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.

Esophagitis in Pediatric Esophageal Atresia

A recent study (JL Yasuda et al. JPGN 2019; 69: 163-70) shows that esophagitis is common with and without proton pump inhibitor (PPI) therapy in children with esophageal atresia (EA).

Background: This study encompassed 310 patients (34% long gap EA) and 576 endoscopies (median age 3.7 years)

Key findings:

  • Erosive esophagitis was found in 8.7% of patients.
  • 15.2% of patients had esophagitis with >15 eos/hpf; 49% of patients had ≥1 eos/hpf (histologic eosinophilia)
  • 87% of endoscopies were preceded by acid suppression therapy; being on acid suppression reduced the odds for abnormal esophageal biopsy (P=0.011).
  • Histologic esophagitis was “highly prevalent even with high rates of acid suppressive medications use.”
  • For example, among those receiving PPI monotherapy, 150 had normal biopsy and 136 had abnormal biopsy.  Among those off all acid suppression, 30 had normal biopsy and 45 had abnormal biopsy.
  • For erosive esophagitis, this occurred in 12 on PPI and was not present in 274 on PPI therapy. Among those off all acid suppression, 4 had erosive esophagitis and 70 did not.
  • Presence or integrity of fundoplication was not significantly associated with esophagitis.

While this is a large study, the findings have several limitations. This is a single center retrospective study and this center attracts highly complex cases of EA.

My take: In addition to fairly high rates of erosive esophagitis and eosinophilic esophagitis, this study shows a high incidence of microscopic esophagitis, the significance of this is unclear.   This study supports the current recommendations of 3 endoscopies in childhood and perhaps more frequent surveillance in those with more complex EA.

Related blog posts:

Sign in Hood River, OR

 

EoP –Biomarker or Balderdash?

One of the categories in the game of balderdash is abbreviations.  Someone with extra time on their hands should invent a medical version with obscure acronyms as one of the categories.

An acronym that I recently discovered, EoP, which stands for eosinophil progenitor came to my attention from Dr. Benjamin Enav and Dr. Oral Alpan. they suggested two articles (both letters to the editor) related to EoP as a biomarker for eosinophilic esophagitis:

  • DW Morris et al. J Allergy Clin Immunol 2016;138: 915-8.
  • JT Schwartz et al. J Allergy Clin Immunol 2019; 143: 1221-3.

Both of these articles came from researchers at the Cincinnati Children’s Hospital.  In the first, the authors studied 31 children (17 with active eosinophilic esophagitis [EoE], and 14 with inactive EoE).  Key findings:

  • With a cutoff of 15.5 EoPs/mL, there were none of the 17 patients with active EoE below this threshold and 8 of 14 (57%) with inactive EoE were below this threshold.
  • At this cutoff, this pilot study predicted active EoE with a sensitivity of 100%, specificity of 57%, positive predictive value of 74% and negative predictive value of 100%.

The second study, also with 31 children, showed that the peripheral blood EoP levels were significantly increased in patients with active disease and correlated with the
EoEHSS (EoE histologic scoring system) composite ratio.

My take: These studies show that a blood level of EoP is a promising biomarker which could help avoid endoscopy in those with low levels of EoP.

Related blog posts:

Dust Mites and Eosinophilic Esophagitis

Given seasonal fluctuation in the activity of eosinophilic esophagitis (EoE), aeroallergens have been considered a trigger in some patients.

Briefly noted: A recent study (A Ravi et al. Gastroenterol 2019; 157: 255-6, editorial 17) showed that dust mite antigen was present in esophageal biopsy specimens at a greater level in adult patients with EoE compared to controls.  With active EoE, patients had dust mite staining in 1.6% of the field which was significantly greater than patients with inactive EoE (0.7). The control group had a complete absence of epithelial dust mite staining.

The editorial (Seena Aceves) notes that these investigators have also shown gluten accumulation in the EoE esophagus.  Whether dust mite antigens or other specific postulated aeroallergens plays a causative role is unclear.  This study shows the presence of these antigens in the esophagus but does not show whether this is an epiphenomenon due to increased permeability or whether these antigens activate the local immune system.

A second study (T Patton et al. JPGN 2019; 69: e43-e48) describes the outcome of coexisting celiac disease and eosinophilic esophagitis in 22 children (from a cohort of 350 children with celiac disease. 17 had repeat biopsies.  Four of 17 (23.5%) had resolution of EoE with a gluten-free diet.  Related blog post: Is there a Link Between Eosinophilic Esophagitis and Celiac Disease?

Sagrada Familia, Barcelona

Head-to-Head: Budesonide vs Fluticasone for Eosinophilic Esophagitis

A recent double-blind, double-dummy study (ES Dellon et al. Gastroenterol 2019; 157: 65-73) found similar efficacy between budesonide and fluticasone for newly-diagnosed eosinophilic esophagitis. They had hypothesized that an oral viscous budesonide would be more effective due to increased esophageal contact time.

Methods: The authors compared an oral viscous budesonide OVB) at 1 mg BID (n=56) to fluticasone (swallowed) MDI dosed at 880 mcg BID (n=55).  Patients aged 16-80 years, with mean of 37 years.

Baseline characteristics:

  • ~95% in both groups with dysphagia
  • ~75% with any atopic condition
  • ~50% with dilatation required at baseline

Key findings:

  • Similar drop in eosinophil count: 73 (OVB) and 77 (MDI) eos/hpf at baseline to 15 and 21 respectively
  • Histologic response (<15 eos/hpf) rates of 71% (OVB) and 64% (MDI).
  • Response to <5 eos/hpf occurred in 61% OVB and 49% MDI; response to <1 eos/hpf was noted in 41% and 35% respectively
  • Symptom scores (DSQ) responded similarly as well
  • Similar degree of candidiasis 12% for OVB and 16% for MDI

In the associated editorial, the authors speculate that one reason for similar efficacy was the detailed instructions given for patients taking the MDI.

My take: This study supports both topical steroid therapies; practical issues like cost and insurance coverage could be influential in selecting the specific treatment for an individual patient.

Related blog posts:

 

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