Disease Burden and Unmet Need in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease of increasing prevalence, characterized by symptoms of dysphagia and reduced quality of life. A dysregulated type 2 immune response to food and aeroallergen leads to barrier dysfunction, chronic esophageal inflammation, remodeling, and fibrosis. Patients with EoE have impaired quality of life because of dysphagia and other symptoms. They may also suffer social and psychological implications of food-related illness and expensive out-of-pocket costs associated with treatment. Disease burden in EoE is often compounded by the presence of comorbid type 2 inflammatory diseases. Current conventional treatments include elimination diet, proton pump inhibitors, and swallowed topical corticosteroids, as well as esophageal dilation in patients who have developed strictures. These treatments demonstrate variable response rates and may not always provide long-term disease control. There is an unmet need for long-term histologic, endoscopic, and symptomatic disease control; for targeted therapies that can normalize the immune response to triggers, reduce chronic inflammation, and limit or prevent remodeling and fibrosis; and for earlier diagnosis, defined treatment outcomes, and a greater understanding of patient perspectives on treatment. In addition, healthcare professionals need a better understanding of the patient perspective on disease burden, the disconnect between symptoms and disease activity, and the progressive nature of EoE and the need for continuous monitoring and maintenance treatment. In this review, we explore the progression of disease over the patient's lifespan, highlight the patient perspective on disease, and discuss the unmet need for effective long-term treatments.

Prospective Endoscopic Activity Assessment for Eosinophilic Gastritis in a Multisite Cohort.

INTRODUCTION: Eosinophilic gastritis (EG) is a chronic inflammatory disease of the stomach characterized by eosinophil-predominant gastric mucosal inflammation and gastrointestinal symptoms. The aim of this study was to prospectively evaluate endoscopic features in a large series of children and adults with EG to better understand the endoscopic manifestations and develop a standardized instrument for investigations. METHODS: Data were prospectively collected as part of the Consortium for Eosinophilic Gastrointestinal Disease Researchers, a national collaborative network. Endoscopic features were prospectively recorded using a system specifically developed for EG, the EG Endoscopic Reference System (EG-REFS). Correlations were made between EG-REFS and clinical and histologic features. RESULTS: Of 98 patients with EG, 65 underwent assessments using EG-REFS. The most common findings were erythema (72%), raised lesions (49%), erosions (46%), and granularity (35%); only 8% of patients with active histology (≥30 eosinophils/high-power field) exhibited no endoscopic findings. A strong correlation between EG-REFS scores and physician global assessment of endoscopy severity was demonstrated (Spearman r = 0.84, P < 0.0001). The overall score and specific components of EG-REFS were more common in the antrum than in the fundus or body. EG-REFS severity was significantly correlated with active histology, defined by a threshold of ≥30 eosinophils/high-power field (P = 0.0002). DISCUSSION: Prospective application of EG-REFS identified gastric features with a strong correlation with physician global assessment of endoscopic activity in EG. Endoscopic features demonstrated greater severity in patients with active histology and a predilection for the gastric antrum. Further development of EG-REFS should improve its utility in clinical studies.

Multiplexed Functional Assessment of Genetic Variants in CARD11.

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

High Patient Disease Burden in a Cross-sectional, Multicenter Contact Registry Study of Eosinophilic Gastrointestinal Diseases.

OBJECTIVES: Clinical features of eosinophilic esophagitis (EoE) have been well-described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient-reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non-EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE. METHODS: We conducted a cross-sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi-square (categorical measures) and the Mann-Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation. RESULTS: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non-EoE EGID), a higher proportion of those with a non-EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating (P < 0.01 for all). Participants with a non-EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain (P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5--4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2--3.3 for elemental formula). CONCLUSIONS: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non-EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.

Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE. METHODS: For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8). RESULTS: The distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11). CONCLUSION: Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT01386112.

Long-term assessment of esophageal remodeling in patients with pediatric eosinophilic esophagitis treated with topical corticosteroids.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic TH2 inflammatory disease characterized by tissue remodeling that leads to esophageal strictures and food impactions. Effects of therapy on long-term remodeling in patients with pediatric eosinophil-associated diseases have not been previously described. OBJECTIVE: We sought to understand the long-term control of esophageal remodeling in patients with EoE. METHODS: We assessed endoscopic and histologic remodeling and TGF-ß1 expression in esophageal biopsy specimens from children (n = 32) with EoE treated with topical corticosteroids (TCSs) over 10 years (mean, 4.5 years). We used standardized EoE scoring tools to gauge endoscopic and symptom features. RESULTS: Seven hundred thirty-eight biopsy specimens from 246 endoscopic procedures were evaluated over 10 years. Four hundred eighty-six biopsy specimens had adequate lamina propria for evaluation of subepithelial remodeling. The severity of epithelial esophageal eosinophilia correlated with epithelial remodeling (basal zone hyperplasia, desquamation, and dilated intercellular spaces; P < .0001), lamina propria eosinophilia (P < .0001), and fibrosis (P < .0001). Sixteen subjects were initial responders (<15 eosinophils/high-power field) to TCSs. Responders and nonresponders spent 54% and 97% of their total disease duration with active EoE (P < .001) and 23% and 53% (P < .02) with maximal fibrosis scores, respectively. Responders had lower endoscopy scores during their disease duration (P = .013). Having less than 15 eosinophils/high-power field at any time correlated with lower fibrosis and endoscopic severity. TGF-ß1(+) cell counts decreased in responders at the first biopsy, but this was not sustained. Symptoms did not correlate with other disease features. CONCLUSIONS: Children with EoE have substantial esophageal remodeling, which associates with inflammation and can improve in a sustainable manner with TCSs. Although endoscopic features correspond to histologic features, symptoms did not correlate with inflammation or fibrosis.