I-SEE for Eosinophilic Esophagitis

ES Dellon et al Gastroenterol 2022; DOI: https://doi.org/10.1053/j.gastro.2022.03.025 Open Access: A Clinical Severity Index for Eosinophilic Esophagitis: Development, Consensus, and Future Directions “The Index of Severity for Eosinophilic Esophagitis (I-SEE)—that can be completed at routine clinic visits to assess disease severity using a point scale of 0–6 for mild, 7–14 for moderate, and ≥15 for severe EoE.”

From AGA: Eosinophilic Esophagitis Index

“The Index of Severity for EoE (I-SEE) is now available for you to use as a tool to help assess EoE patients. Developed by a multidisciplinary team of experts, the new tool is now published in Gastroenterology.

Details about I-SEE 

  • “The I-SEE has three domains: (1) symptoms and complications, (2) inflammatory features and (3) fibrostenotic.
  • I-SEE can be used at initial diagnosis and then at each subsequent visit, with the recall being only between visits so that the severity can be assessed over time and ultimately (when data supports this step) treatment and monitoring adjusted based on severity.
  • As the number of children and adults with EoE increases worldwide, a simple system to assess and track disease activity in a meaningful way in a clinical setting is needed.
  • I-SEE is for use in adult and pediatric patients with EoE. It was created by an international team of more than 30 experts in allergy, gastroenterology and pathology.”

Link: I-SEE Tool Scoring Table

Two Studies for Eosinophiles

ES Dellon et al. Clin Gastroenterol Hepatol 2022; 20: 535-545. Open Access: Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab

Key findings:

  • GI eosinophilia was patchy and that examination of multiple biopsies was required for diagnosis—an average of only 2.6 per 8 gastric biopsies and 2.2 per 4 duodenal biopsies per subject met thresholds for EG/EoD.
  • Evaluation of multiple nonoverlapping hpfs in each of 8 gastric and 4 duodenal biopsies was required to capture 100% of EG/EoD cases.

The 2nd article’s abstract was posted on this blog in July 2020 (Phase 3 Trial of Budesonide for Eosinophilic Esophagitis). Here is the published citation and graphical abstract:

I Hirano et al. Clin Gastroenterol Hepatol 2022; 20: 525-534. Open Access: Budesonide Oral Suspension Improves Outcomes in Patients With Eosinophilic Esophagitis: Results from a Phase 3 Trial

Maintenance Topical Steroid Dosing for Eosinophilic Esophagitis

T Greuter et al. Clin Gastroenterol Hepatol 2021; 19: 2514-2523. Open Access: Effectiveness and Safety of High- vs Low-Dose Swallowed Topical Steroids for Maintenance Treatment of Eosinophilic Esophagitis: A Multicenter Observational Study

In this multicenter, retrospective study with 82 participants (mean age 37 years), the authors examined swallowed topical corticosteroids (STC) for maintenance of histologic remission (<15 eos/hpf). Low dose STC (22 budesonide, 60 fluticasone) was considered 0.5 mg/day or less. Key findings:

  • Histological relapse occurred in 67% of patients. This rate was comparable in patients treated with low-dose (72%) and high-dose (54%) STCs.
  • Histological relapse occurred significantly earlier with low dose STC (1.0 vs 1.8 years, P = .030)
  • Esophageal candidiasis was identified in 6% of subjects

The authors conclude that most of the histological relapse that occurred was due to true steroid failure since “low adherence and treatment cessation during follow-up were exclusion criteria.” Also, they note that “the recently finished but not yet fully published Maintenance of Remission With Budesonide Orodispersible Tablets vs Placebo in Eosinophilic Eosphagitis (EOS2 trial) (NCT02493335) comparing budesonide maintenance doses of 2 mg/d vs 1 mg/d suggest that there is no additional benefit of daily doses higher than 1 mg (1-year remission rates of 75.0% and 73.5%, respectively).

My take: Low dose STCs do not appear to be as effective in maintaining histologic remission; however, there is a high rate of relapse even in those with higher doses.

Related blog posts:

Kaplan Meier curve for time to histological relapse in patients with deep
histological remission at baseline stratified by steroid dose groups

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).

Related blog posts:

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.

Related blog posts:

“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.

Related blog posts:

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.

Related blog posts:

“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.”

Related blog posts: