Disease Activity In Eosinophilic Esophagitis Research Articles

Noninvasive Disease Assessment in Eosinophilic Esophagitis With Fractionated Exhaled Nitric Oxide, Blood, and Fecal Biomarkers.

Eosinophilic Esophagitis (EoE) is a chronic inflammatory condition of the esophagus triggered by food and aeroallergens. There is a need for noninvasive biomarkers that reliably detect EoE in patients with cardinal symptoms and predict treatment response to reduce endoscopic evaluations. Nonasthmatic patients 18 years or above with suspected or diagnosed EoE, gastroesophageal reflux disease (GERD), and control individuals with indication for endoscopy were enrolled prospectively between November 2020 and May 2022. Participants underwent body plethysmography with fractionated exhaled nitric oxide (FeNO) level measurement. Besides, serum and fecal biomarkers were measured by ELISA. A follow-up examination was scheduled after treatment initiation in patients with active EoE. The median FeNO level in active EoE (20 ppb) was higher compared with GERD (15 ppb, P=0.038) and control individuals (14 ppb, P=0.046). Median FeNO did not significantly differ in EoE patients who underwent follow-up assessment after treatment response (20 ppb vs. 18 ppb, P=0.771). Serum EDN, ECP, and the absolute eosinophil blood count (AEC) were elevated in active EoE compared with control individuals but not compared with GERD except for AEC. Serum EDN, ECP and AEC decreased in EoE in remission at follow-up assessment. None of the fecal biomarkers was elevated in active EoE or during treatment. Assessment of FeNO may have diagnostic value in differentiating patients with active EoE from non-EoE patients but is not a suitable marker for monitoring disease activity. Serum EDN, ECP, TARC, and AEC levels are emerging as potential candidates for monitoring disease activity in EoE.

Immunoglobulin G4 in eosinophilic esophagitis: Immune complex formation and correlation with disease activity.

Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co-localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits. This study included adult subjects with EoE (n = 13) and non-EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co-localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4-food protein interactions were confirmed with co-immunoprecipitation and mass spectrometry. IgG4-CMP co-localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p = .02; Bos d 5, p = .002; Bos d 8, p = .002). Co-localization was also significantly higher in the active EoE group compared to non-EoE controls (Bos d 4, p = .0013; Bos d 5, p = .0007; Bos d 8, p = .0013). AutoSTOMP identified eosinophil-derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain-14 in IgG4-enriched areas. Co-immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens. These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression.

Harnessing artificial intelligence to infer novel spatial biomarkers for the diagnosis of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory condition of the esophagus associated with elevated esophageal eosinophils. Second only to gastroesophageal reflux disease, EoE is one of the leading causes of chronic refractory dysphagia in adults and children. EoE is a clinicopathologic disorder and the histological portion of the diagnosis requires enumerating the density of esophageal eosinophils in esophageal biopsies, and evaluating additional features such as basal zone hyperplasia is helpful. However, this task requires time-consuming, somewhat subjective manual analysis, thus reducing the ability to process the complex tissue structure and infer its relationship with the patient's clinical status. Previous artificial intelligence (AI) approaches that aimed to improve histology-based diagnosis focused on recapitulating identification and quantification of the area of maximal eosinophil density, the gold standard manual metric for determining EoE disease activity. However, this metric does not account for the distribution of eosinophils or other histological features, over the whole slide image. Here, we developed an artificial intelligence platform that infers local and spatial biomarkers based on semantic segmentation of intact eosinophils and basal zone distributions. Besides the maximal density of eosinophils [referred to as Peak Eosinophil Count (PEC)] and a maximal basal zone fraction, we identify the value of two additional metrics that reflect the distribution of eosinophils and basal zone fractions. This approach enables a decision support system that predicts EoE activity and potentially classifies the histological severity of EoE patients. We utilized a cohort that includes 1,066 biopsy slides from 400 subjects to validate the system's performance and achieved a histological severity classification accuracy of 86.70%, sensitivity of 84.50%, and specificity of 90.09%. Our approach highlights the importance of systematically analyzing the distribution of biopsy features over the entire slide and paves the way toward a personalized decision support system that will assist not only in counting cells but can also potentially improve diagnosis and provide treatment prediction.

S391 Co-Localization of Immunoglobulin G4 (IgG4) and Milk Proteins Is Associated With Eosinophilic Esophagitis Disease Activity

S391 Co-Localization of Immunoglobulin G4 (IgG4) and Milk Proteins Is Associated With Eosinophilic Esophagitis Disease Activity

A Deep Multi-Label Segmentation Network For Eosinophilic Esophagitis Whole Slide Biopsy Diagnostics.

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus associated with elevated numbers of eosinophils. Disease diagnosis and monitoring require determining the concentration of eosinophils in esophageal biopsies, a time-consuming, tedious and somewhat subjective task currently performed by pathologists. Here, we developed a machine learning pipeline to identify, quantitate and diagnose EoE patients' at the whole slide image level. We propose a platform that combines multi-label segmentation deep network decision support system with dynamics convolution that is able to process whole biopsy slide. Our network is able to segment both intact and not-intact eosinophils with a mean intersection over union (mIoU) of 0.93. This segmentation enables the local quantification of intact eosinophils with a mean absolute error of 0.611 eosinophils. We examined a cohort of 1066 whole slide images from 400 patients derived from multiple institutions. Using this set, our model achieved a global accuracy of 94.75%, sensitivity of 94.13%, and specificity of 95.25% in reporting EoE disease activity. Our work provides state-of-the-art performances on the largest EoE cohort to date, and successfully addresses two of the main challenges in EoE diagnostics and digital pathology, the need to detect several types of small features simultaneously, and the ability to analyze whole slides efficiently. Our results pave the way for an automated diagnosis of EoE and can be utilized for other conditions with similar challenges.

Eosinophil-Derived Neurotoxin Predicts Response to Proton-Pump Inhibitor Treatment in Pediatric Eosinophilic Esophagitis.

There are no tests or patient factors to help predict the best treatment approach for a patient with eosinophilic esophagitis (EoE). The prevalence of proton-pump inhibitor (PPI) responsive EoE in children ranges from 30% to 71% with multiple studies showing similar characteristics in responders and nonresponders. Eosinophil-derived neurotoxin (EDN), an eosinophilic granule protein, measured in esophageal brushing has been shown to be a viable measure of disease activity in EoE. Our aim is to determine if EDN can help predict response to PPI in pediatric patients with EoE. We conducted a prospective cross-sectional study to compare EDN between PPI-responsive and PPI-nonresponsive EoE subjects from 2018 through 2020. Enrolled patients with active EoE were treated with high-dose PPI and underwent repeat endoscopy to determine PPI-responsiveness. EDN was measured at baseline endoscopy, before any treatment, and at follow up endoscopy, after PPI therapy. Subjects were divided into PPI-responsive and nonresponsive groups. EDN, endoscopic reference score (EREFS), and peak eosinophilic count (PEC) were compared. Fifteen out of the 36 enrolled subjects with EoE (age range 2-18 years, 73.3% male) were PPI-responsive and 21 (age range 2-19 years, 95.2% male) were PPI-nonresponsive. EDN concentration was significantly higher in the PPI-nonresponsive group than in the PPI-responsive group (219.1 ± 229 mcg/mL vs 75.7 ± 60 mcg/mL, respectively, P = 0.036). There was no difference between the two groups in EREFS (P = 0.55) or PEC (P = 0.15). EDN measured in esophageal epithelial samples obtained by brushing during endoscopy may predict PPI-responsiveness in children and young adults with EoE.

Esophageal Hypervigilance and Symptom-Specific Anxiety in Patients with Eosinophilic Esophagitis

Patient symptom reporting often does not correlate with the pathophysiological markers of esophageal disease, including eosinophilic esophagitis (EoE). Esophageal hypervigilance and symptom-specific anxiety are emerging as important considerations in understanding symptom reporting. As such, we aimed to conduct the first study of these constructs in EoE. A retrospective review of an EoE patient registry was conducted and included eosinophils per high power field (from esophagogastroduodenoscopy biopsy: proximal, distal), endoscopic reference score, distal distensibility plateau (functional luminal imaging probe), Brief Esophageal Dysphagia Questionnaire, Visual Dysphagia Question of EoE Activity Index, Northwestern Esophageal Quality of Life scale, and the Esophageal Hypervigilance and Anxiety Scale. Correlational and regression analyses evaluated relationships of hypervigilance and anxiety with Brief Esophageal Dysphagia Questionnaire, Visual Dysphagia Question of EoE Activity Index, and Northwestern Esophageal Quality of Life scale when controlling for histology and endoscopic severity. One hundred and three patients had complete data, 69.9% were male, and the mean (SD) age was 40.66 (13.85) years. Forty-one percent had elevated dysphagia and 46% had elevated hypervigilance and anxiety. Esophageal symptom-specific anxiety emerged as the most important predictor of Brief Esophageal Dysphagia Questionnaire severity (44.8% of the variance), Visual Dysphagia Question of EoE Activity Index severity (26%), and poor health-related quality of life (HRQoL) (55.3%). Hypervigilance was also important, but to a lesser extent. Pathophysiological variables did not significantly predict symptoms or HRQoL. Recent food impaction can predict symptom-specific anxiety and proton pump inhibitor use can reduce hypervigilance. Hypervigilance and symptom-specific anxiety are important for our understanding of self-reported patient outcomes in EoE. These processes outweigh endoscopic and histologic markers of EoE disease activity across dysphagia, difficulty eating, and HRQoL. Clinicians should assess hypervigilance and anxiety, especially in patients with refractory symptoms and poor HRQoL.

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Noninvasive biomarkers identify eosinophilic esophagitis: A prospective longitudinal study in children.

Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil-associated proteins to diagnose EoE and predict esophageal eosinophilia. Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein-1 (MBP-1), galectin-10 (CLC/GAL-10), Eotaxin-2 and Eotaxin-3, and urine osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. Of 183 specimens were collected from 56 EoE patients and 15 non-EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre- and post-treatment specimens. Plasma (CLC/GAL-10, ECP, EDN, Eotaxin-3, MBP-1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL-10, Eotaxin-3, ECP, EDN, MBP-1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL-10, ECP, and MBP-1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC, CLC/GAL-10, ECP, EDN, OPN, and MBP-1 each predicted esophageal eosinophil counts utilizing mixed models controlled for age, gender, treatment, and atopy; AEC combined with MBP-1 best predicted the counts. We identified novel panels of eosinophil-associated proteins that along with AEC are superior to AEC alone in distinguishing EoE from controls and predicting esophageal eosinophil counts.

Platelet association with leukocytes in active eosinophilic esophagitis

We previously demonstrated that the percentage of blood eosinophils that are associated with platelets and thus positive for CD41 (integrin αIIb-subunit) correlates with and predicts peak eosinophil count (PEC) in biopsies of eosinophilic esophagitis (EoE) patients after treatment. Thus, flow cytometric determination of CD41+ eosinophils is a potential measure of EoE disease activity. Determinants of association of platelets with eosinophils and other leukocytes in EoE are largely unknown. The objectives of this study were to test the hypotheses that platelets associate with blood leukocytes other than eosinophils in EoE and that such associations also predict EoE activity. Whole blood flow cytometry was performed on samples from 25 subjects before and after two months of standard of care EoE treatment. CD41 positivity of cells within gates for eosinophils, neutrophils, monocytes, lymphocytes, and natural killer cells was compared. We found that percent CD41+ neutrophils, monocytes, and eosinophils correlated with one another such that principal component analysis of the five cell types identified “myeloid” and “lymphoid” factors. Percent CD41+ neutrophils or monocytes, or the myeloid factor, like CD41+ eosinophils, correlated with PEC after treatment, and CD41+ neutrophils or the myeloid factor predicted PEC < 6/high power field after treatment, albeit with lower area under the curve than for CD41+ eosinophils. We conclude that the processes driving platelets to associate with eosinophils in EoE also drive association of platelets with neutrophils and monocytes and that association of platelets with all three cell types is related to disease activity. Clinicaltrials.gov identifier: NCT02775045.

Generic Measures of Quality of Life Are Not Correlated with Disease Activity in Eosinophilic Esophagitis.

The relationship between histologic disease activity in eosinophilic esophagitis (EoE) and generic measures of quality of life (QoL) is unclear. To determine differences in QoL in adults with EoE based on histologic activity and assess changes in QoL over time. We performed an analysis of prospectively collected data from patients in the University of North Carolina EoE Registry. Patients were categorized with histologically active (≥ 15 eosinophils per high-power field [eos/hpf]) or inactive (< 15 eos/hpf) disease. Dysphagia severity was measured with a Likert scale. QoL was measured with 36-Item Short Form (SF-36), compared between active and inactive groups, and assessed longitudinally. Of 147 EoE cases, those with inactive disease (n = 56) reported less dysphagia severity (3.2 vs. 1.9; p = 0.003) and had lower endoscopic severity (3.8 vs. 1.0; p < 0.001) than those with active disease (n = 91). While SF-36 scores did not differ between active and inactive status, lower mental component scores (MCS) were seen in patients treated with empiric dietary elimination (44.9 vs. 50.8; p = 0.005). Dysphagia severity was negatively correlated with both physical component score (PCS) (r = -0.33; p < 0.001) and MCS (r = -0.18; p = 0.03). Despite more cases achieving histologic response over time, SF-36 scores did not improve on either raw or adjusted analyses. QoL measured by SF-36 in EoE was similar regardless of histologic disease activity and was in the range of population averages. General QoL metrics like the SF-36 do not appear to have substantial utility in EoE.

S0404 Improved Histopathologic Features in Patients With Eosinophilic Esophagitis: Results and Analyses From a Phase 3, Randomized, Placebo-Controlled Trial of Budesonide Oral Suspension

INTRODUCTION: The Eosinophilic Esophagitis Histology Scoring System (EoEHSS) is a validated measure that assesses the grade (severity) and stage (extent) of eight histopathologic features in eosinophilic esophagitis (EoE). We evaluated the effect of budesonide oral suspension (BOS) on EoEHSS scores in patients with EoE. METHODS: This was a phase 3, 12-week, randomized, double-blind, placebo-controlled trial of BOS (2.0 mg b.i.d.) in patients 11–55 years old with EoE and dysphagia (NCT02605837). Secondary efficacy endpoints were change in peak eosinophil counts and EoEHSS scores from baseline to week 12. Post hoc analyses examined the change in (1) EoEHSS scores by esophageal region and histologic response threshold (≤1, ≤6 and <15 eosinophils/high-power field [eos/hpf]) and (2) individual features of the EoEHSS, after 12 weeks of therapy. RESULTS: Overall, 318 patients received ≥1 dose of BOS (n = 213) or placebo (n = 105). The mean age (standard deviation) was 33.9 (12.0) years. The trial met its co-primary and key secondary efficacy endpoints (data not shown). BOS-treated patients had greater least-squares mean (standard error of the mean) changes in peak eosinophil counts (−55.2 [3.4] vs −7.6 [4.3] eos/hpf; P < 0.001) and EoEHSS scores than placebo-treated patients (grade, −0.22 [0.01] vs −0.03 [0.02]; stage, −0.20 [0.01] vs −0.00 [0.02]; both, P < 0.001; Table 1); changes in EoEHSS scores were similar by esophageal region (Table 1). Mean changes in EoEHSS scores were similar across histologic response thresholds (Table 1). Significantly greater improvements were observed with BOS than with placebo for all features except dyskeratotic epithelial cells (Figures 1 and 2); greatest improvements with BOS therapy were for eosinophilic inflammation (EI) (grade, −1.36 [0.07] vs −0.22 [0.09]; stage, −1.40 [0.08] vs −0.10 [0.10]; both, P < 0.001) and basal zone hyperplasia (BZH) (grade, −1.56 [0.08] vs −0.28 [0.11]; stage, −1.60 [0.09] vs −0.30 [0.12]; both, P < 0.001). BOS was generally well tolerated. CONCLUSION: Improvements in EoEHSS grade and stage scores were observed for BOS- versus placebo-treated patients in most histopathologic features after 12 weeks of therapy; the greatest improvements were for EI and BZH. This demonstrates that treatment with BOS leads to greater reductions in both severity and extent of histopathologic alterations than with placebo, and shows the importance of the EoEHSS in monitoring EoE disease activity in an independent and more comprehensive way compared with peak eosinophil counts.Table 1.: Change in EoEHSS grade and stage scores from baseline to week 12 of therapy, stratified by treatment arm, esophageal region and histologic response threshold*Figure 1.: Change in LS mean (SEM) grade* (severity) scores for the individual features of the EoEHSS from baseline to week 12 of therapy, stratified by treatment arm.Figure 2.: Change in LS mean (SEM) stage* (extent) scores for the individual features of the EoEHSS from baseline to week 12 of therapy, stratified by treatment arm.

This String’s Attached: The Esophageal String Test for Detecting Disease Activity in Eosinophilic Esophagitis

Ackerman SJ, Kagalwalla AF, Hirano I, et al. One-hour esophageal string test: a nonendoscopic minimally invasive test that accurately detects disease activity in eosinophilic esophagitis. Am J Gastroenterol 2019;114:1614–1625.

Eosinophilic Esophagitis: Existing and Upcoming Therapies in an Age of Emerging Molecular and Personalized Medicine.

Recent research efforts have spurred great progress in the diagnosis and management of eosinophilic esophagitis (EoE). Nonetheless, challenges remain in addressing disease burden and impairment in the growing EoE population. We highlight work from the Cincinnati Center for Eosinophilic Disorders, the Consortium of Eosinophilic Gastrointestinal Disease Researchers, and others that address these ongoing challenges. New tools for characterizing EoE disease activity include the EoE Histology Scoring System (EoEHSS), endoscopic alternatives, validated patient-reported outcome (PRO) questionnaires, and investigational biomarkers. These diagnostic and monitoring strategies have been complemented by advances in EoE therapy. Treatment modalities have refined the traditional approaches of dietary elimination, swallowed steroids, and proton pump inhibitors (PPI), and biologics offer promise for future treatment. This review summarizes EoE advances in disease management and newly defined EoE endotypes that may serve as the foundation for EoE-personalized medicine.

Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis

The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE. We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety. By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity index score, ≤20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%). One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease activity relative to baseline. NCT02098473.

αIIb-Integrin (CD41) associated with blood eosinophils is a potential biomarker for disease activity in eosinophilic esophagitis

αIIb-Integrin (CD41) associated with blood eosinophils is a potential biomarker for disease activity in eosinophilic esophagitis

One-Hour Esophageal String Test: A Nonendoscopic Minimally Invasive Test That Accurately Detects Disease Activity in Eosinophilic Esophagitis.

OBJECTIVES:Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus.METHODS:In a prospective, multisite study, children and adults (ages 7–55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation.RESULTS:One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n = 62), inactive EoE (n = 37), and patient controls with a normal esophagus (n = 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eighty-seven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information.DISCUSSION:The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.

Rapid Recurrence of Eosinophilic Esophagitis Activity After Successful Treatment in the Observation Phase of a Randomized, Double-Blind, Double-Dummy Trial

Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI). This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy. Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52-2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment. EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758.

Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14.

Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease resulting in eosinophilic esophageal inflammation. We recently found that EoE susceptibility is associated with genetic variants in the promoter of CAPN14, a gene with reported esophagus-specific expression. CAPN14 is dynamically up-regulated as a function of EoE disease activity and after exposure of epithelial cells to interleukin-13 (IL-13). Herein, we aimed to explore molecular modulation of CAPN14 expression. We identified three putative binding sites for the IL-13-activated transcription factor STAT6 in the promoter and first intron of CAPN14. Luciferase reporter assays revealed that the two most distal STAT6 elements were required for the ∼10-fold increase in promoter activity subsequent to stimulation with IL-13 or IL-4, and also for the genotype-dependent reduction in IL-13-induced promoter activity. One of the STAT6 elements in the promoter was necessary for IL-13-mediated induction of CAPN14 promoter activity while the other STAT6 promoter element was necessary for full induction. Chromatin immunoprecipitation in IL-13 stimulated esophageal epithelial cells was used to further support STAT6 binding to the promoter of CAPN14 at these STAT6 binding sites. The highest CAPN14 and calpain-14 expression occurred with IL-13 or IL-4 stimulation of esophageal epithelial cells under culture conditions that allow the cells to differentiate into a stratified epithelium. This work corroborates a candidate molecular mechanism for EoE disease etiology in which the risk variant at 2p23 dampens CAPN14 expression in differentiated esophageal epithelial cells following IL-13/STAT6 induction of CAPN14 promoter activity.

The 1-Hour Esophageal String Test: A Non-Endoscopic Minimally Invasive Test to Accurately Detect Disease Activity in Eosinophilic Esophagitis

OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7–55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n 5 62), inactive EoE (n 5 37), and patient controls with a normal esophagus (n 5 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eightyseven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.