Okay, so round two for me. We're going to review pathophysiology and current treatment of EOE. And as Dr. Tierney mentioned, I will be doing some editorials on some of these slides as we go through. So let's start off with a clinical case because I think it's really important to really put everything in a clinical context when we're thinking about EOE and we're thinking about our patients. So this is a 20-year-old college varsity swimmer with EOE dating back to first grade. So he's had dysphagia since he was a kid. He had an endoscopy in 2017, had strictures, furrows, rings, exudates, and the adult scope couldn't pass. And remember from learning yesterday, your adult scope is about 9.8 millimeters. So that's super teeny, normal esophageal diameter is about 20 to 25 millimeters across. So we already know he has severe disease. His only therapy at the initial visit back then was a twice a day dosing of a PPI. He was placed on Budesonide one milligram twice a day. And this was his endoscopy. And you can see here, you know, certain areas look fairly normal, good vasculature. But then there are several areas in the lower part of the esophagus with the furrowing, the edema, and even some narrowing and then subtle structuring at the bottom. And his biopsies came back, 35 eosinophils. So clearly he has EOE. There were no superficial layering of eosinophils, but he did have microabscesses. And he had those additional features of the basal cell hyperplasia and subepithelial lamina propria fibrosis. He then got lost to follow up. And this does happen to many of our patients. We put them on therapy. They feel well. We'll tell them, hey, you know what, you still have eosinophils. Come back and see me. We got to tweak your therapy a little bit. But they feel great. So they go off and do their thing. And so he comes back two years later with a food impaction after noncompliance. And his food bowl is here, significant narrowing. The whole esophagus is now narrowed. This is probably like a 9-millimeter esophagus. It's teeny, so much different than before. He was placed on Budesonide, 1 milligram twice a day again. And so you can see that a lot of the inflammation has subsided. It hasn't resolved completely, but it has subsided. This was his endoscopy pre-dilation. This is probably about an 8 to 9-millimeter stricture right there. So he was dilated with a savory dilator. And the reason why I can tell you that is an 8 to 9-millimeter stricture, that regular scope doesn't pass through. So you can't do balloons with a pediatric endoscope. You can only do the savory dilation, so that long caliber dilation. And here he has an effective dilation effect. So you can see here kind of a renting of that esophageal mucosa. This is actually what you want to see after dilation. It looks scary, but that's what you actually want to do. You want to open up that fibrosis. His pathology now comes back 110 eosinophils. He still has basal cell hyperplasia and that lamina propria fibrosis. So he's obviously not optimally treated at this time. So the learning objectives for this part of the talk are to review our current understanding of EOE pathophysiology. We'll talk about the goals of therapy in EOE. We'll review treatment options in 2023. We'll talk about how we assess response to therapy. What is the data for chronic therapy? What guides us there to tell people they have to be on maintenance therapy? What is the current status of novel steroid therapy systems and biologics? And what do we do with refractory EOE? So I'm going to bring you back to a slightly different schematic of pathophysiology because it's a little bit simplified, but it's a really nice image. And it kind of walks us through the nuts and bolts of the immunology of EOE. And I'm a super big nerd. I love immunology. But this really puts into context how some novel therapies have evolved. So in this patient, they're exposed to these food allergens. The eosinophils drive to that epithelium. It sets off these inflammatory Th2 cells, different types of lymphocytes. This stimulates the Th2 inflammatory cytokines, IL-4, IL-13, IL-5. That results in eosinophils and mast cells getting to that tissue, TGF-beta causing fibrosis, and the whole downstream effect of remodeling, loss of barrier function, and the eosinophilic inflammation. That all leads to that esophageal dysfunction. So this is what's happening beneath the layer of the esophagus. So let's walk through things individually. So we'll start off with the role of TSLP. That's thymic stromal lymphopoietin. It's released by activated epithelial cells. So those cells that Dr. Salaria showed you that looked pretty and pink at the top of that specimen, those are the epithelial cells. It's in response to environmental triggers. It promotes Th2 differentiation, so Th2 are just lymphocytes, those white blood cells that can change and modify and become activated and secrete those hormones. And this is associated with multiple atopic disorders. What about IL-4 and EOE? This induces Th2 differentiation, meaning it changes those lymphocytes to become more active and start secreting those cytokines. That increases the secretion of Eotaxin-3. That'll cause mast cells to proliferate and activate. IL-5, that's required for eosinophil poiesis, so meaning eosinophils coming out of the bone marrow going into the bloodstream and getting to that tissue. It drives mucosal eosinophilia. It mediates tissue remodeling. So those epithelial cells, instead of being soft and compliant, they become more stiff and rigid. IL-13 is associated with other atopic or allergic conditions. It causes eosinophil chemotaxis, collagen deposition. That's all that fibrotic material that you see in those deeper layers that causes smooth muscle to contract that can lead to that esophageal dysfunction. And it disrupts epithelial barriers, specifically a gene called desmoglian protein 1. And that is a tight junction protein, meaning when the cells are close together, you have a good barrier. When they're far apart, you get a leaky barrier. So that can result in that leaky barrier of the esophagus. Eotaxin-3 is a potent eosinophil chemoattractant. So that's one of the key things that drives the eosinophils to go to the tissue. And then mast cells and EOE. So mast cells are present in the mucosa and submucosa. They increase smooth muscle mass. And mast cells are kind of finicky cells. They go hand-in-hand with the eosinophils. And they get very irritated when the eosinophils are there, and the eosinophils break apart. And they, in turn, cause eosinophilic activation. So it's important to kind of know that both of them play a role in this disease. They also increase pro-fibrotic TGF-beta. And TGF-beta is a key hormone that causes that fibrosis or scarring in the esophagus. And it is involved in remodeling. So when we think about it in the actual patient, that results in error allergen and food allergen deposition. It results in rigidity and narrowing and dysfunction of that esophagus. And that results in the symptoms that we see and the variations of the symptoms that we see. For instance, in little kiddos, they present with feeding problems and vomiting. When they get older, they start getting abdominal pain and that difficulty swallowing when they're in adolescence. And later on, they will have more of the dysphagia and food impaction when they're adults. Oh, there are lovely little boxes there to show you what I just did. All right, so what are the goals of therapy in EOE? So this is really important, and I can't stress enough. In EOE, we're really thinking about a treat to target. And you've heard that term from IBD, but it's really, really important. All the guidelines and the task force guidelines that I'll show you a little bit later are based on histologic efficacy, meaning getting those eosinophils down. But histologic efficacy is not the only thing we need to think about when we're treating that patient in front of us. We want improvement in symptoms. We want resolution of dysphagia without the need for that patient to avoid food based on that texture. We definitely want improvement in histopathology. We want improved esophageal inflammation, ideally under 15. And we want improvement in endoscopic features. We want mucosal healing. We want improvement in that inflammatory feature, and ideally, getting those strictures to 15 to 17 millimeters across. So what are the treatment options that we have available? And this is the old slide deck, but that's okay. In 2023, okay? So we will go with some challenges that we face with treatment. And there are certain issues. Right now, there's only one FDA approved therapy. It's great that we have one, but we only have one. There is a need for repeat endoscopies to assess response to treatment, so that can be very challenging. And there's a lack of alternative clinically meaningful options, meaning we don't have good biomarkers to follow this disease yet. And PROs, or assessment of symptoms, are really problematic to date to guide therapy, so that we face several challenges here. When we think about the initial choice of EOE therapy, there are lots of variables we need to consider. The first is efficacy. We want to talk to our patients on the efficacy of all these available products, so that they have an understanding of why we're using these medications to treat them. Patient preference. Patients are a big part of this disease. I mean, there is shared decision making that goes on. And so that patient preference really trumps everything, ultimately, that we tell them. It's their disease. Disease severity. So depending on the severity of the disease is oftentimes how we counsel patients on treatment. Insurance coverage absolutely plays a role in terms of what insurances will cover for us. Dietary resources. Someone may be really motivated to do dietary therapy, but they may not be in a position to have the available dietary resources, so that makes it very challenging. And ultimately, shared decision making really guides these treatment decisions. This was a nice study done out of University of Michigan, highlighting the importance of shared decision making when selecting EOE initial treatments. And what they found is in patients who had providers who shared in high shared decision making, they were much more likely to be satisfied with their care than providers who didn't have the shared decision making. Patients who were treated by GI only physicians also had the highest satisfaction. And I don't think it's just because gastroenterologists are fabulous, which I think we are, but I don't think that's it. It just means that there was one key quarterback. There was someone that was taking ownership of that patient, and there was someone that was actually guiding them through that journey. When there are a lot of people that are playing a role, sometimes if there's not one person, it becomes very challenging for patients. So what about eosinophilic management? Oh, boy. OK. So I took out all these animations, but we'll go with it here. So when we think about eosinophilic management, we really focus on not just the three Ds. There's now the four Ds. We highlighted that from last year. So the Ds in EOE treatment really focus on diet, drugs, including PPIs and topical corticosteroids, dilation, esophageal dilation, now dupilumab as of May of last year. And there are definitely newer agents with novel steroid delivery platforms and different biologics, and I'll review that with you shortly. So let's start off with dietary treatment of EOE, because it was one of the first initial treatments that was described back in the study that I showed you in my last talk in 1995 with Dr. Kelly, who looked at elemental diet. And this is data from the AGA and joint task force guidelines talking about the effectiveness of dietary treatment. Now you should know that the effectiveness that they based all these studies on is the likelihood of achieving eosinophils under 15. So they focused just on hisologic efficacy. So you can see here elemental diet, which is exclusively formula-based hypoallergenic diet, is by far the most effective treatment for EOE, 94%. That's amazing, right? But elemental diet can be really, really challenging from a cost standpoint, a palatability standpoint, but most importantly, for the long process of reintroducing all those foods after you place them on an elemental diet. So it's really fallen out of favor, with the exception of really severe kids with EOE. So the favored dietary approach has really been an empiric elimination diet, meaning taking out those common foods that trigger EOE. And those common foods are milk and wheat, soy and egg, nuts and seafood. And at the time of these guidelines, that's what they focused on, the six-food elimination diet here. And you can see here the overall effect was about 68%, so really pretty good. It was very effective. What about allergy testing-directed elimination? The data here is 52%, and if you take that just in that context, it sounds, wow, it's really pretty good. Why aren't we doing allergy testing on all these patients? But when you actually broke down the data for that allergy-directed elimination, the guidelines had a caveat in that there was a lot of kind of poor variability across studies. And when you look at adult studies, the predictive value is less than 13%, so very bad. In young children who did a combination of ATP patch testing and skin prick testing, they fared the best. So in children, that might be a more reasonable option. But at least in adults, the recommended approach is an empiric elimination diet. The challenge with empiric elimination diets, if you're going to do the six-food, which has been the most common one to do, is that reintroduction process. And people always ask, well, how do you do that reintroduction? This is our protocol at Northwestern, which was published several years ago. Once that patient is in remission, you then want to add foods back so you can find your food triggers, and we add them back from least likely culprits to most likely culprits. So if you're out in the field and you're talking to your physicians and they're saying, oh, this patient was on dietary therapy and they're avoiding this, this is probably the mechanism in terms of how they got there. So after that initial endoscopy, we would add seafood back for two weeks, nuts back for two weeks, and then they would have an endoscopy. If they're clear, which most people clear, you would add soy back for two weeks, eggs back for two weeks, and then endoscopy. If they clear, then we do milk and wheat individually, because they're about 50% to 60% of the most likely triggers. But what you can see here in this slide is that requires four additional endoscopies after that initial endoscopy. So that's a lot of endoscopies for some people, and a lot of people don't want to go through that approach. What about adherence to diet? So that's the other challenge. You know, with anything, we already heard that case from earlier that that patient didn't adhere to their medication. Adherence to any therapy is challenging, and it can be particularly challenging with dietary therapy. So we did a study at Northwestern looking at adherence, and 57% remained on their diet three years after they did it. So that's not too bad for a diet approach, but it's still not perfect. And the reason for them stopping is that they had suboptimal control of their symptoms. Social situations are really hard with dietary therapy, or perhaps diet-related anxiety. What was interesting with this study is that the patients that filled out the survey, even if they weren't on diet right now, the majority of them would recommend diet to their colleagues because they felt some degree of ownership knowing what foods were actually driving their disease. Single food elimination diet has been looked at, mostly in children. And this was a study looking at cow's milk protein, so just eliminating milk in kids. And they found a histological remission in 51%. So that's really good. So for kids, just eliminating milk only is often the favored approach if you're going to do an empiric elimination diet. And since this study came out, there's been two separate randomized diet studies looking at a single food versus four food elimination diet in children, and a single food versus a six food elimination diet in children. And that single food ended up being about 40% effective. So there are plenty of different elimination diets, and what do you eliminate on all of them? This just outlines, for those of you who are not familiar, what the foods are when we talk about these diets. Six food eliminates milk, wheat, egg, soy, nuts, and seafood. Four food, milk, wheat, egg, and soy. Two food, milk, and wheat. And one food is typically the milk. And again, keep in mind, it's just eliminating this for six weeks, and then they're going through that food reintroduction to find their food triggers. And the majority of patients, we did a follow-up study at Northwestern of over 200 patients of ours who did the six food elimination diet, 70% or more had just one food trigger. So that's really helpful for patients to know if they're going to embark on that. So what about PPI therapy for EOE? This was found to have an overall effectiveness of 42%, so really pretty good. So PPIs have been a common first-line therapy for EOE. So we talked earlier that they've moved away from the diagnosis of EOE to now to treatment. And in addition to histologic efficacy, follow-up studies have actually shown that they improve symptoms in EOE, as well as EREF scores, as well as endoscopic features, and even esophageal diameter. So what are potential mechanisms in EOE that PPIs have a role? So there are anti-inflammatory effects, which are independent of anti-acid effects. So they can be an antioxidant. They can inhibit immune cell function. They can decrease endothelial cell adhesion molecule expression. They reduce inflammatory cytokines, such as that eotexin 3, at least in Petri dish studies. And they can down-regulate the transcriptome. So if you've seen studies with different heat maps of genes that are up and down, this normalizes that transcriptome after therapy. And it can improve barrier function. Remember, I was telling you about all that spongiosis and those leaky cells. It can actually help improve that barrier function, which could result in decreased exposure to allergens. So several years ago, there was a lot of scare about the potential adverse consequences of PPI use. And there's a lot out there about heart disease, dementia, strokes, anything under the sun. And people got very nervous about it. And I think we need to take a little bit of caution when we interpret studies. And Dr. Vasey pointed this out. So all of those were observational studies. And essentially, there's a big zone of potential bias here. And causal inferences should be guarded if their odds ratios are in this zone of bias. So all the reflex experts of the world have critically looked at these studies. There is no causal association of any of those things with PPIs. And prospective studies have not even shown an association. So we think that PPIs are safe for long-term use. So those patients who want to be on PPI, it's fine for them to continue to do so. What about topical corticosteroids? That's another very popular treatment for EOE. At the time of the guidelines, they looked at eight different studies. And the overall effect size was 65%. And the recommendation by the guidelines, and this was probably the strongest recommendation by the guidelines because there was the best studies at that time. Keep in mind, this was 2020. The guidelines recommends topical corticosteroids over no treatment. This was a strong recommendation with moderate quality of evidence. Here's an example of a randomized control trial done at UNC with budesonide. So oral viscous budesonide twice a day versus swallowed fluticasone, 80 micrograms twice a day. And you can see here the histologic response for budesonide is 71%. Fluticasone, 64%. This was not statistically significant in this study. Patients often ask, well, is it better for me to be on the slurry? Is it better for me to be on the inhaler? The study is showing that there really isn't any significant difference between the two. But after therapy, there was a significant reduction in the eosinophil count, the endoscopic scores, and even the symptoms. There are certainly issues with current topical corticosteroid options. I mean, we're basically MacGyvering up these things. There's nothing that's been developed for EOE specifically. So we're using asthma medications, which are repurposed for the esophagus. And oftentimes, that delivery of drug is not optimized for the esophagus. There are complex instructions we're telling our patients, you're going to puff this. And this is all off-label use, as you know. Puff this in your mouth, and then try to swallow that air as quickly as you can. Or mix this budesonide, and then swallow it down. It can be very challenging. It's not FDA approved, unfortunately. And there can be costs. So a lot of what we do of treatment is based on what insurance we'll cover for that patient. And patients have concerns with any medication about long-term risk. The task force also reviewed these long-term risks and found that there was no increased risk of adverse events when compared to placebo in short-term studies for these topical corticosteroids. There are scattered reports on adrenal suppression, local fungal infection, and viral infections. So the one thing I would say is in patients who are on these medications for long-term, whether or not it's PPIs or topical corticosteroids, once they're in maintenance, we do try to de-escalate their dose. And then we will do some safety lab checking on them as we go forward. What about dilation? This is a really important part of therapy in EOE. Over 70% of these patients are going to have, adult patients, are going to have profound strictures that need to be addressed. Medical and dietary therapy can affect strictures to a certain degree. And they can even open them up 2 to 3 millimeters just with medical or dietary therapy. But oftentimes, you're left with an area that looks like this or this. And these are big speed bumps in that esophagus. And if you don't get rid of those speed bumps, that patient is going to have a food impaction. And so dilation is going to be really important to do. And while this looks scary, this is the effect that you want to see after dilation. And the recent ASGE guidelines will tell you that dilation is going to be an important adjunct of therapy in EOE with the endpoint of mucosal disruption. So if you're just inflating a balloon and deflating it and you don't do anything different here, you haven't achieved an optimal effect for that patient. So that's really important to know. Different dilators that you guys saw in that sim lab yesterday, the savory dilators are these long, bougie dilators. And the balloons here come in either 5 centimeter length or 8 centimeter length. The guidelines looked at a meta-analysis of dilation in EOEA. And by far, this had the best clinical improvement. 89% will have clinical improvement after dilation. So there's no doubt patients feel much better after a dilation because you're getting rid of that obstruction. But it's important to talk about the adverse events. So about 10 years ago, everyone was very scared of dilating that esophagus because they were really concerned about perforation. But there have been no adverse events. But there have been many studies that have looked at those adverse effects that have shown that hospitalization, bleeding, perforation are really, really quite low. It's very safe to do if you do it conservatively. The biggest problem is chest pain. People can have chest pain and painful swallowing after a dilation. So that's really important for us to talk to our patients about before that procedure. And I talk to everyone about it in the clinical setting even before they get to the endoscopy suite. And I will put people on a liquid diet after that dilation to minimize that chest pain and discomfort. So take-home points for the dilation. It's best to reserve until after the effects of medical or dietary therapy have been assessed. Typical effect can actually last over a year. And a conservative dilation approach is really important. We always talk about starting low and going slow. So really kind of undersizing our dilators, not being too aggressive, stopping when we see that mucosal disruption. And the endpoint of these dilations are a target endpoint of 15 to 17 millimeters because we know that over that diameter, there's a decreased risk of food impaction. Under that diameter, there's an increased risk of food impaction. And you may need multiple dilation sessions to achieve that endpoint. We shouldn't get a patient to 16 millimeters all at once if they start off with an 8-millimeter esophagus. And the type of dilator is really determined by the type of structure. And people asked that yesterday. So if you have a stricture in just one area, that's oftentimes when we'll use a balloon. If you have a stricture very high up in the esophagus or the whole esophagus is narrow, that's when we would do that long tapered dilator, the saparate dilator. What about combination therapy and EOE? It's sometimes common in clinical practice. I don't typically use combination therapy because I never know what's helping that patient. And then we have to untangle and de-escalate all the treatments afterwards. And you get limited data to guide decisions. So oftentimes, I do a step-up approach in terms of therapy as opposed to hitting someone with everything all at once. The caveat might be if there's a new patient really active disease, I might put them on a PPI and a medical therapy or PPI and a dietary therapy up front just to cool them down, so to speak, and get them quiet as quickly as possible. But most people don't do combination therapy. What about response to therapy? I've heard several questions come up about, well, what about just symptoms? You put someone on medication. They feel great. Should we just leave it be? There's been a lot of data that have actually driven the answer to this. And one of the best groups is actually from Switzerland with Dr. Shipburn and Safraneva. And they've looked at various different PRO outcomes. And they've correlated it to multiple different things, endoscopic inflammatory remission, fibrotic remission, histologic remission at various kind of endpoints. And basically, what they found is that there's no correlation. You cannot rely on symptoms to make assumptions about a lack of biological activity. So it really is important to look at that endoscopic outcome. The other reason why you can't rely on symptoms is what we already talked about before, the impact. So I won't go through each and every one of these. But patients modify their diet. So we can't just say, hey, how are you feeling? It's not going to be as accurate. We really need some more objective data. So response to therapy measures, what are our ideal kind of things that we're targeting? Histology under 15, symptoms, resolution of symptoms, an absence of dietary modification, and endoscopy, reduction in those inflammatory features, and ideally maintaining that esophageal diameter over 16 millimeters. Should endoscopy be used to assess EOE after a change in treatment? I think we've answered that. We can't go based on symptoms. So the answer is yes. So this is data from the AGA task force that said use of endoscopy with biopsy to assess disease activity after a change in therapy is reasonable. The same type of statement was reasonably put out by the ASGE guidelines, also suggesting endoscopy with biopsy after a change in any type of treatment is necessary. Now, what is the data for chronic therapy? You've gotten your patient in remission. What do we do now? Do we just stop all therapy and just wait for them to have symptoms come back? Well, that's what was probably done about 10, 15 years ago. And knowing what we know with fibrosis, that doesn't make any sense anymore to shut off inflammation, turn on inflammation. It's really important to keep inflammation quiet. So the rationale for chronic therapy is that disease persists without treatment. I'm looking at my time. OK. Based on natural history studies and the placebo arms of clinical trials show that inflammation persists. Prolonged disease duration without treatment leads to fibrotic complications. You saw that in the studies that I showed you earlier. And disease activity recurs rapidly after stopping therapy. So this was the data from the fluticasone versus budesonide study. And 57% had symptom recurrence prior to a year after stopping therapy. The median time to symptom recurrence was 244 days. So what these are just highlighting is that recurrence happens. This is the time point where they stop therapy. Recurrence happens. And 57% will have their symptoms come back. So that's quite profound. And there was no predictors of recurrence. So that's the other thing. We don't know what patient is going to have recurrence versus not. We know that it's near universal. We don't know how quickly some people are going to have recurrence. But usually within a month or two is when we see it clinically. In that time frame where they took patients off medication, the EREFs increased. So they became more inflamed. The esophageal caliber decreased. And the previous dilated strictures narrowed back down to pretreatment diameter. So we're really doing our patients a disservice if we're taking them off all therapy. This is one of the nicest studies, even if it's a retrospective study. This is from the Swiss group. And they found that swallowed corticosteroids reduced the risk for long-lasting food bolus impaction. So it really shows the impact of being on therapy, meaning that in patients who stayed on their topical corticosteroids, they were much less likely to get food impactions than those that were off those corticosteroids. So it really shows how being on chronic therapy can impact those bad outcomes of the food impactions. The follow-up study done by Dr. Renge also showed that in patients who were on therapy, responders to therapy needed much fewer dilations than those that didn't stay on therapy or those that were not responders. And the data from the Budesonide or a dispersible tablet study, they also did a maintenance arm. And this was really nice to understand clinical relapse. What they found was that in patients who maintain that Budesonide or a dispersible tablet, the median time to clinical relapse was more than 350 days versus only 87 days on patients who stopped their therapy. So it really gives you nice evidence to talk to our patients about maintenance therapy. So who do I think are maintenance therapy candidates? My answer is everybody with EOE should be on maintenance therapy. But if the patients are pressing back on you, I mean, the ones I would push back harder on are those with that narrow caliber esophagus, recurrent food impactions, strictures, rapid return of symptoms off of therapy, prior spontaneous or dilation-induced perforations. This does happen to patients when they're retching. They can spontaneously tear their esophagus. And comorbid conditions increasing the risk of endoscopy or dilation. So if they have other diseases where putting them through an endoscopy does have an increased risk than the average population, those are people I would strongly push back on and say, hey, you really need to be on this therapy. And also, if they're traveling to areas where food impaction causes increased risk. We've all had stories where our patients have traveled to on vacation and ended up with food impactions and have had not so great outcomes. So it's something that we really want to optimize them the best as possible before they leave. So guidance with maintenance topical corticosteroids. And at the time of these guidelines, there was only data with topical corticosteroids, but the same can be true of any type of therapy we talk about. So in patients with EOE and remission following short-term use of topical corticosteroids, the guidelines suggest continuation of topical corticosteroids over discontinuation of treatment. What about the current status of novel steroid delivery systems and biologics? So there are a lot of these novel steroid treatment options. The first was a premixed budesonide slurry, which completed a phase three. The future of that, unfortunately, is not quite known. There is a fluticasone orally disintegrating tablet, which is completing a phase three study. And the Foc-Pharma tablet, the budesonide orally dispersible tablet, which has been approved in Europe, Australia, and Canada. And I'll show you data from that one. And this study was the budesonide oral dispersible tablet found to have an impressive EOE remission. And this was after just six weeks. So typically, when we treat with topical corticosteroids, we treat for about eight to 12 weeks. So this was just a short induction study, six weeks. They had a combined clinical histologic remission as their primary endpoint, seen in 58%. But then when you break it down to clinical histologic or endoscopic remission, really impressive results. Fluticasone oral disintegrating tablet has done a phase two study. And you can see here that there is improvement, histologic improvement in all doses of the fluticasone oral dispersible tablet compared to the placebo. And the number of eosinophils did persist after that initial maintenance stage. The eosinophils did stay low in the treatment arm. Moving now into the biologic pathways, we'll just highlight a few. I'll start with syndacamab. It's an IL-13 monoclonal antibody. It's in a phase three study. Dupilumab, you already know, we'll talk about some of that data is FDA approved. Lyrinetilumab is a Siglik-8 monoclonal antibody. Benrolizumab is doing a completed phase three. It's an eosinophil IL-5 alpha receptor antibody. Atrasamod is an S1P receptor modulator doing a phase two study. And IRL-201-104 is doing a phase two study. And that works a little bit more upstream on that inflammatory cascade. So dupilumab, we know, is an IL-4 receptor alpha monoclonal antibody. It inhibits the signaling of IL-4 and IL-13. And that's why I showed you those pathophysiology slides earlier so we can understand how all these things target those important hormones. And it was previously FDA approved. I'm talking to an audience that knows all this. But previously FDA approved for multiple atopic conditions such as eosinophilic asthma, atopic dermatitis, and nasal polyposis. And recently FDA approved for eosinophilic asthma and recently FDA approved for EOE based on these following studies. This randomized control trial showing impressive reduction in the eosinophil level, 65%, less than six, in the dupilumab 300 milligram sub-Q group. In addition to that, there was an impressive reduction in the symptom scores, the EREF scores, and even some compliance with endoflip data here. Syndacomab is an anti-IL-13 antibody. It inhibits the binding of IL-13 to the IL-13 receptors. It did a randomized double-blind placebo-controlled phase two clinical trial. It's doing a phase three clinical trial currently. In the phase two, they had a 16-week treatment with a low dose or high dose. Their primary endpoint was a change in mean esophageal eosinophil count. And here's the outcome of their data. You can see impressive reduction in both the high and the low dose of patients with histologic eosinophilia. And they found that this reduction was even more profound in steroid refractory patients. They also did an open-label extension and found that after putting people on open-label, they had improvement in their eosinophilia as well as their symptoms in the open-label portion. Last, we'll talk about refractory EOE in the last couple of minutes. And this is persistence after initial therapy. Patients have persistent symptoms, persistent esophageal inflammation, or a combination of both. So things to consider. Compliance. A lot of times it's compliance. Patients aren't taking their medication properly. They're not adequately dosed. They're taking too low of a dose of whatever they're on. They're having inappropriate administration of topical corticosteroids. I can tell you how many patients come to me who say, yeah, my last endoscopy, it wasn't good, and they were being given the nasal steroids and not the proper steroid dosing. They have fibrostenosis. They still have scarring and stricturing, and that's why they're not feeling better. And then there's an important part of hypervigilance, and that's something that we really need to remember, that some things that drive these PROs are that there is a high proportion, this is a data that came out of Dr. Taft, our GI health psychologist at Northwestern, showing a high amount of esophageal hypervigilance and symptom anxiety in EOE, even in patients who had normal histologic eosinophilia. So there is a secondary reason why symptoms are often being driven in some of these patients. So in summary, the goals of EOE therapy are symptom improvement, control of inflammation and prevention of complications of remodeling, shared decision-making informs management of EOE. I can't stress that enough. We have conversations with each and every patient. Each and every patient is an individual. We can't have blanket statements that this is the best therapy for everybody because it's not the best therapy for that particular person sitting in front of me. Both dietary and medical therapy are effective in most but not all EOE patients. Don't rely on symptoms alone to assess response to therapy. Increased attention to esophageal hypervigilance in patients with ongoing symptoms is important. And relapse is the norm after cessation of therapy. There's only one FDA-approved therapy and optimal positioning of dupilumab has yet to be determined. There are multiple compounds to treat EOE that are in the pipeline. So the future really is very bright for our patients and it's fabulous that there are so many people like yourself who really wanna understand this disease. So I thank you for that. I start first all the time. So I have a number of questions, but I want to ask the most pressing one in my mind. We understand that this is a chronic and often progressive disease, and patients still progress with suboptimal therapy, because it may silently progress, because if the clinician is relying solely on symptom improvement, there might be subclinical inflammation ongoing throughout patient's journey with EOE, since it's a lifelong disease. This was, again, an issue in IBD world 30, 40 years ago, and the development of biologics almost 25 years ago hitting the market and diversifying. Discussions moved from step-up approach to top-to-bottom approach, and the argument was that when do you need to hit this disease with an early aggressive treatment to prevent the disease progression in C. coli? Where are we going with treat-to-target approach? Where are we going with focusing on the progressive nature of the disease and determining when is the time to choose what treatment modality to really prevent long-term consequences? The first, in terms of treat-to-target approach, that's very important. Yes, we need to hit all those three endpoints to know we've adequately treated this condition. If someone has ongoing, really active histologic inflammation, that endoscopy looks bad, of course they're going to progress. But once we get people on proper therapy, their disease stays very stable. There is not smoldering fibrosis that's continuing to happen. When we do surveillance endoscopies on people who are actually on therapy and doing well, when we do those surveillance endoscopies, their esophagus is still open. They're still quiet. They're doing really well. But it's a matter of getting that patient to that point. That's number one. Number two, the beauty of the fact that there are all these things in the pipeline are that we can now start comparing some of these things, because we don't have comparative effectiveness studies to say diet is better than steroids, steroids are better than PPIs, dupilumab is better than diet, like all these things. Those studies need to happen to know if the outcomes are going to change. But definitely, I think your point about being on appropriate therapy long term is going to be very important to try and prevent that fibrosis. Thank you. I'm going to ask a follow-up question. In inflammatory bowel disease, we've evolved now and actually have some non-invasive markers to assess disease. For EOE, we're kind of relying a lot on repeated invasive endoscopy. Where do we stand in terms of non-invasive markers or other markers of disease activity? Great question. And I'm going to get to that, because I forgot to answer your second question. And remind me what your second question was about the treat-to-target and top-down step-up. So I think as we learn more in these follow-up studies on who may need that biological therapy or systemic therapy up front versus stepping up to that, we're going to be informed in the next 5, 10 years. I think there are some severity tools that are coming out now to measure disease activity. And that may guide us to who needs that top-down approach versus step-up approach. But I have a feeling, as history kind of repeats itself, we're going to go through the same path that IBD did, where we're going to be forced to kind of think about the step-up approach before we can think about a top-down approach. A lot of this is driven by payers, but I suspect that we'll have that. There's a lot of people that are very motivated to do this type of research. So that will help guide the answer to your second question. In terms of biomarkers, that's really important. Right now, we have to do an endoscopy to check the esophagus. There hasn't been anything that has panned out from a blood standpoint, a stool standpoint, a breath test standpoint that's really been very reliable. There are three different things that have potential. One is the esophageal string test, or the ENTRER test, which is now FDA-approved for assessing the esophageal inflammation. It's a cap... Do you guys... Does anyone know what this is? Or who knows what this is? Okay. So it's a little capsule. It was based on the old ENTRER test that was checking for giardia back in the 70s, and it was revamped and redesigned for EOE. It's a little capsule. It has, like, dental floss in it. Patient swallows that capsule, goes into their stomach, and the string comes up their esophagus, out their mouth, and it's taped to their cheek. It used to be a 24-hour test. It's now a one-hour test. The string gets removed, it gets put in a vial, it goes to the lab, and they give us an EOE score based on those eosinophil byproducts, eosinophil peroxidase, and a bunch of other things. And you'll get a score of active or inactive. So that can be very helpful in utilizing, for instance, if you're doing dietary therapy on patients, if you want to do surveillance on someone to see their disease activity. I think that has a lot of promise. The second thing is the Cytosponge. Cytosponge was developed for Barrett's esophagus screening, and it's, again, a little capsule with a little sponge in it. Patients swallow the capsule, the sponge gets pulled out. That was looked at by many groups, the Mayo Group primarily, in EOE, also showing a good correlation, and they did a follow-up study looking at dietary therapy and using the Cytosponge to help guide their therapy. It wasn't perfect, but it was reasonable. So that's number two. Number three is the transnasal endoscopy has been developed, first published by Dr. Freelander and Children at Colorado Children's using unsedated transnasal endoscopy, also by Dr. Philpott in Australia, looking at the esophagus in an unsedated patient. You can take biopsies with that tool, too. I will tell you, patients aren't yet ready to embrace this. They keep on saying how amazing it was in children. We're bringing this, in addition to the string test, to Northwestern, and I've talked to many a patient about this transnasal endoscopy. I'm like, hey, you don't have to take a day off of work. You just come see me in clinic. We do this in this room. I'm like, wait, you're not going to give me sedation? What? You're going to put something in my nose? What? So again, I think we're not yet there at people embracing this, but it is an option. A lot of work is being done on biomarkers. That's a huge area right now. Yeah, go ahead. I just want to go to the work order for like time of care. Yeah. People are responding, we're doing a learning curve study. Look five years down the line. You're going to diagnose, you're going to say, I think you might have EOE. It's going to be like an ENT doctor. You're going to drop a scope right there. It's like, they don't even go home, and now you make the diagnosis. I think that's where we're headed. I mean, it's really that good, so. So we've done this in patients at Northwestern, we've done this in the model. It is a great tool. Patients just maybe need to be more accepting of it. I think in children, there's a lot of traction, because kids get general anesthesia, you know, it's a big deal. You can do it in a five-year-old. An adult, you're just going to like, you're going to make the diagnosis. Now the question is whether they're like, okay, give me a medicine for this thing I'm experiencing that brought me into clinics. I know. Come talk to my adults. They're wimps. I will say, 10 years ago, I would stand up, I stood up at the ASG postgraduate course, and talked about diet, and frankly, I remember Grace Elta told me, no, you can't talk about diet to adults. They won't cut anything out. And I said, all right. So I took out the slide, and there you are talking about diet, so, you know, sorry. True. And, you know, I've got to say, this is a funny story. This is totally a one-off, but the whole diet therapy study came from a bet that I made with Dr. Chris Leopolis at Children's Hospital in Philadelphia, and we were talking about adults and children with EOE, and if it's the same disease or different, and I was being, you know, I was just a 30-year fellow, and I'm like, it's totally different. Adults don't have food allergies. And he's like, all right, let's, I bet you. Put them on this diet. I was like, I'm never going to get a single adult to stick to this diet. And lo and behold, we had 50, and they responded. So I was totally proven wrong. But it's just funny how life turns out. Other questions? In the back. Yeah. Hi. Thanks for that presentation. It was really great. And I'm like you. I could nerd out on pathophysiology, but there's a lot of the community-based folks who are non-EOE experts. In your opinion, what are some of the things that we need to do to make sure that we're getting the right people to do the right thing? I mean, you know, there's a lot of things that we need to do to make sure that we're getting the right people to do the right thing. I mean, there's a lot of things that we need to do to make sure that we're getting the right people to do the right thing. What do you think are the most important aspects of pathophysiology or type 2 inflammation that they should know that would help with the outcomes of their patients with EOE? Yeah. I mean, I think that's a really great question. Very simple things, really. I mean, the same for us. Like, we put it in very simple ways in our minds as gastroenterologists, right, when we think about immunology. We can talk about the fact that this is a very allergic disease. People with this condition have seasonal allergies. They have atopic dermatitis. They have food intolerances and food allergies and asthma. And those diseases drive certain allergic hormones that are revved up in that esophagus and revved up in the blood. And if there are therapies that can decrease some of those allergic hormones, that can help in multiple ways. And that's how I talk to our patients when I go through different therapies and I explain to them why we're targeting certain cytokines and hormones. But putting it in the context of the fact that that patient that you're dealing with might have all these other allergic conditions as well that may benefit from some of these therapies, targeting kind of that deeper immune system is important. Maybe another question. You showed some data that the Budesonide really had an impressive response. And why did the FDA not approve this agent for the US? That is such a loaded question. So we're still, a group of us that were heavily involved in all the consensus guidelines have been discussing that particular study with the FDA. And it's really not clear why it got shut down. The impressive results were from the Budesonide. They had great results. The impressive results were from the Budesonide or a dispersible tablet. And that was done in Europe. The study was done in Europe. And the EMA approved that so quickly. And shortly thereafter, Australia and Canada. And their results were amazing. There's a lot of interest in bringing that medication over here. But there's been a lot of resistance or nervousness about dealing with the FDA as opposed to the EMA. There are lots of different standards that I'm not necessarily privy to. But we have not been able to convince them to do a study in the US yet. You mentioned shared decision-making. That is one of the most common things that I hear across the spectrum. What are the tools that you would use to help inform, educate, or what else can we do to help give you the tools to inform and educate on that shared decision-making model? That's a great question. I think it's really funny that there's this term shared decision-making because it's something that we've done in medicine and we've been trained to do since we were med students. We've always done this. There's just now a term for it. The idea is that you're having a conversation with your patient about options, and you're not just telling your patient, you're going to take this. You're having that discussion about here are the pros and cons, what is important to you, what are your goals of care, and you're making that together. A lot of us have done this for years, but education, like educating our patients is really important, and them educating us in terms of what they want. A lot of that discussion gets guided based on what that patient wants. That's what I would say. That needs to happen with every patient. The discussion is very different with different people. I wanted to add just two things from questions that came up earlier. One is the seasonality. I wanted to just clarify that. There is absolutely seasonality in terms of eosinophilic inflammation in the esophagus. There are several studies, lots of studies that have looked at that. You can get higher numbers of eosinophils in the esophagus in high pollen months. There's even been an abstract at DDW that suggests that dietary therapy is not effective in high pollen months. Those error allergens can drive eosinophils in the esophagus. The second is the whole question about reflux and EOE and the numbers of eosinophils. I think it all comes down to the fact that it's not a one bucket or another. A lot of people have an overlap. I have seen people with really bad erosive esophagitis, a hiatal hernia, who had 90 eosinophils, but they respond to a PPI because their reflux was the driver of those eosinophils. So we really need to have that clinical discussion with our clinicians and our pathologists. We can't just say, hey, or expect to have a path readout that says this is EOE or this is GERD because that's unrealistic. I had a question about your perception, having dealt with patients with multiple treatment modalities, about whether or not one treatment is more of a topical application of calming inflammation that already exists versus perhaps the biologic therapy now or those to come have more of that preventive, right? So the inflammation doesn't happen in the first place. Proactive versus reactive, and does it matter? I think that's a great question. I don't think we know if it matters yet. I think comparative effectiveness studies need to happen, right, to be able to really understand if one therapy is going to be better than another. We know that PPIs are very effective at histology, symptoms, and endoscopy. We know that topical corticosteroids are very effective at histology, symptoms, and endoscopy. We know diet, same, dupilumab, same. They all are effective at getting those endpoints. Long term, we don't know. I think where the systemic therapies tend to really play a role are people who really have those allergic drivers that are not being optimized with other therapies. I think of dupilumab and biologics as systemic therapy. I think of dietary therapy as systemic therapy, as do most of our EOA experts, because we're taking away the root cause, the main driver. So I think people who are more severe need more of that systemic therapy. I might add to that, because I put question about the extra esophageal manifestations of eosinophilic esophagitis. You see a lot of patients with EOE. So do you typically see a pattern in constitutional symptoms that patients present with that are beyond esophageal dysmotility issues? There are a lot of symptoms that patients may have with EOE that are unexplained. I mean, there's a whole atopic symptoms, right? They have bad atopic dermatitis. They may have bad asthma, seasonal allergies. And basically, that person, not even anecdotally, but in clinical case reports and whatnot, are difficult to treat, because if we can't get all the surfaces under control, you're likely not gonna get that esophageal surface under control. But there are a lot of studies that show a high level of fatigue, depression, anxiety in EOE and non-EOE agents. There are a high increase of myalgias, arthralgias, lots of different nonspecific symptoms that aren't really understood. And that's based on patient advocacy groups doing a lot of survey studies on the patient population to understand headaches, is another one, to understand other symptoms. Yeah, so I've heard that about the headaches and those kind of things. When you put someone on treatment, do you find that those constitutional symptoms improve? They do. Okay, thank you. Yeah, they do, weirdly enough. And I can't explain the mechanism, but they do. So I wanna make sure that I looked at the graph appropriately, but the elimination diet, I believe it said that it starts with seafood. Is that still the case? I've heard recently in the community that a lot of my providers are starting with dairy. Yeah, so that's the reintroduction. That's the reintroduction. So once you do a six food elimination diet and that patient is clear, the question is, how do you reintroduce foods? And we used to, when we started off our study, let the patient pick, and they would always pick milk and wheat because that's the hardest thing to avoid. And they would always react. And then we'd have to stop the food for six weeks. So it just made the process longer. So we've changed it to reintroduce the least likely culprits to most likely. If the data, and I didn't show you the data here, but just so you know, the effectiveness is different depending on what you're avoiding. If you're avoiding the six foods, the effectiveness is 70 to 75%. Four foods, about 50%. Two foods, milk and wheat, about 44%. And that single food, just milk, anywhere from 30 to 40% in a clinical trial and up to 50% if you're doing it in kids. So that's what your providers are talking about. If you're just going to do one, then in adults, it would be milk or wheat I would recommend. You ever do two foods or one food elimination? I have that conversation with a patient. I say, hey, listen, this is what we know. This is the data. What would you like to do? No, and the other big mistake people make is if you do just the top two, like you do milk and wheat, and it doesn't work, you're not stopping milk and wheat and just taking out soy and egg. You're keeping them off milk and wheat and then taking two more foods out. So it's a stepwise approach. So that's just what people need to understand. But yeah, some people we start with just two. One last question based on your experience, if you have this experience, obviously. How do you describe the mechanism of action of different treatment options when you're talking to an adult who doesn't have a scientific background? For instance, if you need to talk about the pig scent, do you mention anything about how it works systemically via IL-4 and 13, or do you not go there? Oh, I go there. My patients know more about EOE. My nurses get so annoyed with me because I spend so much time with them. But no, I think it's important. It's important for the patient to understand why we're giving them the treatment. So I will tell them, here's this medication. It's an injection medication. It targets two allergic hormones that are revved up in people with EOE and other allergic conditions. And how it works is it helps to decrease these allergic hormones to prevent those eosinophils from going to your esophagus and blah, blah, blah. So I do put it in a context where they can understand what the drug is actually doing and how it's helping to prevent the eosinophils. I do the same for diet. I do the same for PPIs and topical corticosteroids. I tell them how it works and why it works. And then we go through the risks and pros and cons and things like that, yeah. Thank you. OK, if there's no other questions, please. Can you sense the passion that she has for EOE? I love this.

eosinophilic esophagitis

pathophysiology

treatment

food allergens

cytokines

PPIs

topical corticosteroids

biologics

shared decision-making

non-invasive monitoring