Gene expression-phenotype associations in adults with eosinophilic esophagitis

Background: Gene expression patterns have not been extensively examined in the context of clinical features of eosinophilic esophagitis (EoE). Aims: To assess whether gene expression is associated with clinically defined phenotypes in adults with EoE. Methods: This was an analysis of prospectively collected esophageal biopsies in newly diagnosed EoE patients. We determined differential gene expression with a 94 gene panel in relation to clinical features and phenotypes. These included: endoscopic findings of esophageal rings, stricture, narrowing, linear furrows, exudates, edema, and dilation; an allergic phenotype; an inflammatory phenotype, and a fibrostenotic phenotype. Results: In 89 EoE cases analyzed, patients with exudates on endoscopy had multiple differences in gene expression compared to patients without exudates, though patients with exudates also had higher eosinophil counts (172 vs 106 eos/hpf; p =.01). Genes associated with esophageal narrowing included CCL26 (q-value = 0.028), ALOX15 (q = 0.011), GRK5 (q = 0.029), CPA3 (q = 0.012), and TRIM2 (q = 0.0027). TRIM2 was also associated with the fibrostenotic phenotype (q = 0.0051). No genes were associated with the inflammatory or atopic phenotypes, or with dilation. Conclusions: Multiple genes are associated with exudates, possibly related to higher eosinophil counts. However, a number of genes, including those related to both inflammation and remodelling, are associated with esophageal narrowing. In particular, TRIM2 is associated with clinical fibrotic phenotypes

Noninvasively Predicting Hemodynamic Response to Carvedilol in Cirrhotic Patients With Varices: You Have Some Ex-Spleening to Do

Gastroesophageal varices are present in approximately 50% of patients with cirrhosis and variceal hemorrhage occurs at a rate of about 10%–15% per year (N Engl J Med 1988;319:983–989; Gastrointest Endosc 2007;65:82–88). Nonselective beta-blockers (NSBB) or variceal band ligation are currently recommended as primary prophylaxis against variceal hemorrhage in patients with large or high-risk varices (J Hepatol 2015;63:743–752; Hepatology 2017;65:310–335). The goal of NSBB therapy is to reduce portal pressures, which can formally be assessed by measuring the hepatic venous pressure gradient (HVPG)

Autoimmune and viral risk factors are associated with achalasia: A case-control study

Background: Achalasia is a rare esophageal motility disorder of uncertain etiology. While past studies have indicated that autoimmune conditions and viral infections may be associated with development of achalasia, these associations are yet to be examined in large, population-based studies. Methods: A matched case-control study was performed using administrative claim data from the IBM MarketScan Commercial Claims and Encounters Database between 2000 and 2019. A history of selected autoimmune conditions and viral infections was assessed using past medical claims. Multivariable conditional logistic regression was used to account for the matched nature of the study design and further control for confounding by demographic and clinical characteristics when reporting adjusted odds ratios (aORs). Key Results: Among 6769 cases and 27,076 controls, presence of any of the autoimmune conditions studied was associated with increased odds of achalasia (aOR = 1.26, 95% CI: 1.11, 1.42). Scleroderma or systemic sclerosis (aOR = 8.13, 95% CI: 3.34, 19.80) and Addison's disease (aOR = 3.83, 95% CI: 1.83, 8.04) had the strongest associations with achalasia. Presence of any of the viral infections studied was also associated with an increased risk of achalasia (aOR = 1.58, 95% CI: 1.23, 2.01). Varicella zoster virus (aOR = 3.84, 95% CI: 1.94, 7.62) and human papillomavirus (aOR = 1.77, 95% CI: 1.15, 2.73) both had strong relationships with achalasia. Conclusions and Inferences: These findings suggest that achalasia may have autoimmune and viral components contributing to its etiology. Future mechanistic studies could target specific diseases and agents highlighted by this research

Propensity score methods to control for confounding in observational cohort studies: a statistical primer and application to endoscopy research

Background and Aims: Confounding is a major concern in nonexperimental studies of endoscopic interventions and can lead to biased estimates of the effects of treatment. Propensity score methods, which are commonly used in the pharmacoepidemiology literature, can effectively control for baseline confounding by balancing measured baseline confounders and risk factors and creating comparable populations of treated and untreated patients. Methods: We propose the following 5-step checklist to guide the use and evaluation of propensity score methods: (1) select covariates, (2) assess “Table 1” balance in risk factors before propensity score implementation, (3) estimate and implement the propensity score in the study cohort, (4) reassess “Table 1” balance in risk factors after propensity score implementation, and (5) critically evaluate differences between matched and unmatched patients after propensity score implementation. We then applied this checklist to an endoscopy example using a study cohort of 411 adults with newly diagnosed eosinophilic esophagitis (EoE), some of whom were treated with esophageal dilation. Results: We identified 156 patients, aged 18 and older, who were treated with esophageal dilation, and 255 patients who were nondilated. We successfully matched 148 (95%) dilated patients to nondilated patients who had a propensity score within 0.1, based on patient age, sex, race, self-reported food allergy, and presence of narrowing at baseline endoscopy. Crude imbalances were observed before propensity score matching in several baseline covariates, including age, sex, and narrowing; however, propensity score matching was successful in achieving balance across all measured covariates. Conclusions: We provide an introduction to propensity score methods, including a straightforward checklist for implementing propensity score methods in nonexperimental studies of treatment effectiveness. Moreover, we demonstrate the advantage of using “Table 1” as a simple but effective diagnostic tool for evaluating the success of propensity score methods in an applied example of esophageal dilation in EoE

Epidemiologic and Economic Burden of Achalasia in the United States

Background & Aims: Achalasia is a debilitating chronic condition of the esophagus. Currently there are no national estimates on the epidemiologic and economic burden of disease. We sought to estimate trends in incidence and prevalence of achalasia by age-sex strata, and to estimate the total direct medical costs attributed to achalasia in the United States. Methods: We conducted a cohort study using two administrative claims databases: IBM MarketScan Commercial Claims and Encounters database (2001-2018; age <65) and a 20% sample of nationwide Medicare enrollment and claims (2007-2015; age ≥65). Point prevalence was calculated on the first day of each calendar year; the incidence rate captured new cases developed in the ensuing year. Utilization rates of healthcare services and procedures were reported. Mean costs per patient were calculated and standardized to the corresponding U.S. Census Bureau population data to derive achalasia-specific total direct medical costs. Results: The crude prevalence of achalasia per 100,000 persons was 18.0 (95% CI, 17.4, 18.7) in MarketScan and 162.1 (95% CI, 157.6, 166.6) in Medicare. The crude incidence rate per 100,000 person-years was 10.5 (95% CI, 9.9, 11.1) in MarketScan and 26.0 (95% CI, 24.9, 27.2) in Medicare. Incidence and prevalence increased substantially over time in the Medicare cohort, and increased with more advanced age in both cohorts. Utilization of achalasia-specific healthcare was high; national estimates of total direct medical costs exceeded $408 million in 2018. Conclusions: Achalasia has a higher epidemiologic and economic burden in the US than previously suggested, with diagnosis particularly increasing in older patients

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

Background & Aims: 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). Methods: 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. Results: 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. Conclusions: 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

Efficacy of Budesonide vs Fluticasone for Initial Treatment of Eosinophilic Esophagitis in a Randomized Controlled Trial

Background and Aims: Topical steroid treatments for eosinophilic esophagitis (EoE) include swallowed fluticasone from a multi-dose inhaler (MDI) or oral viscous budesonide (OVB) slurry, but the 2 have never been compared. We assessed whether OVB was more effective than MDI for initial treatment of patients with EoE. Methods: In a double-blind, double-dummy trial, patients with a new diagnosis of EoE were randomly assigned to groups given 8 weeks of either OVB (1 mg/4 mL) twice daily plus a placebo inhaler (n = 56) or fluticasone MDI (880 μg) twice daily plus a placebo slurry (n = 55). Primary outcomes were post-treatment maximum eosinophil counts per high-power field (eos/hpf) and a validated dysphagia score (dysphagia symptom questionnaire [DSQ]) at week 8. Secondary outcomes included endoscopic severity (validated EoE endoscopic reference score), histologic response (<15 eos/hpf), and safety. Results: In a modified intention-to-treat analysis, the subjects had baseline peak eosinophil counts of 73 and 77 eos/hpf in the OVB and MDI groups, respectively, and DSQ scores of 11 and 8. Post-treatment eosinophil counts were 15 and 21 in the OVB and MDI groups, respectively (P =.31), with 71% and 64% achieving histologic response (P =.38). DSQ scores were 5 and 4 in the OVB and MDI groups (P =.70). Similar trends were noted for post-treatment total EoE endoscopic reference scores (2 vs 3; P =.06). Esophageal candidiasis developed in 12% of patients receiving OVB and 16% receiving MDI; oral thrush was observed in 3% and 2%, respectively. Conclusions: In a randomized clinical trial, initial treatment of EoE with either OVB or fluticasone MDI produced a significant decrease in esophageal eosinophil counts and improved dysphagia and endoscopic features. However, OVB was not superior to MDI, so either is an acceptable treatment for EoE. ClinicalTrials.gov ID NCT02019758

Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.

BACKGROUND &amp; AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263

Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

 Eosinophilic gastrointestinal disorders (EGIDs) affect various segments of the gastrointestinal tract. Since these disorders are rare, collaboration is essential to enroll subjects in clinical studies and study the broader population. The Rare Diseases Clinical Research Network (RDCRN), a program of the National Center for Advancing Translational Sciences (NCATS), funded the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) in 2014 to advance the field of EGIDs. CEGIR facilitates collaboration among various centers, subspecialties, patients, professional organizations and patient-advocacy groups and includes 14 clinical sites. It has successfully initiated two large multi-center clinical studies looking to refine EGID diagnoses and management. Several pilot studies are underway that focus on various aspects of EGIDs including novel therapeutic interventions, diagnostic and monitoring methods, and the role of the microbiome in pathogenesis. CEGIR currently nurtures five physician-scholars through a career training development program and has published more than 40 manuscripts since its inception. This review focuses on CEGIR's operating model and progress and how it facilitates a framework for exchange of ideas and stimulates research and innovation. This consortium provides a model for progress on other potential clinical areas

Eosinophilic esophagitis: What can we learn from Crohn's disease?

Eosinophilic esophagitis (EoE) is an emerging esophageal inflammatory disorder affecting children and young adults. As a relatively new disease, EoE is still burdened by frequent diagnostic and therapeutic pitfalls in clinical practice. This manuscript posits a number of similarities with Crohn's disease, which may help optimize EoE patient management. Commonalities include epidemiologic trends (Westernized diseases, rising incidence, early-life risk factors), diagnostic considerations (symptoms are poor predictors of disease activity, difficulties in disease activity assessment) and therapeutic issues (similar natural history and therapeutic goals, induction and maintenance phases, combination of drug and endoscopic treatment, potential drug interchangeability, long-term unsolved issues). Physicians devoted to EoE should learn from the extraordinary achievements fulfilled in Crohn's disease: increased disease awareness, multidisciplinary specialized clinics, structured childhood and transition programs, and an ongoing roadmap for personalized treatments, including genetic susceptibility, risk factors for progression, genotype-phenotype correlation, drug monitoring and microbial data