More “LIGHT” in Understanding Eosinophilic Esophagitis

Briefly noted: MC Manresa et al. Gastroenterol 2020; 159: 1778-1792. Full text: Increased Production of LIGHT by T Cells in Eosinophilic Esophagitis Promotes Differentiation of Esophageal Fibroblasts Toward an Inflammatory Phenotype

The authors investigated the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE.

Key findings:

  • LIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals
  • Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription

My take: The authors show that patients with EoE had proinflammatory fibroblasts in the epithelium. Further, they show that eosinophil-fibroblast interaction was dependent on intact LIGHT signaling.

Related blog posts:

Using FLIP

A recent review article (E Sararino et al. Am J Gastroenterol 2020; 115: 1786-06. Use of the Functional Lumen Imaging Probe in Clinical Esophagology) is a terrific article for understanding Functional Lumen Imaging Probe (FLIP) techonology and uses. Thanks to Ben Gold for this reference.

Link to patient explanation of EndoFLIP at Univ Michigan

The FLIP “measures luminal cross sectional area (CSA) and pressure in the esophagus using impedance planimetry and serves as an adjunct to existing esophageal investigative tests. A distensible balloon encasing a catheter with multiple pairs of impedance electrodes is used, and the balloon is distended with fluid of known conductivity and volume.”

FLIP can be done at time of endoscopy.

  • Distensibility index (DI). This is the ratio of EGJ cross sectional area to intraballoon pressure is generally considered the most useful FLIP metric. Normal DI values in adults range from 3.1 to 9.0 m3/mm Hg. Lower values indicated reduced EGJ opening.
  • FLIP can complement the diagnosis of achalasia when manometry and barium studies are inconclusive or negative in patients with typical symptoms.
  • FLIP can be used to assess fibrostenotic remodeling of the esophagus in eosinophilic esophagitis.
  • Lumen diameter measured using FLIP in complex strictures can potentially guide management.

This review has several helpful figures to illustrate the type of visual data available. It also provides a standard protocol for using FLIP. The current limitations for FLIP include the lack of real-time software analysis of the data which hinders reporting, and limited data supporting use.

Related blog post: #NAASPGHAN17 Eosinophilic Esophagitis Session

While this picture makes me look like a scofflaw, in fact one can sit on the sand below the median high tide mark. So there!

New Treatment for Eosinophilic Gastritis and Duodenitis

ES Dellon et al. NEJM 2020; 383: 1624-1634. Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis

Background: AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells.

Methods: In this phase 2 trial, the authors randomly assigned adults (n=65) who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo

Key findings:

  • The mean percentage change in gastrointestinal eosinophil count was −86% in the combined AK002 group, as compared with 9% in the placebo group
  • Treatment response  (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo
  • The authors note that AK002 “also resulted in alleviation of dysphagia in patients with a history of concomitant eosinophilic esophagitis.”
  • Limitations: Small study and 10% developed antibodies to drug

My take: Larger phase 3 studies with AK002 are underway (NCT04322604 & NCT04322708). AK002 looks promising for eosinophilic gastrointestinal diseases.

Change in total symptom score over 14 weeks. “Shown is the least-squares mean percentage change from baseline in total symptom score over time.” The total symptom score ranges from 0 to 80, with higher scores indicating greater symptom severity. Each of eight symptoms are given a score of 0 to 10: abdominal pain, nausea, vomiting, early satiety, loss of appetite, abdominal cramping, bloating and diarrhea.

Related blog posts:

Eosinophilic Esophagitis -FAQs

A recent FAQ on Eosinophilic Esophagitis  Ronak Patel, MD  Ikuo Hirano, MD, AGAF: Full Text -GIHepNews (August 2020) Eosinophilic esophagitis: Frequently asked questions (and answers) for the early-career gastroenterologist

One aspect about this review that I liked was the dietary step-up –step-down therapy figure:

Reference: J Molina-Infante et al. J Allergy and Clincal Immunology. DOI:https://doi.org/10.1016/j.jaci.2017.08.038 Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study Results:  A TFGED (2-food) achieved EoE remission in 56 (43%) patients, with no differences between ages. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%), and both (28%). EoE induced only by milk was present in 18% and 33% of adults and children, respectively. Remission rates with FFGEDs (4-food) and SFGEDs (6-food) were 60% and 79%, with increasing food triggers, especially after an SFGED. Overall, 55 (91.6%) of 60 of the TFGED/FFGED responders had 1 or 2 food triggers. Compared with the initial SFGED, a step-up strategy reduced endoscopic procedures and diagnostic process time by 20%.

Related blog posts:

New 2020 Eosinophilic Esophagitis Guidelines

Full text (I Hirano et al. Gastroenterol 2020; 158: 1776-86)AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis

Full text: PDF

This guideline was developed through a collaboration between AGA and the Joint Task Force for Allergy-Immunology Practice Parameters, which comprises the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology. This guideline is jointly published in Gastroenterology and Annals of Allergy, Asthma and Immunology.

Technical review article (MA Rank et al. Gastroenterol 2020; 158: 1789-1810): Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters

 

Link: Clinical Decision Support Tool

Link: Treatment of EoE Spotlight Poster

Related blog posts:

Could Immunotherapy (EPIT) Work For Eosinophilic Esophagitis? & Coronavirus Up-to-Date Tally

A recent double-blind pilot study (n=20) (JM Spegel et al. Clin Gastroenterol Hepatol 2020; 18: 328-36) explored the use of epicutaneous immunotherapy (EPIT) in children with milk-induced eosinophilic esophagitis (EoE). 15 children received active treatment with a “Viaskin” milk allergen extract patch and 5 children received a placebo.

The premise of EPIT for EoE has been based on animal models (mouse & piglet) which have shown that epicutaneous desensitization to peanuts has been successful in preventing development of EoE.

The design of the study involved EPIT during a 9 month milk-free period followed by a milk-containing diet for 2 months.  Biopsies were taken and then there was an additional 11 month open-label phase in which all patients received EPIT.

Key findings:

  • No significant differences in mean eos/hpf in the two groups: 50 vs 48 in EPIT compared to placebo respectively.
  • There were 9 of 19 (47%) had a significant drop in eosinophil count with less than 15 eos/hpf at the end of the open-label phase.
  • Overall, adverse events were similar in both groups, though the EPIT group had more frequent GI adverse events than the placebo group (67% vs. 40%)

My take: The primary and secondary endpoints were not reached in this study.  However, based on the open-label phase response, further studies are warranted.

Related blog posts:

Also, from Johns Hopkins: COVID19 Caseload & Outcomes Worldwide

This screenshot was taken at 2:53 pm on 3/7/20

 

New Therapy for Eosinophilic Esophagitis

In a report (I Hirano, ES Dellon et al. Gastroenterol 2020; 158: 111-22) on a phase 2 trial with 47 adults, the authors show that weekly subcutaneous injections of dupilumab (300 mg) was associated with improvement in eosionophilic esophagitis.

Dupilumab, a fully human monoclonal antibody, antagonizes the interleukin-4 receptor-alpha component of the type 2 receptor, thereby inhibiting signaling of IL-4 and IL-13. Dupilumab has shown “efficacy in pediatric and adult atopic dermatitis, asthma, and chronic sinusitis with nasal polyposis” and is FDA-approved for use in these disorders.

Key findings:

  • Dupilumab was associated with improvement in dysphagia as measured by the Straumann Dysphagia Instrument with a mean reduction of 3.0 compared to 1.3 in the placebo group at week 10 (P=.0304)
  • Dupilumab was associated with improvement in histology, at week 12, the peak eosinophil count had dropped by a mean of 86.8 (P<.0001 vs. placebo)
  • Dupilumab was associated with improvement in endoscopic parameters as assessed by endoscopic reference score which dropped by 1.6 (P -.0006 vs placebo)
  • No serious adverse effects were evident.  Nasopharyngitis was noted in 17% in the dupilumab group compared to 4% of placebo-treated patients.  Injection site erythema was noted in 35% (vs. 8% in placebo group

Of note, the study was sponsored by pharmaceutical companies and many of the authors (including both lead authors) were either affiliated with these companies.

My take: This study indicates that Dupilumab has at least short term efficacy and safety for eosinophilic esophagitis.

Related blog posts:

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How Genetics Influence Response to PPIs in Eosinophilic Esophagitis

About two years ago, James Franciosi presented research at NASPGHAN meeting indicating that the main difference between children with eosiniophilic esophagitis (EoE) who respond to proton pump inhibitiors (PPIs) compared to those who do not was related to their metabolism of PPIs and not related to the nature of their underlying EoE.

Related blog: #NASPGHAN17 Eosionophilic Esophagitis Session

Now, more has been published on this topic: EB Mougey et al. JPGN 2019; 69: 581-7.

In this study with 92 patients, data was collected from participants in a prospective clinical trial of high-dose PPI for EoE.

Key findings:

  • 57 (62%) were responsive to PPIs and 35 (38%) were not responsive to PPIs
  • Carriage of STAT6 allele variant rs1059513 predicted responsiveness to PPIs with OR of 6.16
  • Carriage of STAT6 rs324011 synergizes with CYP2C19*17 to predict PPI-nonresponsive EoE

Discussion: 

  • Carriers of CYP2C19*17 are more likely to fail PPIs for EoE.  Children with CYP2C19*17 gain of function “have a 7.7 fold better odds of failing PPI therapy” than noncarriers.
  • CYP2C19*17 effects “appears to be exerted within a specific range of PPI doses…and does not appear to exert influence at the low and high ends of this dose range.”
  • STAT6, which in this study is a cofactor, “upregulates transcription of CCL26 (eostaxin-3) 53-fold in esophageal eosinophilia relative to levels in peptic esophagitis and 490-fold over levels found in normal esophageal biopsies.”
  • PPIs effectiveness “does not correlate with esophageal” acid exposure; thus, its effects are mediated via an anti-inflammatory mechanism.

My take: This study indicates that genotype-guided dosing of PPIs for the treatment of EoE is likely to be worthwhile.

 

View from Yonah Mountain, GA

Grading Treatment Response in Eosinophilic Esophagitis

Full Text Link: A Conceptual Approach to Understanding Treatment Response in Eosinophilic Esophagitis

Also, related articles:

  1. D Bushyhead et al. Gastroenterology 2019; 157: 944-5. This practical teaching case report noted that oral immunotherapy (OIT) has been shown to trigger new onset EoE in 2.7% (AJ Lucendo et al. Ann Allergy Asthma Immunol 2014; 113: 624-9).
  2. R Alexander et al. Clin Gastroenterol Hepatol 2019; 17: 2371-3. This study compared eating behaviors of adults with active EoE (n=10), inactive EoE (n=10) and control patients (n=10).  Not surprisingly, those with active EoE took longer to eat (18.3 min compared to 12.4 min, and 13.0 min respectively) and had more drinks after a single bite (11.6 compared with 5.1 and 2.5 respectively)

Related blog posts:

#NASPGHAN19 Selected Abstracts (Part 1)

Link to full NASPGHAN 2019 Abstracts.

Here are some abstracts that I found interesting at this year’s NASPGHAN meeting:

NAFLD:

  1. Off-label use of topiramate may be helpful in stabilizing weight and improving NAFLD
  2. Socioeconomic barriers are frequent in NAFLD patients (the 2nd poster did not appear to show a control population):

Primary Sclerosing Cholangitis -Use of Vedolizumab for PSC did not appear to help

Eosinophilic Esophagitis

  1. EoE is four times more likely in this cohort with inflammatory bowel disease
  2. 2nd poster describes very early-onset EoE

Inflammatory Bowel Disease:

  1. Use of infliximab in VEO IBD.  Used in 46/122 (38% of patients) and 50% had persistent use 3 years later

Enteral nutrition –poster from our group describing good tolerance of plant-based formula (with Ana Ramirez).

Celiac disease.  This poster indicates low yield of additional serology for celiac disease besides TTG IgA and serum IgA. This includes testing in young patients (< 2 years) with celiac disease.