Searching for Noninvasive Predictors of the Diagnosis and Monitoring of Eosinophilic Esophagitis—The Importance of Biomarkers of the Inflammatory Reaction Involving Eosinophils (original) (raw)
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Diagnostic and therapeutic strategies for eosinophilic esophagitis
Eosinophilic esophagitis (EoE) is a recently recognized allergic disorder, characterized by eosophageal dysfunction, accumulation of ≥15 eosinophils/high-powered field, eosinophil microabssess, basal cell hyperplasia, extracellular eosinophilic granules in the esophageal epithelial mucosal biopsy and a lack of response to a 8-week proton pump inhibitor treatment. Despite the increased incidences and considerable progress made in understanding EoE pathogenesis, there are limited diagnostic and therapeutic options available for EoE. Currently, the only criterion for diagnosing EoE is repetitive esophageal endoscopic biopsies and histopathological evaluation. Antigen elimination or corticosteroid therapies are effective therapies for EoE but are expensive and have limitations, if continued in the long term. Hence, there is a great necessity for novel noninvasive diagnostic biomarkers that can easily diagnose
Gastroenterology
Primary Outcome Esophageal eosinophil count: P < .0001 for both dose groups Key Secondary Outcome Dysphagia clinical symptom frequency and severity (DSD): Not statistically significant for both dose groups Safety Assessment AEs All low frequency Headache Upper respiratory tract infection Arthralgia Nasopharyngitis Diarrhea Nausea SAEs All unrelated to treatment RPC4046 180 mg or 360 mg treatment for 16 weeks See editorial on page 545. BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P ¼ .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P ¼ .0733). Significant reductions in esophageal
Clinical Immunology, 2021
Eosinophilic esophagitis (EoE) is often misdiagnosed as GERD; therefore, the goal of the current study is to establish a non-invasive diagnostic and monitoring biomarker that differentiated GERD from EoE. Reports indicates that IL-15 responsive iNKT cells and tissue specific IgE have a critical in EoE pathogenesis, not in GERD. Therefore, we tested the hypothesized that the panel of IL-15-responsive T cell and IgE receptors may be novel non-invasive biomarkers for EoE. Accordingly, the receptors of IL-15 responsive T cells (Vα24, Jα18, γδT, αβT) and IgE (FcεRI & FcεRII) were examined. The data indicates that blood mRNA levels of Vα24, Jα18, γδ T, αβ T and FcεRI are significantly reduced in EoE compared to the GERD patients and normal individuals. The ROC curve analysis indicated FcεRII, Jα18 and δ TCR are the positive predictors that discriminate EoE from GERD. Thus, these molecules will be a novel non-invasive diagnostic biomarker for EoE.
Promising Modalities to Identify and Monitor Eosinophilic Esophagitis
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2017
Eosinophilic esophagitis (EoE) is an allergen-mediated condition characterized by symptoms of esophageal dysfunction and histological evidence of intense eosinophilic inflammation involving the esophagus in absence of overlapping conditions such as gastroesophageal reflux disease. Since the initial description as a distinct entity about two decades ago, there has been a remarkable rise in the recognition of this clinico-pathologic entity. Current approach to diagnose and monitor EoE requires repeated esophagogastroduodenoscopies (EGDs), with associated sedation/anesthesia, to visualize mucosal abnormalities, and to obtain multiple biopsies for histologic assessment and to evaluate treatment response. Frequent EGDs with multiple biopsies can increase the risk of procedural complications, place significant financial burden on families, and escalate healthcare costs. In addition, this burdensome approach may contribute towards delayed diagnosis and sub-optimal monitoring thereby increa...
Exploring Potential Noninvasive Biomarkers in Eosinophilic Esophagitis in Children
Journal of Pediatric Gastroenterology & Nutrition, 2011
Background and Aims: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. Subjects and Methods: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. Results: Sixty subjects with EE (46 [75%] boys, mean age 7.5 AE 4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 AE 4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. Conclusions: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.
Diseases of the Esophagus, 2016
Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Other pathologic features have not been emphasized. We developed a histology scoring system for esophageal biopsies that evaluates eight features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces (DIS), surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity (grade) and extent (stage) of abnormalities were scored using a 4-point scale (0 normal; 3 maximum change). Reliability was demonstrated by strong to moderate agreement among three pathologists who scored biopsies independently (P £ 0.008). Several features were often abnormal in 201 biopsies (101 distal, 100 proximal) from 104 subjects (34 untreated, 167 treated). Median grade and stage scores were significantly higher in untreated compared with treated subjects (P £ 0.0062). Grade scores for features independent of eosinophil counts were significantly higher in biopsies from untreated compared with treated subjects (basal zone hyperplasia P £ 0.024 and DIS P £ 0.005), and were strongly correlated (R-square >0.67). Principal components analysis identified three principal components that explained 78.2% of the variation in the features. In logistic regression models, two principal components more closely associated with treatment status than log distal peak eosinophil count (PEC) (R-square 17, area under the curve (AUC) 77.8 vs. R-square 9, AUC 69.8). In summary, the EoE histology scoring system provides a method to objectively assess histologic changes in the esophagus beyond eosinophil number. Importantly, it discriminates treated from untreated patients, uses features commonly found in such biopsies, and is utilizable by pathologists after minimal training. These data provide rationales and a method to evaluate esophageal biopsies for features in addition to PEC.
Clinical and translational gastroenterology, 2015
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition that causes esophageal remodeling and stricture formation. We compared the clinical course of symptoms, endoscopic findings, histology, and changes in phenotype over time in EoE patients with inflammatory and fibrostenotic phenotypes. Data were obtained from EoE patients from three medical centers and followed prospectively. Endoscopic features and histology from index and follow-up endoscopies were recorded. Behavior was classified as inflammatory if endoscopic findings demonstrated furrows or white plaques and as fibrostenotic if endoscopic findings included fixed rings or strictures. Two hundred and fifty-six EoE patients were included in the analysis. The mean age was 32±18 years, 25% of patients were <18 years, 89% of patients were Caucasians, and 74% of patients were male. The mean duration of symptoms before diagnosis was 6.8±7.2 years with a follow-up of 1.7±1.9 years (maximum follow-up of 12 years). Fifty...