Orally Dispersible Swallowed Topical Corticosteroids in Eosinophilic Esophagitis: A Paradigm Shift in the Management of Esophageal Inflammation

Eosinophilic Esophagitis – Recognition, Diet and Drugs

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.

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.

Role of reflux and mechanisms of response to proton pump inhibitor (PPI) therapy in eosinophilic esophagitis (EoE) have not yet been fully elucidated. Comprehensive assessment by impedance-pH monitoring could clarify these issues. Prospective multicenter study comparing EoE patients with healthy controls and gastroesophageal reflux disease cases. Patients with EoE were evaluated off- and on PPI; responsiveness was assessed by histology. Impedance-pH appraisal included chemical clearance, assessed with the postreflux swallow-induced peristaltic wave (PSPW) index, and mucosal integrity measured with mean nocturnal baseline impedance (MNBI). Sixty consecutive patients with EoE were compared with 60 age- and sex-matched healthy controls and 60 subjects with gastroesophageal reflux disease. The number of total refluxes was higher, while the PSPW index was lower in patients with EoE than in healthy controls. Off PPI, a lower MNBI gradient between the mid and distal esophagus distinguished 20 patients with PPI-refractory EoE from 40 patients with PPI-responsive EoE and was a predictor of PPI failure. On PPI, a lower PSPW index was the sole reflux parameter distinguishing PPI-refractory from PPI-responsive EoE; all reflux parameters improved in PPI-responsive patients, whereas the PSPW index was not modified in PPI-refractory cases and was independently associated with PPI-responsiveness. MNBI in the distal and mid esophagus improved much more in PPI-responsive than in PPI-refractory EoE. Reflux plays a role in the pathogenesis of EoE, more relevant in PPI-responsive cases. Low impedance gradient between the mid and distal esophagus may be useful to predict PPI refractoriness. PPIs mainly act by improving chemical clearance, i.e., by an antireflux action supporting long-term prescription in PPI-responsive EoE.

Background: Eosinophilic esophagitis (EoE) is a disorder of the esophagus that has become increasingly recognized in children. Because these children undergo multiple endoscopies, discovering a non-invasive biomarker of disease activity is highly desirable. The aim of this study was to use targeted plasma metabolomics to identify potential biomarker candidates for EoE in a discovery phase.Methods: A prospective, single-center clinical trial was performed on 24 children ages 2–18 years with and without EoE undergoing upper endoscopy for any indication. Blood samples were collected for metabolomics profiling using the subclasses: amino acids, tricarboxylic acid cycle, acetylation, and methylation. Using mass spectrometry and systematic bioinformatics analysis, 48 metabolites were measured and compared between children with active EoE (+EoE) and controls (–EoE). To investigate the effect of proton pump inhibitor (PPI) use on metabolites, patients were also stratified based on PPI use (+PPI, –PPI).Results: Seven children had active EoE at the time of endoscopy. Eleven children were on PPI (4 with EoE). Of the 48 metabolites measured, 8 plasma metabolites showed statistically significant differences (p < 0.05) comparing +EoE –PPI to –EoE –PPI, a few of which were upregulated metabolites involved in the urea cycle. There were 14 significant differences comparing +EoE +PPI to +EoE –PPI. This demonstrated that in EoE patients, PPI use upregulated metabolites involved in the urea cycle, while it downregulated metabolites involved in methylation. Comparison among all four groups, +EoE +PPI, +EoE –PPI, –EoE +PPI, and –EoE –PPI, revealed 27 significantly different metabolites. +EoE +PPI had downregulated methionine and N-acetyl methionine, while both +EoE groups and –EoE +PPI had upregulated homocysteine, N-acetylputrescine, N-acetylornithine, arginine, and ornithine.Conclusion: The present study revealed key plasma metabolite differences in children with EoE compared to unaffected controls. Notable candidate biomarkers include dimethylarginine, putrescine, and N-acetylputrescine. PPI use was shown to influence these urea cycle metabolites, regardless of EoE presence. Therefore, future studies should distinguish patients based on PPI use or determine metabolites while not on treatment. These findings will be confirmed in a larger validation phase, as this may represent a significant discovery in the search for a non-invasive biomarker for EoE.Clinical Trial Registration: This clinical trial was registered with ClinicalTrials.gov, identifier: NCT 03107819.

INTRODUCTION: VARSITY is the first head-to-head trial comparing the efficacy and safety of 2 biologic therapies, vedolizumab (VDZ) and adalimumab (ADA), in patients with moderately to severely active ulcerative colitis (UC). We previously reported significantly higher rates of clinical remission (31.3% vs 22.5%; P = 0.0061) and endoscopic improvement (39.7% vs 27.7%; P = 0.0005) at Week (Wk) 52 with VDZ vs ADA. 1 METHODS: VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study (NCT02497469; EudraCT 2015-000939-33). Here we report the predefined, exploratory endpoints of early clinical response and clinical remission (defined in the Table 1) within the first 14 wks, as well as durable clinical remission (patients in clinical remission at Wk 14 and Wk 52). RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Baseline characteristics were comparable between the 2 groups. A trend for separation in clinical response started to emerge at Wk 6 favoring VDZ vs ADA. Clinical response at Wk 14 favored VDZ vs ADA (257 [67.1%] vs 177 [45.9%]; treatment difference 21.2%). More patients achieved clinical remission at Wk 14 on VDZ vs ADA (102 [26.6%] vs 82 [21.2%]; treatment difference 5.3%). Patients on VDZ achieved higher rates of durable clinical remission (70 [18.3%] vs 46 [11.9%]); laboratory results correlated with these findings. Post hoc analyses showed a larger mean (standard deviation) change of C-reactive protein (CRP) from baseline to Wk 14 (−32.88 [155.77] nmol/L VDZ vs −3.35 [260.81] nmol/L ADA) and to Wk 52 (−50.87 [174.76] nmol/L VDZ vs −37.21 [169.17] nmol/L ADA) in favor of VDZ. Greater mean declines in fecal calprotectin (FCP) levels were seen in patients on VDZ compared with ADA (Wk 14: −1,551.3 [6,236.70] mg/kg VDZ vs −1,167.6 [4,647.67] mg/kg ADA; Wk 52: −2,187.3 [7,440.42] mg/kg VDZ vs −1,846.6 [4,560.55] mg/kg ADA). CONCLUSION: Patients on VDZ had numerically higher rates of both clinical response and clinical remission by Wk 14 compared with ADA. Patients on VDZ also achieved higher rates of durable clinical remission compared with ADA. CRP and FCP results correlated with these findings. These data on early clinical response and clinical remission, as well as durable remission, further support the use of VDZ over ADA in patients with moderately to severely active UC.

Efficacy of Therapy for Eosinophilic Esophagitis in Real-World Practice

Eosinophilic esophagitis is characterized by eosinophil inflammation restricted to the esophagus and the resulting symptoms of esophageal dysfunction. Critical to the diagnosis of eosinophilic esophagitis is a trial of proton pump inhibitor therapy to exclude alternative causes of esophageal eosinophilia such as proton pump inhibitor-responsive esophageal eosinophilia. While consensus guidelines recommend a proton pump inhibitor trial prior to diagnosis, little is known about its implementation in clinical practice. The primary aim of this study is to assess the frequency of proton pump inhibitor trial prior to the diagnosis of eosinophilic esophagitis in community practice. The secondary aim is to assess the frequency of other treatments for eosinophilic esophagitis, including topical steroids and/or dietary therapy, in patients who did not undergo a proton pump inhibitor trial prior to diagnosis or who had an alternative diagnosis to eosinophilic esophagitis upon completed workup. We conducted a single-center, case series of patients referred to the Hospital of the University of Pennsylvania for eosinophilic esophagitis management between 2010 and 2015. This case series consisted of 125 patients who were referred from community practitioners with a presumptive diagnosis of eosinophilic esophagitis. Upon review, 90 out of 125 (72%) patients had not had a proton pump inhibitor trial or esophageal pH testing prior to the diagnosis of eosinophilic esophagitis being made. Of these patients, 77.8% (70/90) had already received either topical steroid or dietary therapy for presumed eosinophilic esophagitis. Of the 125 patients initially diagnosed with eosinophilic esophagitis, 32 (25.6%) were found to have an alternative diagnosis, and 79.2% of this subset of patients (25/32) had previously received topical steroid or dietary therapy. This study demonstrates that a substantial number of patients with presumed eosinophilic esophagitis have not had a proton pump inhibitor trial prior to diagnosis in community practice. This led to the misclassification of patients and potentially to the use of less optimal medical therapies in a substantial number of these patients.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease with eosinophilic predominant inflammation. Symptoms include dysphagia, food impaction, and chest pain. Diagnosis is made via biopsy, requiring more than 15 eosinophils per high-power field. First line therapy is proton pump inhibitors (PPIs) along with dietary modifications and topical glucocorticoid to reduce inflammation. Untreated EoE can lead to fibrosis and strictures, requiring endoscopic dilatation. Given the consequences, it is important to recognize EoE, identify uncommon cofactors, and manage inflammation. We present a case of rumination syndrome found on manometry in a patient with unresolved EoE. CASE DESCRIPTION/METHODS: A 20-year-old male with Autism spectrum disorder, seasonal allergies, food allergies, asthma, and EoE presented for a second opinion for continued symptoms of dysphagia and post-prandial regurgitation to both solids and liquids along with a 10-pound weight loss while on a PPI 40 mg daily. He had been diagnosed with EoE with EGD and biopsies 2 years prior unresponsive to PPI. His PPI was advanced to 40 mg twice daily and he was started on a topical budesonide slurry. Because he continued to have significant symptoms an EGD was performed with high-resolution manometry catheter placement. EGD revealed mucosal changes consistent with EoE, confirmed via biopsy. Esophageal motility testing showed rumination pattern on multiple occasions during the post-prandial period. The patient was given a referral to behavioral health for rumination syndrome and his PPI and topical budesonide were continued. DISCUSSION: This case illustrates rumination syndrome as a possible cofactor in the management of EoE. Rumination syndrome is a functional gastrointestinal disorder consisting of cyclic regurgitation and ingestion of food matter. High-resolution manometry is the preferred test to diagnose rumination syndrome. Historically, rumination syndrome is considered a rare disorder, with scant systemic research, thus it is often missed or misdiagnosed due to lack of awareness. To the best of our knowledge, only two case reports have described the presentation of rumination syndrome in the setting of EoE. In both cases, as well as in our case, EoE was found to be histologically refractory to standard management in the setting of ongoing rumination. We find this an important case that highlights rumination syndrome may be present in refractory EoE and manometry with rumination protocol should be considered in these patients.

Relapse after corticosteroid withdrawal in eosinophilic esophagitis is not well understood. Budesonide oral suspension (BOS) 2.0 mg twice daily (b.i.d.) was evaluated in two consecutive phase III studies (12 and 36 weeks, respectively). For clinicopathologic responders after 12 weeks of BOS treatment, we assessed randomized treatment withdrawal for up to 36 weeks of therapy. Post hoc analysis of a phase III, double-blind, randomized withdrawal study. Clinicopathologic responders (⩽6 eosinophils per high-power field (eos/hpf) and ⩾30% reduction in Dysphagia Symptom Questionnaire (DSQ) score from baseline) after 12 weeks of BOS were randomized to continue BOS 2.0 mg b.i.d. (BOS-BOS) or withdraw to placebo (PBO; BOS-PBO) for up to 36 weeks. Relapsers (⩾15 eos/hpf (⩾2 esophageal regions) and ⩾4 days of dysphagia (DSQ)) could reinitiate BOS 2.0 mg b.i.d. This post hoc analysis assessed a more clinically relevant relapse definition (⩾15 eos/hpf (⩾1 esophageal region) and ⩾4 days of dysphagia (DSQ)) for BOS-BOS versus BOS-PBO patients over 36 weeks. To account for BOS-PBO patients who reinitiated BOS before week 36, patients' last observations before reinitiating BOS were carried forward (last observation carried forward (LOCF)) for histologic, symptom, and endoscopic efficacy endpoints (at weeks 12 and 36). Of 48 patients included (BOS-BOS, n = 25; BOS-PBO, n = 23), significantly more BOS-PBO than BOS-BOS patients relapsed over 36 weeks using this post hoc relapse definition (60.9% vs 28.0%; p = 0.022). More BOS-BOS than BOS-PBO patients maintained histologic responses (all thresholds) and showed improvements in symptom and endoscopic efficacy endpoints. More BOS-PBO than BOS-BOS patients relapsed, determined by a more clinically relevant post hoc relapse definition. Using LOCF, more BOS-BOS than BOS-PBO patients also maintained or had improvements in efficacy endpoints. ClinicalTrials.gov identifiers (https://clinicaltrials.gov/): NCT02605837, NCT02736409.

Biologicals Move Into the Esophagus

INTRODUCTION: Proton pump inhibitors (PPIs) are now considered a treatment option for eosinophilic esophagitis (EoE). High-dose PPI (HDPPI) response rates are 23-63% in pediatric studies. Our primary aim was to determine PPI response rate in children with EoE. Secondary aim was to determine clinical, endoscopic, or histologic characteristics that impact this PPI response. METHODS: A prospective cohort study of children was conducted. Demographics, clinical history, child and parent-proxy Pediatric EoE Symptom Scores version 2 (PEESSv2.0), EoE endoscopic reference scores (EREFS), and histology scores were collected at endoscopies before and after at least 8 weeks of HDPPI. EoE was defined as ≥ 15 eosinophils/high powered field (eos/hpf) on biopsy from any level of the esophagus on initial endoscopy with symptoms of esophageal dysfunction. Children with &lt; 15 eos/hpf on repeat endoscopy were classified as PPI-responsive (PPI-R) EoE, and ≥ 15 eos/hpf were classified as PPI-nonresponsive (PPI-NR) EoE. RESULTS: 72 children were enrolled from 2015 to 2018 (58% male; mean 9.4 years). 40 children (56%) met criteria for EoE, and 25 had endoscopies before and after HDPPI. 11 refused HDPPI, and 4 were lost to follow-up. 32% (8/25) of children had PPI-R EoE. Baseline demographics, clinical history, child and parent-proxy PEESSv2.0 scores, parent-proxy dysphagia subdomain scores, EREFS, and histology scores were similar in PPI-R and PPI-NR EoE patients. Baseline child dysphagia scores were worse in PPI-NR EoE patients than in PPI-R EoE patients (17.8 v 11.0, P = 0.012). Parent-proxy PEESSv2.0 scores improved in PPI-R and PPI-NR EoE groups after HDPPI (P = 0.046, P = 0.005). Child PEESSv2.0 scores, and parent-proxy and child dysphagia scores improved significantly in the PPI-NR group after HDPPI (33.2 to 19.1, P = 0.006; 18.9 to 8.9, P = 0.004; 17.8 to 9.2, P &lt; 0.001). EREFS improved in PPI-R and PPI-NR EoE groups (P &lt; 0.001, P = 0.030), but had more improvement in the PPI-R group (P = 0.017). Children in the PPI-R group had improvement in degranulation and basal cell hyperplasia compared to the PPI-NR group (P = 0.016, P = 0.008). CONCLUSION: 32% of children with EoE responded to HDPPI therapy. No characteristics predicted PPI response. As anticipated, endoscopic and histologic features of EoE improved more in the PPI-R group. We did not expect to find that child and parent-proxy symptom scores would improve significantly in the PPI-NR group. The value of these symptom scores and their role in EoE management should be further studied.

Eosinophilic esophagitis (EoE) is an increasingly recognized disorder whose diagnosis is based on histologic demonstration of eosinophilic inflammation. We previously reported improvement of symptoms in children with EoE on long-term proton-pump inhibitor (PPI) monotherapy despite persistent eosinophilic inflammation. We sought to determine whether PPI monotherapy in children with EoE is associated with decreased eosinophil degranulation. Ten children with EoE had esophageal biopsies assessed for eosinophil, mast cell and Langerhans cell concentration and eosinophil degranulation at diagnosis and following PPI treatment. There was no significant difference in cell concentrations between initial and one-year follow-up. A significant decrease in number of free lying granules was observed at the one-year follow-up biopsies. Prolonged PPI therapy in EoE is associated with decreased eosinophil degranulation.

Best of foregut: esophagus, stomach, and duodenum

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