So, our first speaker, Dr. Iko Hirano, is a professor of medicine at Northwestern University School of Medicine, and he has done extensive research on eosinophilic esophagitis, and we've seen several guidelines come from his work. So, it's an honor to have him provide an update on eosinophilic esophagitis. All right. Good afternoon. It's a pleasure to be here. I want to thank the ASG and our moderators and course directors for the invitation to be part of this esophagology course, and I'll be discussing my favorite disease, EOE, or eosinophilic esophagitis. My disclosures are listed here. I will be discussing off-label use of medications. Up until two months ago, there were no FDA-approved medications. That changed two months ago with the announcement of a medication that I'll briefly mention in my talk today. So to cover this update, I'm not going to give you an overall management. I'm going to focus on what I think are four misconceptions in the management of EOE in 2022. The first is that symptoms are a reliable indicator of disease activity. Excuse me. I think in clinical practice, I think there's a tendency to just put your patient on a medication or diet therapy, PPI, swallow topical corticosteroids, and just follow their symptoms and think that symptoms are good enough. You could just see how they feel afterwards, and I'm going to show you some of the pitfalls with that type of management strategy. The second misconception is that maintenance therapy is unnecessary for most patients. Again, I see a pattern in practice where patients are put on induction therapy with a medication or diet, and then the therapy stopped, and just using the therapy kind of PRN, and I'll show you why that may not be the best approach. Third, we'll look at the idea that endoscopy can accurately detect strictures. You've heard a lot about endoscopy today and careful endoscopy and adequate endoscopy techniques, but I'm going to show you that endoscopy is really not that great for looking at strictures and detecting clinically relevant strictures. And finally, the misconception that treatment for factory disease is uncommon. We have a lot of things in our therapeutic bucket for treating EOE. We have diets. We have PPIs. We have swallow topical corticosteroids. But I'm going to show you that actually there is an unmet need for patients that don't respond to these initial induction treatments. So first of all, what about symptoms? Why is there this dissociation between inflammation and symptoms in Eosinophilic esophagitis? If symptoms were directly correlated with inflammation of the esophagus, the management of EOE would be really simple. You would just have your patient, you'd make your diagnosis, look for the 50 integrator EOs per high power field, and then you could just track their symptoms and say, the symptoms tell me what's happening with their esophagus and what their inflammation is doing. But this is not the case. It's not a direct correlation. And a big reason for that is highlighted in this case scenario. You have a patient. He's got EOE. He's got rings of the esophagus. Scope cannot get through the esophagus. The luminal caliber is too small, so we call these grade three rings. He's shown 94 EOs per high power field in spite of PPI therapy. And the patient has continued symptoms. The biopsies went from 94 EOs down to zero Eosinophils per high power field. So that's a great anti-inflammatory histologic response. But the patient didn't feel any better, continued to have dysphagia, continued to have self-limited food impactions. And the answer for why this particular patient has dissociation is because of that high grade stricture. Look at the endoscopy. It's very apparent. Stricture is still there. He's still got grade three rings. The scope can still not traverse the esophagus. So the answer for dissociation in many patients is because of fibrostenotic complications of disease. Another good example to highlight this type of stenosis-related disconnection is what happens when you dilate. These are three different EOE patients treated with esophageal dilation. And after a dilation, if you go back down, and I always go back down after I dilate to look at what I've done and feel bad about myself and feel bad about my patients, and I look down and I see these pretty nasty-looking disruptions and tears, which are painful to look at and painful for our patients to experience. However, once that disruption heals, which takes several days, the patients feel remarkably better. Studies have shown that dilation alone, without any PPI, without any medication, or without any diet, can alleviate symptoms in 90% to 95% of adult patients with eosinophilic esophagitis. We can treat their dysphagia by doing a dilation without any anti-inflammatory therapy. So I tell my patients, it's short-term pain for long-term gain. They get three to five days of pretty bad oedynophagia, and then they can swallow better. But what does dilation do to the underlying inflammation? Zero. It does nothing to the underlying. It's actually been studied. So their biopsy's done before. And after dilation is monotherapy, there's no change in the eosinophilic count, but patients feel great. Another example where strictures are driving this dissociation. Now there's another important point about symptom histologic dissociation, and that's nicely highlighted when you look at double-blind placebo-controlled trials. Now we have lots of these trials being done now in eosinophilic esophagitis. This is just one example of this. This is the budesonide oral suspension, the BOS trial that was the largest RCT of a steroid ever conducted, phase three double-blind placebo-controlled trial. Patients treated with budesonide, dose of two milligrams BID with a liquid preparation optimized for the esophagus or placebo for 12 weeks. And this trial had the co-primary endpoints. The co-primary endpoints mandated by the FDA is that you show histologic benefit. The FDA put the bar at six or fewer eosinophils per high power field, and that's a very stringent histologic threshold, much below the diagnostic threshold of 15. So to get a success by the FDA criteria right now, you have to get six or fewer eosinophils per high power field. And in addition to histologic improvement, you have to show symptom benefit. And many studies now are using something called the DSQ, the dysphagia symptom questionnaire, which is a validated PRO that measures symptom activity of dysphagia specifically for eosinophilic esophagitis. It was validated for EOE. And in this well-conducted double-blind placebo-controlled trial, budesonide oral suspension worked great for histology. 53% of patients got to that stringent threshold of six or fewer eos per high power field with BOS compared to 1% with placebo. So almost negligible placebo response for histology. But when you look at symptoms, symptoms did significantly improve with budesonide. But the difference from placebo was not all that great. Statistically significant, it met the co-primary endpoint, but the p-value here is 0.02. It's not the most robust symptom differentiation compared to placebo. And why is that? It's because there's a pretty profound placebo response. Patients who went into this trial had a high degree of activity, inflammatory-wise, a high degree of symptom activity, had to have two days of dysphagia per week to get into the study. Most patients had much more than that. But in spite of that high bar of activity, there were 39% of patients who had a placebo response after 12 weeks of therapy. So what is driving that tremendously high placebo response in EOE? Well one reason is that our EOE patients have become very professional eaters. They have developed adaptive eating behaviors to compensate for the fact that they've had EOE typically for five or more years before a diagnosis is made. These adaptive behaviors are summarized with this acronym. Anyone who knows me knows that I love acronyms. That's how I got through medical school. I put everything into an acronym so I could remember it. And the acronym for adaptive eating behaviors is IMPACT. I stands for imbibing fluids with solid food to get the food to go down. N, modifying food by cutting up their steak into small pieces, or in some cases even pureeing food, which some of our patients do. P, prolonged meal times. These EOE patients are typically the ones that are the last ones to leave the table when you go out to a restaurant, or they bring home half their food in a doggie bag. They A, avoid hard texture foods. Not uncommon to see patients with EOE tell you when they go out to a restaurant they will not order a steak because they're afraid they're going to have an impaction of vomit at the table. Socially embarrassing. C, they chew excessively. These patients are meticulous masticators. They take a long time chewing their food, particularly meats and breads. And T is turn away tablets or pills. So the importance of this helps to explain some of this placebo response, but also in your clinical practice it's important that you ask your patient not just can you swallow, but just ask them briefly about some of these adaptive behaviors because they may not even recognize this as abnormal. They've been doing it for five or ten years this way. This has become normal. It's like doesn't everybody chew a lot like this? Doesn't everybody take 45 minutes to eat a sandwich? No. That's not normal. So these behaviors are not normal. They are adaptive behaviors to compensate for strictures of the esophagus. The other important part of the placebo response that we're seeing in clinical trials, likely driven by cognitive factors. This was a nice study done by Tiffany Taft at Northwestern, psychologist who does a lot of work in psychometric testing for different PROs in the esophagus. And she studied 103 EOE patients at Northwestern and studied them with a number of different metrics, histology, endoscopy, PROs, validated PROs, and an anxiety hypervigilance scale. And what she found was the best determinant or predictor for severity of symptoms of dysphagia was not the eosinophil density, it was anxiety and hypervigilance. Most of the variation in terms of intensity of dysphagia once patients had trouble swallowing was driven by anxiety hypervigilance behavior. So putting this together, there are a number of challenges when you're doing symptom-based management with EOE. Inflammation is not the direct be-all, end-all for symptoms of EOE. There's fibrosis, which is a major important factor in this dissociation. But sensory perception, that's important. If you have dysphagia and you don't sense it, it's not going to cause a symptom. So sensory perception is upregulated by anxiety, hypervigilance, and visceral hypersensitivity, and it can be downregulated by tolerance, denial, and acceptance, which many of our patients are doing. In addition, we've talked about the adaptive eating behaviors, which also downregulate whether patients perceive symptoms or not. So all this says that symptoms are not the be-all, end-all. So what do you do in clinical practice? A lot of guidelines now and a lot of people are espousing the idea, which is taken from inflammatory bowel disease, that we treat to target. We don't just ask patients about their dysphagia, but we look at the other outcomes of importance, which are endoscopic outcomes, looking at how the esophagus looks, what happens to the inflammatory features, the edema, furose, and exudate, and also what happens to the remodeling features, what happens to strictures. And I'd like to target a diameter greater than 15 millimeters to consider that patient as having a successful outcome for EOE therapy. And then histologically, of course, we're trying to get the eosinophils to go away. Under 15, if you follow the FDA, you're going to go to under 6 eosinophils per power field. The second misconception is about maintenance therapy, and again, what I see in practices, I think a lot of patients either choose not to do maintenance therapy or a lot of clinicians don't always tell their patients that they have to keep taking the medication once it's started. So what is the evidence, or what's the value of doing maintenance therapy? This is some of the data looking at the natural history of eosinophilic esophagitis. Now, I don't expect you to read all the data that's on the left-hand side of the slide, but it's just to make the point, there have been four independent studies, two from Europe and two from the United States, that have shown the same phenomena. The longer you have untreated or unrecognized eosinophilic esophagitis, the more likely you are to develop an esophageal stricture. In the Swiss study, which was the first study to ever show this, strictures were defined by inability to pass an adult or pediatric operonoscope, and the longer patients had untreated disease, the higher the likelihood of getting that degree of stricturing of the esophagus. This is retrospective data, but it led to this conceptual model where we have the esophagus, and over time, progressive remodeling changes, progressive fibrosis of the esophagus, leading to the complications of strictures and narrow-caliber esophagus, which then leads to the complications of food impaction, need for dilation, and puts our patients at risk for perforation of the esophagus. Now, if you look at the AGA Joint Task Force on Allergy Immunology Guideline for 2020, they reviewed the literature back in 2020, and back then, we only had the retrospective natural history studies, and there was one placebo-controlled trial conducted by Alex Strauman, a steroid trial randomizing patients from maintenance therapy to steroids or placebo. One very small study to inform any decision, but the recommendation was made that in patients who achieved remission with induction therapy, they should be kept on long-term swallowtopical corticosteroids for maintenance. Again, conditional recommendation given very low quality from one placebo-controlled trial. Well, in the past two years, there have now been additional placebo-controlled trials to support this recommendation. The best evidence today comes from this European study using a budesonide tablet, an oral dispersible tablet dosed at one milligram BID for induction. After six weeks of induction, patients were randomized to continue one milligram BID budesonide or get half-dose budesonide, 0.5 milligram BID, or go to placebo. So three different treatment groups after induction of therapy for patients who achieved response to induction therapy, and they followed the patients for about a year. And this is the summary of the data, looking at what percentage of patients are maintaining their response, and response here is both either symptom response or histologic response. Seventy-five percent of patients maintained response if they kept on budesonide one milligram BID, 73.5 maintained the response if they dropped down to 0.5 milligram BID, and 4 percent had maintenance of response if they went to placebo. So I think this is, again, the strongest level one evidence we have for the value of maintenance therapy. This is the same trial, the data shown another way, looking at percentage of patients who were in clinical remission, looking at the Kaplan-Meier analysis going out for the one-year follow-up period. And again, the same phenomena. The green and red are the patients who were kept on maintenance therapy, either low-dose or high-dose budesonide, and the black line are the patients who got placebo. You can see a very short time to relapse of symptoms or histopathology in the patients who were randomized to placebo, compared to a very great maintenance of remission in the patients who were kept on swallowed topical corticosteroids. The third misconception is about endoscopy accurately detecting strictures. Now, you heard a lot this morning, dysphagia, the typical test that we all do is endoscopy. We all do endoscopy. Very few people, unfortunately, do barium esophagrams anymore. So here's an endoscopy being done, and I want you all to think in your mind, what is the diameter of this esophagus? Patient, obviously, with eosinophilic esophagitis, because that's a topic for today. They've got some edema. You don't see vascular markings, and they have some furrowing of the esophagus, maybe some very, very subtle rings if you squint your eyes, but the rings are really subtle. And you see a stricture here. I would argue it's very hard to see a stricture. Esophagus looks fairly compliant here. Scope is passing very easily. Some contractions here, secondary contractions here. The esophagus, the scope, rather, gets through to these junction very, very easily, smoothly. There is no resistance to passage of endoscope. So is there a stricture here, and what do you think the diameter could be? And I would argue it's very hard to know what the diameter. We know it's greater than 10 millimeters, because the scopes sail through. But is it 12? Is it 15? Is it 20? I think I would bet if I polled you, and I've done this with other audiences, and the numbers are all over the map, from 13 to 20 millimeters. And I thought this esophagus looked pretty normal. So I chose to do a savory dilation, and I'll show you what happened from the savory dilation. Here I started off with a 14, and then a 15, and then a 16. So I did a 42, 45, 48, and I felt no resistance to the bougie passage. And there's a large, a lot of blood, obviously, and you're going to see about a 10 centimeter long disruption of the esophagus. Again, these are painful to look at, and painful for a patient to experience, at least for several days after the procedure. It did fine. It looks like a really nasty tear, but just given some Tylenol, and I did go home. No admission required for this particular disruption, although I have had patients who have had to come in for pain control. So again, the concept here is that endoscopy is hard to really guesstimate the luminal diameter, even though we all rely on endoscopy so much. So dilation, in this case, revealed a stricture that I would say was endoscopically concealed. And that's particularly true for these longer, narrow caliber strictures. Well, we now have some evidence about the value of endoscopy, how good are endoscopists. This is a study done from Mayo Clinic. I know we have a lot of faculty here from Mayo Clinic. Study done by Gentile, Jeff Alexander, and Dave Kask, in which they compared radiographic diameters on a barium esophagram, which they were doing systematically, compared to what the endoscopists at Mayo said they saw in the endoscopy. We looked at the endoscopy reports. Did the endoscopists identify a stricture? So if you look at the threshold of 13 or less millimeters in diameter, I think we would all agree a 13-millimeter stricture is clinically relevant. That's the Shastky diameter, right? That's when you generate symptoms for many patients. So for detection of a stricture of 13 millimeters or less on fluoroscopy, how often was that detected on endoscopy? 33%. Two-thirds of those clinically relevant strictures were missed on endoscopy, so I think that's a humbling number when you think about how often we use endoscopy to judge whether or not a stricture is present. So what I would argue here is that given this very limited sensitivity of endoscopy for detection of strictures—now, this is not for peptic strictures. It's not for Shastky ring. This is for EOE strictures, and those strictures in EOE can be subtle. They can be the narrow-caliber esophagus like that image I showed you on the video. So given the limited sensitivity of endoscopy for detection of these strictures, I would argue that you need additional testing. It could be a barium esophagram. It could be impedance splenometry or FLIP, or it could be in the case like I did, just do the dilation and see what happens. But do it cautiously and do it in a graded manner. Just look what happens after you dilate by a couple millimeters and see if you've gotten disruption. You will identify strictures that you were not aware existed. The final misconception is that treatment refractory disease is uncommon. I think there's an idea out there that why do we need other therapies? We've got steroids, we've got TPIs, and we've got diatherapy, and we've got dilation. So if you look at the AGHATF guideline, again, 2020, this actually summarized the data that was available in 2020 regarding the double-blind placebo-controlled trials for swallowed topical corticosteroids. And now there have been, since this publication, there have been about four or five more double-blind placebo-controlled trials. But the bottom line here is that the overall histologic efficacy for swallowed topical corticosteroids in this meta-analysis was 65%. That means that 35% of EOE patients are not responding to swallowed topical corticosteroids overall. And this is including formulations of swallowed topical corticosteroids that are optimized for esophageal delivery, like the liquid formulations and the dissolving tablet formulations. So the point I'm trying to make here is that there is room for improvement. There is an unmet need in our treatment of eosinophilic esophagitis beyond using swallowed topical corticosteroids. And I can show you similar data for PPIs, which is a much lower response rate of about 30% to 40%. And for dietary therapy, maybe 50% to 60% response rates. So to address this unmet need for other therapies, syndacomab, which is a monoclonal antibody, has been studied in a phase II clinical trial. Syndacomab was studied in this double-blind placebo-controlled trial that randomized 99 adult patients to get syndacomab, which is a monoclonal antibody directed against IL-13 or placebo. Two different doses of syndacomab compared to placebo. Primary endpoint in phase II trial was a reduction in the esophageal eosinophil count. And on the left-hand side, you're seeing a very robust histologic improvement with both low-dose and high-dose anti-IL-13 therapy, no change with placebo. The right-hand side is showing the same group's monoclonal antibody placebo response rates for endoscopic outcomes using the validated endoscopic scoring tool, eREFs. And significant improvement with anti-IL-13 therapy, no change with placebo. The other therapy, which has led to the most recent approval, is dupilumab. Dupilumab is a monoclonal antibody directed against IL-4 receptor alpha. It was studied in a phase II clinical trial program, was successful, and this led to the phase III clinical trial program, which has now been presented this year at the allergy meetings and then most recently at DDW just two months ago. The phase III trial had two parts. This is the Part B data, 159 adolescent and adult patients with active EOE randomized to dupilumab or placebo given for 24 weeks, so a longer treatment period. And co-prime endpoints the same as I showed you for the Budesonide trial, histologic improvement and symptom improvement. The study obviously met the co-prime endpoints because I mentioned that it got FDA approval. So for histology, 59 percent of patients who got dupilumab had histologic efficacy getting the EO count to less than or equal to 6 EOs prior to power field compared to 6 percent with placebo. So it met the histology endpoint. And on the right-hand side, the symptom endpoint using the validated PRO DSQ, again, significant improvement with dupilumab compared to placebo. Here the P value was better than was seen with the Budesonide trial, but again, a pretty high placebo response. Keep in mind that about half the patients that went into this clinical trial were deemed to be unresponsive to swallow topical corticosteroids or intolerant or had a contraindication to get swallowed topical corticosteroids. So it does reflect a treatment group that was perhaps more difficult to manage. And again, the success in meeting the co-prime endpoints, the success of the Phase III clinical trial program led to the recent approval just less than two months ago of dupilumab for the treatment of eosinophilic esophagitis for adult and pediatric patients aged 12 and older who have to weigh at least 40 kilograms. This last slide, I'm not going to walk through it, but it just shows that there are a number of therapeutic trials, both small molecules and biologics, being tested for eosinophilic esophagitis targeting a number of these allergic mediators and pathways involved in the pathogenesis of EOE. And we're seeing them move from the esophagus to the stomach and duodenum. They're now active trials in eosinophilic gastritis and eosinophilic duodenitis. So to summarize the misconceptions in the management of EOE, symptoms are relevant, of course, but unfortunately unreliable indicator of disease activity. I think it's important that you assess endoscopic features in histopathology. Secondly, maintenance therapy is important for most, maybe not every patient, but most patients that have EOE should be considered for maintenance therapy. Endoscopy is limited sensitivity for detection of clinically relevant strictures. And finally, biologic therapies will address an unmet need in the management of EOE. With that, I'll conclude and thank you for your attention.

eosinophilic esophagitis

maintenance therapy

endoscopy

strictures

treatment refractory disease

biologic therapies