Society: AGA

Concomitant esophageal dysmotility can be present in up to 2/3 of patients with EoE and GERD. Esophageal dysmotility contribute to symptoms in these patients and can be a reason for a suboptimal response to therapy. Mechanisms for dysfunction of esophageal smooth muscle function in EoE and GERD have been studied in bench models of human esophageal tissues. Understanding and targeting these mechanisms therapeutically may improve symptomatic outcomes in what are otherwise considered mucosal esophageal diseases.

Background: Achalasia has been assumed to be an autoimmune disease that targets esophageal myenteric neurons. Recently, we proposed an alternative hypothesis that achalasia sometimes might be allergy-driven, caused by a form of eosinophilic esophagitis (EoE) in which activated eosinophils and/or mast cells infiltrating esophageal muscle release products that disrupt motility and damage myenteric neurons. To seek epidemiological support for this hypothesis, we identified achalasia patients in the Utah Population Database (UPDB), and explored their frequency of having EoE and other allergic disorders.
Methods: We used International Classification of Diseases (ICD) codes to identify patients with achalasia and allergic disorders including EoE, asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, hives/urticaria, and anaphylaxis. We validated our achalasia ICD code diagnostic accuracy by reviewing medical records of 100 randomly sampled patients in our database who had an ICD 9 or 10 diagnosis code for achalasia (validation review confirmed the diagnosis of achalasia by ICD codes in 87 of 100 cases). We calculated relative risk (RR) for each allergic disorder by comparing the number observed in achalasia patients to the expected number in control patients matched for birthyear and sex, and we performed sub-analyses for patients age ≤40 versus age >40 years.
Results: We identified a total of 844 achalasia patients for inclusion in our analyses (55% female, median age at diagnosis 58 years, Table 1). 355 (42%) had ≥1 allergic disorder(s), with contact dermatitis and asthma being the most frequent, affecting 24.5% and 23.9% of all achalasia patients, respectively. 64 achalasia patients had EoE, whereas only 1.17 EoE cases would have been expected (RR 54.5 [95% CI: 41.96-69.58], p<0.001), indicating a very strong association between the two disorders. 34 patients (54.8%) were diagnosed with achalasia and EoE during the same year, 14 (22.6%) were diagnosed with achalasia before EoE, and 14 (22.6%) were diagnosed with EoE before achalasia. The frequency of co-existing EoE was especially high in younger patients; in 208 achalasia patients age ≤40 years, the RR for EoE was 76.1 (95% CI 52.41-106.92, P<0.001). RR also was increased significantly for all other allergic disorders evaluated (all >3-fold above control, Table 2). Similarly increased rates of non-EoE allergic disorders were found in the younger and older achalasia patients with the exception of contact dermatitis, which occurred significantly more often in older patients (RR 4.77 [95% CI: 4.10-5.53]).
Conclusions: For patients in the UPDB, achalasia is strongly associated with EoE (~55-fold increased risk) and numerous other allergic disorders (all >3-fold increased risk).These data support the hypothesis that achalasia sometimes might have an allergic etiology.

Introduction:
Chronic inflammation in eosinophilic esophagitis (EoE) results in progressive, fibrostenotic remodeling of the esophageal wall and its consequences are more pronounced with longer symptom duration. Using objective measures with functional lumen imaging probe (FLIP), this study aimed to demonstrate the changes in esophageal distensibility relative to symptom duration of EoE disease, and evaluate clinical characteristics associated with progressive reduction in esophageal distensibility.
Methods:
A total of 171 adult patients with EoE (mean (SD) age 38 (12) years; 31% female) who completed a 16-cm FLIP protocol during endoscopy were evaluated in a cross-sectional study. FLIP analysis focused on distensibility plateau (DP) of the esophageal body. The duration (years) from onset of symptoms to time of endoscopy with FLIP was assessed via chart review for use as a surrogate of EoE disease duration.
Results:
The EoE cohort had a median symptom duration of (IQR) 8 (3-15) years. At the time of endoscopy with FLIP, there were 138 (81%) patients on EoE treatment (96 patients on only PPI, 17 on topical steroid, or 25 on elimination diet), of whom 54 (39%) were in histologic remission (<15 eosinophils/hpf). The median (IQR) duration since EoE diagnosis was 1 (0-4) years; 54 patients (32%) had EoE diagnosed at the endoscopy with FLIP. 64 patients (38%) had a previous esophageal dilation performed. Symptom duration was negatively correlated with DP (rho: -0.326, P<0.001). The DP differed across symptom duration strata (P<0.002) and abnormal DP (DP≤17mm) was significantly more frequent with increasing duration (P<0.004), Figure 1. When further stratifying the cohort based on mucosal eosinophil density, patients with active eosinophilia (≥15 eos/hpf) had significant differences reflecting lower DP with symptom duration (P=0.004), Figure 2A. However, among patients in histologic remission (<15 eos/hpf), there was not a significant difference by duration of symptoms (P=0.060). When stratifying the cohort based on previous dilation, significant differences in DP were detected among subgroups both with and without dilation relative to symptom duration (P=0.006 and 0.001), Figure 2B.
Conclusions:
Esophageal distensibility objectively measured with FLIP was reduced in EoE patients with greater symptom duration. This supports that EoE is a progressive, fibrostenotic disease but that this progression may be mitigated by effective anti-eosinophilic treatment.

<b>Figure 1. The association of esophageal distensibility plateau (DP) to EoE symptom duration. </b>In<b> B, </b>the data labels represent the number of patients.<br /> *Significant difference on pairwise comparison (after Bonferroni correction) with <5 year strata.

Figure 1. The association of esophageal distensibility plateau (DP) to EoE symptom duration. In B, the data labels represent the number of patients.
*Significant difference on pairwise comparison (after Bonferroni correction) with <5 year strata.

<br /> <b>Figure 2.</b> <b>Association of histologic response and previous dilation on esophageal distensibility over the EoE symptoms duration. </b>In A and B, markers (error bar) reflect group median (interquartile range).<br /> A) There were no differences among patients with <15 eos/hpf. *<sup>1 </sup>Significant difference on pairwise comparison (after Bonferroni correction) among patients with ≥15 eos/hpf. <br /> B) *<sup>2</sup> Significant difference on pairwise comparison (after Bonferroni correction) among patients with previous dilation (there no significant, post-hoc, pairwise comparisons among patients without previous dilation).

Figure 2. Association of histologic response and previous dilation on esophageal distensibility over the EoE symptoms duration. In A and B, markers (error bar) reflect group median (interquartile range).
A) There were no differences among patients with <15 eos/hpf. *¹Significant difference on pairwise comparison (after Bonferroni correction) among patients with ≥15 eos/hpf.
B) *² Significant difference on pairwise comparison (after Bonferroni correction) among patients with previous dilation (there no significant, post-hoc, pairwise comparisons among patients without previous dilation).

Isis K. Araujo

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