I will say that, as I reflect, one of the things that I very much value in my career is some of the volunteerism that has happened through my career, where you're doing things without getting paid anything, and it's really the connections you have with colleagues and the ability to form relationships and really contribute to some aspect of moving medicine forward, and in particular the ASGE. I think Dr. Kolb yesterday talked about her engagement with ASGE and what that's meant to her, and I think there's opportunities for everyone to kind of get involved with a medical society, whether it's ASGE or some other society, and really make a difference. And so part of my goal today is to really introduce you to potentially an opportunity. I have no financial disclosures to share with you, and it's really about the ASGE Train the Trainers program with eosinophilic esophagitis. The goal of this, and it is, I co-chair our steering committee with Pratik Sharma, and our goal is really to improve the care of patients with EOE, and I'll share with you an anecdote that just happened on Labor Day weekend when I was on call. It is sponsored by some of our industry sponsors, including Sanofi, Regeneron, Olympus and Fuji, but this program is developed and designed by the ASGE, not by any of these industry partners. And some of the information that you're going to see, most of the information I'm going to share with you today, has been developed by our steering committee, which is made up of international experts in EOE. We have dieticians, we have pediatric GI, we have adult GI thought leaders, we have community practitioners, we have APP, we have fellows, and we have primary care physicians, all contributing with their own expertise to the development of these training modules. And these training modules will be available to trainers, and that could be you, to go into your community and really raise awareness of EOE, and ultimately improve the care of patients with EOE. So, anecdote from a week and a half ago, Labor Day weekend. I'm on call, and I get the dreaded call of a food bolus, right? And so we come in, and this gentleman was 58 years old, and his first food bolus happened in 1988. And his request to me was, you just got to dilate me, doc, just dilate me, I'll be fine. And so he has had a total of five food impactions since 1988, suffered with having to modify his diet since 1988. And so we did his endoscopy, and he has a classic feline esophagus, or trachealization of the esophagus, and we'll see some images of that. And he had never had a biopsy taken of his esophagus throughout that whole time period. How many of you guys have seen EOE in your community practice? Okay, great. Everybody raised their hand. When I was a fellow, hardly anybody had seen EOE. This was a disease that was first really described in the late 1970s. And it really wasn't until late 90s, maybe early 2000s, that we really started to accept it as a condition. And it was still a zebra, you know, we really rarely saw it. But now you'll see it's becoming much more common, as other atopic diseases are becoming more common. So we do need to raise awareness of it. This gentleman had gone several decades without attention to his disease, and as a result has continued to suffer and have these food impactions. So anyway, our goal is to help make an impact and change that by improving the quality of care. At the end of this session, we're going to have a little competition. We're going to have some fun today. So there'll be a knowledge challenge. All of you can compete as individuals. And our top eight performers are going to receive some ASGE swag. So you'll walk away here with some ASGE swag if you're paying attention and are one of the top eight performers. And that includes our virtual audience, too. So anybody online that's watching this can participate. Okay, so what is EOE? This is a definition that is from 2022, a consensus definition put out by the British Gastroenterology Association. And it's really a clinical pathologic diagnosis. It really involved you have to have symptoms of esophageal dysfunction. And in adults, those symptoms are a little bit different, as we'll talk about. It's usually dysphagia and food impaction. And in children, it's much more nonspecific symptoms, feeding problems with young children or even abdominal pain and vomiting. So not often what we would classically think of as esophageal symptoms. And then you must have histologic confirmation of that. And that's where the biopsies are quite critical. And that includes eosinophil count of greater than 15 EOs per high power field in the absence of other causes of that esophageal eosinophilia. So let's go over the natural history. As we just kind of alluded to, this is becoming much more common. It is rising in incidence. You can see that over the last couple of decades, the pooled estimates of prevalence have now approached almost one in a thousand patients or 100 per 100,000 patients. And it does differ quite significantly through regions of the world where industrialized areas of the world seem to have a higher prevalence. Similar to what we see with other atopic conditions. Here's another graphic representation of the rising incidence and prevalence of EOE in different areas of the world. And this study that was published last year in CGH really showed the clinical impact of this rising incidence in regards to ER visits. This is data taken from the nationwide emergency department sample. And they used a model to then extrapolate. That represents about 20% of all ER departments throughout the country. And they then modeled it to estimate the national impact of this. And they studied three different time periods looking at ICD codes for eosinophilic esophagitis. If that was in the top one of the first three diagnostic codes, that's what they use to count a patient with EOE. And you can see that the number of emergency room visits in the country has steadily risen and has really tripled from 2009 to 2019. And then they projected based on this trajectory of what it would do over the following 10 years. And it really probably is estimated to double again by 2030. And now some of this maybe is just we're more aware of it and we're diagnosing because of that awareness. But there's clearly also a rise in the incidence of these atopic conditions or type two inflammatory conditions. They also went back and looked at the number of patients that were presenting with dysphagia and particularly young males less than 40 years old, because this is a disease primarily in males, but it can happen certainly in women. But they looked at young males less than 40, and there was over 700,000 ER visits for dysphagia, food impaction, or esophageal stricture in this young group. So this 50,000 visits is probably just the tip of the iceberg of the true number of patients with EOE that are actually presenting. So there's been a tremendous impact on the healthcare system that's escalating even further. Here you can see that other atopic diseases are increasing, and the geographic distribution of some of these atopic diseases also mirrors what we see with EOE, although asthma is obviously much more common than eosinophilic esophagitis. There are some other factors or associations with patients that have EOE. We do believe that this is a food-driven allergic condition or inflammatory condition of the esophagus, but aeroallergens can have an impact, and there may be some seasonal variation of EOE in its presentation, although interestingly in that ER study, the emergency department sample study, there was no seasonal variation in the number of diagnoses of patients presenting with EOE. Helicobacter pylori seems to be inversely associated, so perhaps it's for some reason it's protective. There does seem to be an interesting phenomena if you use oral immunotherapy for your atopic conditions, your seasonal rhinitis. There have been reports that it has induced EOE in some patients, and the mechanism behind that's not entirely clear. It does tend to be more common in cold or arid climates as opposed to tropical zones, and population density seems to have an impact. In rural areas, it seems to be more common. There is an association with other connective tissue and autoimmune diseases, although not very strong. Here you can see the demographics. It is much more common in males than it is in females, again, for reasons that are not entirely clear, and it can happen at any age, but younger individuals certainly seem to be at higher incidence, and maybe there's a peak in young adulthood, but even patients that are in their 60s, and like my patient I mentioned earlier who's in his 50s just now diagnosing, probably had it when he was in his late 20s, but you have to consider this in almost any patient that comes in with esophageal symptoms. Here's again some clinical characteristics. Males predominate, females about three to one. There's a very strong association with atopic disease. About 70 to 80% of patients with EOE will have another atopic condition, such as asthma, seasonal rhinitis, atopic dermatitis. Most of the studies show a white predominance, but it may be biased because there may be some sampling and under-representation in some of the studies, and there does seem to be some family history. Monozygotic twin studies show about a 40% concordance with the disease, and it's most common, as we talked about, in adults in the third and fourth decade. This slide shows you some of the other epidemiologic things that may be related to your practice. You can see that of patients presenting with dysphagia that are undergoing endoscopy for dysphagia, anywhere from 12% to 23% of patients will actually have EOE now in patients presenting with dysphagia. Most importantly, it is now the most common cause of food bolus in patients that come to the emergency room. You can see that in some studies, it's more than half of patients presenting for a food bolus. What is the pathophysiology? We're still learning about this. We do think it is a food-borne allergic condition of the esophagus. It probably is a person with the right genetic predisposition, has some epithelial barrier defects that allows food allergens to then enter into the mucosa and stimulate a Th2 immune dysregulation that then results in eosinophilic-based or type 2 inflammation of the esophagus that leads to remodeling and fibrosis over time. But there is some clinical heterogeneity to it, and a lot of that may be related to genetic predisposition. This slide just really kind of summarizes how this is happening. You have aeroallergens and primarily food allergens that are exposed to the esophageal mucosa. That leads to the inflammatory response in the lining of the esophagus that over time leads to fibrosis. And you have very differing clinical manifestations over time that starts out more with nonspecific symptoms in children and eventually more focused on the esophagus with dysphagia and discomfort in the chest and ultimately food impaction as the disease progresses into adulthood. Here's our underlying molecular mechanisms. The very first thing that typically happens is that TSLP is triggered to be released in the esophageal mucosa by the food allergens, for reasons that aren't entirely clear, probably some component of mucosal leaking or loss of integrity that leads to this. That then leads to Th2 differentiation or type 2 inflammation with the production of associated cytokines and then recruitment of eosinophils and mast cells and other inflammatory mediators. The clinical presentation of patients with EOE, as I alluded to earlier, it's very different in children than it is in adults, especially infants and toddlers. Our pediatric GI docs can attest to this. But in children, it's often infants and toddlers, it's often feeding difficulties or food refusals or vomiting or choking, some nonspecific symptoms. As they grow older, they may have a little bit more symptoms related to the esophagus with reflux type symptoms, but still they may have nausea or vomiting, decreased appetite, some nonspecific symptoms. And then as you get into adolescence, they may have more dysphagia and typical adult type symptoms. And again, the adult type symptoms are usually dysphagia, food impaction, which happens in a large percentage of patients with EOE, as well as chest pain and heartburn reflux. Okay, so it is important to realize that, again, the vast majority of these patients will have an associated atopic condition, and that can be any of them. And so whenever you see a patient in the clinic that's complaining of dysphagia, that also has asthma, that also has seasonal rhinitis, obviously your pretest probability that this patient has EOE is going to skyrocket. And about 70% to 80%, again, will have an underlying atopic condition. So in children, again, it's usually nonspecific symptoms, and then that chronic inflammation over time leads to remodeling of the esophageal wall, fibrosis, and stricture formation. So it's the unchecked inflammation that's leading to what ultimately leads to the poor quality of life and the life-threatening complications of food impaction and potentially esophageal perforation. EOE is the most common cause now of spontaneous esophageal perforation. Okay, so this shows you in diagrammatic form what's happening over time. You start out with a normal esophagus, perhaps early in children, there's inflammation, or childhood there may be inflammation. But at this point, not a lot of stricturing or fixed scarring, and that's why at this age, you don't have the dysphagia or the food impaction risk. But over the course of time, in years or decades, that fibrosis starts to form with the unchecked eosinophilic inflammation, and in the end, as time ultimately goes on, you end up with fixed stenosis and fixed rings due to extensive subepithelial fibrosis, lamina propria fibrosis, and that's when adults present with the typical symptoms of dysphagia and food impaction. It is not uncommon to have 10-year-olds with strictures and with fibrotic. As you get into that, you know, late childhood, early adolescence, that's when you can start to certainly see it. But the young toddlers, you're not going to see that. You're not going to see the strictures and narrowing. Okay, so this shows you why is it important to have an understanding of this and diagnose eosinophilic esophagitis because most patients have a long delay in their diagnosis and it's that opportunity to intervene and prevent the long-term complications. And we have the same idea with inflammatory bowel disease now, right? We've changed our thinking over time that we want to be proactive in inflammatory bowel disease and prevent complications and that's what really needs to happen in this chronic inflammatory state too. These are studies that show that there is a tremendous delay in the diagnosis, often in decades, much like my patient from Labor Day weekend. And this shows you that with each year of undiagnosed EOE, the risk of stricture increases by about 9%. And so we have that opportunity. And it's often decades where these patients have undiagnosed inflammation. So we're an endoscopic society, so what's the role of endoscopy in evaluating and monitoring patients with EOE? The first and foremost is we must perform a high-quality endoscopy. We have to assess findings as we're going in. Sometimes the exudates will wash off. Sometimes you may not see subtle changes if you've already washed everything off and cleaned off. It is important to then wash everything, fully insufflate. Strictures can be very subtle unless you're paying attention and fully insufflating. And particularly at the GE junction and at the area of the upper esophageal sphincter, pay attention there. Sometimes we'll fly by that upper esophageal sphincter and not pay attention. As you're coming back, make sure you're inflating. In patients with MAC, sometimes I'll have my anesthesia colleague apply some cricoid so we can fully distend, cricoid pressure to fully distend the esophagus and see things well. And then take times going back several times, back and forth, do a high-quality. Don't just take 30 seconds to inspect the esophagus. Here are some of the findings that we will typically see. How many people have done an endoscopy in patients with EOE? Again, the vast majority, right? So you've all probably become very familiar with this, but you'll be surprised how many times people in the community do not recognize some of the changes of EOE. There'll be fixed rings that you can see here in A and B. Here's the linear furrows that are indicative of inflammation. In D and E, you can see some examples of the white exudates. In some of these cases, you'll see a combination of furrows and rings. And here's what we often call crepe paper mucosa, just a very fragile mucosa that tears with just simple inflation or scope insertion. So that in and of itself is not necessarily one of the criteria we use for assessing patients with EOE. Here's that example of that upper esophageal sphincter and distending it to actually see the very subtle stricture at that ring at the upper end of the esophagus. So we have a classification system that's been validated. It's called the eREF score. It's actually built into many endoscopic reporting systems now and allows you to quantitatively assess what the esophagus looks like endoscopically. And you should be doing this in every endoscopy that you do for patients with EOE. And the eREF stands for edema, rings, exudates, furrows, and strictures. And we'll see some examples of that. It's important because it's standardized and really can help you follow patients over time. And it is now recommended as part of the ASGE Consensus Conference that came out in 2022 on the role of endoscopy in patients with EOE. And that's a very important document. It's referenced here on this slide, which you should have access to. And it's a great report that gives a lot of very important tips and recommendations for the endoscopic diagnosis and therapy of patients with EOE. So here's some examples of the various components of the eREF system. Edema is, here you can see at the top, is normal. You can see how you can see the vascular pattern of the esophagus. When you lose that, that's a sign that you've got edema, much like in the colon. And the bottom two slides show examples where you've lost that vascular pattern. And so this is graded as either zero or one, either there's no edema or there's absent or decreased vascular markings for edema. And here's an example of rings at the very top. There's a normal on the bottom left here, but at the top, you can see subtle ringing of the esophagus. And this would be graded as one for mild. When you have more pronounced or moderate rings, that would be graded as a two. And then when your rings are so predominant and fixed that you cannot pass the standard endoscope, that would be the criteria for a grade three. And exudates are really graded as none, less than 10% of the mucosal surface or greater than 10% of the mucosal surface. And here you can see some more severe signs of exudate, where it's clearly more than 10% of the esophageal mucosa. Those are graded as one for mild and very subtle, but when they have clearly more depth, as they do on the bottom examples, that would be graded as two. And then strictures is either present or absent. It is the convention to go ahead and estimate what the luminal diameter is of the stricture, and that is also built into some of the endoscopic reporting systems out there. So each and every time you do an endoscopy, I would incur with suspicion of EOE or patient known EOE, please make sure you're kind of going through the EREF score and helping to quantify it. Here's some just examples with various scores. And you can see at the end of the stricture, if there is a stricture present, the number after the S is corresponding to the estimated diameter of that stricture. So here's specific recommendations that came out from our consensus statement from the ASGE that EREF score should be used routinely. In patients with suspected or established EOE, the EREFs is applied to the highest scoring area. So always, whatever the worst part of the esophagus is, that's what you want to do to apply the score. And it can be patchy. So we're gonna talk about biopsy now for EOE. This is obviously what's required to make that clinical pathologic diagnosis. And you want to target, you want to obtain biopsies from multiple areas of the esophagus. You don't necessarily have to put them in different bottles, say convention is distal and proximal esophagus. The consensus statement did not come out with a clear recommendation to put them in different bottles. But you do want to sample at least six biopsies from differing areas of the esophagus. And obviously target areas that look abnormal. So I'm just gonna show you a video of what we call the turn and suck technique. You may already use this, for example, when you're sampling your patients with Barrett's esophagus. But it just kind of walks through. In order to maximize the diagnosis of eosinophilic esophagitis, proper endoscopic biopsy technique is critical. Here we will demonstrate the turn and suction technique of obtaining endoscopic biopsies. You can see the endoscopist advance the forceps out of the channel. The assistant then opens the forceps. And the endoscopist withdraws it to the face of the endoscope. The endoscopist then turns the endoscope towards the mucosa and applies suction to completely collapse the mucosa on the forceps. The forceps is then closed by the assistant and the endoscopist rapidly tugs the forceps to obtain the tissue. And you can see the residual mucosal defect. Okay, so I don't want to talk over myself there, but that kind of gives you an idea of what that is. And this is data that shows you that the reason that we want at least six biopsies is that that increases the yield. You can see that you would have almost perfect sensitivity in detecting eosinophilic esophagitis if you do that number of biopsies. The convention is often to do four from the distal and four from the proximal, but that obviously will achieve your goal of having at least six biopsies. Here's the recommendations from our consensus statement. There's a number of bullet points here. Again, obtaining at least six biopsy samples from both the distal and either mid or proximal esophagus should be obtained regardless of the way the esophagus looks. Even if you have a normal esophagus, you want to sample it. What percentage of patients with EOE have a normal appearing esophagus? Anybody? 10%. So 10% of patients with eosinophilic esophagus will have a normal appearing esophagus. And it's very important to obtain biopsies at the time of a food impaction so we don't lose these patients. This patient that came in Labor Day weekend, oh, just dilate me, doc, and I'll be fine. So you've got to make sure that you do a biopsy so that then you have the information that there's inflammation that needs to be addressed. There are other things that can mimic EOE endoscopically. Here's erosive esophagitis. Most of us would recognize as such, but sometimes erosive esophagitis can mimic EOE. This is a condition called lymphocytic esophagitis, poorly understood, can be associated with celiac disease. But it's not EOE. It has the rings and it has the edema, maybe a little exudate. So remember, all those findings are not specific, and that's why you have to have a biopsy. These are just more examples of a patient with lymphocytic esophagitis that could appear as if they have EOE. Lichen planus, a chronic immune condition of the esophagus, also may appear similar to EOE. And candida esophagitis with the white specks might give you that appearance that there's exudate that would mimic EOE. And pseudodiverticulosis of the esophagus can have this appearance of linear furrows with this pseudodiverticuli, but that's more likely related to candida. Okay, so the summary and takeaways. Always do a high-quality endoscopic exam, and that stands for any time you guys are doing upper endoscopy. Apply the E-REFS score when you have a patient with EOE or you're suspecting it. Make sure you're doing proper biopsy technique. And be aware of the mimics, the endoscopic mimics of EOE. So what about histology? This is a normal esophageal biopsy with the stratified squamous epithelium. And you can see the lamina propria here. This diagnosis requires both clinical and pathologic criteria. And here's the pathologic criteria, greater than 15 eosinophils per high-power field. That's the peak. So, you know, some of your biopsies may have less than that, but you have to have the peak biopsy showing at least 15 eosinophils per high-power field. And it should be isolated the esophagus. So there's other EGIDs or eosinophilic gastrointestinal disorders, such as eosinophilic gastroenteritis that can also have eosinophils in the esophagus. And there are other conditions that we'll talk about that can have eosinophilic infiltrate in the esophagus. There are also other criteria that your pathologist should be aware of, including the basal cell hyperplasia, some of the lamina propria fibrosis, which is typically more specific for EOE than it is for some of the other conditions that are associated with eosinophilia. So here's some examples of some eosinophils in the esophagus. There are also some degranulated eosinophils, where you see these little red specks, but they're not with, you know, a whole cell, but pathologists do not count those. They should not count degranulated eosinophils. They should count really only the intact eosinophils. And again, it's greater than 15 per high-power field. This is a very strongly specific finding for EOE when you have these eosinophilic microabscesses and you see a collection of eosinophils. They often correlate with the very tiny white exudates that you see in the esophagus. So the endoscopic pathologic correlation is represented on that slide. The basal cell hyperplasia is you see these larger blue cells get more prominent. That is often present in patients with the eosinophilic esophagitis. And as I mentioned earlier, the lamina propria fibrosis is often pronounced, especially later in the stage. You know, after this inflammation has been present for many years, you have that develop. It is important to realize there are many other conditions that can cause eosinophilia in the esophagus. The one that is classic, and you may see this in your practice, is acid reflux. So acid reflux can result in eosinophils in the esophagus. But our pathologists, and particularly you as a clinician, have the capacity to really put the information together to understand, is this eosinophilic esophagitis or is this reflux? And it's important to realize they can overlap, right? So 10% of our population, in general, will have significant inflammatory erosive disease of the esophagus from reflux. And so there's a lot of patients with EOE that actually have both EOE and reflux disease. So these are some of the conditions that you can see, including graft-versus-host disease, inflammatory bowel disease, celiac disease, and certain drugs can all lead to eosinophilia. Now in reflux esophagitis, they can have exent eosinophils. About half of patients with reflux esophagitis will have eosinophils. But they also usually have neutrophils and lymphocytes. They can have the basal cell hyperplasia, similar to the EOE. But many of these features are not quite as prominent as in eosinophilic esophagitis. So here's what our pathologists would do to help understand the difference, at least pathologically, between eosinophilic esophagitis and reflux esophagitis. Usually the eosinophils are more diffusely involved in patients with EOE, but more lower in the distal esophagus with reflux. Degranulated eosinophils are much more common in EOE. And the microabscesses, much more common in EOE. The laminar propriofibrosis, much more common in EOE, especially the later stages of disease. So there are pathologic correlates, and particularly clinical correlates, that you can use to distinguish between reflux changes and EOE. So our goal with treatment is really to improve symptoms, as well as histology and endoscopic appearance. And I call this the SHE goals, and that is symptoms, histology, and endoscopic appearance, and ultimately our quality of life, and to prevent complications, such as food impactions or other catastrophes of the esophagus. So our targets for therapy include food. We can do elimination diets, because we think that's the ultimate trigger. We can also use proton pump inhibitors, which don't just, this mechanism of action at EOE is not just acid suppression. There are immune effects of the proton pump inhibitors that seem to suppress the TH2 inflammation, in particular seem to downregulate eotaxin-3 and therefore really help to target the immune response in patients with EOE. Topical steroids, as you probably know, have been a mainstay of therapy and they have multiple mechanisms of action within the inflammatory cascade. And then our biologic that we currently have available is dupilumab and that is a blocker of the IL-4, IL-13 pathway towards inflammation. So how do we choose therapy? It really is, the last point here is the most important. It has to be a shared decision between you and your patient. And there are many factors that go into this. It may have to do with the efficacy. It may have to do with the cost. It may have to do with the convenience or fear over certain side effects from the medications, their willingness to be on medications versus dietary therapy. So the choices are many and you really have to have a shared decision with your patient. The information I'll share with you today will help you and give you the tools to do that, to talk to your patients about it. So this is the data on dietary therapy. You can see elimination diet is great. It's 94% effective, I mean elemental diet, excuse me, is 94% effective but nobody's gonna be on an elemental diet the rest of their life. It's just not practical. If you do a six food elimination diet, you can see that's so close to 70% effective. Importantly, the question always comes up, what about just testing for allergens that are the trigger? And it turns out that allergy-directed dietary therapy is worse than just doing a elimination diet. And so that's why we don't necessarily recommend people get skin prick testing or other allergy-based testing. It's typically not an IgE-mediated inflammatory response and so that's probably why that testing doesn't turn out to be very helpful. These are the elimination diets. The one that is perhaps easiest for patients is the two food elimination diets, which is cow milk and wheat. And then the six food elimination diet removes all six of these food groups, which is obviously much more restrictive. The food group that typically is the highest culprit is the dairy or cow milk. And this shows you those elimination diets with the relative efficacies. You can see that with two food elimination diet, you're probably dealing with about a 40 to 50% effectiveness and again, that's eliminating gluten or wheat and dairy, whereas the six food elimination diet, which removes not just gluten and dairy, but eggs, soy, fish and shellfish and nuts, that's a little bit more effective, at least based on some of the data out there. So when you're relaying the information about dietary therapy to patients, it's really important that they do have several options in terms of how restrictive it's gonna be, but it is important that you work with a dietician to make sure they understand that this is not just, you can cheat a little bit, it's much like celiac disease. They really have to be very restrictive in terms of their food elimination diet. The goal of dietary therapy is not just to necessarily make them to treat it, but it's also in some ways diagnostic. You can try to identify which food is their trigger so that ultimately they have much less restriction in their diet and that does require repeated endoscopies every time you change their or reintroduce a food. And so for a six food elimination diet, that might require numerous endoscopies, four to six endoscopies. So make sure, in summary and key takeaways from this is that food does play the main role in driving the inflammation. Removing the food antigens does result in histologic remission. There are a number of different options. Once you reintroduce foods and repeat your endoscopies, you can help to identify which food is the trigger for long-term maintenance therapy. Now, what about proton pump inhibitors? Yes, they do work as we talked about. This is from the AGA and Joint Task Force guidelines. The overall efficacy is probably, and in terms of getting the EOs less than 15 per eye power field is about 42%. It is important to understand this is not related to acid reduction. And usually you wanna start with double dose. Most of the data shows that if you use double dose twice a day, so 20 milligrams of say omeprazole twice a day, that is more effective than doing it once a day, at least in some data. You're then gonna wanna repeat the endoscopy in eight to 12 weeks so that you can see if the patient responded. So every time you make a change in therapy, you do want to confirm that the disease is in remission or is maintained in remission. Now, for topical steroids, the consensus guidelines came out with this analysis where overall efficacy was about 65%. And up until this year, we've relied on sort of, I guess, reuse of steroid preparations for the use of EOE, because they're not FDA approved. And you can see that both fluticasone, which is an inhaler that's been swallowed, or budesonide, one milligram twice a day, is quite effective. There's not really a lot of great comparative studies out there to know which one is better, but it is important to know the dose. So for fluticasone, it's 880 micrograms twice a day. So if you have a 220 microgram inhaler, it's four puffs swallowed twice a day as the initiation treatment dose. We do now have an oral topical steroid, the budesonide oral suspension, which is available and approved now by the FDA. This is the data that led to its approval. And you can see that this is really stringent histologic response of less than six EOs. 53% of patients on the oral budesonide, two milligrams twice a day, had histologic remission compared to virtually no patients with placebo. And they also had a improvement in their dysphagia symptom questionnaire score. The problem is this is only approved for 12 weeks, and then what to do after 12 weeks is the real question. And it is expensive, and insurance companies, whether they'll approve it beyond 12 weeks is a real question. Then you may have to revert to other maintenance therapy. And we do know that maintenance therapy is important. You stop the steroids and their disease will come back. There is some question about safety for oral steroids, but in terms of adrenal suppression, there's really not any good evidence that it does result in adrenal suppression, but it can result in oral candidiasis or esophageal candidiasis, which you can then treat with topical therapy. So practical tips, we only have one U.S. FDA-approved formulation, and that's the oral budesonide suspension. It's approved for adults and children over 11 years, and the dose is for 12 weeks, and what to do after 12 weeks, we really don't have any, at this point, any good approval for use. You can use the adapted formulations, especially if it's cheaper for your patients, and that includes the fluticasone inhaler, or I will sometimes have compounding pharmacies create the oral budesonide solution. In my compounding pharmacy, it runs about $90 a month, so it's not extraordinarily expensive, and we'll talk about cost in a little bit. Take it, they should be advised to take it after breakfast and then before bed, so you have the maximum dwell time, or coat time, on the esophagus, and it is important to kind of watch out for pitfalls that they're not taking their inhaler or their other medications appropriately. So we have some emerging therapies that are gonna target this disease with biologic agents, and that really relies on the understanding of our pathophysiology that we talked about earlier, and the only agent we have at the moment is the dupilumab, which blocks the IL-4, IL-13. This kind of shows you what that antibody is doing. It's blocking the shared receptor for IL-4 and IL-13, and therefore interrupts that Th2 inflammatory cascade. Here's the New England Journal's study that led to the approval of dupilumab a couple of years ago. It had three different parts. The important data here is that it's a randomized controlled trial, and all these patients that were in this trial had already been on PPI and failed to respond, so that's what you'll often require to get this medicine to your patients is that they've failed a therapy before dupilumab, and you can see that the histologic response was quite robust, about 60% of patients, and then through the maintenance phase, that seemed to hold on. The adverse events are not very significant. They're usually injection site reactions or erythema. Occasionally, patients will have nasopharyngitis. So some practical tips about dupilumab. It is indicated for children as young as one year, as long as they're 15 kilograms and older. There is a pediatric dosing profile that you can see here. You do not need to do the biologic workup that you need to do for, say, patients that are going on anti-TNF agents for inflammatory bowel disease. None of that's required because we're not dealing with an infection risk here. There are some prescription logistics you have to walk through. Getting prior authorization is a big deal for this medication and so having the office mechanisms in place to do that. And they do need monitoring and follow-up, just like any other patients. This might be a reasonable option for first-line therapy in patients that have other atopic conditions because this drug is approved for use in patients with asthma or atopic dermatitis or nasal polyposis from seasonal rhinitis. And if the patient really prefers to avoid dietary restriction or steroids, it may also be an option, but usually you're gonna have to fail at least one therapy to get to it. The step-up approach as opposed to first-line may be as a way to rescue if they're not responding to any other therapy that you have tried. What about combination therapy for EOE? There's not a lot of data on that and so it's usually not necessarily advised, but I can tell you in practice, a lot of times if patients are put on a PPI or a topical steroid and they still have some eosinophilic inflammation, you can then perhaps layer on dietary therapy, again, following up. The key is to get them in remission so that their long-term outcome is good. These are some of the costs of the therapies. Obviously, the cost for any individual patient will depend on their particular pharmacy benefit and their coverage. Over-the-counter PPIs are probably the cheapest, running about less than $500 a year you can get for that double dose. The inhalers and the other topical steroids can be costly. I mentioned to you that one of my compounding pharmacies can get the Budesonide for roughly $1,000 a year, so not quite as much as on this slide here, but cost is one of the things you have to have a shared decision, make a conversation with your patients. What about the role of endoscopy for dilation? Yes, it's important to dilate these patients if they have developed strictures, and you can do that on the initial endoscopy. Usually, though, you wanna be cautious. This is a balloon dilation. Obviously, you can do both balloon or bougie dilation. We talked about the rules of three a little bit yesterday, and for this condition, it's generally most experts in the field that I've talked to, especially some of our steering committees that know much more about UE than I do, they don't follow the rule of threes for this condition. They will actually inspect after every dilation, and when they get the mucosal disruption, they're done, and then they come back in another session, and that includes whether you're doing balloon or you're doing savory, and either one is acceptable, and we talked about that at our sim station yesterday. Here, you can see at the top, you've got a savory wire, and this is after a savory dilation, and I will go back and inspect. I'll leave the wire in, go back and inspect after every dilator, and once I see this, I'm done, okay? I don't wanna push it further than that, and likewise, when you're doing balloon dilation, once you achieve that initial mucosal disruption, you're good. You want to see that, okay? You want to see that mucosal disruption because that's what's gonna lead to the efficacy, and clearly, performing dilation in these patients is effective in terms of improving their response to dysphagia. There are side effects and risks. It turns out that the risk of perforation, historically, we were worried that it was a very high risk of perforation. It turns out it's not as high as we thought. It's probably similar to almost all the other benign conditions of the esophagus, especially if you do it thoughtfully. You start low and go slow is kind of the motto. Chest pain, however, is a common side effect of the dilation. Again, you're trying to get that mucosal disruption, so warn your patients before you do the procedure. You know, you may have some discomfort afterwards. You can inspect the esophagus. You can get a pretty good idea of making sure that they haven't had a deep perforation at the time of endoscopy, but that risk is really quite low if you do this thoughtfully, and especially if you get the medical, if you get the inflammatory condition under control with medications, it appears to be even lower. Okay, so some tips. It's really best to do it after you've had at least some level of medical therapy or dietary therapy to get the inflammation control, but you can do it at least, you know, provide some modicum of symptom control by doing a gentle dilation initially. The effect is usually greater than a year. The motto is to start low and go slow, and I inspect after every dilator, not follow the rule of threes. Don't just trust that that rule of threes is gonna work. Your target endpoint here is 16 millimeters. There's no reason necessarily to go higher than that because your dysphagia symptoms will resolve if you get above 16, and it's also important to warn your patients we may take several sessions to get there. The type of dilator is really up to your choice and maybe perhaps related to the shape and conformation of the stricture in disease, but it doesn't address the inflammation, so you still have to make sure the inflammation's under control to prevent restricturing and long-term consequences of the disease. So here's just a very quick finishing slide that gives you an overview of the management of EOE. Once you make the diagnosis, you have a choice of either medical therapy or dietary therapy. If they don't respond to either one, you can rely on the other. Dilation plays an important role in both of these if they have stricturing disease, and once they do have response, it is critical to maintain them and to follow them over time. This is a chronic disease. It's not a one and done, see you later. You really have to follow these patients, and having them engaged with a gastrointestinal provider, whether it's your APP or you, is really quite critical. Okay, so now we're ready to have some fun. This is a QR code where you can, you'll be taken to a game that our educational technologists have created based on 20 questions that are all covered in our topic discussion today, and we're gonna give you about 10 minutes to complete the game. You'll have to register and then go through the 20 questions. A lot of fun. They'll actually tell you the correct answer after each question, so you're only allowed to do this once. Okay, no double takers here. And while you're doing that, and then at the end we'll announce who, we'll go through the questions and then we'll announce who the winners are.

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