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

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.

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Sign in Hood River, OR

 

What’s Going On in Patients with Reflux Who Fail Proton Pump Inhibitors

A recent prospective study (J Abdallah et al. Clin Gastroenterol Hepatol 2019; 17: 1073-80) examined adults patients with documented reflux at baseline.  Patients who reported heartburn and/or regurgitation at least twice a week for 3 months (n=16) despite proton pump inhibitor (PPI) therapy were considered PPI failures. Those (n=13) who responded to standard dose PPI for at least 4 weeks were in the “PPI success” group.

Standard PPI dosing in this study:

  • Omeprazole 20 mg per day
  • Esomeprazole 40 mg per day
  • Pantoprazole 40 mg per day

Methods: Both groups (PPI Failure group, PPI Success group) underwent EGD and pH-MII studies. Abnormal acid exposure was considered if pH <4 was present for >4.2%.

Key findings:

  • 12 patients (75%) in the PPI failure group had either functional heartburn or reflux hypersensitivity
  • 4 patients in both groups had abnormal pH test result.
  • There was no statistically significant differences in the number of reflux events, acid exposure or nonacid reflux parameters between patients who failed or those who were successfully treated with PPIs.
  • In the PPI failure group: 25% had persistent GERD, 12.% had overlap with reflux hypersensitivity, and 62.5% had overlap with functional heartburn

My take: The difference between PPI failure and PPI success largely is due to the overlapping presence of functional esophageal disorders.

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Royal Palace, Madrid

How Important Are Proton Pump Inhibitors for Intensive Care Patients?

A recent randomized, blinded study (M Krag et al. NEJM 2018; 379: 2199-2208, editorial 2263-4) describes the use of proton pump inhibitor (PPI) therapy in adults (n=3298) in the ICU at high risk for gastrointestinal bleeding. High risk features included liver disease, coagulopathy, shock, anticoagulant therapy, renal replacement treatment, and mechanical ventilation.

Key findings:

  • Stress-ulcer bleeding may be less prevalent than in the past, perhaps due to improved ICU care. GI bleeding occurred in 4.2% of placebo-treated patients compared to 2.5% of pantoprazole-treated patients
  • Overall outcomes were essentially identical. At 90 days, 510 patients (31.1%) in the pantoprazole group and 49 (30.4%) in the placebo group had died (RR 1.02).
  • Using a composite event score to weight potential good and adverse effects (eg C diff infection, myocardial infarction, bleeding, pneumonia) of PPI therapy, the authors found that this occurred in 21.9% of pantoprazole group compared with 22.6% of placebo group (22.6%).

Reduction in GI bleeding could be related in part to the more frequent use of enteral feedings.  And, the combination of enteral feeding with the use of PPI treatment may increase the risk of pneumonia.

In the associated commentary, the authors note that “prophylaxis with a PPI, if initiated, should be reserved for seriously ill patients who are at high risk for this complication.” They acknowledge a lack of a uniform definition of high risk and the “admittedly small (1.7%) difference in bleeding rates.”

 

Updated Consensus Guidelines for Eosinophilic Esophagitis

Full text: ES Dellon, CA Liacouras,  J Molina-Infante, GT Furuta et al. Gastroenterol 2018; 155: 1022-33.

This article provides a thorough review of EoE -including clinical features, differential diagnosis, diagnostic criteria, and treatments.

Key point: “The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.”

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Which Proton Pump Inhibitor is the Most Potent?

A recent study (DY Graham, A Tansel. Clin Gastroenterol Hepatol 2018; 16: 800-808) analyzed 56 randomized trials to determine relative potency of proton pump inhibitors (PPIs) based on time in which intragastric pH was 4 or less (pH4time).

Key findings:

  • Pantoprazole 20 mg was equivalent to 4.5 mg of omeprazole
  • Lansoprazole 15 mg was equivalent to 13.5 mg of omeprazole
  • Esomeprazole 20 mg was equivalent to 32 mg of omeprazole
  • Rabeprazole 20 mg was equivalent to 36 mg of omeprazole

The authors note that peak effectiveness for PPIs was at ‘approximately 70 mg of omeprazole equivalents’.  In addition, they state that twice a day dosing was more effective than increasing once a day dosing; however, three times a day dosing was not more effective than twice a day. “Dexlansoprazole, a quasi-twice-a-day formulation produced similar acid suppression to the lowest twice-daily PPI regimen and 20 mg vonoprazan once daily provided similar efficacy aas high-dose twice-daily PPI.” The authors also compare costs; generics of pantoprazole, omeprazole, and esomeprazole cost as little as $0.02-0.04 per omeprazole equivalent.  Thus, 20 mg of omeprazole would be as little as 40 cents.

My take: Using the lowest effective dose of a PPI is recommended.  In patients needing higher dosing or with suboptimal response to acid suppression, this data can be very helpful.

 

Proctor Creek Trail

PPIs NOT Linked to Cognitive Decline/Dementia & PPIs NOT Linked to Heart Attacks

In a prospective study (M Wod et al. Clin Gastroenterol Hepatol 2018; 16: 681-89), data on middle-aged (n=2346, 46-67 yrs) and older individuals (n=2475) were collected in the Longitudinal Study of Aging Danish Twins.  This study showed that there was no difference in cognitive decline between PPI users and non-users.

The second study (SN Landi et al. Gastroenterol 2018; 154: 861-73) used a large administrative database and reviewed more than 5 million new  users of prescription PPIs and prescription H2RAs.  The authors found no significant difference in myocardial infarctions (MIs) between PPIs and H2RAs over a 12 month period.

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