Economic Evaluation of Budesonide Orodispersible Tablets for the Treatment of Eosinophilic Esophagitis: A Cost-Utility Analysis.

INTRODUCTION: Budesonide orodispersible tablets (BOT) have been approved in Europe and Canada for the treatment of eosinophilic esophagitis (EoE), a rare and chronic disease. The objective of this study was to assess the economic impact of BOT on both the induction and maintenance of clinico-pathological remission of EoE by performing a cost-utility analysis (CUA). METHODS: For both the induction and maintenance settings, BOT was compared to no treatment in a target population of adult patients with EoE non-responsive to proton pump inhibitor (PPI) treatment. Markov models were developed for the induction and maintenance settings over 52-week and life-time horizons, respectively. Analyses were performed from both a Canadian Ministry of Health (MoH) and societal perspective. The resulting incremental cost-utility ratios (ICURs) were compared to a willingness-to-pay (WTP) threshold of $50,000 Canadian dollars/quality-adjusted life-year (QALY). Sensitivity and scenario analyses were conducted to assess the robustness of the base-case results. RESULTS: In the base-case probabilistic analysis, BOT compared to no treatment resulted in an ICUR of $1073/QALY and $30,555/QALY from a MoH perspective in the induction and maintenance settings, respectively. BOT was a cost-effective option for both induction and maintenance in > 99% of Monte Carlo simulations. In the scenario analyses, the deterministic ICUR of BOT compared to no treatment varied from $682/QALY to $8510/QALY in the induction setting and $21,005/QALY to $55,157/QALY in the maintenance setting. CONCLUSION: BOT was cost-effective compared to no treatment for both the induction and maintenance of clinico-pathological remission of EoE in patients non-responsive to PPIs.

Increased risk of eosinophilic esophagitis with poor environmental quality as measured by the Environmental Quality Index.

Geographic differences in eosinophilic esophagitis (EoE) prevalence suggest the possibility that environmental exposures contribute to EoE pathogenesis. We aimed to examine the association between environmental quality and risk of EoE, using the Environmental Quality Index (EQI), which provides quantification of environmental quality in five domains: air, land, water, built, and sociodemographic for all counties in the United States. To do this, we performed a case-control study in a large pathology database. EoE cases were defined by ≥15 eosinophils per high-power field with other pathologic diagnoses excluded; controls did not have EoE. The pathology data were geocoded and linked with the EQI by county of residence. Logistic regression was used to estimate odds ratio (OR and 95% confidence interval [CI]) of EoE with overall EQI and for each domain, after adjusting for sex, age, and proportion minority race or ethnicity at the county level (higher EQI score indicates worse environmental quality). Of 29,802 EoE cases and 593,329 controls analyzed, odds of EoE were highest in the worst quintile of EQI (OR 1.25; 95% CI: 1.04-1.50), which was largely explained by poor scores in the water domain (OR: 1.33; 1.17-1.50). Conversely, odds of EoE were reduced with higher scores in the air domain (OR: 0.87, 0.74-1.03) and land domain (OR 0.87; 0.76-0.99). Poor EQI, mostly reflected by poor water quality, was associated with increased odds of EoE, while poor air and land quality were inversely associated with EoE. Additional work to identify specific water pollutants that may have an etiologic role in EoE may be warranted.

A diagnosis of eosinophilic esophagitis is associated with increased life insurance premiums.

Eosinophilic esophagitis (EoE) is a chronic disease that can be diagnosed at any age, but is not associated with malignancy and does not shorten lifespan. It remains unknown whether an EoE diagnosis affects insurability or insurance premium costs. We therefore aimed to determine whether a diagnosis of EoE affects the costs of life insurance. Our investigation was a secret shopper audit study whereby we contacted national insurance companies in the United States to evaluate the effect of a diagnosis of EoE on life insurance premiums. We constructed standardized case scenarios for males and females, including a 25-year-old and a 48-year-old without other comorbid conditions, who either had or did not have a diagnosis of EoE. Companies were asked for their best estimate for a $100,000 whole life insurance policy. Comparisons between median premiums were made using the Mann-Whitney U test. There were 20 national life insurance companies contacted and a total of 73 quotes were obtained. The median premium rate was similar for EoE and non-EoE cases at the younger age ($828 [IQR $576-1,020] vs. $756 [IQR $504-$804]; P = 0.10). However, the premium for the older case without EoE was 19% less expensive compared to a case with EoE ($1990 [IQR $1,248-2,350] vs. $2,375 [IQR $2,100-2568; P = 0.02]. This finding was not explained by sex or state of residence. Based on these findings, we conclude that life insurance premiums are significantly more expensive in the older patient case with EoE when compared to the same case without EoE. Patients with EoE and their providers should be aware of the additional cost associated with this diagnosis.

Systematic review: adrenal insufficiency secondary to swallowed topical corticosteroids in eosinophilic oesophagitis.

BACKGROUND: Swallowed topical corticosteroids are prescribed for eosinophilic oesophagitis (EoE), but there is a theoretical risk of adrenal insufficiency from their use. AIMS: To determine if the use of topical corticosteroids to treat EoE is associated with the development of adrenal insufficiency. METHOD: We conducted a systematic review of the published literature from January 1, 1950 to April 1, 2017 using Pubmed, Embase, Web of Science and Cochrane Central. Studies and meeting abstracts were included that described patients with EoE who received swallowed topical corticosteroids and any investigation for adrenal insufficiency. RESULTS: The search revealed 1610 unique publications, and 17 met inclusion criteria. There were 7 randomised controlled trials (RCTs), 6 prospective observational studies, 3 retrospective observational studies, and 1 case report. Cortisol measurements were performed on 596 individuals with EoE who received topical corticosteroids. Adrenal testing was abnormal, as defined by each study, in 94/596 patients (crude rate of 15.8%). Only 2 studies were considered to have a low risk of bias, being randomised controlled trials that estimated adrenal insufficiency in the active treatment and placebo groups, before and after treatment. None of the seven randomised controlled trials demonstrated statistically significantly different rates of adrenal insufficiency between topical corticosteroid and placebo over treatment intervals of 2-12 weeks. CONCLUSION: Topical corticosteroids were associated with adrenal insufficiency in a minority of patients. Most cases came from uncontrolled observational studies, with widely varying definitions of adrenal insufficiency. Longer follow-up and larger controlled studies are needed to quantify the risk of adrenal insufficiency with maintenance topical corticosteroid therapy in EoE.

Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

Normalized serum eosinophil peroxidase levels are inversely correlated with esophageal eosinophilia in eosinophilic esophagitis.

Eosinophil 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 < 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.

Impact of smoking, alcohol consumption, and NSAID use on risk for and phenotypes of eosinophilic esophagitis.

There are few data exploring modifiable risk factors for eosinophilic esophagitis (EoE). We aimed to determine if smoking, alcohol consumption, and nonsteroidal anti-inflammatory drug (NSAID) use were risk factors for EoE, and to assess their impact on EoE phenotypes and treatment outcomes. We performed a case-control study analyzing data collected from a prospective cohort of adults undergoing upper endoscopy for symptoms of esophageal dysfunction. Incident EoE cases were diagnosed via consensus guidelines. Exposure data were collected via standardized patient questionnaire. Follow-up assessments for cases were made after treatment, with histologic response defined as <15 eosinophils per high-power field (eos/hpf). Exposures were compared between EoE cases and controls, among EoE cases with and without fibrostenosis, and among EoE responders and nonresponders. A total of 115 cases and 225 controls were analyzed. Cases were less likely to have ever smoked cigarettes (23% vs. 47%, P < 0.001) or currently use NSAIDs (17% vs. 40%, P < 0.001) compared to controls. These relations persisted after multivariate analysis. Although alcohol use was more common among cases (75% vs. 51%, P < 0.001), the effect was abrogated after multivariate analysis. Smoking, alcohol, and NSAID use were not associated with the fibrostenotic phenotype. There was a trend toward improved histologic response among EoE patients concomitantly using NSAIDs (87% vs. 63%, P = 0.08; aOR 6.97 (95% CI: 0.81-60.3). In conclusion, NSAID and smoking were inversely associated with EoE compared to endoscopy-based controls. Alcohol use was more prevalent in the EoE cases, although not an independent risk factor. Concomitant NSAID use may improve treatment response and is worthy of future study.

Control of inflammation decreases the need for subsequent esophageal dilation in patients with eosinophilic esophagitis.

It is unknown if successful control of esophageal inflammation in eosinophilic esophagitis (EoE) decreases the need for subsequent esophageal dilation. We aimed to determine whether histologic response to topical steroid treatment decreases the likelihood and frequency of subsequent esophageal dilation. We conducted a retrospective cohort study. Patients with an incident diagnosis of EoE were included if they had an initial esophageal dilation, received topical steroids, and had a subsequent endoscopy with biopsies. The number of dilations performed in each group was determined, and histologic responders (<15 eos/hpf) were compared to nonresponders. The 55 EoE patients included (27 responders and 28 nonresponders) underwent a mean of 3.0 dilations over a median follow-up of 19 months. Responders required fewer dilations than nonresponders (1.6 vs. 4.6, P = 0.03), after adjusting for potential confounders. Despite undergoing significantly fewer dilations, responders achieved a similar increase in esophageal diameter with dilation (4.9 vs. 5.0 mm; P = 0.92). In EoE patients undergoing esophageal dilation at baseline, control of inflammation with topical steroids was associated with a 65% decrease in the number of subsequent dilations to maintain the same esophageal caliber. This suggests that inflammation control is an important goal in patients with fibrostenotic changes of EoE.

Food elimination diets are effective for long-term treatment of adults with eosinophilic oesophagitis.

BACKGROUND: Limited data describe the long-term efficacy of dietary elimination in eosinophilic oesophagitis (EoE). AIM: To assess the long-term outcomes of food elimination diets for treatment of adults with EoE. METHODS: We conducted a retrospective cohort study at our centre analysing all EoE patients receiving a food elimination diet without concomitant steroids. Baseline data were abstracted using standardised collection forms. Follow-up data from a mean 24.9-month period were collected for patients with a histological response to a food elimination diet during and after food reintroduction. The main outcomes were symptomatic, endoscopic and histological responses. RESULTS: Of 52 patients, 18 received a 6-food food elimination diet, 32 received targeted diet, and two received a 6-food food elimination diet with targeted elimination. There were 21 (40%) patients with an initial histological response. Responders reported less dysphagia after treatment (95% baseline vs 11%; P = .001) and at the end of follow-up (95% baseline vs 33%; P = .008). Significant and durable endoscopic improvements were recorded at the same time points: Endoscopic reference score: 3.2 vs 0.7; P = .001; and 3.2 vs 1.7; P = .06. Histological findings improved after the most restrictive diet in responders (49.8 vs 4.1 eosinophils per high-power field; P = .001) and remained suppressed in the 10 initial responders maintaining compliance at the end of follow-up (5.2 eosinophils per high-power field). CONCLUSIONS: Among EoE patients responding to a food elimination diet and remaining adherent, maintenance dietary therapy produced durable long-term symptomatic, endoscopic and histological disease control. These long-term data confirm that a food elimination diet is an effective maintenance treatment option in select adults with EoE.

A visual analogue scale and a Likert scale are simple and responsive tools for assessing dysphagia in eosinophilic oesophagitis.

BACKGROUND: While symptom scores have been developed to evaluate dysphagia in eosinophilic oesophagitis (EoE), their complexity may limit clinical use. AIM: To evaluate a visual analogue scale (VAS) and a 10-point Likert scale (LS) for assessment of dysphagia severity before and after EoE treatment. METHODS: We conducted a prospective cohort study enrolling consecutive adults undergoing out-patient endoscopy. Incident cases of EoE were diagnosed per consensus guidelines. At diagnosis and after 8 weeks of treatment, symptoms were measured using the VAS, LS and the Mayo Dysphagia Questionnaire (MDQ). The percentage change in scores before and after treatment were compared overall, in treatment responders (<15 eos/hpf) and non-responders, and in patients without baseline dilation. RESULTS: In 51 EoE cases, the median VAS decreased from 3.6 at baseline to 1.4 post-treatment (71% decrease), the LS decreased from 6 to 2 (67%) and the MDQ decreased from 20 to 10 (49%). The VAS correlated with both the LS (R = 0.77; P < 0.0001) and MDQ (R = 0.46, P = 0.001). After stratification by histological response, the LS decreased 70% in responders vs. 13% in non-responders (P = 0.02). In patients who did not receive baseline dilation, both the VAS and LS decreased significantly more in the histological responders. CONCLUSIONS: Both the VAS and LS were responsive to successful treatment as measured by histologic improvement. Because the VAS and LS are simple to administer and are responsive to treatment, they can provide an efficient and objective method for assessing dysphagia severity in EoE in clinical practice.

Mortality and cardiovascular diseases risk in patients with Barrett's oesophagus: a population-based nationwide cohort study.

BACKGROUND: Patients with Barrett's oesophagus may be at increased risk of mortality overall, and cardiovascular disease has been suggested as the main underlying cause of death. AIM: To examine cause-specific mortality and risk of cardiovascular events among patients with Barrett's oesophagus. METHODS: Utilising existing Danish data sources (1997-2011), we identified all patients with histologically verified Barrett's oesophagus (n = 13 435) and 123 526 members of the general population matched by age, sex and individual comorbidities. We calculated cause-specific mortality rates and incidence rates of cardiovascular diseases. We then compared rates between patients with Barrett's oesophagus and the general population comparison cohort, using stratified Cox proportional hazard regression. RESULTS: Patients with Barrett's oesophagus had a 71% increased risk of overall mortality. The cause-specific mortality rate per 1000 person-years for patients with Barrett's oesophagus was 8.5 for cardiovascular diseases, 14.7 for non-oesophageal cancers, and 5.4 for oesophageal cancer. Compared to the general population cohort, corresponding hazard ratios were 1.26 (95% confidence interval (CI): 1.15-1.38), 1.77 (95% CI: 1.65-1.90), and 19.4 (95% CI: 16.1-23.4), respectively. The incidence rates of cardiovascular diseases per 1000 person-years for Barrett's oesophagus patients and for persons from the general population cohort, respectively, varied from 0.4 and 0.2 for subarachnoid bleeding (hazard ratio 1.10, 95% CI: 0.87-1.39) to 8.1 and 5.9 for congestive heart failure (hazard ratio 1.33, 95% CI: 1.21-1.46). CONCLUSION: Prophylactic measures targeted at cardiovascular diseases and non-oesophageal cancers potentially could be more important than measures against oesophageal cancer, for improving prognosis among patients with Barrett's oesophagus.

Prospective assessment of serum periostin as a biomarker for diagnosis and monitoring of eosinophilic oesophagitis.

BACKGROUND: Periostin is highly expressed in eosinophilic oesophagitis (EoE), but has not been extensively studied as a non-invasive biomarker. AIM: To assess whether serum periostin distinguished EoE from controls at baseline, had utility for monitoring treatment response, or was associated with IL-13 levels. METHODS: This was a sub-analysis of a prospective cohort study of adults undergoing out-patient upper endoscopy. Incident cases of EoE were diagnosed per consensus guidelines. Controls were subjects with either GERD or dysphagia without EoE. EoE patients were treated with swallowed/topical steroids and had repeat endoscopy/biopsy. Serum periostin levels for cases and controls were compared at baseline, and pre/post-treatment levels were compared for cases. Serum IL-13 and tissue expression of periostin were also assessed. RESULTS: A total of 61 incident EoE cases and 87 controls were analysed. Despite a marked increase in tissue periostin expression in cases, the median baseline serum periostin level was only slightly higher in cases than controls (22.1 ng/mL vs. 20.7; P = 0.04); there was no change in post-treatment levels. There was also no difference in serum periostin for cases by histologic response or atopic status. There was a strong trend towards higher serum IL-13 levels in cases in the highest periostin quartile (57.1 pg/mL vs. 2.6; P = 0.07). CONCLUSIONS: Serum periostin levels were similar in cases and controls, and there were no changes post-treatment. Given elevated IL-13 levels in the EoE patients with the highest periostin levels, future studies could explore periostin as a biomarker in EoE, perhaps in the setting of anti-IL-13 therapy.

High rate of galactose-alpha-1,3-galactose sensitization in both eosinophilic esophagitis and patients undergoing upper endoscopy.

Eosinophilic esophagitis (EoE) is an antigen/allergy-mediated chronic inflammatory condition. The rapid rise in the number of cases of EoE suggests an as-yet undiscovered environmental trigger. This study tested the hypothesis that immunoglobulin E (IgE) to galactose-alpha-1,3-galactose (alpha-gal), a newly recognized sensitization induced by a tick bite that causes mammalian meat allergy, is a risk factor for EoE. We conducted a case-control study using prospectively collected and stored samples in the University of North Carolina EoE Patient Registry and Biobank. Serum from 50 subjects with a new diagnosis of EoE and 50 non-EoE subjects (either with gastroesophageal reflux disease or dysphagia from non-EoE etiologies) was tested for alpha-gal-specific IgE using an ImmunoCAP-based method. Specific IgE > 0.35 kUA /L was considered a positive result. Subjects with EoE were a mean of 35 years old, 68% were male, and 94% were white. Non-EoE controls were a mean of 42 years, 50% were male, and 78% were white. A total of 22 (22%) subjects overall had alpha-gal-specific IgE > 0.35 kUA /L. Of the EoE cases, 12 (24%) were positive, and of the non-EoE controls, 10 (20%) were positive (p=0.63). Neither the proportion sensitized nor the absolute values differed between EoE and non-EoE subjects. We found a similar but high rate of alpha-gal sensitization in patients with EoE as found in non-EoE controls who were undergoing endoscopy. While our data do not support alpha-gal sensitization as a risk factor for EoE, the high rates of sensitization observed in patients undergoing upper endoscopy for symptoms of esophageal dysfunction is a new finding.

Eosinophilic oesophagitis: relationship of quality of life with clinical, endoscopic and histological activity.

BACKGROUND: Knowledge about determinants of quality of life (QoL) in eosinophilic oesophagitis (EoO) patients helps to identify patients at risk of experiencing poor QoL and to tailor therapeutic interventions accordingly. AIM: To evaluate the impact of symptom severity, endoscopic and histological activity on EoE-specific QoL in adult EoE patients. METHODS: Ninety-eight adult EoE patients were prospectively included (64% male, median age 39 years). Patients completed two validated instruments to assess EoE-specific QoL (EoO-QoL-A) and symptom severity (adult EoE activity index patient-reported outcome) and then underwent esophagogastroduodenoscopy with biopsy sampling. Physicians reported standardised information on EoE-associated endoscopic and histological alterations. The Spearman's rank correlation coefficient was calculated to determine the relationship between QoL and symptom severity. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms, endoscopic and histological findings explain variations in QoL. RESULTS: Quality of life strongly correlated with symptom severity (r = 0.610, P < 0.001). While the variation in severity of symptoms, endoscopic and histological findings alone explained 38%, 35% and 22% of the variability in EoE-related QoL, respectively, these together explained 60% of variation. Symptom severity explained 18-35% of the variation in each of the five QoL subscale scores. CONCLUSIONS: Eosinophilic oesophagitis symptom severity and biological disease activity determine QoL in adult patients with eosinophilic oesophagitis. Therefore, reduction in both eosinophilic oesophagitis symptoms as well as biological disease activity is essential for improvement of QoL in adult patients. Clinicaltrials.gov number, NCT00939263.

Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.

BACKGROUND: Seasonal variation has been reported in diagnosis of eosinophilic oesophagitis (EoE), but results are not consistent across studies and there are no national-level data in the USA. AIM: To determine if there is seasonal variation in diagnosis of oesophageal eosinophilia and EoE in the USA, while accounting for factors such as climate zone and geographic variation. METHODS: This was a cross-sectional study using a USA national pathology database. Patients with oesophageal eosinophilia (≥15 eosinophils per high-power field) comprised the primary case definition and were compared to those with normal oesophageal biopsies. We calculated the crude and adjusted odds of oesophageal eosinophilia by season, as well as by day of the year. Sensitivity analyses were performed using more restrictive case definitions of EoE, and after stratification by climate zone. RESULTS: Exactly, 14 524 cases with oesophageal eosinophilia and 90 459 normal controls were analysed. The adjusted odds of oesophageal eosinophilia were higher in the late spring and summer months, with the highest odds in July (aOR: 1.13; 95% CI: 1.03-1.24). These findings persisted with increasing levels of oesophageal eosinophilia, as well as across EoE case definitions. Seasonal variation was strongest in temperate and cold climates, and peak diagnosis varied by climate zone. CONCLUSIONS: There is a mild but consistent seasonal variation in the diagnosis of oesophageal eosinophilia and EoE, with cases more frequently diagnosed during summer months. These findings take into account climate and geographic differences, suggesting that aeroallergens may contribute to disease development or flare.