Q&A: STAT6 variants linked to relapse of EoE in children who undergo PPI therapy
STAT6 gene variants correlated with relapse of eosinophilic esophagitis in children who are treated with proton pump inhibitor therapy, according to a study published in Clinical Gastroenterology and Hepatology.
Healio Gastroenterology spoke with James P. Franciosi, MD, from Nemours Children's Health System and the University of Central Florida College of Medicine about the recent study on the STAT6 variants in children who undergo PPI therapy for EoE.
Healio: What was the purpose of the study?
Franciosi: There is a condition in children and adults called EoE where there's an increase of inflammatory cells called eosinophils in the esophagus that causes children and adults to have trouble swallowing as well as experiencing various other gastrointestinal symptoms. There are certain medications and therapies that work for some patients but not for others. We wanted to see how we could use a patients’ genetics to better understand who responds to various medications. Currently, we are studying children who are taking proton pump inhibitor medications or PPIs. PPIs are anti-secretory medications that people typically take for heartburn and acid reflux and sometimes for ulcers and so forth. PPIs have been used with variable success to treat EoE.
Healio: What was the design of the study?
Franciosi: Edward Mougey, PhD, and myself have collaborated over the past few years with several of our colleagues from Spain who have really taken an interest and a passion in treating children with EoE with PPI medications. They have identified one of the largest groups of well characterized children with EoE treated with PPIs and have been following them prospectively. Our first study was actually in 2019 and included a little over 90 patients who received high-dose PPI therapy for 8-weeks. In that study patients had close to a 70% response rate to PPI for EoE and we found that there were genetic variants in the STAT6 gene that associated with outcome at 8-weeks. Next, we wanted to see what dosage of PPI medicine is needed to keep patients in remission long-term. Responders (70 patients) of the initial high-dose study were subsequently stepped down to low-dose PPI therapy and were followed for an additional year. At the end of one year, two-thirds of the children remained in EoE remission while one third relapsed to EoE.
We found that the same STAT6 genetic variants that predicted outcome of PPI therapy over the initial 8-week high-dose PPI therapy were also associated with outcomes following 1 year of low-dose PPI maintenance therapy. This makes sense because STAT6 is known to be a key regulator in allergic and autoimmune conditions and there has been other work that shows that PPIs are able to block the pathway through which STAT6 enhances inflammation. We’re trying to figure out if we can predict which children may respond in the short term and then in the long term based on genetic variations. We found some very strong associations with several different variants of STAT6. That was a very exciting finding for us.
Healio: What is the take-home message?
Franciosi: That genetic variation in the STAT6 gene can associate with a relapse of EoE in children receiving PPI medication therapy.
Healio: What is the next step in research?
Franciosi: We want to determine the best dose of PPI to treat EoE children for both short and long term therapy. We would love to develop a bedside test where children get a cheek swab and based on their genetic profile, we identify which PPI medication at what dosage would be the best choice to maximize response. Conversely, we may find that based on the child’s genetic profile, PPIs may not be a good fit and we should consider other medications. We're very excited to take this work to the next level and consider additional genetic variations in genes other than STAT6 to make sure that we're accounting for all genetic variations that predict outcome of PPI therapy for EoE. Eventually this model will allow us to predict how kids are going to respond to PPI medication, not only in the short-term but also in the long-run.
PPI medications do have an effect for EoE, but that effect is highly variable between children. In the United States, clinicians typically see a 30% response rate to PPI therapy for EoE while our colleagues from Spain see a 66% response rate. That is why we entered into the collaboration with our colleagues from Spain to see how they get the PPI medications to work successfully in a systematic way. They use a high dose of medication consistently which appears to be an important factor, but in addition to that, we have clearly shown that there is genetic variation in STAT6 that also associates with response to PPI therapy. We’re very excited to apply these observations to other cohorts of patients, world-wide. Currently, we are looking forward to expanding these collaborations nationally in the United States, and also internationally. In the future the long-term goal is to compare genotype guided PPI medication dosing vs. conventional dosing.