Genetic Basis of Eosinophilic Esophagitis

Cincinnati Children’s Research Horizons: Two Genes Associated with Familial EoE

Researchers (first author Tetsuo Shodaand senior author Marc Rothenberg) at “Cincinnati Children’s have identified two rare gene variants associated with inherited forms of eosinophilic esophagitis (EoE) that may also play roles as acquired mutations among the larger population of people with non-familial EoE.”  

Citation of article: Shoda, T., Kaufman, K.M., Wen, T. et al. Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis. Nat Commun 12, 6795 (2021). https://doi.org/10.1038/s41467-021-26939-9

The findings regarding the genes desmoplakin (DSP) and periplakin (PPL) were published Nov. 23, 2021 in Nature Communications (Link to article: Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis). “The proteins generated by these genes are found in the epithelial layer of the esophagus amid structures called desmosomes that help bind cells together. These variants of DSP and PPL appear to weaken the epithelial barrier, making the tissue more prone to damage from inflammation-causing eosinophils.”

Methods: Using whole-genome sequencing, the researchers discovered the variants among five members of a family that had multiple generations of members with EoE.  The team tested another 61 families with familial EoE and found 13 having either the DSP or PPL variants.

Key Findings:

  • The authors “estimate that these gene variants account for about 21% of patients with familial EoE”
  • “A series of functional analyses using an organotypic-like ALI culture system demonstrated that modulating wild-type DSP and PPL expression in vitro was functionally sufficient to induce changes in epithelial integrity (e.g., acantholysis) and barrier impairment, processes that are dysregulated in EoE”
  • DSP and PPL loss occurs in non-familial EoE, substantiating that the pathway identified initially by rare familial EoE cases is broadly applicable to familial and non-familial EoE”

My take:

  1. This article provides data showing that genetic alterations affecting the epithelial barrier are important in the pathophysiology of EoE.
  2. Often EoE is compared to eczema. This finding of altered epithelial barrier is analogous to eczema where many cases are due to a mutation in a protein called filaggrin, which is important in reducing the gap between skin cells (related blog: Eczema Rarely Linked to Food Allergy).

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Frequency of Strictures in Pediatric Eosinophilic Esophagitis

D Burnett et al. JPGN Reports 2021; Free Access: Incidence of Pediatric Eosinophilic Esophagitis and Characterization of the Stricturing Phenotype in Alberta, Canada doi: 10.1097/PG9.0000000000000136

This retrospective study (2015-2018) identified 185 new cases of eosinophilic esophagitis (EoE).

Key findings:

  • Eight of 185 (4%) patients had endoscopically confirmed esophageal strictures, 4 of which required mechanical dilation. (The authors note a Dutch study which demonstrated a 14% stricture rate)
  • Eleven of 185 (5.9%) patients had more subtle signs of esophageal narrowing, but no focal strictures
  • Pain was reported after 15% of all scopes, including 50% of the 28 scopes with focal strictures
  • For patients <15 years old living in Edmonton, the incidence over the 4 years was 11.1 cases per 100,000 person years
  • EoE was more common in urban setting: incidence 10.6 versus 4.1 per 100,000 person-years, respectively

My take: This article provides useful data on the likelihood of stricturing EoE in the pediatric population in an area with a high incidence of EoE.

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“Esophageal Hypervigilance” and Outcomes in Eosinophilic Esophagitis

TH Taft et al. Gastroenterol 2021; 161: 1133-1144. Open Access: Esophageal Hypervigilance and Symptom-Specific Anxiety in Patients with Eosinophilic Esophagitis

Commentary: RD Naik, DA Patel. Gastroenterol 2021; 161: 1099-1110. Open Access: Unlocking the Mind Might Be Critical in Management of Eosinophilic Esophagitis: Expanding Beyond Drugs, Dilation, and Diet

Taft et al performed a retrospective study of 103 adult patients with eosinophilic esophagitis. Patients completed the following questionnaires immediately before to endoscopy:

  • Esophageal Hypervigilance and Anxiety Scale (EHAS)
  • Brief Esophageal Dysphagia Questionnaire (BEDQ)
  • Eosinophilic Esophagitis Symptom Activity Index (EEsAI)
  • Northwestern Esophageal Quality of Life Scale (NEQOL).

Endoscopic severity of EoE was graded using the EoE Endoscopic Reference Score System (EREFS). Dysphagia was the primary symptom in 73% of the patients.

Key findings:

  • Patient’s symptom severity (via EEsAI or BEDQ) did not correlate with histology (distal or proximal peak eosinophil count), endoscopic severity of the disease (EREFS), or the distensibility index (measured via functional lumen imaging probe)
  • Symptom severity was correlated with the Esophageal Hypervigilance and Anxiety Scale (EHAS)
  • There was no correlation between EHAS and histologic activity, endoscopic severity (EREFS), or the presence of a stricture

The associated commentary emphasizes some of the study limitations including taking surveys prior to endoscopy (increased anxiety).

My take: This study indicates that with eosinophilic esophagitis, similar to other organic diseases (eg. IBD), patient symptoms do not always correlate with disease severity, and addressing the impact of anxiety and hypervigilance is critical, especially in refractory symptoms.

Figure 1 from commentary

Achalasia Frequent in Patients with Eosinophilic Esophagitis

M Ghisa et al. Clin Gastroenterol Hepatol 2021; 19: 1554-1563. Achalasia and Obstructive Motor Disorders Are Not Uncommon in Patients With Eosinophilic Esophagitis

In this study with 109 adults who were newly diagnosed with eosinophilic esophagitis (EoE), the authors consecutively performed high-resolution manometry (HRM). Key findings:

  • 68 (62%) had normal findings from HRM
  • 8 (7.3%) had achalasia (1 with type 1, 4 with type 2, and 3 with type 3)
  • 9 (8.3%) had major motor disorders of esophagus (& not achalasia) and 24 (15.6%) had minor motor disorders

These findings are important because the diagnosis of EoE could result in a diagnostic delay of concurring achalasia and because the presence of esophageal eosinophilia could perhaps play a role in the pathogenesis of achalasia (or vice versa). The finding of achalasia in 7.3% of this population is exponentially higher than the estimated prevalence of achalasia in the general population (10-16 cases per 100,000).

My take: In patients with EoE, further diagnostic workup is indicated if there are persistent symptoms.

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Watersound Beach, FL

Expecting Change in Eosinophilic Esophagitis Treatment

A recent study (EJ Laserna-Mendieta et al. Clin Gastroenterol Hepatol 2020; 18: 2903-2911. Full text: Efficacy of Therapy for Eosinophilic Esophagitis in Real-World Practice) highlights the disconnect between clinical practice and outcomes.

  • Methods: This study relied on the multicenter EoE CONNECT database—with 589 patients.
    • Clinical remission was < 50% in Dysphagia Symptom Score; any improvement in symptoms = clinical response.
    • Histologic remission was eosinophil count below 5 eosinophils/hpf; 5-14/hpf = histologic response.

Key findings:

  • Topical steroids were most effective in inducing histologic remission: 54.8% compared to 36.1% for PPIs and 18.5% for empiric elimination diet; histologic remission and response was 67.7%, 49.7%, and 48.1% respectively.
  • Topical steroids were most effective in inducing clinical and histologic remission or response (in 67.7% of patients), followed by empiric elimination diets (in 52.0%), and PPIs (in 50.2%).
  • However, PPIs were the first-line treatment for 76.4% of patients, followed by topical steroids (for 10.5%) and elimination diets (for 7.8%).

My take: This data (and others) indicate that topical steroids are most effective pharmacologic therapy; at some point, I expect that they will become the most frequently used.

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“Layering two less specialized masks on top of each other can provide comparable protection [to N95]. Dr. Marr recommended wearing face-hugging cloth masks over surgical masks, which tend to be made with more filter-friendly materials but fit more loosely. An alternative is to wear a cloth mask with a pocket that can be stuffed with filter material, like the kind found in vacuum bags.”

Unrelated from NY Times: One Mask Is Good. Would Two Be Better? (Yes)

Most Popular 2020 Posts

I want to thank all of you who take an interest in my blog, particularly those who give suggestions, references, and encouragement. The following posts were the most popular from the past year.

Related post: Favorite Posts of 2020

Sandy Springs at Sunrise

Budesonide for Maintaining EoE Remission

A Straumann et al. Gastroenterology 2020; Free Full Text Link: Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis

Methods: Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given budesonide orodispersible tablet (BOT) 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks

Key Findings:

  • At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo)
  • Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment

In the discussion, the authors state that “we recommend monitoring symptoms and signs of adrenal insufficiency when administrating topical-acting corticosteroids over prolonged time periods, in particular in children and when using higher dosages.”

My take (from discussion): “EoE requires a proper long-term anti-inflammatory therapy because, without active treatment, the vast majority of patients experience a relapse within the first 100 days after cessation of the medication.”

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How Effective Are PPIs for Eosinophilic Esophagitis?

Emilio J. Laserna‐Mendieta et al. AP&T 2020; https://doi.org/10.1111/apt.15957.  Full article link: Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry

“This cross‐sectional study collected data on PPI efficacy from the multicentre EoE CONNECT database.” Overall, 630 patients (76 children) received PPI as initial therapy (n = 600) or after failure to respond to other therapies (n = 30)

Key findings:

  • PPI therapy achieved eosinophil density below 15 eosinophils per high‐power field in 48.8% and a decreased symptom score ≥50% from baseline in 71.0% of patients.
  • More EoE patients with an inflammatory rather than stricturing phenotype accomplished clinico‐histological remission after PPI therapy (OR 3.7; 95% CI, 1.4‐9.5)
  • PPI treatment is more effective in achieving clinico‐histological remission of the disease when used in higher instead of standard or lower doses (50.8% vs 35.8%), and when the duration of therapy is prolonged from 8 to 12 weeks (50.4% vs. 65.2%)

My take: This study confirms previous studies which have generally found that PPIs are effective in 40-50% of patients with eosinophilic esophagitis.  Higher doses of PPIs are needed to achieve the highest response rates.

“Bar chart for histological (A) and symptomatic (B) responses for proton pump inhibitor (PPI) mono‐therapy to induce and maintain remission in patients with eosinophilic oesophagitis. For induction of remission, patients were classified according to the PPI dosage prescribed: high dose was double dosage or higher, and low dose was standard dosage or lower. For maintenance therapy, only patients with dosage reduction from that used for induction were included. eos/hpf: eosinophils per high power field”

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Lingering Histologic Changes with Eosinophilic Esophagitis in Remission, Plus One

A recent study (KA Whelan et al. Clin Gastroenterol Hepatol 2020; 18: 1475-82) examined esophageal histology in 243 patients (mean age 16.9 years) in 3 groups: active eosinophilic esophagitis (EoE), inactive EoE (<15 eos/hpf), and a control non-EoE group.

Key findings:

Basal cell hyperplasia and spongiosis were present in 43 (29%) and 109 (74%) respectively of patients with inactive EoE. In comparison, these findings were present in 98% and 100% respectively of those with active EoE and in 6% and 33% of non-EoE patients

My take: This study provides some insight into the idea that esophageal damage may be ongoing in the absence of eosinophils.  These histologic findings could provide part of the reasons for symptoms in those who have had resolution of esophageal eosinophilia.

Related study: ES Dellon et al. Clin Gastroenterol Hepatol 2020; 18: 1483-92. This study showed rapid recurrence of eosinophilic esophagitis after discontinuation of topical steroids.  33/58  (57%) had symptom recurrence before 1 year (median time 244 for symptoms). At time of symptom recurrence, 78% had histologic relapse (≥15 eos/hpf).

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Phase 3 Trial of Budesonide for Eosinophilic Esophagitis & COVID-19 Deaths in U.S.

NY Times article:  U.S. Coronavirus Cases Are Rising Sharply, but Deaths Are Still Down

This article explains why deaths from COVID-19 have not increased despite increasing number of infections.  Three main reasons: increased testing -detects many with less severe symptoms, younger population are being infected, and new treatment approaches may be helping.  However, “the dip in coronavirus mortality will not necessarily last. As more people socialize, those with milder infections might end up ferrying the pathogen to vulnerable individuals…Recent upswings in coronavirus case numbers leave experts apprehensive of what’s to come. Death, when it occurs, tends to trail infection by about two to four weeks.”


The Budesonide Oral Suspension (BOS) resulted in 62% of BOS patients meeting the threshold of < 15 eos/hpf compared to 1% of placebo patients. From lead author, Ikuo Hirano: “the results of the BOS trial showed that BOS successfully treated both the symptoms and signs of EoE. The positive results will hopefully lead to an approved, safe and effective therapy for EoE.”

Abstract from ACG Meeting October 2019:

Abstract: Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results From a Phase 3, Randomized, Placebo-Controlled Trial

Introduction: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. 

Methods: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed.

Results: A total of 322 patients were randomized (BOS, n=215; placebo, n=107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n=213; placebo, n=105) (Table). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, p< 0.001; 52.6% vs 39.1%, p=0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n=197) than the placebo group (n=89) (−13.0 vs −9.1; p=0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n=202) than placebo (n=93) (−4.0 vs −2.2; p< 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo.  No life-threatening TEAEs were reported.

Discussion: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

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Island Ford, Sandy Springs