So we're going to get started. Hope everyone had a nice break. So now we're going to shift gears and talk more about pathophysiology of EOE and treatment options. So I know we have a couple immunologists in the group here that I've spoke with over the last day. So feel free to chime in. I appreciate learning from you all too. So for this talk, we're going to review the suggested treatment endpoints for EOE, discuss options for standard therapies in EOE. So these include the basic categories of drugs, diet, dilation. Also understand some of the pathophysiology, especially how it pertains to the biologic therapies and, of course, in your arena. So first we'll start with a patient. So this is a 20-year-old that came in, a college athlete, swimmer, and really has had EOE symptoms dating back to early grade school, which is not uncommon for us to see, so going back to first grade for this patient. And the only treatment that was given at the initial visit in 2017 was BIDPPI therapy. And at that time, in terms of the endoscopic features, the adult scope wasn't able to pass. So as Dr. Gonsalves said earlier, our standard scope is 9.8 millimeters. And so there's significant stricturing when you can't pass that scope. So before I show you the endoscopic images from that patient, what kind of questions or what items do you want to ask the patient about or what different things are you thinking you may want to know further about this patient and what's going on? Feel free to shout it out. Just shout out anything. Yep, exactly. Yep, exactly. There's significant overlap, as you all know, so that's really important to ask, especially in you're probably thinking in your domain, depending on treatments, are there other first line indications for certain therapies too, right? What else do you want to know? Yes, exactly. So what compensatory mechanisms are going on? Exactly. So what kind of compensatory mechanisms? So you want to hear more about the process of what they're eating, how they're eating, all of those items that Dr. Gonsalves talked about earlier today. Are they chasing with fluids? Are they the last one to leave the table? Has this been going on since first grade where their family and friends notice they're the last ones to leave the table? Are they having other symptoms, including beyond dysphagia? Are they having heartburn or regurgitation or other symptoms? And really talk to them more about, we mentioned BID-PPI, how long have they been on it? Are they taking it? Are they really taking it twice a day, once a day? What's going on in terms of actual treatment as well? So the endoscopy I'll show you, it did indicate those EREFs features that we talk about, including strictures, furrows, rings, exudates. So here it's listed as budesonide, but for now we'll talk about it on the BID-PPI. So here you can see the endoscopic features. So there's some loss of the vascularity there. You don't see as many red lines. You see those really nice train tracks in there with the furrows. And there's some rings that are going on as well. It's a little harder to see here, but there's some of those eosinophilic absces, exudates that we see on endoscopy as well, and then the abscesses that we notice on the correlating pathology. So here's the pathology results. So 35 eosinophils per high-power field, so of course over 15. No superficial layering of the eosinophils. There's rare eosinophilic microabscesses, which makes sense. We're not seeing a bunch of those white spots in there that you saw in images earlier today. As well as basal cell hyperplasia, subepithelial lamina appropriate fibrosis. So we all understand fully what that means now after Dr. Saleria's talk. So that was really helpful to get a basis for that. So now we fast forward to 2019. So the patient comes in and actually now has a food bolus impaction. And that's in the setting of noncompliance for two years. So what you're seeing here, you can see in the middle of the big circle there, that's the food bolus. And in addition, you can actually see some tearing in the esophagus from the impaction. So that's really our fear, right? In terms of the natural history of untreated EOE is the stenosis that we talk about. In addition with that, the food impactions that can lead to perforations or tears all the way through the esophagus. Thankfully this looks like a fairly superficial tear, similar to what we see when we dilate. And I'll show you that later. So thankfully it doesn't look like a perforation. But certainly we want to avoid this if we can. And so then we have a follow-up endoscopy that's done. And this is done fast forward two months later in April of 2019. So this is after eight weeks of budesonide, one milligram twice a day. And here you can see on the left in the predilation, you can see how narrow the esophagus is there. That circle is really tiny. It's pretty stenosed there. And then this is what it looks like post dilation. So as I mentioned, it looks similar almost to how the food had torn or dilated prior. So this red area here, this is what we call the mucosal defect. So we're looking for a moderate defect there, no matter what type of dilation we're doing. And that's just to open up enough of that scar tissue or fibrosis to have symptomatic benefit without causing a deep tear that's going to lead to a perforation. So this isn't a very adequate dilation. And then our pathology though, as you can see here. So now our eosinophils have gone up. So we went from 35 to 110 despite, we'll say, compliance at this point with budesonide twice a day. We're also seeing some of those other features from Dr. Solaria's talk, indicative of very active EOE. So now what do you want to think about? What do you want to ask a patient that comes in with active EOE despite twice a day steroids? So what do we want to know about now? Feel free to shout it out. Exactly, right. And really, we have to tease that out in explicit detail with patients in clinic, honestly, because as you all know, certainly there's the recent FDA approved budesonide suspension that we'll mention later. But other than that, we're dealing with all different formulations from different institutions, different compounding pharmacies, different ways of mixing, taking medications from asthma physicians and in different ways of using it. So we really, in detail, have to go through with the patient, ask them exactly what they're doing. So how are you mixing it? Is it as thick as that honey consistency that's going to coat the esophagus? Are you really taking it twice a day? Are you busy? You're a varsity athlete. Are you busy taking it only once a day? Are you really waiting the 30 minutes to one hour after taking it to make sure that it's coating the esophagus and you're not having food and liquids that are rubbing it off right after? So all of those things are really important. So a lot of the time it's going to be compliance. However, there are going to be situations, though, as we see, where these patients are truly swallow topical steroid refractory and they're taking everything the best they can in the appropriate way and they have active disease. And so those are patients that were, you know, it's research, but, you know, more information needs to be known in terms of what to do for these patients. And there's that spectrum that Dr. Gonzalves talked about this morning, and we're trying to understand more of the mechanisms of that and who should have what types of treatment. So there are patients that are going to have persistent active eosinophilia despite steroids. There are going to be patients that don't necessarily have eosinophils, but they still have significant stricturing disease because the fibrosis is already there. So more research needs to be done in terms of tailoring therapies to try to figure out which therapy is ideal for a patient in addition to that shared decision-making that we talked about. Was there a question over here? Go ahead. Yeah. Do you, for this patient, would you continue leading on VID, PPI, and then adding the budesonide? So usually I try to streamline therapies. So there are some nuances to that that may be a little bit different in the pediatric population. I really see 17 and above mainly. But for the adult population, we really try to streamline to one therapy. So that's one of the issues I run into. A lot of patients will come to me from outside facilities, and they're on the kitchen sink of EOE treatment. They come to me on swallow topical steroids, PPI, and a partial diet elimination. So a lot of my job is pulling things off, streamlining, and then getting objective data on what's doing what with repeat biopsies with endoscopy. So I try to, if I have a patient where I think their heartburn is probably related more to the EOE pathway, and they're not a PPI responder for EOE, because that's kind of a coin flip, right? Only 40% to 50% are going to be histologic responders. So then I will take them off, switch to steroids, and try to keep them off and just be on steroids. However, there's going to be those patients that have objective EOE and reflux, and I have to treat both. So when I do that, I optimize, for instance, here this swallow topical steroid to the dose that's going to get them in remission, then a lower maintenance dose to maintain that remission. And then I'll also, for their overlapping objective GERD on pH testing, I'll reduce the PPI to the lowest effective dose. So I'm not keeping them on BID PPI, just a low daily one if that's enough to control their objective GERD. Yeah. So that's a great question. Go ahead. So I'm thinking of a patient who just received a dilation, you have the PATH report back with saying high level of active EOE. Very likely this patient's going to say, but I feel great because he just received the dilation. What does your conversation sound like when you were trying to explain, you may feel great because of dilation, but you still have incredibly active EOE with the 110 EOs? Yeah. So most patients in this scenario, so this is a pretty significant structure, as I mentioned. So it's under 10 millimeters because the scope wouldn't pass initially. So with EOE, and we'll talk about this a little bit more later too, we dilate very slowly and carefully, right? So I don't know the exact millimeters on the post dilation for this patient, but we only increase a few millimeters each time. So most likely they're not going to be symptom free after this type of dilation. They're going to have some reduction as you're pointing out, which is a really good point, but they're not going to be symptom free. So we still have to talk about what kind of medical or diet therapy they'll be on. And I upfront, when I see patients in clinic, always talk about that, right? So we need to control the inflammation, but we also need to handle any scarring that's there with dilation. Or if you don't have any yet, we need to get you on the right diet or medical therapy so that we can reduce that risk of dealing with the scarring later and the impactions and those more concerning things. So this type of patient is still going to have symptoms. The other thing is, let's say the structure wasn't as bad and we did dilate a little bit further, even when we get patients above 15 millimeters, their symptoms may or may not be zero just because of the actual inflammation going on there, even with the eosinophils there. So there are some nuances to it. So this patient I would suspect is going to have some improvement in symptoms, but still persistent symptoms because of the active inflammation. That's a great question. And how long will you keep that patient on steroids for? So for getting them into initial remission, you mean? So we'll start at a higher dose, and then we'll assess symptom and endoscopic histology response after 8 to 12 weeks. So we repeat endoscopy with biopsies. And so if their symptoms are reduced to a level that's good for their quality of life and the eosinophils are under 15, and hopefully that correlates with the EREF score going down as well and the stricture starting to open, then we'll cut them to a lower dose and try to maintain them on a lower dose. So we'll go down depending on what type of formulation of budesonide or fluticasone they're using. The maintenance dose kind of varies depending on what you're using. What we tend to do is once we get into the maintenance dose, we try to do nightly just because it's a little bit easier. They don't have to worry about the eating and drinking part. So you just take your meds and you go to bed. So you don't have to worry about accidentally washing it off. So that's what we usually do. Yeah. Wouldn't this just be a great plan to switch to Dupixent? I mean, they're obviously not compliant with what you're offering. So... Yeah. So yes. And that is definitely, you know, there are several indications in clinical practice for Dupixent. And one of them is for patients that don't respond to steroids or have side effects or can't comply. So, yeah. Okay. We'll do these two more questions and then we should probably keep going. Okay. Go ahead. What does a safety conversation with regards to long-term steroid use sound like when you're talking to the patient? Yeah. That's a great question. So, and we'll talk more about some of the studies with steroids. So, and I have a slide on there with adrenal suppression and things. So we'll talk more about that. Yeah. So kind of piggybacking off this young lady over here, her question, why do you think when you're looking at a chronic disease as progressive, providers are more reactive versus proactive? So you mean in terms of how you're treating? Yeah. And it's, and that's transferable, not just EOE, but a lot of this is like, you know, I've listened to you kind of talk about the process of like, you know, ruling out this and this. Like, if you know you're going to get probably too Dupixent with this patient, why go through all the rigmarole and the patient have to deal with everything? Why don't we just kind of jump to the end? Because if you think about the safety profile, I mean, I get it when you would do maybe be preventative on some other diseases, but like on this, it's like, what are we waiting on? Yeah. No, I mean, these are all good points. And take managed care off the table. Yeah. No, they're good points. And this goes back to the core conversation clinic that Dr. Gonsalves mentions to us, you know, during this course over and over is it's all shared decision-making with the patient. So, I basically, when I first meet with them, I lay out all the categories. We got, we have the basic categories. So, I'll talk about PPI, I'll talk about swallow topical steroids, I'll talk about diet, I'll talk about biologics, aka do pill and map at this point, and then clinical trials. So, I lay out all the buckets. I talk to them about how you take them, how well they work, what the side effects are, and then we figure out and game plan together. So, yeah. So, that's how we usually approach it. But understandably, you know, there are going to be certain indications where you want to try to lean towards one therapy over another. But I lay them all out for the patients and then talk about the risk benefits. And that takes time in clinic. And I realize not everyone has that time. But we do the best we can to try to really help the patient understand all the risks and benefits for it. Yeah. One follow-up question too. When you do the shared decision-making conversation, when you talk about the PIGSEN, how many times is a rough number of people give you pushback, say, no, I'm not going to take that because it involves... So, at Mayo right now, we have, I think, 45 patients or so right now that are on dupilumab. And it's pretty rare that I get pushback on that. Most patients feel pretty good about it, especially with the pen. I have one that's on the pre-filled syringe. But most of them are not too concerned about that. So for my practice, it takes sometimes a few visits to get to the comfort zone. We offer, of course, through your company, like support. But the reality is they're really scared, especially if they have not been on any injectable in their life. So the day and age of semi-glutide being here, that is going down significantly. So that's the reality. And it helps us in the GI world because we are like, oh, great. We have another similar concept here. So I think that's going down. There are more educated patients. But there are lots of patients, young patients especially. This is their first medical encounter. So you have to read your patient. You cannot force anything, even though that may be the best thing in their medical care. And they have to come to that decision on their own because they will be non-compliant. They'll be the first one, any kind of side effect that comes about, whether it's related to the medicine or not, that they will blame the drug and come off of it. And that's very hard to get that patient back on track in the future. So you have to make the patient ready. And sometimes it takes a lot of follow-up conversations. We also provide nursing assistance if they cannot give themselves the first shot or so, so scared, or they don't have a family member who can help. We bring them into the clinic, and we give it to them so they learn. So there are many ways to help a patient. But it takes a lot of time. And a lot of community doctors don't have that time. Not a salesperson, per se, obviously. But yeah, I mean, we want to do what's best for our patient. And there's not always a right answer. So that's kind of the bottom line with it. And as I mentioned yesterday, we have esophageal nurses that help us with training patients on how to use it. We use your videos. So there's multiple modalities. So we'll keep going. Because right after this talk is the panel where you can ask all of the questions. So we'll keep going for a little bit to get through this. And then these are all really good questions. So I appreciate it. I'm glad that everyone's engaged. This is good. All right. So overview of what we're going to talk about. So pathophysiology, goals of therapy, treatment options in 2024, monitoring and maintenance. And so initial choice of therapy. So what everyone's asking about. So I talk to patients about efficacy, of course. And then a lot of it, as I just mentioned, is patient preference. So I explain to them how the medicine's administered, the type of work they have to do, especially if it's the swallowed topical steroids. They really need to understand those nuances to make an educated decision on what their preferences are. Disease severity can play a role, of course, as well. I'll show you some data in this in terms of stenosis response rates with PPI and swallowed topical steroids. Insurance coverage is a big one. So right now we have two FDA-approved medications for EOE. A lot of our job is writing letters to get swallowed topical steroids approved. And then dietary resources. This is critical. Patients need to be highly motivated to do diet therapy, and they need the right support, whether it's nursing staff, dieticians. That multidisciplinary support is really important. And again, as I mentioned, the shared decision-making model is really important. So management. So we talk about the Ds. Diet. Drugs. So as I mentioned, PPIs and swallowed topical steroids. Dilation. And then we've added in here, of course, dupilumab. And then other new agents. So obviously there's a lot of clinical trials going on for other therapies. And when we're thinking about our targets. So we mentioned these as well. So it's really important to improve symptoms. But we know symptoms do not always match histology. So we want to improve the symptoms, which improves their quality of life. We want to get those eosinophils under 15. And then ideally, we want to see that EREF score go down. And we want the diameter to be above 15, if able. So now I'll go through the AGA and Joint Task Force guidelines. As Dr. Goncalves mentioned, that the ACG guidelines that are being worked out will come out soon. So these are the guidelines from 2020. And so first, they recommend PPI over no therapy. And this was based on several studies. There were 23 studies, over 1,000 patients. And PPI effect is roughly a coin flip. It's in the 40s to 50% response rate. And when we talk about response rate, as we all know, we're talking about eosinophils under 15. In addition, this was an interesting study. And I'll show you another slide related to this that was done. It's a European EOE Connect database. And they looked at a lot of patients over 600. And there was a pediatric population in here of 76 patients. And they showed that PPIs do improve symptoms. So on the left panel here, at about 71%. And in addition to that, on the right bar graph, there was also histologic improvement. And that was approaching 50%. Sorry, I don't know why it's going backwards now. Let's see if we can fix that. Sorry about that. Okay. There we go. So in addition, there is some evidence that PPIs can reduce features of stenosis or fibrostenosis. And so this was another study. This was a cross-sectional study that was done from that same European database, the EOE Connect. And they did look at clinical histologic remission levels for PPI as well as swallow topical steroids. So similar as what I showed you before, PPI clinical histologic response was 50%. A bit higher for steroids up at 80% or so. But what's interesting here are the two diagrams. So this bar graph on the left, that's showing the EREF score. And it's broken down based on each part. So we have edema, furrows, exudates, rings, as well as stricture. And then we have crepe paper esophagus in there as well. So basically, the important feature here is looking at the rings and the stricturing. And you can see there is a significant reduction in PPI in the darker bar graph. And it was also a significant reduction in swallow topical steroids. However, the magnitude of it, you can see, is greater for steroids. But there was a significant difference for either treatment. And then on the right here in these line graphs, so the Section A here is looking at proton pump inhibitors. Section B is looking at steroids. So the red is the baseline. And then the green is the response after therapy. So this was measuring the diameter of the esophagus. As I mentioned, as Dr. Goncalves mentioned earlier, there's studies going on looking at functional lumen imaging probe or FLIP, measuring distensibility as a surrogate for diameter. And so that was what was done here. You can see an increase in diameter with PPI as well as with steroids. So what are the potential mechanisms? We alluded to this earlier. It's not just treating overlap acid reflux. So there's more to the mechanisms than that. So PPIs have actual anti-inflammatory effects. So again, this is independent of those anti-secretory effects that we talk about with acid reflux. They serve as antioxidants. They can inhibit immune cell function, decrease the endothelial cell adhesion molecule expression that occurs, can reduce inflammatory cytokine expression. So a lot of that is really related to the eotaxin 3 pathway that the PPIs help with. And I'll show you the diagram later. And also can affect transcriptome. And also, in addition to those effects, can improve the mucosal barrier function. So that can be through reflux or other pathways. But if we're improving the integrity of the mucosa, then it's going to be harder for those food and arrow allergens to get in and basically stimulate the pathway in the esophagus for EOE. So now we're going back to the AHA Joint Task Force guidelines, moving on to swallowed topical steroids. So fewer studies here compared to the 20-some for PPIs. There's eight. But these were all randomized controlled trials. So a little bit more effective data. Looking at over 400 patients, the overall effector response rate, meaning eosinophils under 15, was at 65%. And so this is a really important study to point out from a few years ago from Dr. Hirano and colleagues. So this is the budesonide oral suspension study. This was a randomized two-to-one placebo-controlled trial. So they had a little over 200 patients that received this budesonide suspension at 2 milligrams twice a day, and then compared it to the placebo in 100 patients. And the follow-up was done at 12 weeks. So what you can see here, here we're looking at the histologic response. So here's the budesonide suspension group. And 53% had a strict EOE cutoff of 6 or below. And then on the right here, they also looked at the dysphagia scores. And there was a significant response in terms of symptoms as well compared to placebo. So this was a very important study and ultimately gave away the next part, which is that this was FDA approved in February. And so this one is FDA approved for patients over age 11. And remember, it's FDA approved for 12 weeks. So this is really for induction. There's no comment on this for maintenance. So more to come on that. Another important budesonide preparation is the oral dispersible tablet. So this is something that's approved in Europe and Australia, something that's being studied more. This was an important phase 3 randomized controlled trial. And so this was looking at 82 patients over 6 weeks. And the important thing to note here is the left section here. So the clinical histologic remission, meaning symptoms resolved, as well as histologic response. Histologic response in this study was defined as under 16 eosinophils. And they had a good response rate of 57.6%. The other really interesting thing here is actually in the bottom here you can see. So the combined response rate increased to 85% after 12 weeks. So that was excellent. We actually have a colleague that works primarily in Sydney and Australia who's rotating at our institution for this year with us. And he has used this quite a bit in clinical practice and has told us that his clinical experience with this really matched the trial. So they've had good success with this. So another follow-up, what kind of preparation for steroid is best? So this was an excellent study design from Dr. Dahlin and colleagues where they looked at budesonide versus fluticasone. And it was nice because it was double placebo-controlled blinded with dummy. So basically the patients that had the active budesonide slurry also had the meter dose inhaler that had a placebo. And then the ones that had the fluticasone inhaler also had a placebo slurry. So it was really nice that they could compare these. And they found that the histologic response rates were the same between the two formulations at 71% for budesonide and 64% for the fluticasone. So they're both good. And this is with the caveat of patients being able to take it properly. Another study in steroids looking at fluticasone oral dispersible tablet. This study was very helpful because they looked at different doses. So the panels that you see here, A, B, and C, that's the follow-up time frame. So they're looking at 12, 26, and 52 weeks. And so the different colors that you can see here. So the dark blue is 3 milligrams twice a day. The next color here is 3 at night. Light blue is 1.5 twice a day. And then this yellow color is 1.5 at night. So all of these had pretty good efficacy in terms of histology response. And this was defined as 6 or below. However, the authors comment from this study that in terms of the risk-benefit ratio of efficacy versus side effects, they were looking at potentially an ideal ratio of the 3 milligrams at night, mainly because the twice-daily dosing had an increased rate of oral and esophageal cannabis. So having the higher dose but once at night seemed to be a good balance of those two. And then they followed things out to 52 weeks. And symptoms did well over that course. So issues we've been alluding to with these current topical steroid options. So again, sometimes we're repurposing asthma medications for the esophagus. Delivery may not be optimal for the esophagus. We're talking about really complex instructions. The Fluticasone meter dose inhaler. So it really takes a lot of education to explain to someone. I would struggle with it too, in terms of how to hold your breath and swallow an aerosol. That's a really complicated thing to do. So it takes time to educate and really help our patients with those types of things. Same with mixing various budesonide cocktails. Cost is another prohibitive part of this. And as I mentioned, we have to work around insurance quite a bit with these preparations. And then patient concerns about long-term risks. And that we'll talk about. I think that was a good question that you asked. So in terms of the task force guideline, they did not see an increased risk of adverse events comparing placebo with the swallow topical corticosteroids in those short-term studies. There are some reports of adrenal suppression. There are no guidelines for us to be routinely testing for that. However, I believe in the budesonide suspension study, they saw a rate of about 2% for adrenal suppression. But other reports, there's a wide range on that. So I think more to come to really understand that. And some of that data is extrapolated from the lung studies. In addition, as we talk about oral and esophageal candida is something we definitely have to talk to our patients about, because that's more common. Anywhere from 5% to 15% of patients may have that. It's really critical we educate them on rinsing out their mouth and spitting afterward to make sure we try to reduce that as best we can. So next, we'll talk about diet. So here's the task force AGA guidelines summary of that, recommending diet over no treatment. So as we mentioned before, the elemental diet is the most effective. So six studies that they have looking at this with a 94% response rate. However, in clinical practice, instituting that is its own challenge. But in terms of efficacy, it's good. Then we have the six food elimination diet. So we're talking about milk, wheat, egg, soy, nuts, and fish. And so 10 studies, 68% response. And then the allergy-directed elimination. So as Dr. Gonsalves mentioned yesterday, in clinical practice, it's not routine for us to recommend allergy-directed testing. There's other pathways that these allergy tests look at, including IgE-mediated pathways that don't correlate with the antigen food triggers in EOE. So here are the basic diets. As I mentioned, the six food, and those are the six common triggers. Then we go down to the top four, dairy, wheat, eggs, and soy. Top two, dairy, wheat, and then dairy being the most common trigger in the one food elimination. So when you're talking about starting with the full six food elimination removal or hedging your bets on one, two, or four, and expanding as needed, again, that's a really detailed discussion with the patient in clinic so they can understand the nuances of going with one of these diets. And so education is critical for this, in addition to education with the dietician. This is a nice summary to show you the differences in general response rates. As I mentioned, the elemental diet that you can see on top has the highest response rate. The black bars are for adults, and then the white in children. So you can see there are some differences there. Six food, next, the original studies were showing about a 70% response rate for that. There are some other studies I'll show you looking more at 50-some percent, and then moving down the line. However, I will show you here. So there are two randomized studies comparing the dairy, milk, single food elimination with either four food on the left hand here or six food. And so interestingly in these studies, so the one on the left here, you can see at 51 patients looking at milk versus four food elimination, and the response rates were similar in the 40-some percent range. And in addition on the right here, comparing milk to six food and so feed, the response rates, again, were similar. The response rates here are a little bit lower than what I showed you with some of the other data looking at a 70% response rate with the six food elimination. The other important aspect of educating our patients is having them understand exactly what they're going to be going through with this process of diet elimination reintroduction. Because as Dr. Goncalves pointed out, we're not trying to keep patients on this very restricted diet long term, right? We're just trying to localize those triggers and get them back on everything else. And so this process can really take a long time. And so what we normally do is systematically remove everything when they meet with the dietician and then after six weeks or eight weeks, re-biopsy to make sure the eosinophils are under 15. However, the reintroduction process can be quite lengthy and complex. So normally the general principle is to reintroduce the lowest risk triggers first, right? So that's why you're going to start with reintroducing seafood and nuts first. And that's because every time we reintroduce a trigger, if they flare and the eosinophils are above 15, then we have to wash it out again for six weeks before we can continue with the next reintroduction. So we want to reduce how many times we have to delay them another six weeks with a washout because this process is already going to take serial endoscopies and a lot of time and effort. So we try to minimize that the best we can. So start with the lowest risk triggers first and then move all the way up to dairy if you're going to do the formal six food elimination. Yeah. How long are they going to be with us? Six to eight weeks. Six to eight weeks. Yeah, at least six weeks. And then in between each, it's six weeks, yeah. So adherence is another question, right, with diet. So this was an online survey study that was done with 42 patients who had initially responded. So eosinophils under 15 on six food elimination. However, on follow-up at a little after three years, only a little over half of them remained on the diet. And there's a lot of factors related to this. Certainly, you know, some may have more symptoms and didn't feel it was working well enough. It's a lot related to our social situation. So certainly food is very ingrained in our culture, our society. It's part of our livelihood, right? So having to adjust those things can be challenging. There's a lot more options now at the grocery store and restaurants, but it can be challenging. And there can be some anxiety related to that. So now we're going to shift gears and talk about endoscopic treatment with dilation. We had really good questions about this yesterday in terms of what type of dilators and how we approach that. So this is a nice example from Dr. Dellin looking at a stricture in EOE. So the top panel A, you can see how small that circle is in the beginning there, how tight that stricture is. Then I'll draw you to panel C because panel C is important. So that is a balloon dilation. I'll show you what that looks like next. But the key feature here is when we have a balloon is we want to directly visualize what we're doing. So we put that balloon out. And I'm always talking to our fellows about this because they're not necessarily told this by everyone. But it's really important when the balloon goes out and we inflate it that we pull it close to the scope and you see how you're looking straight through there. So looking at the stricture and then straight through. So this is inside the translucent balloon there. You're seeing through so that you get a nice circumferential view here and see exactly what's tearing in real time to make sure you're getting enough but not too much. And then you can see in D here. This is a really nice, like I talked about earlier, moderate mucosal defect. This is exactly what you want to help our patients, but we don't want to go too far. And so these are what the dilators look like that I mentioned yesterday. So the left side, these are the tube dilators I was talking about called bougies. You'll see a lot of different names for these based on different companies that make them. But they're all in general called bougies. And so these are passed while the patient is asleep during the endoscopy, but the scope is out of the patient. So the scope is on the table. And so basically we place a wire first with the endoscopy scope to figure out exactly a guide for the bougie dilator. And then we're drawing over the wire, this dilator, through the patient's mouth into the esophagus and out. And then we go back in with the scope to see what kind of mucosal defect that we have because we want to get it just right, not too much, not too little. And so we go very carefully with this. And as I mentioned, there's some theory that this is a tube, so it has a longitudinal and an axial effect. So it may help some more with strictures, but we certainly use the balloons a lot too. And it's really endoscopic physician preference. So these are the balloons. And as I showed you in that other picture, they're see-through, right? So you pull up the balloon really close to the scope so you can see right through and see the whole circle of the pipe system of the esophagus. You can know exactly what you're doing. So bougies, you're going in after to check what you did. With the balloon, you're in real time seeing what you're doing with the dilation. So this was a meta-analysis that showed numerous studies here that the efficacy of the dilations is great. We're looking at 90% in the pooled data. So it really does help our patients. They're also safe. So there was a question of whether you can really dilate patients, especially up front with active inflammation. But numerous studies have showed this is very safe. The perforation rate is low. It's about 0.4%. In addition, hospitalization, bleeding, all of that's low. However, the critical piece, though, we have to educate our patients on, and I do this whether I'm seeing them in clinic or right before the endoscopy, tell them about chest discomfort. That's really common. As high as three-quarters of the patients can have that. It usually lasts a couple days. But I want them to know about that because I don't want them to be alarmed. If it's very severe, though, of course they need to let us know, or if they're having other symptoms like a fever, shortness of breath. That's when we start worrying about perforations. But some discomfort for a couple days is expected in EOE. In terms of summary of this, this is a comment that sometimes you may reserve dilation until later. But we really are pretty aggressive about dilating up front. That's a caveat. Typical effect, about a year or so. It really depends on what size you're starting with in terms of the stricture and where you're going with it. It really depends on the patient. But these are general principles. We're very conservative about it. If they have a really tight stricture like our patient earlier, under 10 millimeters, can't pass the scope, you're not going to dilate them from 10 millimeters to 18 millimeters in one session usually. You're going very slowly, incrementally, several sessions because we want to improve symptoms, but we don't want to cause a perforation. So we're thoughtful about how we do that over time. And again, dilator depends on type of stricture, length, size, width, and the person that's doing it. So should repeat endoscopy be used to assess EOE after a change in treatment? And the answer to that is yes. So we know that there's data that symptoms do not correlate with histology. So it's really important. So we talk about after that 8-week period or sometimes even after 12 weeks depending on what treatment we used, we will re-biopsy to really get objective evidence. Is the EOE improving? We're looking at the EREF score. We're looking at the stricturing. We may be doing a dilation. We're looking at the biopsies in addition to the symptom improvement. So rationale for chronic therapy. So as Dr. Goncalves talked about earlier, the natural history of EOE. So we know if patients are not on therapy or there's a delay in diagnosis that there's going to be more stenosis over time. And we also know this not only because of the natural history studies but also the placebo arms of a lot of these clinical trials. And we also know from some of the observational follow-up periods in these clinical trials that patients when they come off therapy may have symptoms as well as endoscopic and histologic features coming back quickly. So this was an example. So this was the trial I had mentioned earlier where we compared the budesonide with fluticasone and this was a follow-up phase that they did where they monitored patients. After they completed the treatments, they took them off and followed them. And what they saw is 57% of the patients had symptom recurrence prior to one year. So pretty quickly. And the median time for all of the patients for recurrence was 244 days but it was only 130 days for those 33. The other important factor for this is there were no clear predictors for recurrence. So that's something we need to figure out. So in these graphs here, that's basically showing that whether they were treated with the budesonide or fluticasone in the treatment phase of the trial didn't matter in terms of recurrence. It also didn't matter if they had dilations during the treatment phase. There were no dilations during the observational phase here because we were just trying to look at symptoms not related to dilation. But they may have had dilations earlier in the study during treatment. And again, that wasn't a predictor. So they saw that the EREFs had increased. The caliber diameter had gone down. And those strictures as I mentioned that were treated with dilation in the treatment phase of the study were starting to narrow down again. This is just another example of that. So we'll keep going based on time. So in terms of maintenance therapy, as Dr. Gonsalves said, this will be stipulated further in her upcoming ACG guidelines. But in terms of maintenance therapy, what was recommended at the time in the 2020 guidelines was that for those patients that are inducted with the topical corticosteroids, they should consider continuing with a maintenance dose. Again, at that point, that was a very conditional recommendation. So it sounds like we'll have more robust information on that coming up. So who should get maintenance therapy? So from a clinical standpoint, really all patients are candidates for that because we know it's going to happen if they're off therapy long term. We're particularly concerned though if they have a narrow caliber esophagus. Are they getting food impactions? Do they already have stricturing disease? Are they going to have quick symptoms once they come off therapy? So did they have a history of a perforation? So if someone already had a history of a food impaction with perforation, we're going to be very cautious with them. We want to control things the best that we can. Do they have another atopic condition that warrants a treatment that would overlap? Or are they requiring a lot of dilations? Are they in an area where they may not have quick access for an endoscopy if they have a food impaction? Because that can be quite dangerous. So there's a lot of factors. As you've seen, the general theme with EOE is it takes a lot of discussion in clinic for patients to have a good handle on exactly how to approach their treatment options. So now we're going to shift gears. We have a little bit of time left quickly to go through pathophysiology. And so there's a lot of components to this. Genetics, as was mentioned earlier with those slides with mono and zygotic twins and siblings, there's a different rate for all of those. So it's not just genetics, right? Because there is a difference between fraternal twins that are sharing the same in utero environment and siblings, right? So it's not just genetics. Epithelial barrier defects, food and aero allergens, the Th2 pathway, and that's what we'll show on these slides coming up, esophageal inflammation dysfunction, and this is what it looks like endoscopically. So this is one of the best slides looking at the pathophysiology from the O'Shea study from 2018 that we often reference because it's laid out really nicely. So initially we can see those food allergens coming in, the aero allergens, microbes, stimulating that epithelial barrier dysfunction leading to this whole cascade of cytokines. So we'll talk about some of those individually and really with a focus of the areas that are being targeted with biologic therapies. So the first path here is through the TSLP. So that's the thymic stromal lymphopoietin. So that's one of the first pathways in the cytokines that's released once the epithelial cell is activated by an environmental trigger. And this is kind of the initial step that sends off all the Th2 pathway with the different types of T cells and is not just associated with EOE. It's other atopic conditions too. So next is IL-4, which all of you are experts in that area. So this induces Th2 differentiation, increases that eotaxin-3 that we talked about before, as well as mast cells, IL-5. So this is the one that really helps for development of the eosinophils and really is driving those eosinophils in the mucosa, as well as playing a role in some of the tissue remodeling. IL-13, another important one, and related, of course, IL-4 and 13 have some shared association. So associated with other atopic diseases, as we know, part of the eosinophils getting into the region, part of the collagen deposition pathway, as well as how that can influence the smooth muscle reduction and contractility, as well as the disruption in the epithelial barrier. So eotaxin, another important one that's going to attract those eosinophils to the site as well. In addition, as mentioned with Dr. Salaria, so mast cells are really important too. So they're also going to be playing a role here in addition to eosinophils. Eosinophil counts may not be the ideal in terms of our only metric to use for treatment response. So we'll go more quickly through this part. So I can show you a few of the biologics here in the last couple of minutes. So this is a nice slide, again, showing dupilumab there, mediating through the IL-4 alpha subunit, and then syndacumab that works to inhibit IL-13 that you can see up here. But certainly there's going to be other areas to target. We mentioned earlier how the PPIs work through the eotaxin pathway. And then there's other targets for eosinophils and mast cells. So the interesting point to bring up about the anti-IL-5 therapy. So there's three listed here, mepolizumab, reslizumab, and benrolizumab. So the issue that's been seen with the studies on these is they do significantly reduce the eosinophils. The issue is the symptoms aren't responding. And the benrolizumab trial was just published in the New England Journal, I think in June. And again, same issue. So there's theories related to this. Some of it may be related to the fact that, again, eosinophils are not necessarily our only marker that we should be using for response. And there are other complex pathways involved that could be driving patient symptoms. So more to come on that. And then of course dupilumab. And this is your area, so I don't have to lecture you too much on this. But we all know dupilumab's action that it works on the IL-4 alpha subunit. So it's a monoclonal antibody. And so ultimately, that's going to inhibit IL-4 and IL-13. As we know, it's approved not only for EOE, but also moderate to severe asthma, eczema, allergic rhinitis with polyposis. And this was some data from the phase two trial with 12 weeks showing here that you can see the 65% response rate with eosinophils 6 or below, and then up to 80% or so with eosinophils under 15. And this is showing a lot of metrics here. We won't focus on all of this. But it's showing great improvement in several metrics, including eosinophils, EREFs. And then to make a note that there was an improvement in the distensibility on endoflip as well. And I know that you're also running the trial now that's looking further at that. Zendacumab, as I mentioned. So that's a humanized monoclonal antibody that's selected for IL-13, inhibiting the alpha-1 and the alpha-2 pathway for that. Again, a phase two trial. So this was randomized double-blind placebo-controlled trial looking at a little under 100 patients above 18, and 16-week responses. So this one looked at 180 milligrams or 360 milligrams plus placebo. So the primary endpoint for that was the eosinophil counts. And I'll show you here on the next slide. So here you're seeing in the left diagram here. So this is reduction in the mean eosinophil counts. So for placebo here, you can see a limited reduction. What you're seeing here for Zendacumab is the 180 milligram dose here at baseline in week 16 versus the 360 milligram dose. So both of those had a very significant reduction in the mean eosinophil counts. And then on the right panel here, that's looking at whether they met the cutoffs under 6 and 15. So you can see the significant reduction here for under 6 and 15 with the 180 dose as well as the 360 dose. And then what was done after that, I'll show you that in a second. So first, this is a breakdown looking at the steroid refractory patients. So as you can see here, again, even in the steroid refractory, there was a reduction in terms of the mean eosinophil count. And then there was also a reduction in the EREF score, which was a good sign as well. And then here's the follow-up that I was going to show you. So this is the 52-week follow-up. So basically, the colors that you're seeing on the lines here, so that's based on whether they had the placebo in purple, whether they had the 180 milligram dose or the 360. So no matter what they got initially in the first part of the study, everyone after that in this 52-week open label part got the 360. So no matter what they started with, they got 360. And looking at this, you can see that they had good response rates. So it didn't matter what they initially started with. And then one common trasmod is another one, oral medication, working through a different pathway that potentially affects how the lymphocytes get out of the lymphoid tissue and get into the esophagus. And so there was a reduction in eosinophils with this as well. So summary, the goals of EOE therapy, as we talked about, are certainly symptom improvement. Quality of life is key, but we also need to control the inflammation. So we want to see that reduction in EREFs as well as histology. The pathophysiology, as we overviewed, it's complex. There's more to understand in this, especially some of the gene pathways. Food allergens, genetics, Th2 immunity are all really important. And both diet and medical therapies are useful in EOE, but not necessarily one therapy is going to work for any given patient. As Dr. Gonzalves mentioned earlier, we really need to sort out who should have what ultimately. We don't rely on symptoms alone. We know that doesn't match our objective data. The other important factor to think about is hypervigilance. So Dr. Gonzalves and the Northwestern Group have studied this where, unfortunately, when you have patients that have an anxiety-provoking disease that caused a lot of symptoms, they can really focus in on their symptoms. So sometimes symptoms may not be fully reduced, even though the biopsies look good. And that may be because, of course, we miss something on biopsies, but sometimes it's also related to esophageal hypervigilance, and we have to use other types of modalities like cognitive behavioral therapy, hypnotherapy to really help our patients to feel better. Dilation is an excellent effective treatment and safe. And again, EOE is a chronic disease, so maintenance therapy is really important. And there's multiple targeted pathways, as I mentioned, that are coming down with clinical trials running. All right. So we're going to stop there.

Eosinophilic Esophagitis

pathophysiology

treatment endpoints

biologic therapies

PPIs

budesonide

dietary changes

endoscopic dilation

dupilumab