Remodeling and Eosinophilic Esophagitis (EoE)

Description:

Co-host Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and co-host Holly Knotowicz, a speech-language pathologist living with EoE, who serves on APFED’s Health Sciences Advisory Council, speak with Dr. Amanda Muir, an Assistant Professor of Pediatrics at the Children’s Hospital of Philadelphia.

In this episode, Ryan and Holly interview Dr. Muir about tissue remodeling and eosinophilic esophagitis (EoE). Dr. Muir describes remodeling and stiffening, its effects, and how it relates to treatment and inflammation.

 

Listen in for information on remodeling and a pediatric study Dr. Muir is planning.

Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.

 

Key Takeaways:

[:48] Co-host Ryan Piansky welcomes co-host Holly Knotowicz. Holly introduces Dr. Amanda Muir, an Assistant Professor of Pediatrics at the Children’s Hospital of Philadelphia (CHOP). She has a translational lab that investigates esophageal remodeling in the setting of EoE. Holly thanks Dr. Muir for joining us today.

 

[1:51] Dr. Muir became interested in eosinophilic disorders as a GI Fellow. There were so many patients with eosinophilic esophagitis and eosinophilic gastrointestinal diseases but there weren’t many good therapies and little was known about the long-term results for children.

[2:24] Dr. Muir’s first eosinophilic interest was eosinophilic esophagitis. She joined a lab that was looking at how the esophagus changes over time in the setting of inflammation. After being in the lab, training, and learning all the skills and techniques, she was able to launch her career and lab.

 

[2:46] Dr. Muir started her own EoE clinic at CHOP (Children’s Hospital of Philadelphia) as part of their Center for Pediatric Eosinophilic Disorders. She sees patients at the clinic, then she can bring questions from the clinic to the lab and talk about them as a group.

 

[3:28] Dr. Muir explains esophageal remodeling. There is remodeling that happens in the epithelial compartment of the esophagus. Then there’s remodeling that happens underneath the surface in the lamina propria. For the most part, when people talk about remodeling in eosinophilic esophagitis, they refer to the remodeling happening below the surface.

 

[3:50] There is a burgeoning field dedicated to studying the surface of the esophagus, and Dr. Muir is also very interested in that. For today’s purposes, we are talking about the remodeling that happens under the surface.

 

[4:03] Eosinophils that get to the esophagus secrete chemicals that excite the cells below the surface to secrete collagen. Collagen is the glue that holds the body together. They’re secreting glue to help the esophagus hold together, and the esophagus gets stiffer and stiffer, over time. That is remodeling. It’s the body trying to heal itself.

 

[5:04] Are children and adults equally at risk for remodeling? Patients develop a stiffening of the esophagus more, later in life. It is thought that the more years you have this inflammation, the more stiff your esophagus gets. There are patients six to nine years old who already have signs of stiffening.

 

[5:28] Dr. Calies Menard-Katcher from Colorado published a paper where she described all of the eosinophilic esophagitis patients at her institution who got dilated. Dilation is the process of a balloon stretching your esophagus open when it’s too narrow. She had patients as young as six in her cohort that she described as having EoE strictures.

 

[5:49] Remodeling happens with younger patients but we’re not as good at finding it.

 

[6:08] Any type of inflammation in the GI tract can lead to some stiffening. The typical gastrointestinal disease that we think of as remodeling is Crohn’s Disease. An inflammatory process happens in the small bowel or colon that leads to narrowing and stiffness in the intestines.

[6:28] Also GERD (reflux) can lead to stricture, over time. It is just much more rare to see a GERD-induced stricture as opposed to EoE.

 

[7:13] We are not sure, but to some extent, we think of remodeling as not being reversible. Once there is a certain degree of stiffness, the esophagus does not seem to open up without these dilations. If you can control the inflammation, you can halt the stiffening. Maybe there is some degree of reversibility.

 

[7:44] In the Phase 2 dupilumab trials, investigators found that patients on dupilumab were seen to gain two millimeters in diameter of the esophagus, compared to the patients on placebo. We may be able to prevent some remodeling if we catch it soon enough. More research is needed.

 

[8:33] Dr. Muir tells of the work she is doing in her lab. They take biopsies from patients and grow collagen-secreting fibroblasts in a dish. The research is to find out what calms the fibroblasts down from actively secreting collagen.

 

[9:22] It’s tough to follow the symptoms of EoE when patients only have difficulty swallowing foods that are hard to swallow. If patients are not challenging their esophagus, they might not notice having daily trouble swallowing. It’s hard to ask a young kid who is eating a lot of soft foods if they feel like anything’s getting stuck.

 

[10:06] Dr. Muir will ask teenage patients, “Do you ever want to eat chicken? Do you ever want to eat steak?” A lot of times they don’t want to eat it, perhaps because it felt uncomfortable at some point in their life and they don’t want to eat it, not based on taste but on repeated bad events. It’s hard to tease out the symptoms, sometimes.

 

[10:27] Dr. Muir says, based on our Functional Luminal Imaging Probe (FLIP) studies, patients who had feelings of food that felt stuck in the last 30 days did seem to have a more narrow caliber esophagus. There is not a 100% correlation between symptoms and remodeling, but there seems to be some correlation.

 

[11:31] Ryan tells how patients have tendencies to get around their EoE symptoms, with a personal example of keeping food in his mouth and chewing it for a long time before swallowing. A scope would show he had bad inflammation of the esophagus. He had been diagnosed when young and was under treatment and on a restricted diet.

 

[12:26] Biopsies don’t always get a sample below the surface to check for fibrotic cells so it is hard to find remodeling with biopsies. There are some visual signs. Seeing rings or trachealization in the esophagus, or narrowing, can be signs that there is some remodeling under the surface.

 

[13:38] For kids who have a lot of trouble swallowing, Dr. Muir performs an EndoFLIP test regularly. The test catches subtle narrowing that may not be visible to the endoscopist. Doing this test gives the doctor more information and a better sense of the patient's phenotype, such as inflammation, the esophagus being stretchy, or being stiff.

 

[14:49] The EndoFLIP is a balloon with an imaging probe that includes a TV for the doctor to see how many millimeters the esophagus is in diameter as the balloon inflates along the whole body of the esophagus. It’s not an imaging test that goes to radiology. It’s a balloon that is blown up slowly with salt water and that gives this measurement.

 

[15:18] The EndoFLIP is a helpful tool to help determine who may have some more stiffening or determine exactly what the diameter of the esophagus is before starting treatment.

 

[15:33] One of the things that Dr. Menard-Katcher of Colorado, Dr. Ackerman of the University of Illinois, and Dr. Muir collaborated on was to look and see if they could find any markers in the esophagus that would relate to some of the things that are obtainable on biopsy or the esophageal string test.

 

[15:57] What they found was that periostin — a protein made by the epithelium and by the fibroblasts, which is known to activate fibroblasts, and is very high in EoE — seemed to correlate with the EndoFLIP measurements. This makes Dr. Muir think that there might be some potential for biomarkers to detect remodeling.

 

[16:16] The thing that everyone wants for this disease is to find a biomarker where we don’t have to do a scope. As far as finding a non-invasive biomarker, we’re not there, yet. There are some things going on at the tissue level that might clue us in on how distensible the esophagus is.

 

[17:18] The thing Dr. Muir worries about the most with long-term inflammation is that the esophagus is going to get more narrow over time. That will make patients more susceptible to food impaction (although not all patients with food impaction have a stricture).

 

[17:36] One worry is that the esophagus will get so narrow that an endoscope will not be able to pass a stricture. That will lead to more swallowing problems. That is what Dr. Muir hopes to be able to prevent as we get better at treating this.

 

[18:09] Any of the treatments that stop the inflammation and help get you below that “magical” 15 eosinophil count that we all strive for, will help prevent remodeling. So, once you get everything calm, hopefully, the remodeling process will stop. However, with the stiffening, the fibroblasts get more excited and have a hard time turning off.

 

[18:53] Simply turning off the inflammation will not turn off the fibroblasts. Many people within the GI space are looking at fibroblast-directed therapy, especially in Crohn’s disease, there’s a real need to prevent a lot of surgeries that are happening. Dr. Muir hopes to apply some of these to the esophagus, as well.

 

[19:16] In the study by Dr. Menard-Katcher, Dr. Ackerman, and Dr. Muir, there were 80 patients. Some were on swallowed steroid treatment and others were on an elimination diet. There were not enough patients on each therapy to find a significant difference in remodeling between the therapies. Patients in remission had better distensibility.

 

[19:44] Dr. Evan Dellon showed in a paper that patients who have sustained remission have fewer dilations, in the long term. While we don’t have a way to reverse the fibrosis that’s happened, we hope to prevent it from getting any worse. Dr. Muir’s research goal is to find something to calm fibroblasts down and prevent fibrosis or even reverse it.

 

[20:31] Dr. Muir explains that cells under the surface level are fibroblasts. When eosinophils and T cells come in and secrete antagonizing chemicals, the fibroblasts turn on and start secreting collagen. The fibroblasts also turn on when the epithelium is angry and inflamed. There is also evidence that surface cells can secrete collagen.

 

[22:46] Dr. Muir says it’s hard to know how far along in development some anti-fibrotic drugs are. We have many promising targets. Understanding how the remodeling happens is very important to be able eventually to treat this disease. Even though it seems like incremental progress, Dr. Muir believes research is moving the field forward.

 

[24:16] Dr. Muir says her EoE patients at CHOP are generous with their blood and tissue. Getting consenting control patients for lab studies involves a lot of leaps of faith and trust that scientists will grow your cells ethically. Dr. Muir feels lucky she has a good research team that explains things in lay terms to control patients.

 

[26:50] Dr. Muir’s team has videotaped pediatric EoE patients and control patients’ eating. The time EoE patients spent chewing and how long it took to swallow correlated to their esophageal distensibility measured by the EndoFLIP test. She believes that how we feed and the difficulty we have swallowing have to do with esophageal remodeling.

 

[27:41] That’s Dr. Muir’s next area of study. It’s being spearheaded by Dr. Kanak Kennedy, a fellow in Dr. Muir's lab, trying to figure out the relationship between pediatric feeding and remodeling.

 

[28:08] As part of their research, they are videotaping as many kids eating as they can. This involves many control patients who don’t have EoE. Another area of research is on the enzyme lysyl oxidase which organizes collagen into bundles and makes it stiff. She is looking into ways to decrease the organization of the collagen.

 

[29:08] Ryan thanks Dr. Amanda Muir for coming on the podcast and giving a crash course on remodeling and EoE.

 

[29:14] To learn more about eosinophilic esophagitis, visit apfed.org/eoe. To learn more about Dr. Muir’s research, read her paper.

 

[29:30] To find a specialist, visit apfed.org/specialists. To connect with others impacted by eosinophilic diseases, please join APFED’s online community on the Inspire Network at apfed.org/connections.

 

[29:47] Ryan and Holly thank Dr. Amanda Muir again for joining them. Holly thanks APFED’s education partners, linked below, for supporting this episode.

 

Mentioned in This Episode:

Amanda Muir, MD.

Children’s Hospital of Philadelphia (CHOP)

American Partnership for Eosinophilic Disorders (APFED)

APFED on YouTube, Twitter, Facebook, Pinterest, Instagram

Real Talk: Eosinophilic Diseases Podcast

 

Education Partners: This episode of APFED’s podcast is brought to you thanks to the support of AstraZeneca, Bristol Myers Squibb, Sanofi, and Regeneron.

 

Tweetables:

 

“I was able to start my own EoE clinic at CHOP as part of their Center for Pediatric Eosinophilic Disorders. I see patients who have eosinophilic gastrointestinal diseases and then I can go back to the lab and bring those questions from my clinic to the lab.” — Dr. Amanda Muir

 

“The thing that everyone wants for this disease is to find a biomarker where we don’t have to do a scope.” — Dr. Amanda Muir

 

“Any of the treatments that stop the inflammation and help get you below that ‘magical’ 15 eosinophil count that we all strive for will help prevent remodeling. So, once you get everything calm, hopefully, the remodeling process will stop.” — Dr. Amanda Muir

 

About Dr. Amanda Muir:

Amanda B. Muir, MD, Attending Physician, Children’s Hospital of Philadelphia, Research Institute. Dr. Muir investigates the mechanisms underlying esophageal fibrosis to improve therapeutic and diagnostic approaches.