsurgical group; P = 0.02), increased mean T2 ratio (4.6 vs. 3.6 for the nonsurgical group; P = 0.03), different enhancement patterns (P = 0.03), increased mesenteric edema (P = 0.001) and increased stricture formation (OR = 8.2; 95% CI: 1.8-36.4; P = 0.005). Nineteen of 22 ileocecectomy specimens showed severe inflammation and 21/22 showed severe fibrosis, with significant correlation between inflammation and fibrosis scores (ρ = 0.55; P = 0.008); however, correlation with imaging findings was limited by the uniformity of findings on histopathology. CONCLUSION: Children with terminal ileal Crohn disease requiring surgical bowel resection demonstrate more severe manifestations of imaging features traditionally associated with both active inflammation and chronic fibrosis than those managed medically on US and MRE, findings that are corroborated by histopathology. These features may potentially serve as imaging biomarkers indicating the necessity for surgical intervention.

Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease.

BACKGROUND: Vedolizumab is effective for inducing and maintaining remission in adults with inflammatory bowel disease (IBD); however, there is limited pediatric data. This study aimed to describe the adverse events and clinical response to vedolizumab in refractory pediatric IBD. METHODS: Disease activity indices, clinical response, concomitant medication use, and adverse events were measured over 22 weeks in an observational prospective cohort study of children with refractory IBD who had failed anti-tumor necrosis factor therapy and subsequently initiated vedolizumab therapy. RESULTS: Twenty-one subjects, 16 with Crohn disease, received vedolizumab. Clinical response was observed in 6/19 (31.6%) of the evaluable subjects at week 6 and in 11/19 (57.9%) by week 22. Before induction, 15/21 (71.4%) participants were treated with systemic corticosteroids, as compared with 7/21 (33.3%) subjects at 22 weeks. Steroid-free remission was seen in 1/20 (5.0%) subjects at 6 weeks, 3/20 (15.0%) at 14 weeks, and 4/20 (20.0%) at 22 weeks. There was statistically significant improvement in serum albumin and hematocrit; however, C-reactive protein increased by week 22 (P < 0.05). There were no infusion reactions. Vedolizumab was discontinued in 2 patients because of severe colitis, requiring surgical intervention. CONCLUSIONS: There is limited experience with vedolizumab therapy in pediatric IBD. There seems to be a marked number of subjects with clinical response in the first 6 weeks that increases further by week 22 despite the severity of disease in this cohort. Adverse events may not be directly related to vedolizumab. This study is limited by small sample size, and larger prospective studies are warranted.