Our next speaker is Dr. Crystal Lynch. Dr. Lynch completed her gastroenterology fellowship at Johns Hopkins Hospital, and she's currently the director of the Saphage Lin Swelling Center at the University of Pennsylvania. She'll talk to us today about optimal treatment and disease monitoring in EOE. Thank you, Dr. Lynch. Good morning, everyone. Thank you so much to the ASG for having me today. I'll be rounding out the esophageal session talking about treatment and disease monitoring in EOE. My disclosures are listed here, and we will be discussing off-label use of therapies. The objectives today are to define the goals of therapy in EOE, to review the therapeutic options, and to understand optimal disease monitoring. We know that EOE is an immune-mediated condition characterized by esophageal eosinophilic infiltrate, and this chronic inflammation leads to dysmotility and dysfunction. In adults, we'll classically see dysphagia, food impaction, as well as heartburn. And the diagnosis is made via symptoms and dystopic findings, as well as histology with the eosinophil count of at least 15 per high-power field. When EOE was first described, our therapeutic endpoints were easy, largely consisting of histologic improvement in the eosinophil count. But now we know that it's more complicated than that, and we should assess the patient as a whole, looking at symptom improvement as well as endoscopic improvement. And this is where we are in 2024. So our therapeutic options, interestingly, also 3Ds, are drugs, diet, as well as dilation. And first, we're going to divulge into looking at the drug options. PPIs, as you know, are widely used for EOE. They're off-label, but they're a very common first-line therapy. So we're seeing a 42% pooled histologic response rate in the AGA Joint Task Force guidelines that were published recently. There are multiple proposed mechanisms of action of PPIs for EOE, some of which are listed here. However, we know that many of these are independent of the acid blockade. PPIs, as you know, are widely available, typically affordable, and have a favorable side effect profile. We know that most of the adverse events reported in retrospective studies are really thought to be an over-extrapolation of small estimates of effect size. Next, we often move towards topical steroids in medical management. We have budesonide, as well as fluticasone, and it's a pretty successful treatment option overall as a group, with about a 65% pooled response rate. Which steroid should you choose? Well, when you compare the budesonide slurry head-on with the fluticasone inhaler, this randomized trial by Dellin and colleagues showed that the post-treatment max number of eosinophils was similar between the two groups. Now, until this year, we have been using these medications regarding topical steroids off-label only, and so it can be confusing for the patient as well as the pharmacist, especially in locations where there isn't a lot of EOE. So I will remind patients that these medications are being borrowed from asthma, but for fluticasone, you should remove the spacer and then inhale, then take the medication and swallow it. We're not trying to treat the lungs. Additionally, for budesonide, I give my patients a checklist, as this medication is in a respual form, and so patients will actually pour it into a small glass, mix it with a thickener, many of which are listed here, and then swallow the medication. We could also consider pre-made budesonide formulations, including compounded budesonide that can be made at a compounding pharmacy, but not all patients have access to that, and it can be costly. As of this year, we have an FDA-approved budesonide oral suspension in the United States. Looking at the large trial on this of over 300 patients, they were randomized 2 to 1 to the budesonide versus placebo and assessed over 12 weeks. And when you look at the main outcomes, stringent histologic response, as well as the dysphagia symptom response, patients in the budesonide group did significantly better than the placebo group. If you want to compare apples to apples, looking at a histologic response of less than 15 eosinophils per high-power field, you see a response rate of 62.4% in this study, which is similar to the previous ones we have mentioned. There are additional steroid formulations. Unfortunately, we don't have time to discuss all of them today, but if anyone here is using Gervaisa in Europe, the budesonide effervescent tablet, this really harnesses the mucoadhesive properties of saliva to result in enhanced mucosal contact time, and that's widely used in Europe. The fluticasone disintegrating tablet, which completed its randomized trial in 2022, has further trials ongoing, with data being discussed later at this meeting. What about adverse events to steroids, to topical steroids? Well, Harado and colleagues looked at six randomized trials of budesonide oral suspension and looked specifically at esophageal candida, decreases in serum cortisol, and abnormal ACTH stimulation tests, which have been reported in other studies, and the response rates across these trials are noted here. Additionally, GI adverse events have been reported, most commonly nausea, vomiting, and diarrhea, and the rates of those were about 1.6% to 2.1%, and they were also seen at low rates in placebo groups. So that brings us to biologics, so dupilumab, the first FDA-approved medication for EOE in May of 2022 for adults. This, as you know, is an IL-4R-alpha subunit receptor antagonist, and it's currently approved in children as well. Looking at the large study in adults, essentially this study had parts A, B, and C, but the first part where they randomized patients, it was placebo, dupilumab weekly, and dupilumab every two weeks for 24 weeks, and then the open-label extension had dupilumab weekly as well as dupilumab every two weeks, and the primary endpoints intuitively were the percent of patients with a max number of eosinophils less than or equal to 6 as well as the change in the DSQ score. I've summarized the results of the first part here, the randomization, and you can see that patients on dupilumab at both doses had a significant histologic response rate over placebo. However, when you look at the symptom response rate, the patients on the dupilumab weekly had a significant change in baseline DSQ score, more so than placebo, but the patients on dupilumab every other week did not. So currently in adults, it is FDA-approved for use at a dose of 300 milligrams weekly. What are the adverse events in this study? You can see the Table 2 here, but I'll highlight that the most common side effects revolved around the injection site, and that is what we're seeing in clinical practice. So injection site reaction, injection site erythema, news of pharyngitis and headaches were also reported, and one serious adverse event that was considered related to the study drug was systemic inflammatory response syndrome. The patient continued to be followed, and the event did not recur over this trial. So we have been using topical steroids, diet, which we'll talk about, and PPIs for the treatment of EOE for many years without dupilumab. So how do we integrate this into our practice? And Aceves and colleagues published a nice paper looking at clinical guidance for the use of dupilumab and EOE. So in my practice, I really do consider it in patients with multiple comorbid conditions, including asthma, atopic dermatitis, and sinusitis with nasal polyps. And as you know, dupilumab is already approved for these indications in adults at a dosing of every other week. It also could be considered first-line therapy in patients who, for various reasons, cannot tolerate the other therapies. And step-up therapy, of course, is reasonable to use dupilumab in patients with poor growth, severe dietary restrictions, patients who are requiring frequent rescue therapies. So this is rare, but patients who are requiring frequent dilations or even oral steroids, and patients refractory to other therapies. So this is the pathophysiology overall for EOE. So we know that the patient's diet interacts with the esophageal epithelium, leading to a large cascade of events, ultimately leading to loss of barrier function, remodeling, and eosinophilic inflammation. But when you look at this complex network, it actually lends for many potential targets for therapy. I wish we had more time today to talk about all the emerging therapy, including the biologics, but I've summarized some of the recent ones here, and then the non-biologics as well. Von Epperson was mentioned in a previous lecture, but there have actually been case theories in Japan in EOE for Von Epperson, finding that it was not inferior to PPI for EOE. So clinical trials are planned for that as well. So next for EOE therapeutic options, we'll be talking about diet therapy. You can see a nice summary here from the AGA and Joint Task Force paper, looking at the pooled histologic response rate overall for EOE regarding the targeted diet, the empiric elimination diet, and the elemental diet. So regarding the targeted diet, this is the allergy testing guided diet. In adults, the studies are really limited. We have these single arm observational studies, and the type of testing is heterogeneous depending on which study you look at. Overall the response rate is not robust, and we don't feel that EOE is a primarily IgE mediated disease. So we do not recommend routine allergy testing to guide diet in these patients. So next the elemental diet, a diet formulated to meet nutritional needs without any supplements. So we have a couple studies in adults with EOE on the elemental diet. And there are many patients, about 30, who signed up for these studies. But up to 23% of these patients actually abandoned the trials on day one due to the diet being unpalatable. Additionally, if you look at these studies, over the course of the study, many patients could not comply to this diet. It is very difficult, but there was a 72% histologic response rate. So patients actually did really well histologically on this diet. After resuming a normal diet, however, we can see that the eosinophils and that inflammation is returning in as quickly as three to seven days. So overall the elemental diet in adults, it is efficacious as it is in children, but it's really difficult to implement. So that brings us to the empiric elimination diets. The six food elimination diet you well know has been well described and eliminates the six most common food allergen groups that are listed here. Typically patients will strictly eliminate all of these six food groups and then for six to eight weeks and then upper go and upper endoscopy with biopsy. If they are in remission, then they will reintroduce one to two food groups at a time at four to six week intervals with endoscopies each time. So if you did the six food elimination diet and reintroduce each food group one at a time, that would take up to nine months. So significant time cost endoscopy burden. There are many variations of the elimination diets, including the four food, two food and single food group elimination diet. There also have been step up diets described. So the two, four, six, for example, eliminates first wheat and dairy. And if that is unsuccessful, then it additionally adds two more food groups. So step up approach and studies on the step up diets have shown that compared to the six food elimination diet, it does decrease the time to remission and the number of endoscopies. As you can see from these sites intuitively, they can be very challenging. They're not necessarily nutritionally balanced and is ideal to work with a trained dietician. So I've summarized for you here the six food, four food, two food and one food elimination diet. Don't take your picture yet. I have the range of response rates from various studies. Now you can take your picture here for reference. So our dietary algorithms, so how do I actually implement this? I'll have the patient eliminate the food groups for at least six weeks. We'll do an endoscopy with biopsies. If they are not in remission, I would consider transitioning towards medical therapy or discussing that diet because if maybe there was a trigger that they were unable to comply with at a certain point, maybe they need more resources or to be referred to that dietician. If they're in remission, we reintroduce food groups and reassess with biopsies. And if they're still in remission, they could continue those food groups and add back in further food groups and continue the process. But if they're not, that dietary food group is a diet that is a food group that they would avoid long term. And that's something to remind them. This is a long term therapy. And then they would continue to add in further food groups until all the food groups are reintroduced. So overall for dietary therapy for EOE, it is costly. It is time consuming. It is nutritionally challenging. There's a high endoscopic burden and it's difficult to maintain over time. We don't have time to get into all of those studies, but one study showing that after patients are in remission after three years, 10% of patients were still on that diet and complying with that diet. Major pro though of dietary therapy, a medication free therapy for a chronic disease, which you really can't save for a lot of diseases in GI. Lastly, we'll touch on dilation. So esophageal dilation is unfortunately used daily in my endoscopy practice. We see strictures occurring in up to 40% of EOE patients. And patients do really well with dilation. Studies reporting up to 95% of patients having clinical improvement after dilation. And we're talking about a careful dilation performed to a controlled tear. And the perforation rates in recent publications at high volume centers are remarkably low. We do feel that this is safe. Careful dilations may be required because again, we're doing these careful dilations only going up, you know, three to four millimeters at a time. And in EOE studies are showing us that a goal of 16 millimeters is really reasonable. We can consider using either Bougie or balloon type dilators, Bougie dilators having those shearing effects covering the entire esophagus. I do favor balloon type dilators because you're able to see that dilation effect or that nice tear in real time. And then I'll often do a pull through of the entire esophagus so that we're able to also have the shearing effects as well as the radial force. But just a reminder that dilation does not control underlying disease. So one thing I'll just mention is that in patients with histologic remission with EOE, if they're still having symptoms, I think we should be expecting subtle strictures, looking for and expecting them. So I had a patient referred to me from a gastroenterologist exactly in this situation. And I went in and sure enough, in the mid esophagus, I saw the subtle structure and I thought, oh, this is causing her issues. I'm going to dilate this and this will be great. So I dilated this with a balloon. I got a nice tear and I did a pull through. And as I'm pulling through more proximally, I did feel mild to moderate resistance. And sure enough, when I went in, she actually had two strictures that I dilated. And you see a nice controlled dilation effect here. And so overall for my EOE therapeutic algorithm, I think about inflammatory therapy and fibrostimulantic therapy. So both of these should be done. Within inflammatory therapy, do they want medical or diet? And you really sit and you counsel the patient on all of the treatment options. Typically we'll start with proton pump inhibitors if they're not in remission, considering escalation to topical steroids. And we also talked about specific situations where you may want to escalate to dupilumab. If they're still not in remission, we could consider the other therapy or consider transitioning over to dietary therapy. If patients have tried all of that and are still not in remission, that's when we refer to our clinical trials or I would consider combination therapy. So I rarely start with combination therapy. Usually you can get patients in remission on medical or dietary therapy. If patients for inflammatory therapy choose not to have medical therapy and want to go towards diet, we talked about that process. And if they're not in remission on that, we would consider medical therapy. And then for fibrostimulantic therapy, we'll do our careful control dilation. Our goal is 16. If the dilator size is greater than or equal to 16 and they're still having symptoms, I would consider distensibility evaluation via endoflip, which can sometimes be helpful in these specific cases. And so briefly I'll touch on maintenance therapy. There are many, many graphs that I could choose from to show you that look like this. So this on the Y-axis is the proportion of EOE patients in deep remission for months. And then at time zero, we stop their topical steroids. And you can see relapse quite quickly in this study, 82% of patients with clinical relapse off therapy at a median of 5.5 months. So EOE is a chronic disease and relapse is common after treatment cessation. And so lifelong maintenance therapy is recommended and the patient should be counseled on that. So if you put a patient on therapy and you allow them to stop it, Andy will come to your house and punch a hole in your wall. And lastly, for long-term management, an international expert panel did note that unchecked inflammation may lead to fibrostimulantic complications and treatment may become ineffective over time, even when patients are taking it perfectly or patients may self-cease therapy. And so after deep remission is achieved, regular clinic follow-up at 12 to 24 month intervals is recommended, but also to check in on the new therapies, what's new for EOE. There's a lot of things emerging as we have discussed. And so our summary and key points today, the goals of EOE therapy are to improve symptoms, control inflammation, and prevent fibrostimulantic complications. Drug or diet therapy alone will achieve remission in most patients. And shared decision-making is really key given the diversity of our treatment options. Maintenance therapy and regular follow-up is recommended. And I think the future is bright with numerous potential novel therapies. Thank you.

EOE

immune-mediated condition

treatment options

biologics

dietary therapy