High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders

Abstract

Background: Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling.

Objective: We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs).

Methods: We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features.

Results: We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs.

Conclusion: There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.

Keywords: BMI; Body mass index; CCHMC; CTD; Cincinnati Children's Hospital Medical Center; Connective tissue disorder; EDS; EGID; EMR; Ehlers-Danlos syndrome; Electronic medical record; EoE; Eosinophilic esophagitis; Eosinophilic gastrointestinal disorder; FBN1; Fibrillin-1 gene; GERD; Gastroesophageal reflux disease; Informatics for Integrating Biology & the Bedside; JHS; Joint hypermobility syndrome; LDS; Loeys-Dietz syndrome; MFS; Marfan syndrome; PPI; Proton pump inhibitor; connective tissue disorders; eosinophil; eosinophilic gastrointestinal disease; hypermobility syndrome; i2b2.

FIG 1

Phenotypic and genotypic features of EoE-CTD. A, Typical facial features seen in 2 patients with EoE-CTD. B, Heat map from a large panel of differently regulated esophageal genes in patients with active EoE, patients with EoE-CTD, and control subjects (NL). C, Quantitative analysis of COL8A2, PTGFRN, SAMSN1, and CD200R1 by means of quantitative PCR, all of which are differentially expressed in patients with EoE versus patients with EoE-CTD. Data are graphed as means ± SEMs of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH)–normalized relative expression values. *P < .05, **P < .01, ***P < .001; EoE-CTD versus EoE; 2-tailed, unpaired t test.

FIG 2

Esophageal, gastric, and duodenal biopsy specimens from a patient with EoE-CTD. A, Numerous intraepithelial eosinophils (upper black arrows) align near the surface of this biopsy specimen. The basal epithelial layer is expanded, and intercellular spaces are dilated (lower black and white arrow). B, Lamina propria in this biopsy specimen from a different patient with EoE-CTD shows dense fibrosis (arrow). C, Numerous eosinophils are found in the lamina propria and epithelium (arrows) of this gastric biopsy specimen. D, Numerous eosinophils are found in the superficial lamina propria (arrow) and crypt epithelium (inset, arrow) of this duodenal biopsy specimen, which exhibits chronic architectural damage.

FIG 2

Esophageal, gastric, and duodenal biopsy specimens from a patient with EoE-CTD. A, Numerous intraepithelial eosinophils (upper black arrows) align near the surface of this biopsy specimen. The basal epithelial layer is expanded, and intercellular spaces are dilated (lower black and white arrow). B, Lamina propria in this biopsy specimen from a different patient with EoE-CTD shows dense fibrosis (arrow). C, Numerous eosinophils are found in the lamina propria and epithelium (arrows) of this gastric biopsy specimen. D, Numerous eosinophils are found in the superficial lamina propria (arrow) and crypt epithelium (inset, arrow) of this duodenal biopsy specimen, which exhibits chronic architectural damage.