First Therapeutic Approval for Eosinophilic Esophagitis.
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ABSTRACT:
SUBMITTER: Al-Horani RA
PROVIDER: S-EPMC9364827 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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First Therapeutic Approval for Eosinophilic Esophagitis.
Al-Horani Rami A RA Chiles Raquel R
Gastroenterology insights 20220730 3
Eosinophilic esophagitis (EE) is a chronic, immune-mediated or antigen-mediated esophageal disease. Treatment for patients with EE can be challenging with no previously approved medications. Current management strategies follow the four D's paradigm of drugs, dietary elimination, dilation, and disease anxiety and hypervigilance therapy. On 20 May 2022, dupilumab was approved by FDA for EE. A dose of 300 mg dupilumab weekly significantly improved signs and symptoms of EE compared to placebo in a ...[more]
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Project description:ObjectiveTo review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Data sourcesPeer-reviewed articles on EoE from PubMed searching for "Eosinophilic Esophagitis and fibrosis" in the period of 1995 to 2013.Study selectionsStudies on the clinical and immunologic features, pathogenesis, and management of EoE.ResultsRecent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.ConclusionThe incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.
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Project description:When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid-based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti-IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti-type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus.
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Project description:Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation, whose incidence is rising. It significantly affects patients' quality of life and, if left untreated, results in fibrotic complications. Although broad consensus has been achieved on first-line therapy, a subset of patients remains non-responder to standard therapy. The pathogenesis of EoE is multifactorial and results from the complex, still mostly undefined, interaction between genetics and intrinsic factors, environment, and antigenic stimuli. A deep understanding of the pathophysiology of this disease is pivotal for the development of new therapies. This review provides a comprehensive description of the pathophysiology of EoE, starting from major pathogenic mechanisms (genetics, type 2 inflammation, epithelial barrier dysfunction, gastroesophageal reflux, allergens, infections and microbiota) and subsequently focusing on the single protagonists of type 2 inflammation (involved cells, cytokines, soluble effectors, surface proteins and transcription factors) that could represent present and future therapeutic targets, while summarizing previous therapeutic approaches in literature.
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Project description:ImportanceEosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disease of the esophagus that affects an estimated 34.4/100 000 people in Europe and North America. EoE affects both children and adults, and causes dysphagia, food impaction of the esophagus, and esophageal strictures.ObservationsEoE is defined by symptoms of esophageal dysfunction, such as vomiting, dysphagia, or feeding difficulties, in a patient with an esophageal biopsy demonstrating at least 15 eosinophils per high-power field in the absence of other conditions associated with esophageal eosinophilia such as gastroesophageal reflux disease or achalasia. Genetic factors and environmental factors, such as exposure to antibiotics early in life, are associated with EoE. Current therapies include proton pump inhibitors; topical steroid preparations, such as fluticasone and budesonide; dietary therapy with amino acid formula or empirical food elimination; and endoscopic dilation. In a systematic review of observational studies that included 1051 patients with EoE, proton pump inhibitor therapy was associated with a histologic response, defined as less than 15 eosinophils per high-power field on endoscopic biopsy, in 41.7% of patients, while placebo was associated with a 13.3% response rate. In a systematic review of 8 randomized trials of 437 patients with EoE, topical corticosteroid treatment was associated with histologic remission in 64.9% of patients compared with 13.3% for placebo. Patients with esophageal narrowing may require dilation. Objective assessment of therapeutic response typically requires endoscopy with biopsy.Conclusions and relevanceEoE has a prevalence of approximately 34.4/100 000 worldwide. Treatments consist of proton pump inhibitors, topical steroids, elemental diet, and empirical food elimination, with esophageal dilation reserved for patients with symptomatic esophageal narrowing.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-01 | E-GEOD-55795 | biostudies-arrayexpress
Project description:ObjectivesNo formal comparative effectiveness studies have been conducted to evaluate the effect of eosinophilic esophagitis (EoE) treatment choice on long-term growth in pediatric patients. Long-term studies of inhaled corticoid steroids in asthma, however, suggest possible effects on linear growth. The aim of this study was to compare longitudinal, anthropometric growth in children with EoE according to treatment approach.MethodsWe conducted a retrospective, multicenter cohort study of anthropometric growth (height and body mass index [BMI] z scores) in pediatric (<18 years of age) patients newly diagnosed with EoE across 5 clinical sites between 2005 and 2014. We compared differences in growth according to treatment approach over a 12-month period. Modification by sex and age was examined and sensitivity analyses were conducted to assess robustness of results given study assumptions.ResultsIn the 409 patients identified, the mean age and proportion male differed by treatment (P = < 0.01 and P = 0.04, respectively). Baseline growth measures were associated with slight impairment of height at diagnosis (median baseline height z score of -0.1 [interquartile range -0.9, 0.8]). In general, treatment approach was not associated with any significant increase or decrease in expected growth over a 12-month period. Subtle decrease in linear growth was observed with treatment using a combined elemental and topical steroid (Δ height z score [adjusted]: -0.04; 95% confidence interval [CI]: -0.08, -0.01). Differences in linear growth differed by sex (P for interaction <0.01). For elemental formula in combination with topical steroids, only girls exhibited a significant decline in linear growth (Δ height z score [adjusted]: -0.24; 95% CI: -0.32, -0.17). A slight reduction in BMI was observed for patients treated with a combination of elemental diet and dietary elimination (Δ BMI z score [adjusted]: -0.07; 95% CI: -0.13, -0.01).ConclusionsTreatment of EoE, in general, is not associated with major anthropometric growth changes in most pediatric patients. Slight linear growth impairment was observed for topical steroid treatment, and sex differences in growth by treatment approach were observed. Future prospective studies should evaluate the effect of treatment on optimal growth and development and over a longer period of follow-up.
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