Melanie Cole, MS (Host): Welcome To Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And joining me is Dr. Nirmala Gonsalves. She's a Professor of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine. And in today's episode, we delve into the fascinating world of eosinophilic gastrointestinal disorders. Our guest is an esteemed expert in this field, and she'll be shedding light on crucial aspects of diagnosis, treatment, and patient care.

Dr. Gonsalves, thank you so much for joining us today. I'd like you to start by telling us about your areas of clinical and research focus.

Dr Nirmala Gonsalves: Good morning, Melanie. And thank you for having me for this podcast and giving me the opportunity to talk about my area of clinical and research expertise. So within the division of gastroenterology, I'm one of the esophageal physicians. And within the esophageal group, I focus on an area of disorders called eosinophilic gastrointestinal disorders. And I co-direct the Northwestern EGID Program together with Dr. HIrano. I've been in this space for the last 20 years. I think the spring will be my 25th year at Northwestern, and it's been a really exciting place to work in and grow.

Eosinophilic gastrointestinal disorders are described as chronic inflammatory conditions of the gut. They are an immune-mediated, food allergy-driven condition. And patients are exposed to various food and air allergens, and that results in eosinophilic inflammation trafficking to the gut, and resulting in various forms of gut dysfunction and symptoms.

The most common of these disorders is eosinophilic esophagitis, which focuses on the esophagus, esophageal inflammation, eosinophils traffic to that esophagus, resulting in symptoms of dysphagia and food impaction. The other eosinophilic disorders are much more rare. They include eosinophilic gastritis, eosinophilic enteritis and eosinophilic colitis. Similar to EOE, eosinophilic esophagitis, these conditions occur secondary to exposure to food antigens, and that results in eosinophilic inflammation of the gut, resulting in GI symptoms.

Melanie Cole, MS: Thank you for that, doctor. And while this is a very exciting time in your field and things are moving very quickly with advances, we're learning more all the time, how has diagnosis and treatment of eosinophilic gastrointestinal disorders evolved over the years?

Dr Nirmala Gonsalves: We think about EGIDs as being relatively new disorders. But when you look at the history of EOE, for instance, it's actually been around for quite some time. The first case reports were described back in the late '70s in adult patients with concomitant motility disorders. Then about a decade later, there was some literature in the pathology literature suggesting that eosinophils in the esophagus really were refluxed. So, that led to a delay of diagnosis in these disorders for about a decade.

In the mid 1990s, EOE was described as a food-mediated condition in children. That was further outlined to be a food allergy condition in adults by our group in 2012. The first consensus guidelines hit the stage in 2007, second consensus guidelines in 2011, third consensus guidelines in 2013, and the most recent consensus guidelines in 2020. The CEGIR Consortium, which is a consortia of eosinophilic GI researchers, came about in 2018, and our first FDA-approved medication came about in 2020. So really, there's been a tremendous amount of work and evolution of these conditions over the last several decades.

Melanie Cole, MS: Well then, speak about some of the challenges that exist with diagnosing these conditions. Why is early diagnosis so important for these diseases? I'd like you to speak a little bit about diagnostic criteria.

Dr Nirmala Gonsalves: So when we think about diet, and I'll break it down between EOE and the non-EOE EGIDs, because there is a different approach. So with eosinophilic esophagitis, normally, there are no eosinophils in the esophagus, so anytime there are eosinophils there, we think, "Well, this could be reflux disease. This could be eosinophilic esophagitis." And there are different criteria in terms of cut offs for that inflammation.

 So, standard way to approach diagnosis with EOE is if you have a patient with characteristic symptoms and those symptoms in adults include dysphagia and food impactions, and they have those typical endoscopic appearance with the concentric rings in the esophagus, linear furrowing, edema, exudates, and strictures, and you take biopsies and see more than 15 eosinophils per high prior field, then you have made that diagnosis.

It's important to diagnose this condition early on because we know, based on natural history studies that if patients are not treated, unbridled inflammation leads to progressive fibrosis and scarring of that esophagus. So, patients really do present with strictures over time. So, early diagnosis and treatment is very, very important. And we can talk about treatment in a bit.

Diagnosis with non-EOE EGIDs is much more challenging. And the reason being is that unlike the esophagus, where any eosinophil is abnormal, in the stomach, small intestine, and colon, you have normal resident eosinophils living there. Right now, we don't have consensus guidelines in the non-EOE EGID space. Northwestern is leading that charge. But currently, we suggest a cutoff of 30 eosinophils in that stomach, 50 in the small intestine, and the colon, it really does vary based on the location of chronic involvement from 65 in the lower colon to over 100 in the upper colon. So definitely, you need that histologic inflammation for the non-EOE EGIDs. You also need the clinical symptoms, and that's where it becomes a big challenge in non-EOE EGIDs because those symptoms are a bit all over the map, they're non specific, unlike EOE where dysphagia and food impaction are really the most common things. Patients with non-EOE EGIDs can present with a myriad of symptoms including abdominal pain, nausea, vomiting, bloating, early satiety, and diarrhea. So, sometimes these symptoms are misdiagnosed as other disorders. Patients are not sent to the gastroenterologist, biopsies are not obtained, and that diagnosis is not made. And that also results in a delayed diagnosis. Similarly to EOE, we think that if inflammation persists in non-EOE EGID, it does lead to complications, including ulcerations, stricture, GI bleeding, and malnutrition. So, earlier diagnosis and treatment is really critical in these disorders.

Melanie Cole, MS: Thank you for that comprehensive answer. Now, speak a little bit about common approaches to treating patients with EGIDs, and both short term and long term, doctor. What are some of the advancements that you've been really excited about that have been made in these treatments?

Dr Nirmala Gonsalves: As we know with EOE, it's a food antigen-driven condition and treatment really hinges either on medical therapy or dietary therapy. There are different approaches to medical therapy. The first being proton pump inhibitors, and that results in response in EOE in about 42% of patients. So, that's often a good first line approach to start treating EOE. If those patients don't respond to that medication, then oftentimes we can escalate to further medical therapy. And the other option for medical therapy is swallowed topical corticosteroids. These are asthma inhaler-type medications that are swallowed into the esophagus and decrease esophageal inflammation.

Other medical therapy and exciting things that have recently occurred. We have two FDA-approved medications now after decades of not having anything. The first was an injectable medication, a biologic therapy, a monoclonal antibody against interleukin 4 and interleukin 13, and that's dupilumab. That's a weekly injection that patients can take to treat their disease. And just a month ago, we have a FDA-approved medication with a budesonide oral suspension, EOHILIA, that is used for induction therapy.

Now, if patients don't want to do medical therapy and they want to embark on dietary therapy, we advocate for an empiric elimination diet, and that is taking out common food triggers that trigger this disease in patients. And those common food triggers, we think about in the context of a six-food elimination diet. Common triggers include milk and wheat, soy and egg, nuts and seafood. So if patients were to do a six-food elimination diet, they would take all of those things out for six weeks and see if they respond. That response rate is about 65 to 70%, depending on which diet you pick. You can do a four-food elimination diet, taking out milk, wheat, soy, and egg; two-food, milk and wheat; or even a single-food, just taking out milk. So basically, to summarize, either medical or dietary therapy is very effective.

Now, you asked a question about long-term. When we think about treatments, there are two phases of treatment. One is induction, meaning we want to get patients in remission. We want to decrease that inflammation. And two is maintenance. We want to keep them in remission. So once patients start on a therapy, they will continue on that therapy. So if they start on a proton pump inhibitor or acid suppression, we will do that following endoscopy in about eight weeks. If that inflammation is quiet, we'll keep that patient on that medication. If patients are on the swallowed topical corticosteroid, typically, we do it at a twice-a-day dosing for the first eight to 12 weeks and then follow up with an endoscopy. If the disease is quiet, typically, we reduce that dose down to just a nightly dose and keep patients on maintenance therapy. Same is true for the budesonide oral suspension or the dupilumab.

If patients respond to either of those, they will stay on that medication for maintenance therapy. Dietary therapy, if we embark on dietary elimination and we find that it's helpful, and it induces remission, then the next phase of dietary therapy is to reintroduce those foods back to the diet to try and find the ultimate food trigger with the goal of eliminating that food trigger moving forward for that maintenance part.

Melanie Cole, MS: Dr. Gonsalves, what makes Northwestern Medicine uniquely qualified to treat these cases? And please, while you're telling us, share some of the ways that EGID research at Northwestern has contributed to better treatment and care of these patients.

Dr Nirmala Gonsalves: When I think about how our EGID program has evolved, I really have felt very, very lucky to be a part of it and to be a part of it from the ground up, so to speak. So when I was a fellow, we did not have very many patients with EOE. As my fellowship progressed, this was the area of my research and together with Dr. Hirano, we started to see many patients coming in with food impaction and started to really want to understand why they were coming in to the emergency room with food impaction and how can we better diagnose them.

And over the span of several decades, we have upwards of 5,000 or more patients that we're treating here at Northwestern. We have one of the world's largest numbers of patients with eosinophilic GI disorders, both EOE and non-EOE EGIDs. So, we've been very vested in the clinical care of these patients. We have been part of TIGEERS Consortium, which is the international GI researchers, as well as the CEGIR consortium. which is a U54 Rare Disease Network grant focusing on 18 different centers in the country that take care of these patients and work towards research of these patients.

So, we have a lot of clinical and research expertise. Some of the things that we have been involved with over the years have really led to a lot of paradigm-shifting changes in the diagnosis and treatment of eosinophilic GI disorders. For instance, one of the first things that we worked on is looking at histologic criteria for EOE and looking at histologic variability. That research project that I did as a fellow actually led to the recommendations that EOE is a very patchy disease with histologic variability and we need at least five to six biopsies along the length of the esophagus to make the diagnosis. This recommendation has been incorporated into every single consensus guidelines as well as clinical trials, so that really helped shape the field of diagnosing EOE.

Following that, we worked on trying to understand the role of food antigens in adults and completed the first dietary treatment trial in adult EOEs showing that treatment with a six-food elimination diet resulted in a 70% response, improved histology, symptoms, and endoscopic features. And that really gave some guidance to the field that food antigens were driving this in adults, similarly to children.

We then looked at an endoscopic reference score and development of an endoscopic reference score under the guidance of Dr. Hirano and really work towards getting a score and a reporting tool so that physicians can report in endoscopy the features that are seen during their care of patients. This tool has also been incorporated into consensus guidelines and multiple clinical trials. We further went on to look at this tool in non-EOE EGIDs and really helped to understand treatment of non-EOE EGIDs. Northwestern completed the first food trial in non-EOE EGIDs. I was a principal investigator of the ELEMENT study looking at elemental diet or an amino acid-based formula in patients with eosinophilic gastritis showing 100% remission. That was the first study to show the link of food antigens driving this condition in non-EOE EGIDs.

In addition to that, we are also heading up the consensus guidelines process for non-EOE EGIDs to really help further inform the field on how to best diagnose these more rare conditions. We feel very passionate about our patients and their care and feel very rewarded that we've been given the opportunity to take care of them, be involved in research, and help guide better treatments, which hopefully there will be more to come.

Melanie Cole, MS: As we wrap up, doctor, and this is such a fascinating topic and it's come such a long way in the past couple of decades, as you said, what's important? What do you want other physicians to take away from this episode and your message about what you're doing at Northwestern Medicine?

Dr Nirmala Gonsalves: I think the important take-home points are really to think about early diagnoses for these patients, because that is really critical to their care and helping to prevent remodeling of their organs and help improve their quality of life. So when we're thinking about EOE, really thinking about this as the top diagnosis and patients that are presenting to you with dysphagia and food impaction, making sure you're taking biopsies at the time of the food impaction to diagnose these conditions earlier, really thinking about getting patients on treatment and keeping them on treatment to prevent all those complications.

In terms of non-EOE EGIDs, I hope to share some exciting news with newer consensus guidelines coming up in the next year, but really thinking about this diagnosis in patients who are presenting with those varied GI symptoms, abdominal pain, nausea, vomiting, bloating, early satiety, and diarrhea who may be atopic, meaning having other allergic conditions or having a peripheral eosinophilia, thinking about these non-EOE EGID diagnosis and making sure you're taking biopsies during that endoscopy so that they can also get started on earlier therapies.

This is a really exciting area for EOE and non-EOE EGID in that there's so much research going on, so many opportunities for clinical trials, and this is such a win for our patients in that there is a spotlight on these previously very, very rare disorders. So if anyone has patients that would benefit from clinical trials or benefit from a comprehensive care approach, we are here for them at Northwestern. Thank you for giving me the opportunity to share our research and our clinical work with you.

Melanie Cole, MS: Well, thank you so much for sharing all of that with us and your expertise in this area. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/gastroenterology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.