What I'll say is for this one, this is going to be the more heavy hitter in terms of your statistics, but I say when you meet your physicians or when you try to posit how this drug goes into our care, it'll help you sort of learn what's going on for you. So you get your 30-second spiel for elevator speech for us as well. It may help us know. I'm also from Nashville, so I see some friendly faces here as well. So Nashville is known for really three main things, and I don't know if anyone knows those three things. Country music. Not me. Well, yeah, we are building like crazy. Bachelorette parties and hot chicken. So Friday night, if you go down Broadway, there's all these honky tonks left and right as well, too. And I always see the guys, and they're all hanging out, great live music as well, too, and they're all eating their hot chicken. It's all in Hattie B's, and it's really spicy. And I always look around, because I'm usually on call that weekend, and I see this one guy who's swallowing really slowly, and he's drinking his drink, and he's trying to get his beard down, and he's jumping up and down nonstop over and over again. I'm like, I'm going to tell my wife, I was like, am I on call tonight, because in two hours, he's going to be in the ER with a food infection. And it almost always happens to me. So I'm going to flip the script a little bit. I'm going to have you guys be the physicians, and I'm the patient asking for help, okay? So I'll pick on you guys a little bit. This is not my patient, but this is pretty classic to what Walter just went through. This is a patient who has an upper endoscopy done, and this person is already on Budesonide, which is a therapy we can use for topical steroids for Eosinophil esophagitis. As Dr. Chan noted, there are some furrows, these long lines there as well, too. You're not getting a great sense, but this is a more narrow caliber esophagus. And you guys are brought up the question, what happens if you stop your medicines? What happens to people? And that's the wrong way. And on this initial biopsy, there were Eosinophils present as well, too. So this is what happens. This is a guy, Friday night, who goes downtown Broadway and swallows a bunch of chicken, and he sees me with free air in his neck, and he perforated his esophagus as well. So we're not doing the endoscopy on that person, but this person maybe is a little easier. He's just got food stuck in there. He's sitting there with saliva coming out of his mouth, because we make about a liter and a half every day of saliva, so you cannot get it to go down, it's got to come up somewhere as well. And he looks terrible. He's like, please help me. I try to drink water, I try to drink Coke, meat tenderizer, nothing is going to make this feel better for me as well. So I've got to come in, we've got great fellows who are already triaging the patient, getting ready for intubation as well, too. We've got to go in there and actually try to remove this bolus, because he's got active Eosinophil esophagitis, after non-compliance as well, too. So we can't trust him always to say, I feel better, because he's still got stricturing disease as well. So this is now, he's now back on his medicine, this is two months later, and you can see the food bolus is gone, but you also see nearing of the esophagus. Now this esophagus is very narrow, so that's probably about less than the size of my endoscope. And just passing the endoscope, you're seeing tearing of the esophagus. Most community providers are sending patients to Vanderbilt or to the Brigham, because they're very worried about doing dilations on them, because this mucosa is very thin, about before two millimeters of the esophagus. If you rupture that one, that's a perforation, that's a complication, and people can die as well. So this patient needed dilation, just with a scope, to help out with stricturing disease as well. Now the ESMFLs are 110 per high power field, so that's over our goal, and there's also these changes on pathology, we'll talk about more tomorrow as well. So the question is, what are you going to do? So Tyler from the Mid-Atlantic. This is me, this is my esophagus, doctor, what do I do now? I don't know, just tell me what to do, I can't swallow. Stop eating things. Okay, stop eating things. Okay, that's one option we have. Well I would probably, the first questions I would ask is, how often are you feeling this way? What foods do you notice that trigger it, and what are you currently doing? What changes in your diet are you making associated with it? Love it, love it. So a couple of objectives today, you're going to understand how those questions help our patients. What is the EOE pathophysiology? What are our goals of therapy? What are options we have in 2022 based on the guidelines that we'll change probably as well? And how do I assess responsive therapy? So questions that are bridging Dr. Chan's talk as well. Are there data for chronic therapy, and also what's the newest options for biological therapy as well? Now one common interest is that I run, as of Monday, I will have ordered every drug you'll see today. So both off-label and label as well too. So I will give you an unbiased opinion of all these drugs as well. And what do we do with refractory EOE? So the first question is, how do we understand the pathophysiology of EOE? So this is a busy slide. And Jennifer, what are things that on your mind, you've got to worry about your drug on this slide? Which ones? And why do they matter? For your drug? Yeah. What about all these other ones, the other pathways? Do they matter? And does your drug help with those? So when we think about medicines for therapy, we have different ways to attack eosinophilic esophagitis. So one way besides using medications is doing dietary elimination. So we have all these food allergens and air allergens. And what you'll see in your practice is that some patients don't want to be on medicines. They don't want to inject themselves at all. They don't want to take any PPIs. And they can control things dietary-wise for them as well. That happens more for my youth. So my son has really bad eczema, throws up eggs and milk, and probably is going to be a young EOE person as well, too. So I do not want him on a biologic. He's two years old. I don't want him on a medicine either for him. So we just remove those foods for him, and he does great. Has no allergies, no eczema anymore as well. So you'll have patients like that as you get older to understand the pathophysiology disease as well. We also have other ligands, so TGF-beta. And you're going to see some cells, the eosinophils, mast cells, which are really interesting pathology part of what's going on as well, too. But ultimately, you're going to see what's called this TH2. So TH2 is a signal that allows you to then escalate some therapy options. And that's what your drug is helping with. But other drugs can also hit these same receptors for ILO4, 13, and 5. The downstream effects are complex, but I will say we're still naive at what all is actually happening in the body. We do know STAT5 and STAT6 gets upregulated. A key marker here is eotaxin. That's like a humming beacon for eosinophils to then drive into your esophagus. So I'm going to ask, but why do these molecules matter for ILO4 and 5? But when they become dysregulated, they lead to increased humming beacons that cause eosinophil inflammation, probably the loss of barrier, remodeling, but remodeling for us is fibrosis. So that's not always a good sign when there's remodeling to a negative feature as well. So one of the markers we saw earlier was in the IL-33 and also what's called thymic stromal lipoprotein protein. The reason why these are important is they're pretty early phases for how we actually get transitions of eosinophils into the esophagus. It's released by some environmental response, which Dr. Chan went through as well, but it helps promote this Th2 differentiation. So those of us who have used Regeneron or other drugs, what are the indications for your drug right now? Right, and so those options are all Th2 high symptoms. Now is there a Th2 low eosinophil esophagitis? Probably right? So we have it for pneumonia, we have it for asthma, and there's probably a Th2 low. So that may be one person for which Th2 low EOE, this drug may not help. We don't know that yet as well, but it's good to know about why we get differentiation of different responses as well. But when you have Th2 high, you have multiple atopic disorders. That's why your drug works so well for them. So we're hitting that mechanism for why they actually get eosinophil esophagitis as well. I went through IL-4 already. So IL-4 helps also induce this Th2 differentiation. It increases the eotoxin 3, and also has this mast cell proliferation, a growing theme throughout. We talk about young men, and women also get EOE, but my young women typically get what's called mast cell activation syndrome. So this would be a nice option for them if this drug would work for them as well too. So your drug is mindful for EOE, but it may have other implications that we have no orphan disorders for right now as well. IL-5 is required for eosinophil poiesis, a fancy word that means we just drive eosinophil growth. Someone asked a question, if you drop all these levels, does it hurt me? You know, one thing, if you look at your packed insert for Dupixan, it says you need to check for parasites. If you have intestinal parasitosis, you cannot give this medicine. That's what's helping you with that. Now that we see that often, pretty rare. Giardia is probably the one we see the most in the southeast at least. We'll check if you have chronic diarrhea. Diarrhea is a little bit less common in the U.S. as well. And finally, IL-13. So IL-13 is associated with multiple atopic disorders, and it also drives eosinophil driving as well. This also leads to collagen deposition, which is why we think we may get fibrosis and some of this remodeling as well. So that's a nice move for some changes of contractility. So patients sometimes can't swallow because there's fibrosis, but also we know eosinophils is not just on the surface layer, it may be in the muscularis layer. So we cut all the esophagus open for patients who had other disorder of the esophagus, and when I flay it open, you see on the muscular just chock full of eosinophils there as well. We don't know if this drug will work for them, but it would be nice to know if there's eosinophil disorders deeper than not just the mucosa of the esophagus as well. This helps disrupt the epithelial barrier, and so it's really important for why we think about IL-13 for your drug obviously, but also other mechanisms of how we can help those patients as well. And finally eotaxin, this potent eosinophil chemotractant, that's your homing beacon as well. Mast cells and eosinophils kind of roll together. So we often see them together in biopsies. We don't systematically biopsy for mast cell activation, but in my young women's who have diarrhea or nausea, vomiting, I always send samples for them, and it's usually missed on most community providers as well. Kind of similar idea, and the real trigger here is the TGF-beta helps with pro-fibrinotic remodeling. So when you keep being strict for disease and changes, you start remodeling more, and that leads to some downstream remodeling of this TGF-beta as well. So this is a nice picture of how we think at that time, which is 2018, how we thought eosinophils were happening. So based on the last lecture we had, what are the causes of eosinophilic esophagitis? You can cheat on that page. So my med students, they look on the slide real quickly, and then they ask questions. I like it. Group think. Yeah. So food. There's probably food triggers. There's environment. We don't know all of them. And someone asked a question, do you send your patient an allergy? Well, I don't know if that's the cause of all this. So I'm like, Dr. Chan, I don't always refer my patient to allergies because I don't know if that's a cause. And then doing skin testing and blood testing doesn't always help me. What we do know, though, is that it does change over a lifetime. So you can have changes from infancy to adulthood. So my son's here, younger, vomiting, nausea, and feeding issues when he was a kid. As they get older, he'll probably get dysphagia and food infection unless one of you guys help him. And that happens because you change the muscle of the esophagus. Tomorrow's pathology will help you understand this better. But you basically become this nice, flexible tube. So if you do your pig model tomorrow, you'll see this tube just change, and it kind of squeezes for you. But imagine now it's a lead pipe, and it can't squeeze. And your esophagus is pretty dumb. That's why me and Dr. Chan like it. It just pushes stuff from your mouth into your stomach. So not many things can go bad with it. Until they go really bad, then we're in trouble, and we can't get food to go down as well. But as we get progression disease, we start worsening, remodeling, and dysfunction as well. Who's here? The accepted trigger of EOA, is that something like across the community that people will recognize? It's a good question. So that study was done cross-sectionally, looking when you look at codes of eosinophilic esophagitis and PPI use. And we'll go through a slide about that as well. You can associate PPI with everything. So maybe you missed a left toe. It's probably because of your PPI use as well. So I think a lot of us would say it's come up environmentally as a prescription pattern as well. But do we have a prospective study looking at PPI use of eosinophilic to cause it? No. And we use it as a therapy. So that's not well accepted, as we're going to say, that's why you got EOE. Stop the medicine. Let's use a PXEN instead. So associative studies are not causal, and I'd be mindful of those as well. All right, let's ask you. What is our goal for therapy and EOE? Hope it's remission. Remission. Symptoms. So you can pick one. Let's raise our hands. Histological remission or symptom remission? Symptoms. Histological remission. So there was a drug that was provided for oral budessinide steroids, and it went up for FDA approval before your drug went up, and it got shut down. Why? It showed histological remission, but not symptom response. So do I care if the eosinophil count from 60 to 45? If I'm still throwing up, I don't care. If I get food still stuck, I don't care. So one thing to know as you go through your medicine, and other ones that will outcompete maybe as well, too, is that are they going to drive symptom response? So when we talk about IBD drugs is that we're helping not with just histological remission, but people who are feeling better, not having blood in their stools, not having cancer formation as well, too. So really the goal, and for all of our studies, when you look at your papers as well, too, is getting symptom improvement. If I don't take care of that, the patient does not care if my esophagus is more distendable. If I can't swallow, what do I care about using a new medicine for me as well? So it's a good question, and this is where we fight nationally about this. So just because we can biopsy a cell, is that really the driver of all this disease? So we went through that complex slide to say TGF beta, IL-13, IL-5. But the eosinophils is a downstream path. So they should be interconnected, and that hopefully is a response. But when you see some disconnected studies, you're saying, well, maybe eosinophil counts are not the only driver, or it's deeper, and we can't measure it. So eosinophil counts are not the only driver, or it's deeper, and we can't market that as well. So they should be related, but when there's discrepancy with drugs that we know help, we're going to say, well, maybe we don't understand the disease as much as we think we do. We don't, honestly. So that's where I think symptoms always drive it. Now, if they work together, which it does for some drugs, it's perfect. But if you only have histological remission and no symptom response, that's a problem. So we do want to reduce mucous inflammation, and we also want to prevent complications and 5% disease as well, too. So we call this EOE Treat-to-Target. It's kind of our working model about how we want things. So, yes, we want symptom improvement. I want patients happy and see me. The most gratifying thing about EOE patients is they're really young and healthy, and they do so good. I mean, they'll tell you what they want to get done in life, what their options are as well, and they do so well with treatment options for them. We want them histologically responsive, because if they do, they're not going to stricture. I don't have to worry about them on Broadway. I can enjoy my night, and they can enjoy their night as well. And the endoscopy doesn't matter. You know, I want to limit endoscopy as I can, but when I do them, I don't want strictures present, and I really don't hide EOS in the full counts, because that's going to portend to worsen diagnosis for them as well. So what are my treatment options? I've kind of picked a good question. Those were the patient goals, or those were the physician goals? You're talking about for the clinical trials? No, when we were just talking about symptomatic remission versus histologic remission. Oh, symptom response is patient symptoms. I mean, for any EOE drug, which we'll go to now, the goal really should be controlling symptoms and also histologic remission, ideally. But the priority was perfect, which is patient symptom response first. And in theory, histologic remission should come with that as well, but EOS in the full count alone should not drive a drug to then be FDA approved, is what we want when we market that as well. So they should come together. Patients want to feel better. They don't care the Eosinophil is all. It doesn't matter to them. We care, but once again, we use words like remission like we do for IBD, but this is not a pre-cancerous condition. So we know increased Eosinophils will lead to fibrosis over time. I want it better and improve. I do less than 15, but I don't need to drive it to zero. So going from five to zero, does it make a difference? From 15 to six, maybe a little helpful. But if I drive it to zero, does that make a difference? Probably not, honestly. So I would improve, definitely less than 15, maybe even less than six in some studies. But going from four to zero, am I going to increase their medicine for that way? Absolutely not. But you could have other pathologies of the epithelium, such as a dilated intracellular space or basal zone hyperplasia or such. So I guess my question is this. If you have resolution of symptoms, does that then cover epithelial dysfunction? I'm trying to identify, basically, if you have an epithelial barrier improvement, does that automatically cover signs of dysphagia as well? Twofold. One is, there can be strictures present that are dominant, which you can still, on the distal esophagus, are normal. So if you have a stricture in the proximal esophagus, and you only biopsy the middle and distal, they'll have symptoms still for them. But your chloralate, which I'll show later, is that the absence of symptoms does not mean there's endoscopic histological remission. And that's the problem. That's what Dr. Chan and I agree with, following them up with endoscopy for them. Because like IBD patients, if you have any IBD patients as well, too, you can't trust them. Because they are actually feeling much better than they were before, but their symptoms do not respond to eosinophil count always, or dominant strictures. I had a patient yesterday who has had no problem swallowing at all, but he had ATIP and eczema, so they're warning him he has some GERD symptoms. I couldn't get the scope to go through. I mean, I ripped his entire esophagus, putting a camera to go down the esophagus. So he had no symptoms at all. So he's learned to live with this over years and years as well. So your corollary is true that if you have a purely patent esophagus with no stricture, they probably shouldn't have symptoms to them. But the patient's symptom getting better does not always collate to histology or endoscopy, unfortunately. So that's where endoscopy still matters, unfortunately. So this is the old slide because now, thanks to you guys, we have FDA-approved therapy. And there's probably going to be more in the next six months beyond your drug as well, too. So we'll put it in context here shortly. The need for repeat endoscopies is still there. We're looking for non-invasive ways of testing this one, both on an index endoscopy, which our group is working on, but also on saliva testing as well, and microbiome testing, which has still not been proven yet. Patient-reported outcomes is really what the standard of care is to get your clinical trial drug approved. There are multiple of them, and as we just discussed, there's problems with just symptom alone to say that's what's helpful to get you approved for FDA. So what are initial choices for EOE? And we think about a lot of things. So one is, is it effective? What does a patient want? And this is where it comes to shared decision-making with a patient as well. How severe is the disease, and will insurance cover it? So in my patients with a VA, it's a little bit easier because I can get coverage pretty much automatically for them. For my private payers, though, it's tricky, and definitely Medicare, a little bit harder. Now, most patients on Medicare don't have EOE, so it's a little bit lucky right now, but hopefully get cover later on as well. And then also dietary resources. So my favorite patient is the one whose wife or husband is a nutritionist because they're always going to go dietary elimination, and they never go on drugs, and they do 100% better. So most of them can't do it past the year, which we'll go through, but those are the ones who I know are motivated and have family support for this as well. And we just have a discussion. Any drug is an option for them, typically, or medication or dietary elimination, but we just spend our entire clinic talking about what we want to do with this long-term as well. So this is just a slide saying that when you see a gastroenterologist, the best thing that we do to offer your patients is shared decision-making. Can you take this medicine? So when I talk about Dupixent, I say, can you inject yourself? Are you afraid of needles? Can you take the pen with you? Can you refrigerate it? Can you travel with it? Are you okay just taking a pill? Can the pill go down? Will it get stuck when you swallow PPI as well? Can you be MacGyver and use a stairway slurry as well? I mean, those are hard things to do as well. So when you see one of us, the patient decision-making is better. They usually have better compliance as well. And that's why I think this drug for a lot of EOE studies will still be by one of us and not yet allergists. Now the allergist will usually get it first for Dupixent because it's used for other causes. But if we're using it just for EOE, it's probably better to see one of us right now because we just understand the pros and cons of this a little bit better right now. But hopefully that won't be the case forever. So management, we call this really the 5D method. This is a little bit not caught up to where we are now. But one's diet, so we can do elimination diet. Two is drugs, which include PPI and topical steroids. Three is dilation. And then we have dupilumab as well. And then new agents. These include the biologics we'll go through. So this was one of the cohort studies from 2020, which is why it's going to take a while to re-update some of these. It takes about a year to make us the new guidelines. But we have six studies on elemental diet. Elemental diet is nasty if you ever have to try it for your family before. No adult can really tolerate it. We put it through NG2 for my kids who need to be on elemental diet as well. You cannot really take a pure diet. But six studies, highly effective. So 94% had actually got improvement. There's six elimination diets, so we'll go through those foods shortly. That's only using the six most common foods that cause changes for them. Ten studies, better. So 68%, but not as good as elemental. But at least this is something you can use for your adults. And then this is a question they brought before, allergy-driven. So if I send it to my allergist, they say, oh, you have a dairy allergy, let's just remove that one. About 50% of the time, they'll get improvement. So not perfect, and that's why I don't always refer to allergy on the front end. Now, elimination diet and the purest method is very expensive. So if I want to be purest, I say, let's go ahead and start seafood. I actually do it different order, but we'll start one option, which is seafood. Then a few weeks later, we add nuts. I do my endoscopy, that's cost. And if I have less than 15 EOs per hydropower field, I'll then add soy. If it's elevated, I'll wash out and I'll resume the soy. If I don't have any increased EOs in the fields, I'll then add eggs. And I'll do my other endoscopy, that's cost and time to the patient. And then if there's not any increased EOs in those, I then add wheat, because wheat's kind of a more common driver. And once again, I then add dairy. Dairy is really the most common cause, and gluten as one of the most common causes as well, too. That's one, two, three, four times a patient came in for an endoscopy, IV put in, patient had come with a family member as well, too, missed out of work as well. So it's a pretty cost-intensive procedure. I do this maybe more my veterans for where cost is all covered as well, too, but it's pretty hard for any patient to come in who has a job, honestly. So I don't always do the full elimination diet this way. Adherence, so they online surveyed 42 patients who did this one, and only 57% got stable on it for about 39 months. For me, most patients after a year fall off. Even with their family as a nutritionist, I say, I can't do this. There's no way I can avoid gluten and dairy for the rest of my life. It's not going to happen. I'm 42 years old, been doing it my entire life. I cannot continue this for a whole year. And they yelled at their wife. I'm like, don't get a divorce. We have other options for you as well, too. So it's not an easy elimination diet for all six foods as well. The reason you don't always get symptom control, when you guys go out to eat, you can't always get those food eliminations. So my son, we can't get dairy from a lot of places or gluten from as well, too. Easier now, but we carry our own stuff with him as well. I'm also having a lot of anxiety about eating now and dietary changes. A lot of changes have now moved, especially in the pediatric, to this called OneFed. So let's just remove dairy as well. And this was a nice study showing that OneFed elimination diet is actually really helpful. And this is what I usually do in my patients as well, too. If we just eliminate dairy alone, that's easier than six whole foods out of your whole diet. And really, dairy and gluten are your one-two bangers for what's going on for EOE as well. So the full six-fed is actually going to be cow's milk, wheat, egg, soy, peanut, and fish. Most of us, clinically, for the adults, will do either one-fed or two-fed. And I usually do a combination, depending on what the patient says. Now, one thing to say is a lot of patients will say, well, I had cinnamon and I can't swallow anymore. That cinnamon is not what caused their eosinophilic esophagitis. If I go and pull meat out of there, they say that's what caused it. The meat did not cause their eosinophilic esophagitis. These foods cause fibrosis, inflammation, which in time causes stricture, and the food got stuck afterwards. So they'll start avoiding high-protein foods, and those may not be the cause, and usually are not the cause, of these foods as well. So PPI. So this is probably where we use a lot of drug use. So 23 studies over 1,000 patients. And overall, pretty high effect rates. So 42% got improvement. I would say clinically, it's probably even higher when you ask the patient to take it at the right time. So a lot of times, it's the wrong dosing and wrong timing of the PPI. And so with a highly motivated patient, this is much higher in clinical practice as well. Yeah, that's called a measure of how heterogeneous the studies are. So if they're really heterogeneous, that's not a good study, but that's a good study as well, too. So yeah, those I-squared, you'll see them come through. It's just showing how heterogeneous the study population is as well. So PPIs. So let me ask you here. So I have no heartburn symptoms, and you're telling me to be on PPI. How does it help me? Well, the top process is it drops the EOS count. But how? Yeah, I guess it would be unknown. Right? Okay, so the studies this morning showed PPI is helping with this parietal cell and the top of this, let me go back to hour one, and that's helping prevent acid. So are we thinking acid's causing eosinophilic esophagitis for these people? No, I don't think so. Right, that wasn't on our little rubric, right? So what we think, though, is it does block Eotaxin-3 and TH2 response. So I tell patients, I know you don't have heartburn symptoms, and I know you don't have reflux at all, and that's not why we're using this medicine for you. It's actually to block that driver, just like your drug is trying to do as well. It does the same mechanisms for them as well, too. So that's how this one's helping for them as well. So a lot of people don't want to be on it, because like, well, I don't have any heartburn, why even take this medicine for me as well? It's actually probably effective when it does help for them. So this is my mentor's paper in Gastro, going through all the side effects. So every time in clinic, which I see about 20 patients in a full day, 19 of them will ask me, I'm worried about BMI-PPI. So Peter, what are your worries that you believe in currently in 2022 about BMI-PPI? Uh-huh. I guess, I mean, maybe acid suppression with maybe other diseases, other bacterial infections, like H. pylori, things like that. So it would treat H. pylori, but you're right, it does block acid, which, so if I eat contaminated Taco Bell tonight, and I get Salmonella or Shigella, I need acid to kill that. So that's actually the biggest effect. How about osteoporosis? Fractions, things like that. And you think that's a real side effect? There was a thought that perhaps with distal fractions with- Heart attack, as well. Lupus, dementia, kidney problems. So once again, I think someone asked about EOE earlier as well. You know, when all these studies are done, they're all associated. Let's look at all these cross-sectional databases of using PPIs with drugs and diseases. And it hits all these things you'll see behind here. Kidney problems, lupus, gastric polyps, osteoporosis, and it becomes tricky, right? So you have this much noise, how do you make any signal out of this as well? So when we talk about these studies, and it's important for you to know because PPIs are still a powerhouse for this disease process, we have areas of what's called zona bias, more statistical, but there's areas that we say we really believe that this is an increased risk, which is over three, but somewhere in the middle is probably just bias studies, and if it's less than that, it's not even, it's protected probably as well, too. So the best thing was Paul Mollietti. He did a randomized control study, about 40,000 patients looking on the risks of PPI in them as well. And this is what I quote every single day. Actually, my fellows know it by heart now as well. They're probably tired of me hearing this as well. But looked at all those concerns, gastric atrophy, C. diff, CKD, dementia, pneumonia, fractures, COPD, and diabetes, and the only ringer here, and Peter got it right, which was enteric infection. So it's still low, 1.3 times normal, but that's really the biggest side effect we know that we believe in for PPI use. Now, C. diff probably is still a real signal. They only had 10 events in this whole study, so in the author's report, that C. diff probably is something to be mindful of, and it's the same mechanism. But really, the other ones have been largely debunked, and this is a three-year study, so some of these will be found later on. But the worry for the use of PPIs is less concerning now. But it'll be still hot-pressed, because any reports you have high risk of dementia, well, let's stop it. But as you get older, you probably have heartburn symptoms, you got plenty of PPIs, it's so easy and effective right now as well. What are the PPIs? Which PPI? Yeah, so what's the FDA indication for twice-daily dosing? There's no FDA approval for twice-daily dosing. So we're using an off-label. Right. All the PPIs are generally effective, except that there's some people who can't metabolize certain PPIs. That's not super common in the U.S. population, and some of my patients who are from Asia, they don't have the right CYP2C19, which we don't usually test genetically here, but I'll use rabiprazole for them if I have to. But in the U.S. population, it doesn't really make a difference. Once a day, if you have to, and I don't really pick different dosing. Now, pantoprazole is IV, so if you're in the hospital, I may give you IV dosing. But if it's the right time in dosing of it, the PPI is overall, they have different efficacy, but if you write the right dose, for a patient with heartburn symptoms, the dosing doesn't really make a difference for them. So doing it twice-daily, more is not always better. We use the off-label for a lot of symptoms. Heartburn? Tears? Guys? For what reason? Why are they on it? Heartburn? Yeah, so the reason to be on acid suppression is to make sure you're not, you've found Barrett's esophagus, so we're actually bringing cancer for you. Symptoms alone don't always, I always try to risk coming off their medicine for them. So if there's a true pre-cancerous condition they have, I will keep them on their acid suppression. So if you have Barrett's or low-grade dysplasia, you're gonna get cancer if we don't keep you on some medicine for you as well. If you have dyspepsia or bloating, I'm gonna come off that medicine. Or test you to say, do you need to be on this medicine still? It's pretty easy to prescribe them. The de-prescription is what I do, in the esophagus, more than anyone else probably, because it's easy to write more and more meds for. So when they see one of us, you'd say, oh, we're probably asking more and more PPIs. We actually have to stop most PPIs in our clinic. Either it's neuromodulation or hypervigilance going on with them as well. So yes, definitely concerns if there's not a good indication. And most times it's just bloating. What are you treating with that medicine for them as well? So it's been over-prescribed, certainly. So steroids, eight RCTs, 437 patients, also very effective. So this was also given a strong recommendation for use for EOE as well. I'm gonna fast forward some of these slides. Some of them show a lot of bar graphs. And I'll just highlight why they're important, but what's here helpful for you. So you may see as a words like budesonide and flucicosone. These are two different types of steroids you can get. One of them is very easy to use. You kind of use it as an inhaler. And you can puff it and carry it with you in your pocket. The budesonide comes usually in a respule and you have to smash it into five packs of Splendid apple juice or applesauce and then take it after meals for you. So my patients are having kind of walk them to the pharmacy with them as well. So sometimes it's really expensive. It's hard to always get these drugs available. But the key of this study was that both are pretty much effective. So whichever one you're on can help induce histological remission and sometimes insurance drives which one we use for them as well. So concerns is that asthma has been sometimes reported with issues. The drug delivery was not optimized. So we're using the stuff like puff twice a day and then don't swallow for an hour and a half and swish a raffle of water and mix with applesauce. And it's not easy because it's not delivered for the esophagus. So you'll see some newer generations now built for esophageal delivery as well. And still currently there's not FDA approval for any of these medications as well. Patients have concern for long-term risks. Really it's Canada yeast infections the biggest thing. We don't get systemic steroids because those risks do include bone risks to them. These people are usually underweight and we'll get osteoporosis and bone changes when they get older as well. So overall but no increased risk compared to just placebo for them. There's concern maybe some from adrenal deficiency where you have too many steroids in your body which is a little uncommon with the oral steroids. And then local fungal like yeast infections or other viral infections from as well. So dilations. Have you guys seen a dilation yet? Tomorrow you're gonna dilate with a savory. So in that room they have a 45 French cook catheter. So it's pretty small if you'll see it. You'll be able to dram it down that pig esophagus and I want you to do it and go as hard as you can. So last week I got a call from my colleague who is fantastic and he was doing a patient he's had done for years and he put a 45 French down the patient and he perforated the esophagus. So that looks really small. I want you to get a sense how is that big in your hand for you as well. And so we sometimes have a difficult sizing where we're at with this. So on A, is that a 45 French to you Joy? You have no idea. I mean I actually have no idea either. I mean we're sort of sizing. I can tell you have a guide wire down there and this person's gonna put a balloon over the guide wire to help open out a focal structure for them as well. So dilation for EOE is higher risk. That's why they're seeing Dr. Chan and myself and Dr. Obstine for these as well. Because it's so thin and one wrong move for an oversized dilation will cause a perforation for them. And in the hospital with a feeding tube in them, not having food for six weeks as well too. It's someplace they never really wanna be for them as well. So higher risk procedures than just a normal esophagus. We also will work our way up slowly. So we don't usually go to the biggest size. And when I see a patient with EOE I tell them this may be a lifelong thing we'll do or next few sessions we'll have it together. Not just one only for them. So these are options, go ahead. I mean how often is too often in dilating a patient? So if you look through, even just look at our clinical trials, patients have been dilated quite a few times. And some GIs I talk to are like yeah, I like doing dilations first. And some are like I just hate doing them for all the reasons in which you were just talking about. I think it's a good question. I think it's twofold. One is is it an inflammatory EOE for which medications and dietary limitations more effective than just doing dilation for them. But they're fibrostimulantic or dominant stricture. So when we have some patients who are on trial with other drugs we're doing now, they got a stricture and I cannot dilate them on trial. And they're gonna have symptoms the entire time for trial. They'll kill their drug probably as well too. So there's not necessarily a limit how much you can dilate them. But you always need to have a good reason for why doing it. So if there's fibrostimulantic, medications and diet won't help them. You have to open an esophagus in those as well too. There are conditions in the esophagus when you dilate them and actually it makes it worse. This is not one of those conditions. So it's safe to dilate them if you need to. And most of them are very thankful that when you do it, you're the only one that would try it. And we open them up and they can swallow from now on as well too. So it's a very gratifying thing to do when you get them in the right place as well too. But there's not necessarily a limit on when to do it. But you wanna have someone who can size things properly as well so it don't cause problems for them as well. Different ways of doing this, you'll see this tomorrow in the endo lab. The one you're gonna see mainly is gonna be this bougie dilation. So for EOE, we put a wire down into the stomach. We'll come all the way out and put a dilator right through. When we use this approach, you actually can't feel stricture so well. And that's why people can rupture the esophagus. You're kind of going over a wire instead. On this right side, you're gonna see a balloon dilation. So this is where you can either use a wire or just go straight. I usually use it without the wire. And you can put a balloon and kind of dilate a focal stricture. So if you got a stricture right at the lower area or the high area Dr. Chan showed earlier, you can open that up for them and they'll get automatic symptom response from that as well too. So dilation does help. This is just a figure showing that 95% of people actually get better when you actually do dilation for them if there's a stricture present for them as well. There are adverse events, chest pain, bleeding, and definitely the one we worry about the most is perforation. That's something that we don't wanna see for them as well. We do still wanna treat any active inflammation. Let me see what I'm doing on time. And usually the effect is about over a year for if you have a stricture that's present for them as well. And we usually just need a size dilator based on the stricture size for them as well. So combination therapy is what we do often. It's not just dilation. It's just not medication adherence or dietary elimination. It's usually a combination of both and a lot of factors why we have that as well. So we assess response using multiple factors. So in this situation, we're gonna use both histological response and fibrotic remission. And sometimes they do correlate. That's what the goal is, that they all line up together. It's a good sign that we're actually getting better for them as well. But here you can't rely on symptoms alone. So you kind of need to do your endoscopy and make sure they're actually getting better endoscopically because that alone by patient report outcomes is usually inadequate to say you're actually feeling better as well. So our adaptations for what's called impact is to drink fluids with meals, modify food, prolong meal times, avoid hard textures, chew excessively, and turn away tablets. That's showing that you probably still have symptoms that you may not reporting to us otherwise as well. We do what's called responsive therapy. So we want to drive ESN bills less than 15. We don't know if less than five makes that much of a difference, but we want to go at least less than 15 for them. And we want them to be able to start eating their food and not having such modification at present as well. The size matters. The higher the stricture, the higher risk of a retained food or food bolus for them. And that can cause perforations and tears. So we want to open up their esophagus if there's a dominant structure present. So this is a question is, do I need to repeat my endoscopy after I treat them as well? So this is our joint guidelines. But the use of endoscopy with biopsies is helpful to assess disease activity after change in therapy. So I just had a patient go from PPI to Bixin on Monday. So I'll bring her back in an endoscopy about two months from now as well too, once she's actually got it covered. Or if I go to steroids as well too, because if they're not getting better, you're in trouble. You need to change over drug for them as well too. So we do repeat endoscopies at that time. If there's change of drugs, change of dosing for them as well, or new symptoms present, we'll repeat the endoscopy then. The target, the EOS, is that what you're talking about? Yeah, both symptoms and EOS, yeah. So we want to combo both of them. So we're not going to give up. If they're ESF on 60 and they have no symptoms, that's when I'll still either escalate therapy for them or maybe change class and potentially as well too. Yeah, that's because we're seeing all this from our IBD colleagues. So that's like all over their literature as well too. So we're kind of adapting them to ours as well too. So treated targets are pretty common now with rheumatology disorders and also IBD as well too. So yeah. We're just stealing it from them. They stole from rheumatology, so then we take it from them. And then we're taking the allergy drugs to us and using their same terminology. So when you meet with your providers, though it's important to talk, they're going to know about biologics and weekly infusions or weekly injections as well too. They're not uncommon things for us to be mindful of. So it kind of helps us speak the same language, but it's a different disease process. So we know that the disease will always be present if you just use nothing. So some people want to come off all medicines. So if you do this, you're going to probably get a stricture disease and have to come back to see me at some point. Now when that may be, six months, a year, two weeks from now, I don't know, but that's why we do keep maintenance therapy present for them at long-term. Helpful for you guys, because you're gonna have weekly injections all the time as well too. But not so helpful for the patient where we can't stop all medicines from totally because they can't always go into remission on their own. And unfortunately, it does come back pretty fast after you stop all therapy for them as well. Is it even worth, like for Dupixent, obviously the patient still has type two inflammation, so we're going to have that high eosinophil count. Is it a lost cause or could you, because with the scar tissue that's built up, can there be, if that's not recoverable, is it still worth putting a patient on drugs? Yeah, you're typically not going to get a fibrous stenotic. I mean, it's really fibrosis. So when you biopsy, there's no eosinophils there. So you're not going to get high eosinophil count with a fibrous stenotic strictured esophagus. Now you can get strictures with active eosinophils, but we're referring to as an esophagus that is all almost like crepe paper throughout. And you biopsy everywhere, there's zero eosinophils everywhere. It's just all strictured. So those patients using PPIs or any therapy for you, even Dupixent, is not going to help them because they need to get dilated at that point as well too. That's their only relief. That's what's going to help them because it's all scar tissue now from this one. So this is just a study showing that there's recurrence of inflammation, even with ophibudecine and fluticasone present as well. So this is a little bit, most patients, about half of them after about a year, and it takes about less than a year for them to start getting symptoms again for them as well too with eosinophilic. Unfortunately, we don't know who's going to get worse. And that's what we're trying to work with nationally is figure out, well, maybe there are people who are not the same. Maybe it's TH2 high, TH2 low, or microbiome change. We're not sure yet. That'll happen in our lifetime about who can predict response to therapy and who doesn't come back as well. So once again, kind of the same, increased changes of endoscopic scores and esophageal dilation and increased narrowing as well present for them. Another study showing the impact of bolus impactions. So this patient's had changes with when you see no steroids, but also then increased dose of steroids for them as well. And you can see changes for their bolus impaction for how they had to follow up for them as well too. So there is definitely improvement by using steroids for them to help them with versus placebo control for them. So inflammation otherwise improves and the need for dilations also improves being on therapy for them overall. This is kind of more of the same, but the budescent oral dispersal tablet, that's probably going to be one of your competitors. So one of them failed because it didn't have a symptom response to them. It had histological response. But this is really what we think contact time does matter. So they actually had a lot of improvement with overall changes for their eosinophil count for them as well. It's just they didn't have enough symptom response to help treat them a long-term, which is why it got killed by the FDA, at least in the prelim study right now. So once again, we want to prevent all these changes, narrow caliber esophagus strictures, symptom response, and dilation as well. So we'll bypass a little bit. So currently the guidelines say that EOE does recommend short-term use of topical steroids as well over discontinuation. So don't just stop everything. It's better on some therapy than nothing at that point, which makes sense at this point now as well. So this is a funner part. So what do we have now? So Shire and Takeda had a pre-mixed budecinine slurry. That basically got killed earlier as well for failure to have improvement. At Xera, Elodi, you're gonna see these budecinal oral dispersal tablets. This is really what patients want, I will say. They want something they can put in their mouth and let dissolve and go down. We use this a lot for esophageal spasm and other diseases of esophagus. So they're used to using meds that go in their mouth and dissolve for them. So there's gonna be probably a lot of emphasis for these kind of drugs available as well. So this will be something to be mindful of as you guys go through your marketing. And the reason is because this was nicely done by Luchendo in 2019, showing that these medicines actually did help endoscopic remission for them as well. So in the early stages, this is a phase three one, they did show a lot of histological and endoscopic remission. They just didn't have a lot of patient response overall. And it's because it's complicated. If you have a stricture, when I do the studies and I see the patient enrolling, I can't open up the stricture because it's off-label now. So if there's a dominant stricture miss or not, I can't treat, they actually say I don't feel better when the insulin actually may have gotten better for them as well too. So it's a bit tricky as well. Once again, showing oral tablets for fluticasone, showing response at 12 weeks, 26 weeks, and also after about two years for them. They also did follow-up studies over a longer time, showing that different dosing did help. It looks like nighttime dose at three milligrams is probably one of the better doses to be on. So something you'll probably see out moving forward as well. Now we're gonna go back to where we started, which is all the biologics as well too. So you already have your drug here. We also have RPC-3046, which is Sendakumab now, and then Lirinolab as well too. This helps with mast cells, and this one's helping with the IL-4 and 13. So this is the most closest one to your drug that you're gonna see and that we're running for. It's an infusion, or actually this is a weekly injection as well too. So Celgene, which we're running right now at Vanderbilt, it's in phase three, so IL-13 alone. Regeneron, as you guys know, has already been FDA approved, blocks IL-4-alpha, so it's gonna block IL-4 and 13 together. Allocose has worked for both eosinophilic esophagitis, but also eosinophilic gastroenteritis. So one question you might get is, if I've got ES on my stomach, can I use your drug? So that's one thing to be mindful as you guys think about your patient population as well. You have eosinophil IL-5-alpha, which is gonna be running now as well too. Estrosimod, anyone remember this drug from earlier today? When that data back out? $100 right now, whoever gets that one. It's hard. So that came in our IBD lecture. So this is now approved for ulcerative colitis. So it's now getting marketing for EOE as well too. It's an oral tablet running as a trial as well. It causes bradycardia. So young people, it's not so big of a deal, but I gotta get an EKG before I start the drug for them. And that's kind of been a pain for me as a provider, I get an EKG every time and monitor them long-term as well too. Yeah, you gotta get a QTC beforehand. So it's an oral therapy. So we want patients, most of them wanna be in oral therapy overall, or some do prefer injections. But for those who went oral, that may be an option for them as well too. And then Rivola has an option going out as well too for them. So just kind of briefly went through this already, but you guys know your drug. So IL-4-4-alpha receptor blockade. It's gonna block both IL-4 and then downstream IL-13. And we saw before the uses of this one, which is over six for atypic dermatitis, over six for moderate to severe asthma with eosinophil phenotype, and then also as an add-on for chronic rhinocytosis with nasal polyposis, and now also for EOE as well. The EOE indications for over 12 and over 40 grams. So you can't be younger than that or less than that weight to get it used for eosinophilic esophagitis. You guys know your study, but this is EcoHeronos from Northwestern showing that this drug does work. So when they did a 12-week RCT of the sub-Q injection, you had histological remission at less than 15 and actually driving less than six and less than one. We don't know practically if driving less than one makes that much of a difference, but obviously if it's working eosinophil count and they feel better, it's probably a good thing. Whereas we do extension studies looking at changes, and one important thing is actually what's called distendability. So if the esophagus can squeeze more and better, it probably can take your bolus and not get a food impaction for them. So you're able to show changes in both for not only inflammation, but also the ability for it to actually have peristalsis, which is actually a good sign for patients to swallow overall. RPC-4046 is another one that you're gonna compete against, and this is gonna be an IL-13 blockade. It's also a very similar mechanism that you guys have. We're running this drug right now as well, too, and I'll say it's pretty similar. It's a sub-Q injection, so it's fairly similar to the drug delivery that you guys have total as well. Maybe not as much IL-4 blockade, but it helps the downstream blockade of eotaxin, which it should work similarly to your combination as well. In the prelim studies of this one, we had efficacy at different dosing as they try to find dose changes for them overall, and then as we did escalation therapies for different timing of this at 16 weeks, we also showed they improved, especially if you failed steroids. They used steroid patients who didn't do better, and they gave them this medicine, and actually had a response to them as well, too, probably because of a different mechanism, but actually it's a nice drug to use probably for that patient population overall. They then went open-label, which means every patient we enroll, go and get drug, and you can see everyone, even those who are on placebo starting off with, and those who are actually on drug, they actually got better in terms of the eosinophil count, symptom response for them as well, too. So this drug does help, and it's not just a placebo response we're seeing for these patients. So last thing, refractor EOE. This is tricky because what if you have symptoms? We give your medicine to you. If inflammation or combination of both is still present, what are you gonna do? So the first thing I say is, are you taking your medicine? And I'll say a lot of them don't take it, and it's not their fault. They're busy, they're working, they're traveling as well, too. So before I start messing around with escalation of therapy, I just kind of go through a compliance. So I had a guy who had normal eosinophil count. I saw him again two months later because he had some change of symptoms. It was up to 60. So we gotta change your medicine. He's like, well, I didn't take anything. I'm like, well, why did you come in for your endoscopy? You should at least start at something because now I'm gonna do it again in two months. That's cost you as well. So that becomes tricky when they have problems with compliance, and most of them, if they talk to one of us, can get back on the board, or they gotta go to different delivery. Maybe oral therapy's not enough. Maybe swallow steroids or an injectable instead for them as well. Sometimes they're not on the right dosing. That's usually a little rarer, how they do that as well. If they're fibrostenotic, medications won't always help them. And some get hypervigilance, which we'll talk about later as well. So Tiffy Taff, the Northwestern group here, wrote this paper showing that let's just look at patients who they were told they may have symptoms, let's do the endoscopy on them. And they gave them this survey called Hypervigilance Survey, and they said, well, if you feel better, tell me how anxious you are about your diagnosis. And at that time, they did an endoscopy, which you guys have seen before. They did the sensibility as well, too. And they realized pathophysiology in terms of how many Eosinophils were there did not predict how anxious they were about the disease process. They were more anxious, regardless if they had no endoscopy as well, too. And so they're concerned that we have what's called hypervigilance, and we see this pretty common for a soft disease. Sometimes using PPIs actually help with them, but if they've ever had any food infection before in the past, those patients particularly are very worried about getting it again. I've had patients I've scoped three or four times, they say, I got it stuck again. I go in, it's wide open, there's no Eosinophils, there's no motor disorders as well for them, too, and they need to be on neuromodulation instead. So escalating them to another therapy is not gonna help them. It's also about hypervigilance and anxiety about their disease process as well. We know this is true in IBD, and it's true also in the Eosinophil world as well. So in summary, we went through the goals of therapy in a whirl whirlwind, and you're gonna see why we struggle sometimes with which medicine to be on, patient preference, and how we kind of put it together overall. We always have a decision with a patient on how to make that call, what they need to be on as well. Dietary medicine is effective, and so are medical therapy as well, too. But we can't trust our patient. I tell them, I can't trust you. I love you, but I cannot trust you. I gotta bring you in for endoscopy, and let's take a look how it looks for you as well, too. And if there's any hypervigilance, we don't escalate therapy. We actually put them on neuromodulation or cognitive behavioral therapy, and meet with my psychiatrist as well, too, then talk about how to get that better from this as well, too. Unfortunately, relapse currently is still the norm if we stop therapy. And at this point, you guys are front leader on FDA approval, but there will be several behind you coming up, so giddy up for those to come up as well, too. All right, any questions for me?

eosinophilic esophagitis

treatment options

dietary changes

biologic therapies

eosinophil counts

symptoms improvement

complications prevention

individualized treatment plans

medication compliance