Improving Early Recognition of EoE to Reduce Patient Burden

Dr David Katzka (University of Colombia): Let us start first with improving early recognition of EoE to reduce patient burden and hopefully get the disease earlier than we have been doing. Let us hear from 1 of our patients first, please. Thank you.

[00:20:10]

Patient Perspective: How a Delayed Diagnosis Affected My Life

Morgan Gilbert: The challenges I faced with my EoE diagnosis were related to the fact that we did not know what it was when I started experiencing symptoms. When we detailed those to a doctor, we just were not aware of its existence. I can remember from a young age having trouble swallowing things like carrots and rice and it was often blamed on me not chewing well enough, even though I was insistent that I was. I remember in middle school having trouble at lunch sometimes with similar foods and even peanut butter sandwiches.

We did not really know that I had EoE until I had a food impaction and had to have an emergency endoscopy in order to clear my esophagus. From that procedure we knew that I had EoE. From that moment on, I was able to receive the treatment I needed and was able to start a food elimination diet that found what triggers my EoE and then also find some medication that works for me to let me eat gluten and dairy still.

Dr Katzka: Thank you, Morgan. Let us talk about some of the basics of EoE.

[00:21:24]

Clinical Features

First, some of the clinical features we are seeing. One is that EoE associated visits, particularly for the emergency room for food impaction, have increased by 11.5% each year from 2009 to 2019. We know it is 3 times more common in men than women, and that is not clear why that is, whether there is some wildly determination.

It affects all ages, although as we show in the graph on the right, there is some favoritism towards people in their 20s, 30s, and 40s. The prevalence is up to 23% of those undergoing endoscopy for dysphasia. In fact, it is the most common cause of bolus food impaction for those who trained what I did, whereas always a Schatzki ring. Now, it actually is eosinophilic esophagitis.

You will see on the right, the age distribution. Interesting, compared to a lot of other allergic diseases like asthma, or food allergy, or eczema where it can start early on in childhood, again, this disease starts really as a middle aged, late teenage, early 20s, middle aged disease. We could talk about why that is.

[00:22:34]

Epidemiology

Part of the epidemiology. We know that it is chronic. We will talk about maintenance later. It frequently relapses. The case estimate is about 5 to 10 per 100,000 with an estimated US prevalence of 1 in 700. When you think about it, that is a very common disease. I mean, just think of how many people could fill Busch stadium if 1 in 700 have EoE. That is a lot of patients with EoE.

We know that the incidence and prevalence is increasing at a higher rate, and it is more than disease recognition. Although we are more knowledgeable, we do more endoscopies than we ever did before. If you calculate the increase in incidents, it is clearly a biologic increase. It makes sense because after all, we are a much more allergic society and all allergies are increasing, not just EoE, asthma, eczema, peanut allergy, for example. It makes sense that we should see a new allergic disease, if you will, and that it would be increasing in incidences beyond patient and physician recognition.

[00:23:45]

Pathophysiology and Risk Factors

We learned a lot about the pathophysiology in the past 25 years of studying this, and is clearly a complex disease. We know that certainly atopy or allergy is very important because there is a high rate of atopic condition. Seasonal variation can sometimes affect it, and even oral immunotherapy can sometimes induce EoE.

Cellular pathology is very important. Although we call this disease eosinophilic esophagitis, the eosinophil is really 1 cellular player here. Activated mast cells, we will talk about the epithelial barrier, T-cell mediated lymphocytes as part of a delayed hypersensitivity are all very important to the etiology of this disease.

Then there is the environment. We know that food allergens are key in EoE because you take patients with EoE and you put them on an elemental diet, that is when completely devoid of all food antigens, anywhere from 80 to 100% will get better. Antibiotics may be important, formula feeding. We know that some of the preterm factors such as lack of breastfeeding, cesarean section, which changed the neonatal microbiome could also could be very important in EoE.

Interestingly, H. pylori is inversely related to EoE. H. pylori, in addition to causing damage also has some healthy aspects in that it regulates Th2 responses and helps downregulate some of the allergic pathways. So without H. pylori, which of course is much more common in this population now, they are more likely to have an unopposed Th1 delayed hypersensitivity, which represents EoE.

We also know that there is probably a genetic basis, and you will see on the right that we have genes there and they have identified 4 genes associated with EoE. The importance of this is if there is a genetic basis, of course the disease is never going away. Just as importantly, we know that it tends to run in families and older estimates are that if you have EoE, a first degree relative who have a 4% chance of having EoE, and I have many families where there are multiple siblings, parent, child who have EoE, and personally I think it is a lot higher than that. A genetic predisposition is important.

[00:26:09]

Pathophysiology

Now, 1 of the interesting things about allergy, which we did not talk about, is why does it present in late 20s, 30s as opposed to other diseases? One of the proposed theories of this by Jonathan Spergel is the so-called allergic march. It is a great term for characterizing what is a series of atopic diseases that ultimately predisposed to EoE.

Patients may start with eczema and asthma in childhood, food allergy syndrome progressed to seasonal rhinitis, and then develop EoE. It appears that part of EoE is being primed by previous atopic diseases, if you will, that span the first 10 to 20 years of their life, a fascinating hypothesis to explain why EoE comes later in life than we see in other allergies.

Now, 1 of the key parts of EoE is the esophageal epithelium in the so-called leaky esophageal epithelium. We read a lot about the leaky gut right now, but there is also a lot about the leaky esophageal epithelium. The reason it is so important is because with this leakiness and this dilation of spaces between the epithelial cells, it allows the antigen to penetrate, be it milk, or gluten, or some of the other food antigens that trigger this. Once that food antigen penetrates the mucosa and gets exposed to the submucosa, then the cascade starts with antigen presenting cells, Th2 cells, interleukins are secreted, eotaxin attracts eosinophils, and then finally this leads to what we see endoscopically and clinically, esophageal inflammation, fibrosis, possibly some dysmotility.

But it all begins here with this epithelial leakiness, which may to some degree be determined by the microbiome or genetically as well in these patients.

[00:27:59]

Delay in Diagnosis of EoE

Now, 1 of the key features of this disease clinically is the delay in diagnosis. If you look at some studies that suggest the median overall diagnostic delay is 3 years. In fact, it is probably longer than that. A recent study from Denmark showed it was actually 7 years from onset of symptoms to diagnosis. We know that the median patient diagnostic delay is 18 months before they have to get to see a doctor. This is problematic, because we know that complications are directly related to time of untreated disease.

In fact, if you look at a patient who has gone 20 years without seeing a doctor, and we know that is not uncommon, by the way, stricture formation will occur in 85% of patients. Then there is the risk of esophageal perforation, particularly with the Boerhaave's syndrome when they come in with a food impaction and they are retching, obviously a catastrophic presentation of EoE. Bleeding, in my experience, is actually pretty rare. But stricture formation and esophageal perforation is what we are trying to prevent with early diagnosis, if possible.

[00:29:01]

EoE Association With Atopic Diseases

We know again that atopic diseases are commonly associated, not only for the pathophysiologic reasons I discussed, but because patients who are allergic to 1 thing usually have other atopic diseases. For example, we know that patients with the EoE have approximate 6-time higher chance of atopic dermatitis and eczema. They have almost a 20-time greater chance of food allergy, particularly oral allergy syndrome, their throat tingles, their throat closes, particularly with pitted fruits and skin fruits.

They have almost a 6 times higher prevalence of asthma and a 6 times higher prevalence of allergic rhinitis. The importance of this clinically is because there may be an interaction between all of these and the esophagus. It is important to keep these under control as well as part of their recognition and management.

[00:29:49]

Conditions Associated With Esophageal Eosinophilia

We know there were other conditions which were associated with esophageal eosinophilia you have to consider, but quite frankly, most of these are rare. Crohn's disease, connective tissue disorders, pill-induced esophagitis. I think these are rare. The main 1, of course, is gastroesophageal reflux disease. We know studies back into the 1980s show that people with reflux can have eosinophils in their esophagus. We showed years ago that patients with Barrett's could have eosinophils in their esophagus.

The problem with this is that it is sometimes very hard to tell the difference. We think that studies like ambulatory pH studies would help us, but unfortunately they do not. They do not predict whether patients will respond to PPIs or to steroids. Unfortunately too, patients, particularly when they get into their 40s and 50s, often have coexisting GERD and EoE. Sometimes this is one of the hardest part clinically in determining does a patient have EoE and how to treat that patient.

Then there were these rare disorders, eosinophilic gastritis, gastroenteritis, and colitis. These are exceedingly rare compared to EoE, but sometimes they can either have esophageal involvement or they could be associated with EoE, which I think is a similar but not identical disease to these other eosinophilic gastrointestinal disorders.

[00:31:06]

Signs and Symptoms Vary Based on Age

Now, when you see a patient with EoE, as adult gastroenterologists, we always think about dysphasia. But it is important to remember that the symptoms will vary greatly on age. For example, children will have feeding difficulties, feeding refusal, poor weight gain, failure to thrive is not uncommon in young children, regurgitation, abdominal pain, chest pain, and then dysphagia.

The reason we think this happens is because in early childhood and early adolescence, we are seeing most of the inflammatory manifestations of EoE. But as this inflammation progresses in adulthood, we see the fibrotic manifestations, the mechanical obstruction. Keep in mind the age of the patient when you are assessing symptoms.

[00:31:54]

Adaptive Behaviors Mask Symptoms of EoE

Now, 1 of the things we talked about was the long delay in diagnosis. One would say, well, if someone is having trouble swallowing, I would think I would see the doctor immediately. But we know that EoE patients, like any patient with a chronic disease, learns to accommodate. They adapt. They figure out what are the things they can do to get by without having dysphagia.

Ikuo Hirano developed this acronym, he was fabulous at acronyms, called IMPACT. I stands for imbibe, in other words, these patients oftentimes will drink a lot of water to help the food go down. They are the person at the restaurant where the waiter has to keep coming back and filling their glass with water. They modify their foods. They will take their steak, they will cut it into small pieces, their chicken, their pork, they will chew their bread extensively, they prolong meal times. These are the children and adults who are the last to finish. They are being bugged by their parents, by their friends. Why can you not finish the same time as everybody else? They sit there and concentrate and take much longer time to eat.

They avoid food with hard textures. Yes, maybe at home they will try it, but they will go to a restaurant and they will say, I am not going to have any meat or I am not going to eat that bagel. It is going to be too difficult to get down. They chew excessively and they turn away tablets or pills. Certainly, the quintessential hardest food to swallow, if you will. Or they will demand they take it in liquid form.

Keep in mind this IMPACT acronym, because after all, if we just ask about dysphasia, we are going to miss the boat on a lot of patients. Unfortunately, it is one of those diseases where you really have to explore the symptom to the ultimate degree to understand how well the patient is doing or not well, if you will, when you see them in follow up and diagnosis.

[00:33:44]

Endoscopic Reference Score

The second part about assessing a patient with EoE, also developed by Ikuo, with another acronym is the EREF score. I am sure all of you have this on your probation at this point in which we grade the various common endoscopic findings associated with EoE, including edema, rings, exudate, furrows, which is by the way EREFS, as well as endoscopic reference score.

For those of you who have not read the original article in Gut in 2011, it is basically the best atlas there is for eosinophilic esophagitis. The reason I bring this up, it is not just recognition of the signs, but the grading. This is 1 disease where we really emphasize grading as best you can. Part of this is because we see these patients so frequently, we do so many endoscopies to really figure out what treatment is going to be best for them, that if you just say better or worse or dysphasia improved, you are really not going to get an accurate picture of how they are doing and comparing from visit to visit.

Symptom scores, endoscopic scores, we feel are essential in trying to monitor these patients. We use these in our clinical practice for all our EoE patients.

[00:34:59]

EoE-HSS

Then there is histology. We always think about the eosinophil, rightly so in histology and what is the count of the eosinophils? But we know that eosinophilic esophagitis is much more than eosinophils now. Whereas eosinophils were the [inaudible] of this disease, we know now too that oftentimes they are not as crucial as some of the other pathogenic factors.

Now we may have patients who have eosinophil counts of 20, but their EREFs are zero and they are asymptomatic. That will be more important to us than the EoE count. Conversely, we may eosinophil counts with the so-called normal range, but other disease parameters are active. The eosinophil is still important, but we cannot define the disease anymore by that 1 single parameter.

Similarly it goes for histology. There are many other features that are abnormal in the biopsy of patients with EoE, such as basal zone hyperplasia. We talked about dilated intercellular spaces, these cells that look like ghost cells, because after all, that is the abrogation of the tight junctions, the dilation of the spaces where food antigens can now enter. Lamina propria fibrosis, very important and perhaps a marker of fibrosis in general and stricture formation.

Margaret Collins developed a score called the EoE-HSS score. When she reads slides, she reads all of these and comes up with a scoring system in addition to the eosinophil count, which in fact is a much better measure of activity in EoE. Again, keep in mind that EoE is important, but we are following so many other things now when we assess patient severity and response.

[00:36:40]

Diagnostic Algorithm for EoE

As far as the diagnostic algorithm for EoE, this is basic. You get a patient who has clinical science suggestive of EoE, we do an endoscopy with biopsy. Notably, we do at least 6 biopsies from 2 different levels. Some people will take 3 and 3 and 4 and 4 from the distal esophagus, the proximal mid esophagus. Personally, I start the distal esophagus and then go up every couple centimeters and take up to 6 to 8 biopsies. I feel I get a better sampling that way.

But multiple biopsies is key because we know this is a patchy disease, and I am sure many of you have already seen in your practice you will get 5 biopsies, some will say 3 and some will say 50. If you do not get an adequate sampling, you may not really understand how severe the disease is. We evaluate for non EoE diseases, we have talked about that already.

[00:37:33]

Posttest 1

Now, a posttest. Which of the following statements correctly differentiates EoE from other eosinophilic conditions?

1. EoE is a systemic condition characterized by peripheral eosinophilia and multi-organ involvement;
2. EoE is characterized by esophageal dysfunction and histologic evidence of esophageal eosinophilia;
3. EoE is associated with allergic responses and is unrelated to esophageal fibrostenotic remodeling; and
4. EoE can be diagnosed solely based on an endoscopic evaluation without the need for symptomatic or histologic evaluation.

Please vote. Thank you. I feel good about that. We talked about this already, almost all of you got it right. You really need all the factors to be abnormal. Most of them you need a abnormal endoscopic appearance, you need abnormal symptoms, and you need esophageal eosinophilia. About 5% of adults will have a so-called normal looking esophagus. It does not exclude it. Children are much more likely to have a normal looking esophagus. But those are more the exception than the rule, particularly in adults with EoE.

[00:39:06]

Things Are Looking Up! Recent Advancements in the Management of EoE

Now, advances in management, where have we come?

[00:39:13]

Challenges in EoE: Setting Treatment Goals

I think we have talked a little bit about what our treatment goals would be. Although most of the trials on efficacy look at eosinophil count, the more recent ones look at all these parameters as far as assessing remission. We will get some patients with complete response, partial response, but ideally we are looking for this overlap here. Some studies will define what is called deep remission or borrowing from the IBD literature that unfortunately is not as common as we would like. Probably about 10% to 15% where we get everything to zero if you will. But that is the goal of course if we can.

[00:39:51]

Pathophysiology and Risk Factors

Here is the algorithm that we developed for the most recent guideline. We first start with treating inflammation, assess patients for fibrostenosis. We initiate anti-inflammatory treatment, and at that point we make a major decision, do we use pharmacologic treatment or do we use diet elimination treatment?

For first-line, if we do pharmacologic treatment, we choose between PPIs and topical steroids, both acceptable first-line therapies vs diet elimination and empiric elimination. We will talk about that. We then assess response. I emphasize this part because in my opinion, every time you change therapy, you have to assess response with histology. Then we assess with either a non-response. Do we change or modify the treatments, increase the dose, or do we go to a biologic? If there is response, then we talk about maintenance therapy and what dose that should be.

I will emphasize this because I would say of all the patients who come to me with refractory EoE, they are refractory because they are probably on an inadequate dose of steroids or PPI. Remembering for PPI, it needs to be at least 40 mg twice a day to start, and for steroids at least 1 mg twice a day. We will talk about that as well. Make sure when you treat these patients, it is on an adequate dose. Later on you could try to reduce the dose and see how they do. But start with the right dose please.

[00:41:20]

Therapeutic Pyramid for EoE

Another way of looking at this is the pyramid. I think with most patients we try to get by with monotherapy. Indeed, some patients will come to me, they are on milk avoidance, they are on PPIs, and a little bit of steroid. I think because this is a lifelong disease, we want to make the therapy as simple as we can.

Using 1 therapy at the right dose, in my opinion, will go a lot farther than using 2 or 3 therapies at lower doses. We may have to switch therapies. Sometimes we will combine therapies, particularly if we think they have coexisting reflux and EoE. Then at the top of the pyramid we think about biologics. Elemental diet are used in some children, but we rarely use them in adults.

[00:42:05]

Elimination Diets: Pros and Cons

Now, what about diet? Well, diets have been the stepchild of EoE for many years, and they have been the stepchild for many reasons. The first is that patients do not want to have to restrict their foods. We have difficulty with long-term adherence. We know that it may require multiple endoscopies. If you put a patient on a 6-food elimination diet, they go into remission, you start to add back a food, that is another endoscopy. You add back another food, another endoscopy. That does not work, you have to put that food back. So you can see what the pattern is.

Investigators like Alfredo Lucendo showed in his trials up to 10 endoscopies were required in some patients to figure out what were the foods that were triggering the disease. Obviously requires organization and motivation, difficult to implement when feeding difficulties are present. You need to get a specialized dietician involved. Obviously, costly for a patient and society point of view as far as work loss, all those endoscopies, etc, etc.

But there certainly are benefits to diet. One is it is effective. It obviates the need for medication, and avoids the adverse reactions of systemic medications. It is a shame that for years we were not encouraging patients to take advantage of that.

[00:43:21]

Types of Elimination Diets

Now, we know there is several types of elimination diets. There is the classic 6-food, cow's milk, wheat, eggs, well actually not legumes, more soy, nuts, and seafood. Legumes are used more in Europe. Legumes are probably the seventh or eighth food. There is 4-food, 2-food.

Then 1 thing of note here is that if you send the patient to the allergist to get skin and blood testing, unfortunately there is only about a 40% response. The testing the allergist does, does not correspond to the esophagus because it is an IgE related test or a RAST test. This is a different type of allergic reaction. Unfortunately, this is not helpful for EoE.

[00:44:08]

Histologic Remission Rates With Elimination Diets

But fortunately, times are changing and they changed to a large degree with this trial. This was a trial we did, headed by Kara Kliewer in the Cincinnati group in which we said, well, we know that milk is the most common food antigen followed by gluten, soy, eggs, nuts, and seafood. What happens if we just eliminate milk? When we did that, we found that a 1-food elimination diet of animal milk protein compared to a 6-food elimination diet, if you examined less than 15 eos per high power field, although a little bit less, in fact there was no statistically significant difference between the 2, well, no matter which EO count we looked at, except for maybe the very lowest at less than 1. We did milk vs 4-food, it was the same thing.

[00:44:58]

Step-down vs Step-up Approach in EoE

The good news is, as opposed to having to start patients on a 6-food elimination diet where it is a non-starter for many people and understandably, now we can say, “Well, let us go the other way and start just with elimination of animal milk”. That is a lot more acceptable to people. As opposed to the step-down diet that we always used, starting with 6, 7 foods and then endoscopy at every time when we changed the food, now we can start with 1 or 2.

Patients at this point may say, “Well, that is it for me. I think I will go on medication”. At least we are giving them a very good shot, almost a 45 to 50% chance, they may not need a medication. I think diet is really making a renaissance as far as therapy for EoE, particularly with the milk only elimination diet.

[00:45:45]

Proton Pump Inhibitors

Now, what about proton pump inhibitors? Well, proton pump inhibitors are fascinating because for years we thought it was the antisecretory mechanism. It must be coexisting reflux and that is why they respond. But work from Stuart Spechler and Rhonda Souza showed that, interestingly, PPIs have an anti-inflammatory effect on esophageal epithelial cells. We never knew that. If you put them in a completely neutral culture with no acid, PPIs block key cytokine secretion from epithelial cells.

In fact, proton pump inhibitors work in part and sometimes completely because they are blocking inflammation in esophageal eosinophilia. Again, start with twice daily dosing. The benefits of use, we have a longstanding safety profile. We have had omeprazole since 1990. It is easy to use, they are low cost now. We get a histologic response rate of about 42%, long-term, 60%. They are certainly suggested as a first-line treatment.

Now 1 of the keys of course is long-term use associated with risks. As gastroenterologists, we know how many times patients and primary care physicians have stopped the PPIs because of long-term risks. But we know now from all the recent long-term prospective trials that many of these earlier reports such as osteoporosis, fractures, dementia, etc., etc, were no different than control groups. We do feel now that these are still very safe medicines to start on and continue on.

[00:47:24]

Swallowed Topical Corticosteroids

Then there are steroids. Steroids have been our first-line therapy for many as well. It provides a topical coating to the esophagus. There is very little systemic absorption. Similarly, we start with twice daily dosing, may reduce to 1 nighttime dose for remission. Histologic remission in 50% to 70% better than PPIs and seem to be safe.

Yes, although it is relatively new in EoE, we have been using topical steroids for asthma for years and years and years, and those patients, it is safe to use. About 5% of patients will get a yeast infection.

Now budesonide oral suspension was the first steroid FDA approved for EoE just last year, even after dupilumab, which was interesting indicated for 12-week treatment and approved for greater than 11 years, and gets a strong recommendation from our recent ACG guidelines, and is effective up to 36 weeks in trials.

[00:48:22]

Oral Budesonide Improved Histologic and Symptom Response vs Placebo in Patients With EoE

Now, part of the reason I find steroids interesting is comparing the various preparations we have. Here is what the trial from oral viscous budesonide. When they looked at a histologic response, and you will see now we are measuring less than 6 and more stringent endpoint, you can see this about a 50% response. You will also notice that this is at 2 mg twice daily. You will also notice too that the symptom response is rarely as good as the eosinophil response. That is because we know that these patients often have fibrostenotic disease, and it is not clear to us that these medications do anything about stricture formation. Unless these patients are dilated, oftentimes we will not see as robust a clinical response as we would like. Less than 6, about 50%, 2 mg twice daily.

[00:49:15]

Budesonide Oral Suspension: Safety and Tolerability

Safety as far as nasopharyngitis, others. The important ones we have seen clinical adrenal insufficiency extremely rarely. A few patients will develop chemical adrenal insufficiency, but otherwise seems to be a very safe medication, at least in 2-year follow-up.

[00:49:37]

Continuing BOS Up to 36 Wk Reduced Occurrence of Relapse: Post Hoc Analysis

Now, up to 36 weeks, it remains effective. You will see at 36 weeks here, and here it still remains about 60% effective. It seems to be a very good medication for maintenance of therapy. Again, you will notice it is at a high dose, 2 mg twice daily.

[00:49:56]

Budesonide Orodispersible Tablet Maintained Remission for 48 Wk

Now, look at this. Here is the budesonide orodispersible tablet. It has been approved in Europe for several years and 1 is coming up for approval of the FDA made in the United States. Now look at the results: less than 6, 75%. Look at the dose—1 mg twice daily.

Why is it that this works so much better than the oral suspension? It is because it is the same medication, it is budesonide, and it really underscores how important the delivery system is for steroids. Not only far as the way you get it from the drugstore, but how you tell patients to manufacture it. I think that is the Achilles heel of steroids. We tell patients to take budesonide, mix it with honey, swallow it. We have no idea how standardized that is, whether they are taking the right amount, whether they are mixing it enough, whether the viscosity is right.

Although steroids are very good, it is a mixed bag as far as making sure they get the right dose. This, I think will be a big advance because there is no preparation, there is not a slurry involved. Just 1 tablet under the tongue will be enough to put most patients in remission. This will be a big advance as far as steroid therapy.

[00:51:13]

Posttest 2

Posttest 2. Your patient with EoE who achieved histologic and symptomatic remission following a 12-week course of BOS asked if they can stop taking their medication. Which statement is correct regarding the long-term efficacy of BOS?

1. BOS can be discontinued as there were no differences in relapse rates between patients who continued BOS and those who withdrew to placebo;
2. Continuing BOS will maintain symptom remission but not histologic remission;
3. Continuing BOS will maintain histologic remission but not clinical pathologic remission; and
4. Patients who continue BOS after 12 weeks are at greater risk of relapse.

Please vote.

Wonderful. Great. Thank you. We assume this is a lifetime disease. We talk about the genetic influences. Many atopic diseases remain lifetime and we know that the relapse rate is virtually 100% once we stop therapy. It may vary in terms of when the relapse occurs and some patients when they stop steroids, may have 6 months of remission, whereas some within a week are going to have relapse. We assume that at least at this day and age, all patients need lifetime therapy.

[00:52:59]

Dupilumab

Then we get to dupilumab. Dupilumab obviously has been a revolutionary treatment for EoE. Approved as a first-line treatment, although quite frankly, I am not using it for first-line, except in special circumstances, we will discuss that. It is approved for patients greater than 1 year of age, the only medication which certainly has that status. It works more specifically by binding IL-4 and IL-13, which are key cytokines in the inflammatory allergic pathway in patients with EoE, which is why it works. These 2 pathways are the cornerstone, if you will, of type 2 inflammation.

Although it is new to EoE, it has been around a little while because it was approved about 10 years ago or more for asthma and atopic dermatitis, now using it for chronic rhinosinusitis and nasal polyps. That is important, because if patients have coexisting diseases like this, particularly if they are severe, dupilumab has the greater advantage of being 1 therapy for multiple atopic diseases, if you will. That would be a first-line indication in my patients with EoE. It has weight-based dosing, and at this point, every week dosing is used.

[00:54:20]

Dupilumab LIBERTY EoE TREET: Histologic Remission

This was the LIBERTY EoE TREET trial done by ECO[?] and Evan Dellon in The New England Journal. These graphs show 24 weeks, 52 weeks, number of patients in remission. Notably, if you look at 300 mg weekly compared to every 2 weeks, it is pretty close. If you look here weekly it maintains remission. I emphasize this because I think it is a matter of time now before we change weekly dosing to every 2 weeks, particularly for the sake of remission.

This will make it much easier because of some of the side effects. Some of the side effects we know of dupilumab that we will talk about particularly site injection prohibit its use a little bit.

[00:55:06]

Dupilumab LIBERTY EoE TREET: Dysphagia Symptoms

This is a longer trial with 52 weeks. Here you will see every 2 weeks, the reduction in symptom score is not quite as good as weekly. But I still think ultimately it is going to be worth a try to put these patients on every 2 weeks after you put them into remission every week.

Notably too, this trial did not start endoscopies for 6 months, and so if you start a patient on dupilumab as opposed to PPIs and steroids, where we typically wait 2 to 3 months, this is a drug where you normally wait 6 months before you do your repeat endoscopy.

[00:55:42]

Dupilumab LIBERTY EoE TREET: Safety

One of the big concerns, new drug, what are the side effects? I think the most serious side effect that people see is site injection. For those of you who have used it on your patients, it is a pretty big volume to inject with a pretty big needle. I think this is particularly important in children where their tolerance of a weekly, very painful injection is difficult. Although adults have problems with this too.

Nasopharyngitis, headache. I think the other ones we mostly see we are seeing now are conjunctivitis in about 5% and arthritis in about 5% are newer side effects as well. It is by no means free of adverse effects, but I think overall for what it does, it is still a very safe drug.

Now, do we know the 30-year applications of this? We do not. Is it immunosuppressive? It is, but so far we have not seen opportunistic infection, at least data during the COVID period to not show any increase in infection in patients who are in dupilumab. So far it seems to be a very safe medication to use.

[00:56:48]

Dupilumab EoE KIDS: Efficacy and Safety

We discussed that it is approved in children as well and works extremely well in that population too.

[00:56:53]

Cendakimab Provides Symptomatic and Histologic Improvements Through 24 Wk and 48 Wk

Now, there are new drugs coming out which may imitate this. This is cendakimab, which also works through IL-13. Unfortunately, this was just withdrawn because its results were not quite as good as dupilumab. The company decided to suspend trials. Still it is a reflection of good news that with the understanding of the biologic pathways, there are many more drugs in the pipeline.

[00:57:17]

Biologics Currently Being Investigated for Use in Patients With EoE

TSLP, thymic stromal lymphocyte protein inhibitor, which is very effective in asthma, may be useful in EoE. Another IL-13 inhibitor, a sphingomyelinase inhibitor. All these parts of the delayed hypersensitivity pathway, which may be advantage points to attack this disease are in trials now.

[00:57:37]

Maintenance Therapy and Monitoring

Now, as far as maintenance therapy goes, this slide is to emphasize the need to do endoscopy. After we do endoscopy after 8 to 12 weeks and get them into remission, if we are going to reduce the dose, any change in dose, we have to repeat the endoscopy. Loss of response, change the dose, repeat endoscopy. Yes, patients do not want to go through these endoscopies. We would like to think that we could just rely on their symptoms, but again, we cannot rely on their symptoms because fibrostenotic disease probably does not resolve or at least it does not over any short term time period. Therefore, persistence of dysphagia by no means, means a lack of histologic response.

Until we come to market with the various non-invasive therapies like cytosponge, transnasal endoscopy I think is catching on the esophageal string, and I think eventually they will replace endoscopy for monitoring disease. At this point, we are still very dependent on endoscopy to keep track of these patients.

Now let us go to our patient again. Let us go to Morgan.

[00:58:47]

Patient Perspective: Successful Transitions of Care

Morgan Gilbert: My transition from the pediatric side of things to the adult side of things was very smooth. I was very lucky to have 2 great doctors that communicated well with one another. Also, my EoE was very well managed when I transitioned, so I knew a lot of the information that I needed going into that. A lot of what ended up happening was adjusting dosage amounts and trying to figure out an exact combination that worked for me, and also starting college and eating at a dining hall, making sure that I had the medication that let me eat what I needed to eat.

I had very minimal challenges, but I think part of that was also 2 great doctors that communicated very well.

Dr Katzka: Thank you, Morgan.

[00:59:37]

Challenges for Shared Decision-making in EoE

This brings us towards the last part of our talk, and that is, we know as doctors we can come up with the right diagnosis and the right therapy, but it does not mean a thing if the patient, the family, do not embrace it and do not take the therapy. This is 1 disease where shared decision-making is essential, because after all, we have 4 approved first-line therapies: diet, PPIs, steroids, and dupilumab.

Patients, as you know, they read extensively now. They know your CV before you have even seen them. They have very strong opinions sometimes on which therapy they want to use. We really have to have very good communication and involve them in these decisions. All the pros and cons of each of these therapies to really come up with something they are going to stick with, even if you may not have exact agreement on the plan as long as you feel it is a reasonable alternative. I think shared decision-making is essential in this disease.

[01:00:36]

Team-Based Approach for EoE Management

It is also important I feel to have a team. Because it is a lifelong disease because things are changing, we need to continue to provide education. That is where seeing these patients on a regular basis is important. It is not good enough to put them into remission, say they feel well, and say come back when you see me. I see these patients even if they are doing wonderfully at least every year so I can keep them informed, I can monitor them, I can hear if their subtle symptoms are coming back, I can let them know about the new therapies. We have to assist the parent with transition. We will talk a little bit about that, and we have talked about education.

[01:01:16]

Transitions of Care

One of the hot topics in EoE as well as I think in diseases in general is now transition of care. The idea that for years with the children grow up and get taken by pediatric gastroenterologists and then they were lost to follow up. We never had a program to make sure they transition to adults. I think that is something we are doing now, not only for EoE, for liver disease, for inflammatory bowel disease. It is important because the kids and parents have to make that transition from children taking control of their care when they pass 18 or the appropriate age, parents letting go of their care, which is also a very difficult milestone for many patients.

What we do with these patients is we make a rough plan over what their transition age is going to be, whether it is 18, and we will start well in advance. Sometimes it is 16 or 17 where we may have a joint visit with the pediatric gastroenterologist. It is a wonderful position for a nurse practitioner in your practice to start the transition from a child into adult practice.

It has been shown clearly that not only these patients get better care, they do not get lost to follow up. They are happy to continue with care in the same institution, in the same community. I think institution of transition of care plans is really a very important trend and becoming essential to make sure our patients stay in care and get the right care.

[01:02:42]

Challenges in Transition of Care

Now, there are obviously challenges. We talked about that kids are not independent from parents. Teenagers are hard to keep and 20 year olds in college are hard to keep on their medications, so why we have to stay on top of them. Children may not be familiar with the location of our practices in a completely different building, different office. There are systemic barriers, provider-specific barriers. But these are all easy to overcome if you really take the time to formulate a plan.

[01:03:17]

6 Core Elements for Adolescent Transition of Care

We will go through this. You could read up on this.

[01:03:20]

Posttest 3

Posttest 3: How often do you plan to engage in shared decision-making with patients and caregivers to optimize outcomes for EoE?

I am expecting 100% on this answer. I will take it. I like the honesty. Thank you.

[01:03:58]

Key Takeaways

What are the key takeaways of this lecture? One is EoE is increasingly common. Where it was originally classified as a rare disease, it is now a very common disease, estimates of 1 in 700 within the United States and in the western world.

Early diagnosis is key to prevent complications. We know the earlier we treat these patients, particularly as children, the less likely they will develop strictures as adults, get food impactions, and impair their quality of life.

PPIs and topical steroids remain first line options. However, newer biologics and emerging therapies are and will become potential options for patients who do not experience remission or who have specific situations like other atopic diseases, extremely severe disease where we may want to start them on a biologic straight away.

Most importantly, the successful management of EoE requires a team. We need shared decision-making. Parents have to be part of the team, dieticians, allergists, a transition team to make sure these patients come to us and stay with us and get the appropriate lifelong care they really need.

Thank you very much for your attention. I would be delighted to answer any questions.

[01:05:10]

Case-Based Question and Answer Session

Let me go to the chat. Thank you. One of the questions from Dr Landowski[?]. Can patients select to stay on Jorveza, which is the oral budesonide tablet available in Europe for greater than 3 years? Would you escalate a patient with 13 eos per high power field on Jorveza to dupilumab?

Great questions. Thank you. The first is I have had patients with EoE on steroids for 15 years, 20 years. The same applies to Jorveza. So far they have tolerated very well. I try to get to the lowest dose I can, mostly 1 mg before bedtime because if they do not, if you stop the Jorveza or the first-line therapy, we know they are going to relapse.

Now, 1 thing we have to figure out with this diagnosis we are working on are what are the different phenotypes. Like IBD, there are some patients will probably progress more quickly, some patients less quickly or not at all. There are some patients who will develop a mild stricture, some patients will develop a small-caliber esophagus. We are working on it, but we do not have perfect predictors at this point to help guide therapy, particularly maintenance therapy. But at least in this day and age, we continue patients on some therapy, be it Jorveza to keep them under control.

Would you escalate a patient with 13 eos on Jorveza to dupilumab? My general answer would be no. But I think the more specific answer would be, it really depends on what the other parameters are. If a patient has an EREF score of 8 and they are highly symptomatic, well, then those 13 eos may not belie the severity and that may be a patient I am going to escalate to dupilumab.

On the other hand, we talked about the patient has 20 eos or 30 eos in 1 spot, 5 at another, but they are feeling great. All the inflammatory signs and endoscopy have cleared up. I am going to keep them on their steroid and not worry about dupilumab. I emphasize taking in all aspects of the patient when you decide I am making that step from a steroid to a biologic.

Another question. For patients with more severe initial presentation with strictures, would you perform a dilation before starting an anti-inflammatory therapy or would you treatment or reassess? Great question.

I think it depends how severe the stricture is. If these people come in with a 7-mm stricture and multiple food impactions, I do not think you are going to wait for them to respond to therapy because you do not want them back in the ER again. I will dilate those patients hopefully at the index endoscopy when I start the anti-inflammatory treatment. I think if patients have a stricture but they are not severely symptomatic, then I will try to treat them first and do the dilation if needed at the follow-up endoscopy to assess treatment. Severity will dictate to a large degree when I do that initial dilation.

Cancer risks. Thank you. Great question.

Fortunately, there have been 2 studies now. One we did a big database study, and then Jonas Ludvigsson in the Scandinavian database showed there is no increase in cancer in patients with EoE. That is a fascinating topic because some experimental data shows that eosinophils may be protective against cancer. At least we can reassure our patients that cancer is not a long-term risk.

Thank you, Dr Kornberg[?]. Dr Mansour[?], the gold diameter of 16 to 18 for dilation is more than what we see in clinical practice. Is there good evidence to support that or should we dilate to symptomatic improvement?

I think you are absolutely right. The literature shows generally once you get to 16, it is unusual for patients to have persistent symptoms of dysphasia. Now, as you intimate, a lot of this depends on how much they are accommodating. If these are patients who are going to eat slow, cut their food into small pieces, chew carefully, drink lots of water for the rest of their life, because that is what they do and they are not going to change, you are right. They do not need a diameter of 18 mm. They may get by with 14 or 13. I think it is patient dependent, but I think most will recommend try to get to 15 if you can.

The other aspect too, which I am sure you all know quoted by Joel Richter, is start low and go slow. You are not going to bring in a patient with 9 mm and get them to 15 on the first try. You often have to tell these patients, it may take 2 or 3 sessions of dilation before you get them to where they need to be because we do not want to risk, of course perforation these patients.

Let us see. From Dr Landowski can you comment on eculizumab in this position? I think it is still in trials, so I am afraid I do not know where it is going to be at this point. We are excited to see. But thank you for that question. We talked about cendakimab and unfortunately, they are not proceeding with the trials at this time, which is sad.

Dilation criteria, basically their symptoms, particularly if they still have persistent symptoms despite effective anti-inflammatory therapy, we get their mucosal eosinophil count within the range we want it, we reduce the inflammation in their esophagus, meaning their exudates, their furrows, their edema, but they are still symptomatic with a stricture. We have to go in and dilate.

From Dr Kurtz, can you discuss the risk of esophageal perforation with dilatation in these patients?

When the reports started coming out, the perforation rate was very high, but then subsequent reports including ours from Mayo, those from the Swiss group showed that actually the perforation rate is very low. It is less than 1%, if again, you start low and go slow.

The other aspects of dilation we reinforce is that we look after every dilation and we dilate to the endpoint of a rent. If we see mucosal disruption or rent, we stop there, even if it is the first dilation. I think as long as you are careful, the perforation rate is very low in these patients and not much different in more recent studies from dilation, from peptic strictures, or other aspects of other needs for esophageal dilation.