We are now going to move on to consider more on the management of eosinophilic esophagitis. It is my pleasure to introduce Dr. David Katska from Mayo Clinic at the other Rochester, but Rochester, Minnesota. Okay, thank you. Hello, this is Dave Katska from the Mayo Clinic, and I'm very honored and delighted to give you a talk on behalf of the ASGE on an update on the management of eosinophilic esophagitis. These are my disclosures. When we discuss the management of eosinophilic esophagitis, the first thing we need to update are what are the proper endpoints we're seeking in our treatment. This has become rather complex and controversial over the past 10 years as we learn more about this disease, whereas initially the endpoint was considered getting the biopsy to less than 15 eosinophils per high power field. Now we know that there are various parameters used depending on the study. For example, some studies now use less than 6 eosinophils per high power field, and indeed following the field of inflammatory bowel disease, we are embracing the concept of deep remission to zero eosinophils per high power field. I think at this day and age, still less than 15 is probably the overall goal, but obviously we want to get the eosinophil count as low as we can when we treat patients with eosinophilic esophagitis. On the other hand, the biggest change I think with endpoints of treatment for eosinophilic esophagitis is the concept of using multiple parameters to assess treatment response. For example, we are now embracing the use of symptom scores, and there are several symptom scores which can be used. These include the Mayo Dysphagia Questionnaire, the EOE Activity Index developed in the Swiss group, the Dysphagia Symptom Questionnaire developed by Evan Dellin, and the Pediatric EOE Symptom Scoring System. Although one might think of these as useful only in clinical trials, I think more and more we're adapting these to practice such that either formally or informally, the series of questions which constitute these questionnaires need to be recorded in a systematic and regular basis to truly assess a response to treatment in eosinophilic esophagitis. In addition to symptoms and histology, the next parameter we use, which is essential in judging the activity of EOE, is in the endoscopic appearance. This has been studied extensively by Dr. Iko Lerano and colleagues at Northwestern, in which they developed the E-REF score, E-REF standing for adjugates, rings, edema, furrows, and stretch. Iko's landmark paper in GUT really is a wonderful atlas of all the appearances and grading of these endoscopic appearances of each of these features, and the E-REF score has been shown to be reproducible and a very important parameter with which to follow these patients as well. Most endoscopy software at this point actually incorporates the E-REF score, so it's become very easy to incorporate this into your clinical assessment of patients with EOE as regards their treatment response. As accurate as endoscopy is, we have to realize that it has its limitations. This is particularly in the evaluation of strictures. In this study by Jeff Alexander, corroborating findings of strictures on barium esophagography with endoscopy, Dr. Alexander showed that for strictures 13 millimeters or greater, 25% of patients had missed strictures, and this makes intuitive sense, because after all we know from peptic strictures, esophagography has always been better, and more importantly, this is what we call normal as far as esophageal diameter on endoscopy, yet had food impactions or strictures, obviously they had a stricture that they were missing. So it's important to realize that sometimes other tests, such as esophagography or the use of endoclip, is better than endoscopy in assessing esophageal diameter and compliance. So to summarize, the use of endpoints in EOE, rather than relying purely on the example count, we assess EOE by a compendium of complementary tests, which include the symptom scores, particularly for evaluation of the subtle symptoms of EOE, an EREF score for endoscopy, perhaps some assessment of the esophageal diameter compliance with the esophogram or the endoflip probe, as well as new parameters of assessing histology, such as the EOE-HSS score developed by Margaret Collins, which grades multiple features found on biopsy, rather than just the EO count. And then finally, we're considering the concept of deep remission, where patients have a very low EREF score, are symptomatically well, and no eosinophils with a low EOE-HSS score at the ideal endpoint in EOE, although again, hard to achieve in many patients. When it comes to therapy, one of the big changes in EOE has been the use of proton pump inhibitors. Since this original study from Javier Molina and Bonte, demonstrating that in patients with a typical phenotype of EOE, PPI use can be successful in up to 60% of patients who've incorporated PPIs as a first-line therapy in EOE. And whereas for years, there was debate about this concept of what type of patient responds to PPI, hence the name of this subset, PPI-responsive esophageal eosinophilia, it's become quite clear that this is really a subset of EOE altogether. And this is demonstrated by studies such as this, in which if you look at the genetic makeup of patients with EOE and PPI-RR-EE, there's marked overlap, just suggesting again, this is a different phenotype which happens when you respond to PPIs, but within the subset of eosinophilic esophagitis. So PPIs, again, have become a first-line therapy, and often the first therapy we use in patients with EOE, particularly if we feel there's an ongoing component of gastroesophageal reflux. Eosinophilic esophageal steroids have been the backbone of therapy for eosinophilic esophagitis, and there are two formulations which we use. They are fluticasone and budesonide. There are two very important aspects of using these therapies. The first is the right dose. Indeed, many patients who come to me with so-called refractory EOE have just not received a high enough dose of the steroid. For fluticasone, this is 880 micrograms twice daily, which is basically four puffs twice daily. For budesonide, it's one milligram twice daily. The second aspect, which is very important, is making sure the steroid is delivered the right way. In a classic study by Evan Dell and shown on the right, when the steroid was traced with a radionuclide tracer, you can see in the top panel, when patients take budesonide, it goes right from the mouth to the stomach, whereas when patients took fluticasone, they unfortunately inhaled a lot of the fluticasone into their lungs, which of course did not help the esophagus very much. So when patients take fluticasone, we have to make sure they spray it at the back of their mouth and then exhale after taking it, as opposed to inhaling. For years then, we assumed that budesonide was much more effective than fluticasone, but a recent randomized trial, which I'll show you next, showed that this is not the case. In this more recent trial by Dr. Dell and comparing budesonide to fluticasone and looking at various parameters of response, such as the eosinophil count top left, the dysphagia symptom questionnaire top right, percent response bottom left, and the EREF score bottom right, you can see that fluticasone and budesonide are equally effective compared to placebo and the like rate. This underscores the fact that steroids, if taken the right way, can be very effective, but careful instructions from the physician or caregiver are imperative in making sure this works as we expect. This is further demonstrated by an oral dissolvable tablet, which goes under the tongue, in a preparation which is available in Europe. And in this controlled trial, ultracenter performed within Europe, you can see that comparing the two formulations of the budesonide, BET1 and BET2, to the oral viscous budesonide, in this trial, there was almost a 95% response in looking at histological emission. Certainly this preparation is not available in the United States, unfortunately, but showing you that how variable the response can be to the steroid, depending on the preparation in which it's given. One of the most interesting ways in which therapy has changed for EOE is the use of diet therapy. Whereas initially diet therapy was seen as onerous and difficult because of the restriction of so many common foods to make this work, we're now finding that diet therapy is having a marked resurgence in EOE. And this is because, after all, we're supposed to avoid medications such as PPIs and steroids. Gluten is bad for us, whether you have celiac disease or not. And animal fat, particularly milk protein, as well, is thought to be something we shouldn't do as well. And this leaves diet therapy as an option, which is seen as important for many patients with EOE. When we look at the effectiveness of diet therapy, we can see that it's almost 75% to 80% effective. And this meta-analysis by Arias et al, it was shown also to be equally effective to topical steroids and better than protopump inhibitors. So from an efficacy and effectiveness point of view, a properly instituted elimination diet is extremely important and is a first-line therapy in patients with eosinophilic esophagitis. One of the biggest reasons that diet is also becoming much more mainstream in EOE is the concept that now we've moved from a six-food elimination diet to a one-in-two food elimination diet. Studies like this from Alfredo Lucendo and the Spanish group, they have shown that in up to 45% of patients, there may be only one food that causes EOE, which is most common are milk and gluten. So now, as opposed to eliminating the six foods, which you know well, patients can get by just avoiding milk and gluten most of the time. Although it is hard, it's certainly a lot easier to do and therefore much more palatable in comparing therapies such as lifetime protopump inhibitors or topical steroids. Another aspect which has caused diet therapy to become much more popular amongst patients with EOE is the fact that as we've reduced the number of foods that need to be withdrawn, we've also reduced the number of endoscopies. Initial study from Alfredo Lucendo, putting patients on six to eight food elimination diets, you can see that after 10 endoscopies in the trial and error process of assessing histology between diet changes was needed to really figure out what diet these patients needed to be put into remission. Now because only one or two foods may cause this, as opposed to starting with six to eight foods, we start oftentimes with a one or two food elimination diet and then maybe go from one to three or two to three and then to five or six. So as a result, patients need far fewer endoscopies than they ever did before, starting with a step-up therapy as opposed to a step-down therapy when it comes to instituting diet therapy. The other hope that should hopefully make diet therapy much easier to follow is the advent of non-endoscopic instruments to assess treatment response. In the top left is the string device developed by Glenn Garuda. This is a capsule with a string that's deployed and left in for an hour. The string is withdrawn and the secretions from the string are analyzed for various e-xanthophyll markers. In the bottom left is a heat map looking at tissue to assess response from Mark Rothenberg's lab. The bottom right, some work that we've done with Michael Bayesian, looking at an impedance measurement, which is a probe which assesses the presence of dilation of intracellular spaces, a histologic hallmark of VOE. And on the top right is what we're using mostly now, which is the sponge on string device, or the SIRIS sponge. And although this was developed originally for Barrett screening by Dr. Rebecca Fitzgerald in the UK, and will be used broadly for that, we've adapted it to use in epileptic esophagitis as an easy bedside instrument that avoids endoscopy. As you can see, it is easy to swallow. I promise it's not just sitting in my mouth, and there I am with a SIRIS sponge in my stomach. We only keep it down for five minutes and then withdraw it quickly. This is our most recent study looking at the accuracy of SIRIS sponge compared to endoscopy and biopsy. And here you can see on the left with the linear relationship and the ROC curve on the right that this seems to be a fairly good concordance of the sponge with the endoscopy. Interestingly, there are some patients who have positive biopsies and negative sponges, but there are patients who have positive sponges and negative biopsies. We think this is likely because by pulling the sponge up to the esophagus, you probably get a much more generalized sample of the esophageal mucosa as opposed to point-directed biopsies. We are currently doing a trial now predicting the ability to identify foods this way, so please hang in there and stay tuned, and hopefully this will become a tool of the future to, again, easily follow these patients in response to therapy, particularly in sorting out diet therapy. I think one of the most exciting aspects of treatment of EOE is the emergence of biologics, and I'm not quite sure if Paul Revere said this in his famous ride, but if he were, if he had EOE and were riding today, perhaps this might be his cry. So just as, in keeping with the theme that we are following the field of inflammatory bowel disease carefully, it's a chronic, stricture-free disease, so we are adapting new biologic therapies for Eosinophilic esophagitis. For Eosinophilic esophagitis, potentially useful in the future. This is a recent study by Eco Arano, Avigdala, and others looking at dupilumab and EOE. Dupilumab is an inhibitor of IL-4, a key cytokine in Eosinophilic esophagitis, as well as in a disease such as atomic dermatitis, an asthma for which dupilumab has also been shown to be extremely successful and has been approved by the FDA for those indications. You can see in this study, in looking at the numerous parameters of EOE, such as symptom scores in the top left, the Eosinophil count in the top middle, the EREF score in the top right, that there's a dramatic improvement in all these assessments of EOE compared to placebo. This is another multicenter study from Eco Arano, who was the first author, looking at another biologic which inhibits the cytokine IL-13, as well as IL-4, again, two key cytokines in the pathogenesis of EOE. Here you will see the responses after 16 weeks of therapy. For example, at these two different doses, the mean esophilic count in the top left, in the medium gray, you can see where it goes from baseline to response in the gray and the black. This carried through the entire study, looking at other parameters, such as the reduction of Eosinophil count to less than 6 or 15 in the middle panel left, the change in symptom score in the middle panel right, in figure D and in figure F, the overall change in histologic adjustment score. So similar to dipelumab, this compound is extremely efficacious in improving all aspects of the eosinophilic esophagitis at 16 weeks. Here you will see in the medium gray and black are responses to these two doses of this compound at weeks 8 and 16. Also of interest is the use of this compound for maintenance, the only biologic which has been tested this way. In this study from Evangeline, one can see in these panels, the assessment of previous responses judged not only in week 12 or week 24, but week 52, so a one-year trial. And if you look at these responses in panel A, the esophilic count, C, the EREF score, and D, EO count less than 15, and D, the EESAI score, you can see that this compound, PARPY4046, is extremely effective not only in inducing remission, but in maintaining remission up to a year in patients with EOE. Also of interest is you may note that some patients who had a partial or incomplete response in week 24 have more of a full response in week 52, showing that although we treat patients with whatever therapy for 6 to 8 weeks, there are some patients who will need longer whatever medication you use to get a full response. But it still remains to be seen once these biologics are hopefully approved by the FDA what their place will be, and obviously there's hesitation. Using biologics, they're expensive, they cause immunosuppression, we don't know exactly the long-term risks of EOE, and we have to weigh this against the fact that no one dies with EOE. When we think about using biologics in inflammatory bowel disease, this is obviously a very different situation where the morbidity and mortality is much higher. There's no prevalent potential in EOE. But on the other hand, there are some things we have to consider, and that is the occurrence of esophageal perforation. Although uncommon, it can obviously be a life-threatening event in these patients. But more importantly is the mark impingement on the quality of life of patients with EOE. Although we think of it as a much less severe disease than perhaps Crohn's disease, quality of life studies show that patients with EOE feel they suffer just as much as patients with IBD, not only because of the difficulty of swallowing, but more importantly the social stigma, the fear of going to restaurants, the limitations in diets. So we cannot underestimate that in the mind of most of these patients, EOE is a severe and in some cases debilitating disease. There's no prevalent potential here. The only main side effect is esophageal perforation, but we have to think about the fact that EOE does have a mark impingement on the quality of life. In fact, if you look at quality of life scores in people with EOE and compare them with Crohn's disease, they come out the same. So we're in this battle here of deciding, assessing the risks of biologic. Another new aspect of therapy in EOE is the concept of maintenance, specifically asking which patients with EOE need maintenance therapy. Do all patients need maintenance therapy? After all, studies clearly indicate that the relapse rate once we stop therapy is 95 and not 100% over time. Should we just reserve maintenance therapy for high risk patients such as those with known small caliber esophagus, rapid recurrence of symptoms or even histologic abnormalities after therapy stops, patients with frequent or severe food impactions, patients who travel worldwide such that they don't want to have an impaction in a foreign country or have other comorbidities such as frequent endoscopy or recurrence of perforation could be problematic. Because after all, the goal of maintenance therapy is to prevent the patient on the left becoming the patient on the right, evolving from a normal esophagus to a severely strictured small caliber esophagus. And will this happen in every patient? Probably not. I suspect that small caliber esophagus is a subset of patients with eosinophilic esophagitis, more common in younger patients we see with very early onset of symptoms. But then again, we know from work from Alan Schoepfer that if you go through 20 years without treatment, 85% of patients will already have a stricture. Therefore, at this point, the question becomes if we can't identify that subset, who will progress clearly, which is one of the holy grails of the OE, of course. It begs the question should all patients for the OE should be on some kind of chronic therapy, if not diet therapy, at least steroids or PPI if they're shown to be responsive. One of the looming questions in maintenance therapy for eosinophilic esophagitis was what was the correct dose that they should take of a steroid preparation to keep them in remission. Prior studies looking at doses of one quarter of what we used or perhaps on every other day basis were not as effective. But in this study of the oral dissolvable compound available in Europe, you can see when it comes to maintaining remission histologically, clinical remission, deep histologic remission, or deep endoscopic remission, looking at doses of one milligram twice daily and even 0.5 milligrams twice daily, up to 75% of patients maintain remission across the board. Now our concern, of course, is what are the long-term side effects of using chronic topical steroids? One of the concerns is shown in the bottom panel is that of adrenal insufficiency. In this study, there were no changes in serum cortisol after a near time, except for one patient who had chemical adrenal insufficiency. To date, no patients have been reported with clinical adrenal insufficiency taking long-term steroids. We worry about things such as bone density, although Jeff Alexander has a study in press showing no change in dexascane. What will be the 20, 30, 40 year repercussions of daily steroid therapy? Obviously, we don't know as a concern, but we have to weigh the risks of what may happen in the future versus the benefits of keeping patients in clinical remission, out of the ER, not having food impactions, and not having such impairment on their quality of life. At this point, I do treat virtually every patient with some sort of maintenance therapy, particularly the younger patients where at this point we're looking at 40 to 60 years of ongoing disease that's expected. So at least we have a dosage range now we know that works for these patients. So how can we summarize this talk? First, use multiple parameters to assess treatment response. Two, consider PPI, steroids, and diet-responsive EOE as the same disease on the spectrum. Three, use steroids in the right dose with careful instructions to patients. Four, reconsider diet therapy as part of what you may offer these patients. Five, watch for the biologics, particularly for refractory disease. And six, consider some type of maintenance therapy for most, if not all, patients with EOE. Thank you so much for your attention.

eosinophilic esophagitis

management

treatment endpoints

proton pump inhibitors

steroid therapy

diet therapy