Dellon, Evan S.

INTRODUCTION: It is becoming clear that eosinophilic esophagitis (EoE) activity cannot be measured by eosinophils alone, and that a more complete assessment is needed. The EoE Histology Scoring System (EoE HSS) measures the severity (grade) and extent (stage) of 8 histopathologic features in EoE: eosinophilic inflammation (EI); basal zone hyperplasia (BZH); eosinophilic abscess (EA); eosinophilic surface layering (SL); dilated intercellular spaces (DIS); surface epithelial alteration (SEA); dyskeratotic epithelial cells (DEC); and lamina propria fibrosis (LPF). We aimed to assess EoE histology at baseline using the EoE HSS, and to compare correlations between this and endoscopic and symptom outcomes. METHODS: This study analyzed baseline data from a 12-week, phase 2, randomized, placebo-controlled trial of budesonide oral suspension in patients with EoE (MPI 101-06; NCT01642212). Patients were eligible for inclusion if they were aged 11–40 years and had EoE with dysphagia. Esophageal biopsies from patients were examined, and mean EoE HSS total score ratios and mean individual feature scores were calculated at baseline for all patients (irrespective of treatment allocation). A correlation analysis was then performed to compare these scores with Dysphagia Symptom Questionnaire (DSQ) scores and those from the EoE Endoscopic Reference Score (EREFS) system at baseline. RESULTS: In total, 87 patients were included for analysis. At baseline, mean (standard deviation) EoE HSS grade and stage total score ratios for all patients were 0.5 (0.2) and 0.4 (0.1), respectively. For individual EoE HSS features, a summary of mean grade and stage scores at baseline is shown in Table 1; the most severe features for grade and stage were EI, BZH, DIS and LPF. At baseline, mean EoE HSS grade and stage total score ratios did not correlate with mean DSQ score, but did correlate significantly with mean EREFS score (grade: R = 0.3166; P = 0.0028; stage: R = 0.3344; P = 0.0015; Table 2). Similarly, mean scores for individual EoE HSS features did not correlate with mean DSQ score at baseline, but did correlate with mean EREFS score for 4 and 3 of the 8 features for grade and stage scores, respectively (Table 2). CONCLUSION: The most severe EoE HSS features at baseline for grade and stage were EI, BZH, DIS and LPF. At baseline, there were significant correlations between the EoE HSS and endoscopic severity, but not dysphagia. This suggests that the EoE HSS could become an essential and independent tool to measure EoE activity.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. METHODS: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed. RESULTS: A total of 322 patients were randomized (BOS, n = 215; placebo, n = 107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n = 213; placebo, n = 105) (Table 1). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, P < 0.001; 52.6% vs 39.1%, P = 0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n = 197) than the placebo group (n = 89) (−13.0 vs −9.1; P = 0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n = 202) than placebo (n = 93) (−4.0 vs −2.2; P < 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo. No life-threatening TEAEs were reported. CONCLUSION: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

Budesonide oral suspension (BOS) is a novel topical corticosteroid, which has been shown to improve symptoms and endoscopic appearance, and reduce peak eosinophil counts in patients with eosinophilic esophagitis (EoE). This trial evaluated the effect of BOS or placebo on the severity (grade) and extent (stage) of 8 histopathologic features observed in EoE, using the validated eosinophilic esophagitis histologic scoring system (EoE HSS). Patients with EoE aged 11 to 40 years with dysphagia were randomized to receive either BOS (2.0 mg twice daily) or placebo for 12 weeks. Mean (SD) EoE HSS grade and stage total scores at baseline for placebo and BOS groups were: grade, 0.42 (0.16) and 0.49 (0.14), respectively; stage: 0.38 (0.14) and 0.46 (0.11), respectively. These scores significantly decreased (improved) from baseline for patients receiving BOS versus placebo (grade: least squares mean change [SE]: placebo vs. BOS, −0.04 [0.03] vs. −0.24 [0.02]; P<0.0001; stage: −0.01 [0.02] vs. −0.19 [0.02]; P<0.0001). EoE HSS total scores improved for 6 of the 8 and 5 of the 8 histopathologic features for grade and stage, respectively, versus placebo. Change in EoE HSS total scores correlated moderately but significantly with change in endoscopic severity (endoscopic reference score; grade: R=0.5349; stage: R=0.5416; both P<0.0001). Change in EoE HSS stage total score correlated weakly with change in Dysphagia Symptom Questionnaire scores (grade: R=0.1925; P=0.0740; stage: R=0.2135; P=0.0471). These data demonstrate that the EoE HSS is a valuable endpoint of treatment response in randomized clinical trials and should be considered for future trials for EoE.

SUMMARYEosinophil peroxidase is an eosinophil-specific, cytoplasmic protein stored in the secondary granules of eosinophils. While eosinophil peroxidase deposition is increased in the esophagus in eosinophilic esophagitis (EOE), its potential role as a peripheral marker is unknown. This study aims to examine the relationship between serum eosinophil peroxidase and esophageal eosinophilia in eosinophilic esophagitis. Prospectively collected serum from 19 subjects with incident EoE prior to treatment and 20 non-EoE controls were tested for serum eosinophil peroxidase, eosinophilic cationic protein, and eosinophil derived neurotoxin using ELISA. Matching esophageal tissue sections were stained and assessed for eosinophil peroxidase deposition using a histopathologic scoring algorithm. Mean peripheral blood absolute eosinophil counts in eosinophilic esophagitis subjects were significantly elevated compared to controls (363 vs. 195 cells/μL,P = 0.008). Absolute median serum eosinophil peroxidase, eosinophil cationic protein, and eosinophil derived neurotoxin did not differ between groups; however, when normalized for absolute eosinophil counts, eosinophilic esophagitis subjects had significantly lower median eosinophil peroxidase levels (2.56 vs. 6.96 ng/mL per eos/μL,P = 0.002, AUC 0.79 (0.64, 0.94 95% CI)). Multivariate analysis demonstrated this relationship persisted after controlling for atopy. Esophageal biopsies from eosinophilic esophagitis subjects demonstrated marked eosinophil peroxidase deposition (median score 46 vs. 0,P &lt; 0.0001). Normalized eosinophil peroxidase levels inversely correlated with esophageal eosinophil density (r = −0.41,P = 0.009). In contrast to marked tissue eosinophil degranulation, circulating eosinophils appear to retain their granule proteins in EoE. Investigations of normalized serum eosinophil peroxidase levels as a biomarker of EoE are ongoing.

Consensus diagnostic recommendations to distinguish GORD from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPIs) unexpectedly uncovered an entity called ‘PPI-responsive oesophageal eosinophilia’ (PPI-REE). PPI-REE refers to patients with clinical and histological features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that patients with PPI-REE and patients with EoE at baseline are clinically, endoscopically and histologically indistinguishable and have a significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in patients with PPI-REE, similar to the effects of topical steroids in patients with EoE. Additionally, recent series have reported that patients with EoE responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunological mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic and therapeutic features cannot be reliably distinguished. For patients with symptoms and histological features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment before diet and topical steroids. The reasons why some patients with EoE respond to PPI, while others do not, remain to be elucidated.