All right, let's get started with this program. So the first topic is eosinophilic esophagitis epidemiology definition and clinical presentation. Just some disclosure slides, which you've seen already throughout the course. So what I'm going to try and do with this period of time is to review the definition and history of EOE, talk about the epidemiology. We'll review clinical presentation and natural history. So what is eosinophilic esophagitis? What is the definition? EOE is a chronic immune-mediated food antigen-driven disease. It's a clinical pathologic diagnosis. So clinical patients need to have symptoms, pathologic, they need to have abnormal biopsies. So symptoms related to esophageal function, pathologically one or more biopsy specimens must show eosinophil predominant inflammation. And when the pathologist looks at that microscope and looks at that high-powered field, they need to see more than 15 eosinophils per high-powered field. And that's considered a minimum threshold for diagnosis of EOE. It's important in EOE that that inflammation is isolated to the esophagus after ruling out other causes of eosinophilia. Now, many people think that EOE is this brand-new diagnosis. But it's actually been around for decades. So the first case reports were back in the late 70s. And they were in two adult patients who happened to have concomitant motility disorders. And I know someone asked the question yesterday about motility disorders, achalasia, and EOE. These two first case reports were actually reports of adults with eosinophils in their esophagus who had concomitant achalasia. Then in the early 1980s, an unfortunate thing happened in that there were some publications in the pathology literature that equated eosinophils in the esophagus with GERD. So any eosinophil in the esophagus was read out as GERD. And that happened in that early 1980s. So there was probably a decade of time that patients were getting misdiagnosed as acid reflux. It wasn't until the early 1990s where there were three separate case reports that came out describing dysphagia in young males with allergies and describing this as a new entity and showing these rings in the esophagus. And this really was the first thing that put EOE on the stage. Interestingly, it was in the adult literature. Then EOE kind of took a little pivot to more of the pediatric space, where in the mid-1990s, EOE was diagnosed as a food allergy by Dr. Kelly and Sampson after they put young patients on an elemental diet and found that that completely got rid of their EOE. First consensus guidelines hit the stage in 2007, second consensus guidelines in 2011. EOE was described as a food allergy in adults in 2012 and 2013, the third consensus guidelines in 2013. Biologic trials hit the stage in 2015, the AGREE guidelines in 2018. Those were the guidelines that took PPI out of the requirement for diagnosing EOE. The Seeger Consortium or the Consortia of Eosinophilic Gastrointestinal Disease Researchers came about in 2018, the AGA guidelines in 2020, the ASGE guidelines in 2023, and someone asked the guidelines question yesterday, the ACG guidelines will be coming out in the next few months. And as you know, the first two FDA-approved medications also came about in the last two years. So this has been an amazing trajectory for EOE in just a few short decades. Let's talk about epidemiology behind EOE and the prevalence of eosinophilic disorders compared to other atopic conditions. You've heard over and over again about EOE and its link to ATP. Well let's look at this with other atopic conditions. Now asthma affects 7% to 8% of the U.S. population, seasonal allergies, 40% of the U.S. population. Now EOE is hovering here around 34 per 100,000 or 0.034%. And eosinophilic non-EOE agents is even lower, 0.005%. So really EOE is a very, very small piece of this larger atopic pie. But if you flip it, what you can see is that 78% of patients with EOE had more than one atopic disease. So EOE patients are really allergic. Now this graph I really like because it describes what's called the atopic margin EOE. This is what we think happens in allergies. So in young children, and the x-axis here is the age of diagnosis and the incidence density of disease, first things that happen in kids is they start to get eczema, this atopic dermatitis. Then they start getting IgE-mediated food allergy. It's not until later on they start getting asthma. And here is where allergic rhinitis and EOE hit the stage. So the peak EOE incidence is after that of atopic dermatitis, IgE-mediated food allergies, and asthma. It really kind of comes about when patients start getting seasonal allergies. Many patients will ask us, well, are there risks? Why did I get EOE? Are there risk factors? And this is really nice data from the North Carolina group looking at early life factors and their association with the risk of development of EOE in adulthood. And what they found was the things that really increased the odds of getting EOE included any antibiotics in infancy, a C-section delivery, preterm delivery, and NICU admission. Those are the things that really increased risk. Now, one can speculate what is the common theme behind those things. Well, exposure to antibiotics probably affects different microbiomes, C-section delivery. Infants are not exposed to maternal flora. All of those things could have some sort of pivot on the microbiome. There's a lot of active research in terms of understanding the whys behind this increased risk. Next thing that patients will often ask us is, well, does it run in families? What's the likelihood that my child is going to have this or my sibling is going to have this? And this is really nice data from the Cincinnati group that looked at rates of EOE in twin cohort and nuclear family cohort sibling non-proband. So what that all means is that if you are a identical or monozygotic twin, the chance of that other twin having EOE is 41%. If you're a dizygotic or fraternal twin, the chance of that twin having EOE is 22%. If you have just a sibling with EOE, the chance of you having EOE is 2.4%. So slightly higher in a sibling or a first-degree relative, but not as high as other genetic disorders. But certainly, if you look at the risk with the general population here, much higher than the risk of general population. Now we all, treating physicians that treat EOE, have families that multiple siblings have EOE. The parents, the children, there's lots of this clustering. So there is this common family environment and an additive genetic infertility, which explains this familial clustering. It just means that it heightens and amplifies these genes in these patients. Now we know that EOE has a global presence. It has been seen across almost every single continent except for Africa. And irrespective of the location that you're seeing or that you're studying, whether or not it's Switzerland, Spain, Hamilton County, Ohio, the Netherlands, there is a very steady uptick in the incidence and prevalence of these disorders. Looking at epidemiology based on insurance database claims, you can see the epidemiology is about 51 to 57 per 100,000. And what this graph shows you is that it can affect just about any age with a slight clustering in this third decade. And males are affected three times as more commonly as females. Now if you break this down into specific groups, which is done in these clustering of studies, you can see that EOE is found in 2% to 7% of patients undergoing endoscopy for any reason. Now that number increases to 12% to 23% of patients undergoing endoscopy for dysphagia. And it is the most common cause of food impaction, occurring in about 50% of patients coming into the emergency room with food impaction. So back to the usual question, is EOE common or uncommon? And I think it really depends on what study you read, because you can spin it in any different way. So if you read this one, which is a global study, we think it is somewhat rare, 1 in 4,400. If you read this study by Dr. Dullen, 1 in 2,000. This one in the US, 1 in 1,500. And the population-based study in Sweden, as common as 1 in 100. Where is the actual truth? Probably somewhere in the middle here. But I think it's likely still under-recognized and under-diagnosed. And the reason why I say that is patients will have incredible adaptive behaviors, which mask their symptoms. They have been living with this disease for years and years. There was a significant delay in diagnosis. And so their symptoms really have evolved over time, and their adaptive behaviors have evolved to minimize these symptoms. So these adaptive behaviors are highlighted by this acronym, IMPACT. So if you were to ask patients, and I always harp this on our fellows, don't just ask patients, are you having difficulty swallowing? Because the majority of times, we'll say no. And they don't, because they've done things to account for this. So ask them instead how they're eating, what they're eating, what they're doing to prevent the dysphagia. And what they might say is that they imbibe fluids to facilitate passage of solid foods. They modify their foods. They cut them up into really small, itty-bitty pieces. They puree their foods. They have prolonged mealtimes. A lot of our patients will say, you know what, growing up, I was the last one to leave the table all the time. They avoid harder texture foods because they don't want to have that episode of dysphagia or food infection. So they don't eat some of this bread or meats altogether. They chew excessively. They really like masticate incredibly to make their foods a puree. And they will turn away pills and tablets. They will avoid social situations and won't eat out because of that fear of food infection. What about EOE and the association with other risk factors? So this is a table, and I'll walk you through it. It has a lot of data. But there have been a lot of studies and a lot of interest in really understanding risk factors behind EOE. Why is EOE occurring? So these are just some of the ones that I'd like to highlight. So error allergens. Error allergens might contribute to causing EOE or definitely increasing disease activity. They can cross-react with food allergens, and it can explain seasonal variation. So there's definitely seasonal variation with this disease. And sometimes when we think about someone being refractory or not responding to a certain therapy, we need to take this into account. So just check on the status of their error allergens and if that is kicking up and if that is kicking up, maybe we need to treat this concomitantly with their esophagus. Food allergens, we know it's irrefutable that foods directly trigger EOE and elimination can lead to disease remission. What about H. pylori, an infection? Well, that is inversely associated with EOE. So decrease in H. pylori prevalence has accompanied an increase in EOE prevalence over the last 20 years. We currently don't understand the mechanisms behind why, but there is some speculation that this is linked with our hygiene hypothesis and we're kind of doing a little class switching of our immune system. Infections such as herpes simplex virus or mycoplasma have been associated with EOE. Oral or sublingual immunotherapy have been associated with causing or inducing EOE in certain patients. The tricky part of that is that all the patients going through this type of therapy did not have the baseline endoscopy. So we don't know if they had underlying EOE at baseline. PPIs have been shown to induce IgE antibodies to certain foods in some small studies. This really hasn't panned out. Cold or arid climates increase the odds of EOE in these climate zones. And this is why I always joke that we have such a hotbed in Chicago because it's so cold. But population density, the odds of EOE increase as the population density decreases. We talked about early life factors. Connective tissue disorders. This is another interesting one and this was data published from Cincinnati Children's showing an association between EOE and connective tissue disorders such as Ehlers-Danlos, Marfan syndrome, and Louise Dietz syndrome. So sometimes on physical exam when you're examining a patient, it's oftentimes you can actually notice some of them doing some funny things with their joints because they're double jointed or they have this weird hypermobility where they can like bend their elbow backwards. So those are little clues if you see that in the exam room to go the next step and ask if they've ever been evaluated for this. Celiac disease has been associated with EOE. EOE is more common in celiac disease. Autoimmune conditions, IBD, rheumatoid, IgA deficiency, MS, Hashimoto's have been associated with EOE. Let's move on now to clinical presentation. So we'll start off with a clinical case. This is actually a patient of mine. He was a 36-year-old male who presents with persistent dysphagia for six years. He's had five emergency room visits for food impactions. He's had ongoing symptoms despite chewing carefully and drinking water. He often avoids eating at business lunches and dinners, and he has a history of ATP. He has really bad allergic rhinitis as well as asthma. So we did his endoscopy, and this is what I saw. So his esophagus, this is his proximal esophagus, has a very significant obstructing stricture here. And you may or may not be able to see it, but just distal to that, there's a series of little subtle ridges. So the regular camera could not go through, and the pediatric camera could not go through. We did a barium esophagram on him. This is his esophagram. His whole esophagus is narrow, about maximum 10 millimeters across here, about 7 millimeters across here. And this was about a 2 to 3 millimeter stricture, and you can see in his stricture here. It's amazing that he was actually able to eat and maintain his nutrition. And he nicely represents a classic clinical presentation in adults. Male predominant in 3 to 1, presents in the third to fourth decade, atopic history in about 78 to 80% of patients. 71% of patients are white. However, there's lots of data that suggests that it can affect any race or ethnicity, so we really need to have EOE at top of mind when we're thinking about someone with difficulty swallowing. If you ask patients about their family history, they may tell you they have a family history of EOE or a family history of other allergic disorders. Dysphagia is the most common symptom in about 70 to 80%. I have that asterisk there just because it's not enough to ask about dysphagia. You really want to ask about their eating patterns or what they're avoiding eating, more importantly. And a third to half of patients have been to the emergency room with food impaction. Other symptoms include heartburn, reflux, and chest pain. Now, symptoms of EOE can really vary by age. So infants and toddlers present with vomiting, food refusal, feeding aversion, and failure to thrive. When they get a little older, they'll start getting choking and gagging with coarse textured foods, belly aches, vomiting, regurgitation, nausea. When they get to be a little bit older, they'll start to get dysphagia and food impactions. And adults, by far, the most common thing is dysphagia and food impactions, but we can't forget about other symptoms of refractory heartburn, regurgitation, and refractory chest pain, which can also signify EOE. Now, what do we see on endoscopy? Many of us went into gastroenterology because we love these pretty pictures. I love these pretty pictures. It's so cool. You all got a chance to be in the lab yesterday and see all the tools that we use. But this is what we see on endoscopy. This is the E-REFS-IV developed by Dr. Hirano and our Northwestern group. Looking at the common endoscopic features of EOE. And these are like the prototypical pictures here in this panel, but we talk about edema, rings, exudates, furrows, and strictures. And here you can see really profound rings in one of my patients. They look like the trachea. These linear furrows here, white plaques or exudates, which equate to those eosinophilic microabscesses. And of course, that dreaded food impaction. This is one of my patients who came in with a piece of chicken in his esophagus at around two o'clock in the morning. Everyone always comes in with food impactions at two o'clock in the morning. So how do we break down this E-REFS grading system? This is a really, really important tool for us as clinicians to be able to objectively assess inflammation in the esophagus. It has now been incorporated into the majority of tools that we use to report these out. And we can report these out in our reports. So these are just examples for you to see. Furrows here can be very subtle, these little railroad tracks, or they can be very deep in crease. So they're graded from a zero to two. The edema, this is normal. Normal is that you can see these blood vessels in the esophagus. The esophagus is nice and pink. Present or a low grade is just subtle movement here in the blood vessels. And more prominent here, you've lost all sorts of that blood vessel and really like red inflamed esophagus. Exudates can be very mild. So occupying less than 10% of the lumen to severe. You can see here all the way across. Rings can be very subtle. Just these ridges, more prominent and distinct. And grade three rings here, like my patient, means that the regular scope, which is a diameter of 9.8 millimeters, cannot go through. You need a pediatric scope, which is about six millimeters across. And then strictures are graded as either present or absent. So I wanna just mention that that EREF tool is very important for us as clinicians to use and grade every single time. It has also been used in various clinical trials. Let's now look at the histologic features of EOE. This is really the crux of the diagnosis. We think about this being a clinical pathologic diagnosis. We've gone through all those clinical symptoms. You also need abnormal pathology. And Dr. Solario will be talking about this much more extensively, but I just wanted to highlight a couple of things because I just think this slide is so pretty. It is a patient of mine with EOE. And what you can see here are all the classic features of EOE. These are all the eosinophils, these pretty pink sparkly cells at the top of the lumen. Clusters of more than four are microabscesses. Spongiosis or intracellular edema are all these white spaces around the cells. It's swelling of those cells. You can see that here. Epithelial hyperplasia or multiplying of these cells, degranulation or breaking apart of these granules and lamina propria fibrosis is not seen on this slide, but that indicates increased collagen deposition or fibrosis. And Dr. Solario will be going through all sorts of these features in the next lecture. Many patients will ask, well, how many biopsies are we taking? How, you know, why are you taking so many biopsies? A question was asked yesterday about the biopsies. And this is a really nice study that we did at Northwestern highlighting that biopsy variability in EOE. It's a super patchy disease. So the one on the left is in adults. So if you take just one biopsy, you have a 55% sensitivity of making this diagnosis. Five biopsies gives you a hundred percent sensitivity and in children, you need up to six biopsies to get a hundred percent sensitivity to make those diagnosis. Now, this has now been incorporated into every single consensus guidelines. So it is known that this needs to happen. And the most recent consensus guidelines at ASGE, at least six or more biopsies should be taken from the distal or mid proximal esophagus to assess patients with suspected EOE. Our own protocol at Northwestern is to take four quadrants of biopsies around all four areas in the lower esophagus, the top esophagus, so we take eight. And then the other important thing is to really target the abnormal features. I mentioned that yesterday. Not only is it important to just take these four and four, but really target those areas of the exudates, the furrows, because that's going to increase that yield. The question came up yesterday about the consensus guidelines. The next ASGE consensus guidelines will also highlight this as well as the ASGE did. What about natural history? What happens with EOE over time if we don't treat this? I think this is really important to understand because this is how we frame our conversation with our patients in terms of thinking about the various therapies. And there have been numerous studies and consistent results showing that diagnostic delay can lead to fibrostenosis. So what you're seeing here is the prevalence of fibrostenosis in the EOE. What you're seeing here is the prevalence of fibrostenotic features increase from 47% with a diagnostic delay of two years to up to 88% with a diagnostic delay of over 20 years. And in every 10-year increase of age, the odds of the fibrostenotic phenotype more than doubled. So people over time are getting a more narrow esophagus and a stiffer esophagus. Again, you see here in additional studies, the longer the diagnostic delay, the increased prevalence of stricture. So if you've had disease for about 40, 50 years, there's 0% chance that you don't have a stricture. And with each year of undiagnosed EOE, the risk of the stricture increased by 9%. And this shows the risk of strictures and the risk of food infection events. So just look at that, how high the risk of food infection occurs with fibrosis. And this cartoon I really like because it really helps us understand what's happening underneath the surface. And I oftentimes will share this with patients. So basically, you're starting off with a normal esophagus, signals and genes get turned on, and you'll hear about the pathophysiology from Dr. Snyder a little bit later. Eosinophils start trafficking to that esophagus. The esophagus gets very red and inflamed, and you start to see those inflammatory features. As time goes on, more and more eosinophils persist. You start seeing collagen deposition in the deeper layers. You start getting a stiffer esophagus. You start seeing strictures. As time goes on even further, that's when you get more and more stricturing, more and more rigidity in that esophagus. We think about this happening as a continuing over time with little kiddos starting off on the left side of that panel, and as time goes on, moving on into adulthood. So in conclusion for this section, EOE is a chronic immune-mediated inflammatory condition of the esophagus. Males are affected more commonly than females, and it typically affects the third decade. Common clinical presentation includes dysphagia and food impaction in adults, reflux, vomiting, abdominal pain, and failure to thrive in children. Progressive fibrosis can occur with longer duration of disease, so earlier diagnosis and treatment is important. So I will be happy to take questions. My only ask is please, please, please use the microphone because I cannot hear anything if you don't use the microphone. So thank you all. Yeah, so I get a lot of questions from physicians. It's on. Yep, can you hear me? I can hear you. Awesome, thank you. I often get the question, and there's a lot of physicians that will tell me that all patients don't fibrostenose. They've got patients that have been fine for 25 years and no issues, they don't get any worse. Is there a certain phenotype that, one, is that true? And if it is, is there a phenotype that we just don't understand who's gonna progress faster or who's not gonna progress? Is there any data on that? Yeah, I mean, that's an excellent question. So I think there are definitely different phenotypes of this disease, right? They're different. There's some people that may always stay in this inflammatory phenotype. There are some people that will be in this mixed inflammatory and fibrotic phenotype, and there will be some people in this fibrotic phenotype. And then there's also another phenotype where we call rapid progressors, meaning in the span of the year, they can really scar down significantly. And I don't think we know enough about them in terms of who is falling into which one. There are, I would say that patient that you're describing is probably not the norm. It's probably the exception to the rule. There are some people that have very mild form of the disease. I mean, I definitely have patients who are on PPI therapies and have maintained great esophageal lumen as long as they've stayed on their PPI. I see them every year to year and a half. I check in on them. We don't necessarily do endoscopies every year on those patients once they're stable. But yeah, there is a group of patients that can maintain their disease in a very quiet fashion. But usually it does require some type of therapy. I don't see people not being on any therapy and still being super quiet. I suspect that over time, they probably do have some subtle stricturing that may not be recognized. But this is what's great about research. We need to learn more about all of this. Sure, thank you. Dr. Stein or Dr. Gonzalez, can you guys talk to a little bit more about kind of the shifting demographics of EOE itself? I know it's typically like male dominated, 30 to 40, but speaking for my territory specifically, I'm noticing a shift in like more female patients as well as the patients are starting to get younger as well in age. And I'm wondering if you could talk a little bit starting to get younger as well in age, is there anything that may be kind of contributing to kind of that shift in demographics of patients or is it kind of just here and there kind of like a one-off in various places? Yeah, I mean, I think that's a really great question and something that the Seeger group is really looking into in terms of the epidemiology and trying to follow the incidence and prevalence in all these different age groups. What's interesting, and you may see these pockets of being diagnosed a little bit earlier and maybe this female shift. And I think part of that is increased awareness. I think professionals now have learned a lot about EOE. They've learned that we need to be biopsying the esophagus, where they learn that we need to take dysphagia seriously and send patients to the gastroenterologist. So I am hopeful that we are diagnosing some patients earlier, which is why you're seeing this earlier age group. In terms of the female shift, I still think there's some genetic component, which is continuing to make this male predominant. Although we definitely have female patients with severe disease. And I, because I think, because I'm a female gastroenterologist, I have a lot of females that come to see me too. So my split is probably not 75% to 25%, but I do think there's something unique to EOE that is still a little bit male predominant. That's very different than non-EOE agents. So non-EOE agents, when we're talking about gastritis, duodenitis, and so on, that is more of a one-to-one male-female ratio. So there is something that that whatever gene is not being like protective in non-EOE agents. And the other thing I will tell you about the demographics changing a little bit is we're seeing also an increase in a step up in severity of EOE. And I think that that is related. There's lots of speculation on why that could be, and maybe it's the heightened aero allergens, heightened seasonal allergies, but we're seeing more of a highly atopic population. We're seeing more of a refractory population. And again, we are a big referral center, so that might be my spin on it too. But overall, in the last two decades since I've been doing this, I have substantially seen a higher kind of risk population. Dr. Gonzalez, thanks for your talk. You mentioned about progression of fibrosis with EOE. Is there the ability to undo that tissue damage in the epithelial esophagus with therapies or just as the disease has been modified? Yeah, that's a great question. So yes, I mean, we talk about this fibrosis that happens over time. And I should also comment that we think about fibrosis as this continuum, right? Older patients tending to have this more fibrosis, but they've also seen, based on doing something called endoflip, which is the endoluminal functional and luminal imaging probe, looking at decreased compliance in the esophagus even in young children. So even in young children who may not have the classic fibrotic features, they're also seeing this thing. Now, the beautiful thing is that medical and dietary therapy can reverse this to a certain degree. And we've seen this based on studies we've done on Northwestern with our motility group, looking at endoflip studies before and after therapy without dilation and showing that that compliance actually improves. So that's a surrogate marker of fibrosis. So yes, you can remodel the esophagus. There's also been some nice studies looking at lamina propria fibrosis and collagen deposition before and after treatment. And you can see that that reverses after treatment. So there is a certain degree that we can reverse. However, if someone has a profound stricture and you've got them super quiet, their esophagus is quiet, their eosinophils are zero, but that stricture is persisting, that patient really needs a dilation because that part is not gonna go away completely. And so I think sometimes people are a little afraid of doing dilation. We know that there's an incredible safety information, safety data around dilation if you do it properly. So if there is still persistent dysphagia and stricturing, that person needs to be dilated. But the good news is, bottom line, this can be reversed, acting early, and keeping people on maintenance therapy is going to be very important. Oh, and then I just wanted to chime in on one other thing, a question was asked yesterday about that association with motility disorders and EOE, and Dr. Snyder did an excellent job of kind of going through that chicken-and-the-egg phenomenon. There has been studies that we did at Northwestern looking at endoflip patterns in EOE, and there are some very distinctive endoflip patterns, so motility patterns that happen in people with EOE, and some of it is more of this like spasm, like a spastic picture, some of it is almost achalasia-like, some of it is a decreased compliance and a decreased motility, like decreased peristalsis, and what we're doing as a next step is trying to understand outcomes of these patients in these different categories. So it's very fascinating. Not every EOE patient is the same, there's lots of different phenotypes, both clinically as well as mechanistically and motility-related. Hi, thank you so much again for that wonderful presentation. My question is around, you know, once you get patients into remission, patients diagnosed with EOE, you know, and you go in and they have zero eosinophils, the therapy that they're on is working, at any point in time do you have a conversation with the patient that you're going to take them off of therapy? Do you stop therapy? This is the conversation many physicians are asking, you know, should they continue or should they just stop at some point? Yeah, so, I mean, a really good question, and I think that comes back to that natural history data as well as what we know with maintenance studies. So the natural history data suggests that if you stop patients off of therapy, they're going to progress to fibrosis. So that is a really, like, strong evidence that patients should stay on maintenance. There have also been maintenance arms of clinical trials that have shown that patients who have been randomized to a placebo versus treatment, they have recurrence in their symptoms on the placebo, and their recurrence to symptoms is much faster on placebo than on maintenance therapy. So another evidence to do that. There's been a retrospective review looking at patients on topical corticosteroids and patients who stopped topical corticosteroids, and what they found was that patients who stopped topical corticosteroids had a much, much higher risk of getting food impaction in the years following. So there's really, and that's a really bad outcome. Food impaction is a very scary outcome for that patient, because some cases it can be resolved beautifully on its own. Some cases it's resolved very simply with an endoscope in the ER, but some patients can have some dreaded complications of esophageal tears, perforations, or aspirations. So that is really what we're trying to avoid. So I do really hone in and say maintenance therapy is imperative. We no longer do this one-off, on-and-off, on-demand therapy. That being said, we don't have to necessarily keep patients on the high doses of medications or the strict elimination diets that we've used to get them in remission. There are two phases of this, it's similar to IBD. We're trying to induce remission, and then we're trying to maintain remission. So no matter what treatment I pick, I usually try to de-escalate therapy to the lowest dose of medication possible, or if you're doing diet, try to liberalize their diet to see if they can still maintain that remission. It's a hard conversation to have with people, but there's lots of evidence now that suggests maintenance therapy is important. And the other thing, too, is AGA guidelines, as well as ASG guidelines, and the upcoming ACG guidelines will all harp on maintenance therapy being imperative. That was a good question. I have one question. So regarding your patient group that is responding symptomatically, at least, to PPIs, have there been any studies done for that group of patients? Are they still coming back in at any point to get re-scoped to see if the fibrotic nature is progressing despite them maybe feeling better symptomatically? Yeah. So, I mean, I think you raised two important questions there, and feeling better symptomatically. So when someone's placed on a PPI, we always, always will repeat that endoscopy at that eight-week, minimum of eight weeks after treatment. We're not just saying, okay, do you feel better? Okay, fine. Just stay on your PPI. So that's a really important thing, right? PPIs are a treatment for AOE. We want to follow up with endoscopy to make sure that treatment is working. Let's just say it is working. We either de-escalate or keep them on their dose. What I do is I have them come back and see me in about a year in clinic. We talk about their symptoms. We talk about really probing them on their eating. We'll do that endoscopy at a year, and I will say that 97% to 99% of patients who started on a PPI are still in good remission on a PPI, meaning endoscopically they're quiet, their ERF scores are quiet, their eosinophils are quiet. If I can maintain that PPI, I don't just send that patient on their way. They will come back and see me every year to year and a half. We will sit down, have a conversation. We will probe them about their eating. And then at that point, we may do an endoscopy every three to five years perhaps, but no, I think these are a different phenotype of patients that maintain beautiful remission, no fibrosis on this therapy. And I think whether or not they're just being caught earlier on, they have a milder phenotype. We still have to understand that a little bit more, but the same is true for other types of therapies. If we can get people on decent therapy, they stay on their therapy. We follow their endoscopies over time. We do a similar kind of approach to topical corticosteroids, diet, dupilumab. They tend to maintain that remission. Thank you. And just to follow, do one last follow-up comment about that is that, again, a lot of these guidelines, AGA, ASG, and the new ACG, all will say endoscopy and biopsy are needed to document remission and after change in therapy to assure that you're still in remission and not going based on symptoms because there's a big symptom histology disconnect. So that's where people get into trouble is that they feel better, and they are going to feel better for a lot of reasons with that PPI. It's going to heal some of the barrier. It's going to decrease some of the acid. We know 25% of adults have concomitant reflux. They're going to feel better for a lot of reasons, but we just want to make sure their esophagus is fine. Awesome. Thank you so much. Dr. Gonzalez, thank you for a great talk. One of the answers that you just provided actually sparked another question about timing of endoscopies. You were very specific about your algorithms with your timing after PPI for follow-up endoscopies, and then you also noted that the ASGE guidelines for endoscopy just say follow-up. Do you know or have any insights regarding specific timelines in future consensus guidelines or recommendations? Yeah. I mean, that's a really good question. I mean, I will tell you what we do and what the majority of the EOA experts do is after PPI is about a minimum of eight weeks, we'll do that follow-up endoscopy to make sure patients are in remission. After swallow topical corticosteroids, it's typically about that eight to 12-week range. Diet therapy is a little shorter because diets are hard. It's hard to stick to a diet, but the data is that within six weeks, you can repeat that endoscopy to make sure that it's working, and then, of course, you're going to do some serial endoscopies when you add foods back, and then do PILIMAB. It's typically about four months after starting, and we may do it a little bit earlier if patients have significant stricturing, then they may need to have an endoscopy a little bit sooner than those four months. But those are kind of rough guidelines and guardrails in terms of those durations. In terms of the guidelines, the guidelines don't create this hard, fast specification on this is exactly when you need to do it because there are a lot of factors that may play a role into why someone may not do an endoscopy right at that time. So it comments on repeat endoscopy, but it doesn't put fast, hard timeframes on that. That's a very difficult thing to place in a guideline. Thank you. I had a quick follow-up question to a question that was asked earlier. When you talked about putting a patient on maintenance medication, the lowest possible maintenance med, and I apologize if you already covered this, I missed it, but do you ever deviate from the once a week from Dupixen, or what does that look like if you're keeping somebody on Dupixen long-term? Yeah, so really good question. And I think the data with the every other week Dupixen, and the fact that it did maintain histological remission, but some patients did have symptoms come back, I think what's happening in real world is that patients are asking to decrease that frequency and it's been effective for other conditions. I think it really depends on that patient, right? I mean, I have some patients who are so incredibly refractory, they are on multiple different therapies and then they got on Jekyll and Mab and have done beautifully, but they're like a highly atopic individual, they have other atopic conditions for which they're being treated. They have significant structuring disease and they were on multi-modality therapy before they got on this. They are probably not the person that I would try to space out. There are definitely some patients with a slightly milder phenotype that have done beautifully spacing out on the medication and going to every other week medication, and I know that's not indicated, it's indicated for weekly dosing, but in the real world, patients are asking to be spaced out and I think this is a beautiful area for research to partner with physicians doing things like this, is to really understand as your group would obviously want to, who are those patients that can do well and have good outcomes with spacing and who are those patients that really have to maintain that very tight control of that atopic condition. Dr. Gonsalves, thank you again. You've mentioned phenotypes quite a bit in your answers here and I just, my question is do you have any insight or are there any ongoing studies about the different phenotypes of EOE such as patients who do great on PPI, PPI refractory, those who progress significantly quicker to a fibrostenotic state, and what kind of insight do you have just from your own practice that you could share with us to help us understand truly like who is an appropriate patient that we are trying to help here? Yeah, I mean I think that's a really good question. These phenotypes, it's an area that's really a hot button in terms of research. People really trying to not just lump EOE as one big category, but really trying to understand the nuances behind the different presentations because it's really not a one size fits all. There's lots of great genetic work being done out of Cincinnati Children's and other centers trying to understand if there are different signatures, gene signatures with these patients. We're doing similar studies at Northwestern, so they're very early on in that process in terms of understanding like how those things will link with outcomes. The endoflip data too has been looked at in terms of looking at different endoflip features and outcomes with treatment, and we have seen certain endoflip features do better with certain treatments, and again, that's kind of early on in the process. I think it's important to really think about that physician and that patient because it's the person in front of you that you're going to help understand what phenotype that person is falling into, and a lot of things play into that. What was their EREF score at baseline? How severe were their symptoms? Maybe consider use the IC score, which is an AGE tool looking at the severity of their symptoms, but really just asking them like how bad their swallowing is, what they're doing in terms of avoidance, how many self-limited food impactions they've had, how bad is their atopic disease, and those people are going to naturally fall out in different categories versus the patient that might have a very low dose PPI who's done beautifully and has never, ever had another food impaction episode after being started on that. So, I wish I had a better answer for you, and I could say, oh, yeah, we know exactly who is going to be that rapid progressor and who should be the best for this treatment versus another. I mean, the good news is there are a lot of really awesomely talented people that are looking at this to try and figure that out, and hopefully in the next five years to a decade, we'll know exactly that. Thank you. Dr. Gonzalez, my question is around what you said earlier around the AGREE guidelines where it was decided to remove PPIs as a part of the diagnosis for EOE. Could you explain what that means? Because quite possibly there may be some old school doctors who might still be doing that. I'm not too sure. Yeah, yeah. Usually there is. So, yeah, that was a really fun guideline to be a part of. You know, we housed it at Northwestern around a DDW and got about 70 of the key stakeholders to talk about this. And what was happening was that, you know, the initial guidelines were that you needed to have persistent esophageal eosinophilia after PPI therapy. And if you had esophageal eosinophilia after PPI therapy, then only could you be diagnosed with EOE. However, we started seeing more and more patients with a classic EOE phenotype that responded beautifully to PPI, and they started being called PPI responsive esophageal eosinophilia or PPI-RE. Once more and more data was done, we started to look at the genetics behind these conditions, the endoscopic features behind these patients, and they were virtually identical to EOE patients. So, it started to become known that PPIs were an actual treatment for EOE. And so that's when the AGREE guidelines came about to say, you don't have to fail a PPI trial to be diagnosed with EOE because PPIs can actually treat EOE. And there are different mechanisms behind why PPIs treat EOE. There's lots of different nuances behind that, but that's the crux of the guidelines. So now, those guidelines left diagnosing EOE up to the clinician. You didn't need to fail a PPI trial. If you have a patient with esophageal eosinophilia over 15, classic clinical symptoms, and you've ruled out other things, meaning you don't think they have reflux, they don't have a huge hiatal hernia or rosive esophagitis or other causes of esophageal eosinophilia, you can diagnose that patient with EOE, and you can start them on any of the treatments, PPIs being one of them. So that's the main difference that the AGREE guidelines came in on. It changed the PPI to a treatment from a diagnostic tool. I hope that answered your question. Thank you. Any other questions? Okay, all right. Thank you, Dr. Gonzalez. I think those are all the questions for right now. I'm sure there will be more later. Okay, great. Thank you all. Thank you.

eosinophilic esophagitis

EOE

immune-mediated disease

dysphagia

endoscopy

genetic predisposition

fibrosis prevention

individualized treatment