All righty. So polling question, is this a good time to do that, Michelle? Yes. Okay. So what is the most important resource for you as you diagnose and treat EOE patients? Is it access to endoscopy, access to dietician, insurance approval for medical therapies? Those are the three that came to mind as I was thinking about what would be important to us. We know we need EOE to be diagnosed endoscopically, so making sure that we have access to endoscopy is crucial. Insurance approval is essential as well. I think access to a skilled dietician is also critical, and we'll talk a little bit more about that, of course, through the course of the day. All right, another polling question, which approach to treating EOE do you think will be received best by your patients? PPI therapy, swallowed steroids, dietary elimination, dilation, or biologics? Well thank you for your participation in that. Let's get in to a big overview. I hope this presentation will serve as a solid foundation for all of the other presentations that our esteemed faculty are going to be delivering today. We'll talk about the definition in history. We'll go into the epidemiology. We've got attendees from all over the world, so that tells us that EOE is being seen in parts of the world perhaps that weren't being seen before. It's important to understand that epidemiology. How do we make the diagnosis of eosinophilic esophagitis? How we patients will present, and we'll show you that with some basic studies and then case studies that will be presented through the course of the day. And then we're going to go through some treatment options to discuss with your patients on how we're going to treat them with their EOE. All righty, I have no relevant disclosures. Here's a case presentation. We have a 21-year-old male college student who presented to the emergency department with a sudden onset of inability to swallow water, even saliva, while eating turkey at Thanksgiving. That's obviously coming up here. While in the emergency room, his symptoms suddenly resolved and he was able to swallow water again. He presents to the office for evaluation. He describes having years of this uncomfortable, slow transit while he's eating. His history is notable for some asthma as a child. He has seasonal rhinitis as well. Doesn't really report having much acid reflux symptoms. GERD is not a major concern for him. And he does take antihistamines over the counter for his allergies. And his physical exam was normal. What are the causes of his dysphagia? Of course, EOE is going to be high on that list, right? Let's not forget that. One of the things as we're trying to work through seeing patients with dysphagia, is there anything else that might be the case, right? We don't want to jump to EOE right away if a certain patient shows up with what we think are classic symptoms. Could it be a Schottky ring? Could it be a peptic stricture from significant heartburn over the years? Could there be a motility disorder? Less likely because the history didn't seem to suggest that. And then a variety of different things that we have to think about whenever we're seeing patients and whenever we're about to perform endoscopy. Are there anything, is there anything else in the differential that we're potentially missing? So this patient does get an upper endoscopy. And what we see on endoscopy are classic findings of eosinophilic esophagitis. We see the linear referrals. We see edema. We can see concentric rings. We can see some whitish plaques here that are corresponding to eosinophilic microabscesses. But as an endoscopist, when I see this, EOE becomes the highest on my differential diagnosis. This is what a normal esophagus looks like to give you some contrast. So this is what we'll typically see in patients that are coming in for other GI symptoms. And if you contrast that to what we see here, you can imagine this can cause some significant symptoms for our patients. So we're going to spend a lot of time talking about what EOE is defined as, and it is defined as a chronic immune mediated food antigen driven disease. We know that it's an allergic condition, right? When we're talking to patients, we're describing it. I think of, I call it the asthma of the esophagus, but really isn't aero allergens that are driving most of the inflammation. It is food. And we'll talk about which foods those are. And the symptoms are related to years potentially of esophageal dysfunction. Dysfunction that's happening underneath the surface is causing symptoms that can lead to dysphagia and fibrosis and other concerns. And we'll talk about that. The way that we make the diagnosis of EOE, of course, is with biopsies and pathologically we need one or more biopsies to show eosinophils predominant inflammation. We've decided over the research that greater than 15 eosinophils is considered the minimum threshold. So we can see eosinophils in GERD, five, six EOs per high power field. So once you get above 15, 20, 30, 70, for example, you might see that in your patient's biopsy specimens, EOE is way up there. Now there are other causes of eosinophilia and it could be a more systemic eosinophilic process. But to make the diagnosis of EOE, it has to be isolated to the esophagus and you have to rule out in the right case, other causes of eosinophilia. Dr. Saleri is going to spend a lot of time talking about histology. She does a great job in terms of laying out the importance of understanding the pathology behind it. But what we'll see later in the lectures is that there are some eosinophilic infiltrations, we get micro abscesses, there's all this epithelial hyperplasia, the cells are growing in response to the inflammation. We get fibrosis over time and that kind of inflammation over a period of weeks, months, and in most cases, years, is what leads to the symptoms that we see in EOE. Most of the respondents said that they're treating predominantly adults, but EOE was first really diagnosed in children or really appreciated in children. We can see there's a bimodal distribution. First generation of EOE patients present somewhere between five to 10 years and then life kind of gets busy and then the next diagnosis shows up perhaps with a food bolus impact in patients in their 20s or 30s. One of the things that I wanted to highlight here is that there are significant years of living with an incorrect diagnosis and patients somewhat just think it's no big deal. Maybe they're just having a little bit of reflux or they chew more slowly at the table compared to their families, but there is a long time between the onset of symptoms and the correct diagnosis and that's opportunities that we are missing to be able to prevent fibrosis, long-standing inflammation, and potentially complications with EOE. I mentioned earlier that EOE is associated with other atopic symptoms and diseases and I think Slide is important to know that when you're talking to patients about trouble swallowing in your clinic, one of the first questions after you ask, is it solid, liquid, or both? Is it dysphagia from solids or liquids or both? Asking them what type of atopic allergic history they have and you'll find that in children especially but also in adults, there are quite a bit of sensitivities and various manifestations. Sometimes EOE is the first manifestation in what they call the atopic march, but a lot of times you'll look and you'll find that there's some other symptoms they had either as a child or even as a younger adult. As I mentioned, EOE now has a global presence. The fact that we've got guests from Malaysia and Brazil and Europe and Africa tell us that EOE is something that is on their radar and most of the studies have come from North America and Europe, but what we're seeing is that as the amount of atopic disease increases globally, not surprising, EOE is going to come as well. Same thing happens with ulcerative colitis and Crohn's. There are parts of the world where we hadn't seen that for many years, but now as the dietary landscape, the environmental landscape is changing, whatever the reasons are, we're seeing it globally. In the United States, this is a busier slide, but basically we're looking to see what the age range is for patients. You can see that most of the clusters happen between, we'll say, 15 and 45 in terms of patients coming in with various symptoms. This is data from Dr. Dellon and his group in North Carolina. When you compare EOE to other disorders, just to give you some perspective, obviously, if you've ever taken care of patients in primary care, you're going to see asthma. That affects about 7% to 8% of the population. Seasonal allergies hits about 40% of us in the US. We think EOE probably affects about 34 per 100,000. It just seems like EOE is everywhere in our world, but in the grand scheme, it doesn't seem like it's that prominent. There might be some data that's changing and showing us that we're just at the tip of the iceberg. Then eosinophilic gastrointestinal disease, EGID, is even much rarer. As I mentioned to you, about 78% of patients total have at least another atopic condition that we need to look into. The pyramid, as I mentioned, the tip of the iceberg or the pyramid, there's different prevalences depending on what studies you're looking at. It just gives you some perspective that we're looking at it from a global landscape. What happens in EOE? This is a diagram from a paper that I had written as a fellow. There's a lot more information that we know now compared to what we did 15 years ago when the paper was written. What essentially we think happens is food allergens get swallowed, and then what we see is an intense immune-mediated reaction, Th2, a ton of cytokines that are going to be secreted. Those cytokines and those pro-inflammatory mediators will be some of the targets for the treatment. Over time, we'll see, and what Dr. Olson will show us, is the esophagus gets pretty angry and it loses smoothness as it loses its contractility, and we get narrowing and rings. That's what it looks like radiographically. You already saw one slide with EOE endoscopically, and then what we see is an intense eosinophilic infiltration at the cellular level. Why do we care? Well, EOE doesn't cause cancer, at least we don't think it leads to. It's not a precancerous condition like we think of, say, Barrett's esophagus or colon polyps or other things that we see in the GI world. We do know that with persistent inflammation, we go from a normal caliber esophagus and normal histology to intense inflammation to the development of fibrosis and inflammation, and eventually to the point where patients are going to need dilation to help improve the caliber of the esophagus. It's this diagnostic delay of seven years on average that is why patients are showing up in the emergency department with a food bolus impaction, and that's why sometimes they need both anti-inflammatory treatments and eventually what I call the reset button with a dilation. To emphasize that, the natural history and the diagnostic delay, the slide on the left showed that the prevalence of fibrotic features increases from 47% to 87% when we have diagnostic delays of two to 20 years, and every 10-year increase in age, the odds of a fibrostenotic phenotype more than double. We've heard fibrostenotic, right, in Crohn's disease. Any type of inflammation is going to recruit fibroblasts, you're going to get intense deposition of fibrin and basically scarring, if you will, if you want to talk to patients about that. Every time we wait when we're talking to our patients, the odds increase that they're going to come in with longstanding, with more complicated esophageal dysfunction. Same kind of idea, just to emphasize that the risk of stricture is increased by 9% each year. If you're having patients that say, you know, I don't think I want to get on any treatment, this is hopefully some information you can provide to them and say, time is important here, that we are losing valuable time in trying to prevent the disease from getting worse for you. All right, so we know that patients present in a variety of ways. I'll leave the majority of the talks on pediatrics to our pediatric colleagues, but children don't present with food bolus impactions. In infants and toddlers, we see feeding difficulties, failure to thrive, fussy kids, things that we think of could be related to anything. So you have to have a higher suspicion in much younger kids. But in older children, they might present with atypical reflux, not classic symptoms. They may have dysphagia. They might have some choking or gagging with meals or vomiting or regurgitation, not being able to sleep and decreased appetites. In the adult world, dysphagia accounts for the vast majority of patients that we see. Food impaction is certainly higher on the list. Heartburn, perhaps. Patients have been on a variety of acid suppression medications and have not found the same type of response. Chest pain, certainly we see from time to time, and possible, but less likely, some upper abdominal pain. And this is a chart that you can use as a resource to look at what the typical presentation is by age. Obviously the further along we move in this march to inflammation, the more fibrosis there is in that one continuum picture, our slide that I showed you, and not surprisingly, as we get further along in age, symptoms of food impaction become more prominent. All right, as far as adults are concerned, male predominance, three to one at this point, presents typically in the third or fourth decade. As I mentioned, there's an atopic history, 71% of patients in the initial studies were white. As EOE becomes global, we're going to see that demographic portion shift. There is a family history and some case studies of EOE and atopic disease, dysphagia, food impaction, the other symptoms that we discussed as well. All right, so this is what we encounter as endoscopists when we are taking care of patients with EOE. There's a score that's developed called eREFS that looks at ways of objectively determining how serious the patient's endoscopic EOE findings are. This kind of feels a little bit uncomfortable. You can imagine these rings can make pieces of chicken challenging as it's going down there. There's linear furrows here, again, can influence how food is being moved from the proximal to the distal esophagus. When we see these exudates, those are all eosinophils that are clustered. Usually, we find a pretty significant amount of eosinophilic infiltration on biopsies. This is what I see sometimes at 2 in the morning when patients are coming in after having swallowing some meat 12 hours prior and thinking they could just let it sit there and it'll pass. I'm not on call on Thanksgiving this year, so I'm happy about that. Now with time, these strictures can become pretty serious. This is an endoscopic finding as well as radiographic findings of what we see. You see quite a bit of scarring. This is where the food gets stuck. This is where food gets hung up. Then radiographically, you'll see that rather than having a nice smooth esophagus, we have a significant ring that is impairing the transit of contrast through that area. It's a pretty severe case, of course. All right. I think we're doing pretty good on time. How do we treat this? Let's go back to the definition, chronic, immune-mediated, food-antigen-driven disease whose symptoms are related to esophageal dysfunction. We need the pathology to confirm that we have this eosinophilic inflammation, and we need to see 15 eosinophils per high-powered field. The goals of treatment should be deep remission. We hear that term in patients with Crohn's disease, and I think it takes a little bit of a paradigm or mindset shift in terms of EOE, because we know Crohn's disease patients end up getting surgery, and they end up getting fistulas, and getting deep remission in those patients seems like the ultimate goal. Now that we realize with EOE that this is a chronic condition that can lead to fibrosis, trying to achieve deep remission is essential. Now, how do we consider the initial choice of therapy? Obviously, we want to look at efficacy, right? Which one works better? We want to see if the side effect profile is something our patients' preference in terms of how they want to get their treatment. We have to look at disease severity. Not every EOE patient has severe disease, and so that's going to make a difference. In the United States, insurance coverage for these medications can sometimes be problematic. Some of the newer medications can be more expensive, and so sometimes there has to be some failures of other therapies to get the treatment covered. Dietary resources, which we'll learn more about later today as well, and then depending on the age of the patient. I mean, in the pediatric space, there's a lot of shared decision-making. There's going to be a lot of things that need to be considered when you're taking someone who's 17 years old to now being an adult at 18, and having some more autonomy and agency in the way they're getting their treatment. All those things are very important, and it comes from establishing a good relationship with your patients over a long-term horizon. All right, this is a busy slide, and you've got to have one slide that has all these mechanisms and everything else, but essentially what we're looking at is we've got milk, we've got eggs, we've got meat, we've got maybe some microbes that are touching base and contacting and kind of talking with the esophageal epithelium, and in patients with EOE, we've got a ton of different things that kind of go off, right? So here we've got opportunities to eliminate the causes, food-driven immune-mediated processes. Here we've got an opportunity for proton pump inhibitors to potentially work. We'll talk a little bit about how that might work. Topical steroids, right? Whenever we think of inflammation, whether it's prednisone for our IBD patients or asthma inhalers for patients that are obviously with asthma, steroids can work by controlling inflammation on a pro-inflammatory cytokine level here. And then further along the road, we find the places where dupilumab, which is the biologic that's been approved for EOE is located, and then proton pump inhibitors can also work in different places to help control inflammation. So this is just a way to show that when we're trying to find targets, understanding the basic mechanism is essential. All righty. So what are our goals for therapy? Symptom improvement, right? Any patient we take care of, we want to make sure that they're feeling better. We could talk about how many eosinophils are in their biopsy specimens, but if they're suffering, that really isn't the most important part. We certainly want to control inflammation because we know that this is a chronic condition and remodeling from fibrosis can lead to long-term esophageal issues. And so we want to try to prevent that. And depermission, as I mentioned, trying to make sure that they're clinically in remission, that they're endoscopically looking healthy, but then the biopsies are telling us that we're back down to what we would think of as a normal eosinophilic concentration. Proton pump inhibitors, of course, any of us in GI know that we use these on a daily basis. And what we found over the task force recommendations is that the overall effect of getting eosinophils down to less than 15 was about 42%. That's not bad. The data isn't super strong, but anecdotally speaking, we have a lot of patients that can do better with just PPI. And I'm not surprised on that survey that a good chunk of the respondents felt like that was a good place for us to start. We're familiar with the medications. Patients are familiar with the medications, despite hearing in the news about all the potential side effects of PPIs as a whole, they're very well tolerated and they're safe. So not surprising, PPIs can and are oftentimes the first line therapy for patients with EOE. Practical tips. So what I tell my patients is if I'm living in a bad neighborhood and people are trying to break into my house, if I open up the windows, it's going to be a lot easier for them to break in. And so what we think PPIs do is by decreasing the acid, by mediating eotoxin and other things kind of on a cellular level, they close all those cells up from getting provoked by those food allergens. And so that's the way that I, when I talk to patients about PPIs and it seems to resonate with them, that what we're trying to do is create a tighter barrier so that that the food allergens don't provoke the immune system underneath the cells. One of the questions I'll talk to you about, it will say is, but I don't have heartburn. Why are you putting me on a medication for heartburn? So explaining to them why we're using a PPI is crucial. We typically start with twice daily dosing, and if it's effective, we can wean the dose down to a lower dose. And what we will talk about is, you know, we need to bring these patients back at some point to confirm that the treatment is working. Patients will often say, but I'm feeling good. Do I need to come back in? Now that I hope we understand a little more about the way that eosinophilic esophagitis causes inflammation, the answer is yes. Topical corticosteroids, again, that was, this is an old Pepto-Bismol commercial that back in the days when I was a kid where you would see the Pepto-Bismol coating the lining of the esophagus. And so when we're talking about topical steroids, I use that as an example. I don't know if anybody even knows how that works, but that's a cool picture. So in any case, we have topical steroids, they work, they're effective, and we have now a new FDA approved version of budesonide called eohelia. And when I talk to patients about topical corticosteroids, I mentioned that what we're doing is basically, you know, treating the inflammation like we do in asthma. Here's number four, topical corticosteroids. I mean, overall effect is 65%. That's a strong recommendation with moderate quality evidence. But these treatments work. This is the studies that looked at the eight week randomized controlled trial of budesonide versus fluticasone. And the histologic response was anywhere from 64 to 71%. So we know that when the patients are on the medications, when they're taking the medications, we can get the eosinophil counts down and get them into remission. This is the study that came out on the now FDA approved version of budesonide, brand name is eohelia. And what they were able to show is they used stringent histologic response, they said less than six eos. We don't want to have any confusion that we're getting the job done. We don't want to base this on any, you know, sort of potential background noise. And what they found in this particular study, 53% were able to achieve stringent histologic response and their dysphagia symptoms improved. 62%, I should say, of patients got less than 15. So it works. So with the oral suspension, anytime we're obviously dealing with topical steroids, there's always a chance for esophageal candidiasis. That's usually 5% or so. We typically can treat that without having to stop the budesonide if the patients absolutely need it. Oral thrush, of course, there's a decrease in serum cortisol. Some discussion about, you know, checking, you know, AM cortisols on a yearly basis in certain patients that have been on the medication long-term, it's not an unreasonable thing to do. I've not seen any patients with an abnormal serum cortisol in the patients that I've been checking. And then I don't know who does ACCT simulation tests, but they're available and they're abnormal in about 5%. All right, so this is some take-home, some practical tips. We use the budesonide oral suspension two milligrams twice daily for 12 weeks. So then what? That's the problem. So this medication is approved for 12 weeks, but we know that unless we do something with the allergic environment, there's going to be relapse. There's some compounded adaptations you can do as well. If you can't get your hands on the brand name now, you can get budesonide suspension. Sometimes insurance don't cover them. They can be, you know, quite expensive on the order of $100 or more per, you know, month. And then you can typically, you can use fluticasone inhalers at 1,760 milligrams, typically in divided doses. We want them to take them after breakfast or before bed, no eating or drinking for 30 to 60 minutes. And that dosing is important to explain to patients because this is a new journey for a lot of them, especially if the patients are younger and this might be the first time that they're using this medication. And it's important to stress that even though they might start feeling well at week one or week two, really ideally you want to treat them for at least 12 weeks before we start making decisions about continuation after that. All righty. There are, there is a biologic that is approved for eosinophilic esophagitis and that's dupilumab, brand name Dupixent. And it is a monoclonal antibody to IL-4 and IL-13. So that pathway that I was showing you about where those things can get interrupted, it has been used for a variety of atopic conditions that preceded eosinophilic esophagitis, atopic dermatitis, asthma, COPD, patients with rhinocinusitis and nasal polyps, and then recently, relatively recently got approved for EOE for adults and children aged one and older, weighing at least 15 kilos. What does the results show? These are again, stringent, deep histologic remission. We see that compared to placebo in the first group, there was a 60% of patients that achieved histologic remission. It did not look like there was much of a difference between dupilumab weekly or every two weeks at week 24. And when that was spread out to one year, the numbers were about the same. So we're noticing that regardless of the treatment, you're looking at any about any way, anywhere from 40 to 60% response. This is just a slide that shows what the change in dysphagia scoring was compared to placebo. It looks like patients noticed a significant improvement in their symptoms as well, which of course is important. Anytime we're talking about medications like a biologic, patients get scared about that because they watch commercials and they hear all the potential side effects when they go through their list of things, at least here in the United States. Just like any other medication, we have to have an informed discussion with them about what makes sense. So 17 to 22% of patients will have some injection site reaction, some erythema, some nasopharyngitis might occur. What I tell my patients whenever I start them on biologics, whether it's for EOE or for Crohn's or ulcerative colitis is, if something doesn't seem right to you, it doesn't matter what it is, just call. That way we can determine whether this is an adverse event from the medication, whether this is something else related to the underlying condition, or maybe it's not related to anything at all. But I always stress the importance of just call, reach out to us, let us know so we can determine if we need to change or pivot in a different direction. Practical tips, as I mentioned, it's indicated for anyone one year or older. The dosing is with an autoinjector, depending on the weight, you can give it every week or every other week. There really hasn't been any significant recommendations for routine labs, pre- or post-treatment at this point. We're trying to figure out where to bring these patients back as far as endoscopy is concerned. Typically, three months is a reasonable time, three to four months, potentially, maybe six, depending on how they're doing. It's not practical for most patients to have their endoscopies every two to three months. If they're doing well, they're tolerating the medication, you could potentially space that out a little bit. How do we think about using dupilumab? If these patients are coming in with significant dysphagia symptoms, significant eosinophilic infiltration, they've got other comorbid atopic conditions, at that point, you should be thinking about maybe escalating the care. If they are on maintenance therapy with, say, topical steroids, and every time they cut off of the budesonide or the fluticasone, they flare up again, that's another potential indication to start as a first-line therapy. We haven't talked much about dietary, we're going to wait a little bit later when Bethany talks about that with us. Some patients are saying, look, I have a patient who was a dairy farmer, and I'm asking him to avoid dairy, and he says, I really can't do that, and I really don't want steroids and I'm scared of PPIs, can't I just do something that I don't have to think about very often? That's potentially one option for that. With step-up therapy, obviously, you failed the first-line approach, perhaps it's PPIs, perhaps it's topical therapy with steroids, perhaps it's dietary elimination, and it really hasn't worked well. Or you're showing up with some pretty advanced fibrotic changes that some patients' phenotypes just move much quicker than that time frame that we showed, at that point, you really want to be more aggressive about modifying the disease as opposed to just treating the inflammation or the downstream consequences of it. So Bethany Dorfler from Northwestern is going to talk to us about dietary elimination today. She'll certainly provide a comprehensive assessment of what we typically do, and I'm really looking forward to that. Our colleagues, Sarah Anslin and Dr. Tawani, are going to talk about endoscopic dilation, what I mentioned earlier is the reset button. Sometimes you can give these patients a variety of different treatments, at the end of the day, you have to improve the caliber of the esophagus, you have to open up the esophagus to let them swallow, and then you can deal with the ability to treat their underlying disease to prevent them from having more problems with a narrow-caliber esophagus. This is a treatment algorithm. Sarah will present another one that we had provided in a paper that we had published last year, but this is one that I think is pretty easy to move through. You've got the diagnosis of eosinophilic esophagitis, you sit down with your patients and you ask them, what do you want to do? These are the options. Do you want to try medical therapy? Do you want to try dietary therapy? As we go through response or non-responses, we can add them to their armamentarium. It says here, allergy testing directed. Sometimes in certain patients, if they have significant atopic conditions, we can offer them allergy testing, but the consensus is that it's really a coin toss about certain foods. Patients will ask, hey, well, why don't I just get tested for wheat rather than just avoiding wheat? Why don't I just get tested for dairy rather than avoiding dairy? The correlation isn't very, very strong. It's about 50%. We don't typically recommend that. As I mentioned, sometimes they need that reset, they need the dilation, and then all of our patients with EOE will need maintenance therapy. It's not periodic dilation. It's being on the medical therapies, the dietary therapies, whatever is necessary to control inflammation long-term. That's it for me. Thank you.

eosinophilic esophagitis

endoscopy

treatment approaches

proton pump inhibitors

biologic treatments

symptom improvement

patient assessment