During this 20-25 minute pre-recorded lecture, Dr. Mirna Chehade discusses the topic of eosinophilic esophagitis. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Sept 22 Hello everyone. Thank you for tuning in to the talk on S. And Felix esophagitis which is part of the G. I. Intensive board review course. My name is marina Jihadi and I am the director of the Mount Sinai Center for S. And Filic disorders at the Icahn School of Medicine at Mount Sinai. Before I start, these are my disclosures. I do receive research support and consultant fees from several commercial entities, none of which pose any conflicts of interest for this talk. Just like every other presenter I'm going to start with a case 23 year old male presents to your office a week after a visit to the emergency room with the sensation of food stuck in his chest along with retro sternal chest pain that occurred while eating chicken associated with retching and excessive salivation but no vomiting. He underwent an urgent endoscopy and a piece of chicken was removed from the mid esophagus. His medical history reveals no heartburn but occasional need to chew carefully and drink plenty of water with meat and bread. Review of systems reveals asthma, allergic run artists and peanut allergy. He is an athlete with a normal BMI no history of smoking or alcohol consumption. He drinks away based supplement every day when working out in the gym. So what I painted for you is a healthy young man with this fee Jha no heartburn. He has a topic history and he's consuming a lot of dairy in the form of way supplements. So the question for you is the most likely cause for these patients suffered your food imp action is a gastroesophageal reflux disease. Be ankle asia, see a salvageable tumor and D. Eosinophilic esophagitis, what do you think is the right answer? That should not be too hard. I hope that you all chose D. Eosinophilic esophagitis. In fact the only prevalence has been increasing worldwide. What I'm showing here is a graph summarizing prevalence rates over time from several countries from the United States and Europe showing an increasing trend with the current prevalence estimated at 0.5 per 1000 inhabitants. Now who gets mostly er we usually occurs most often in those aged less than 50 years old. It is three times more common in males than in females. It is found in 2-7% of patients undergoing endoscopy for any reason And it's found in 12-23% of patients undergoing endoscopy for this v. Asia in particular, it is more common in patients with food allergies or A to B in general and it is the most common cause of bolas, food imp action. So how do we define? E. L. A. Is a chronic immune, energy mediated esophageal disease that has to have two pillars for its diagnosis clinically you have to have salvageable symptoms and histological e you have to have you seen a full predominant self general inflammation, you is caused by mainly food allergens. Now, while the evidence for food triggers has been established in several studies where foods were removed or added to the patient's diet with a result and change in disease activity. The role for environmental allergens as triggers has been so far indirect, resulting from observations of patients whose symptoms and a soft Julius anopheles worsened during the pollen season. How bad symptoms symptoms do vary with age on this graph. Blue bars represent adults and dark pink bars represent Children. I'm going to start with Children showing you here that most commonly Children present with non specific symptoms such as abdominal pain, reflux symptoms including vomiting and failure to thrive and adults. It's easier the vast majority of adults present with this phase ASIA and soft gel food imp actions note however, that one blue bar, which shows adults With reflux symptoms. So up to 35% of adults present with reflux symptoms including refractory heartburn and regurgitation. Therefore, if you do not have history of dysplasia, please do not rule out you and a patient that has the right clinical context. Another thing to watch out for is that patients do not always report their dysplasia because of compensatory feeding behaviors that they develop over time, such as prolonged chewing, drinking with every bite of food, cutting food into very small pieces and lubricating tough or lumpy foods with condiments or dunking them in liquids. Therefore, if you ask a patient if they have this for ASIA and they deny it, then go ahead and ask for these compensatory feeding behaviors to really know whether they have them, Therefore leading to their negative answer regarding this facia. So how do we diagnose E. O. E. An endoscopy with Asafa Geo biopsies is the main way to diagnose it. So an endoscopy you could find inflammatory features such as shown here the left panel showing you photos along the length of the esophagus. You could have white plaques or even plaques lining up along the photos. All of these fall into the inflammatory features of E. But then if we have a disease that has been ongoing for a while untreated now we will start seeing fabulous dramatic features in patients with and these include drinks as you can see here on the left panel or structure as you can see in that patient in the right panel. Now biopsies will of course show you infiltration with your cinephiles as the disease name denotes. So to illustrate this, what I'm showing you here on the left panel is a section from or a him a toxin in your sin stained section from a biopsy of a healthy individual and normally you should have zero your cinephiles but high power field. The right panel however shows you a section from a biopsy of a patient with E. And you could see these eO cinephiles infiltrating the south Aegean mucosa. By definition 15 or more years. NFL super high power field and the most involved area would meet the histological criteria for E. It is Apache disease. Therefore multiple biopsies are needed to establish the diagnosis. Typically 6 to 8 biopsies from the esophagus are needed so that you do not miss the diagnosis. So back to our patient after he removed a piece of chicken from his middle esophagus, you noticed deep photos and white plaques scattered throughout the length of the esophagus, no strictures or rings, no erosions or ulcers and no hiatus hernia. You took biopsies from the distal and proximal esophagus and you found up to 92 years in Fallsburg High power field in the distal area and up to 72 years in Fallsburg High power field approximately. Now the question for you is do you need to do a trial of a high dose PP. I before you confirm the diagnosis of E. That's a little bit of a tricky question. And the correct answer is. Now we used to think that we need to do a high dose BP trial two before we call the patient as having To rule out other causes. But now with the new diagnostic criteria, you really do not have to do that. So if you have a clinical presentation suggestive of and you perform an upper endoscopy with biopsies demonstrating Assaf Julius in Ophelia as defined by 15 or more years on the force for high power field. Then the next step for you is to evaluate for non disorders that cause or potentially contribute to a salvageable yes in ophelia. And by that what we mean is not to have a certain battery of tests that you are obliged to do. But to exercise your clinical judgment and decide whether this patient may have other causes of salvageable ears and ophelia. And if you don't think there's any and the history and the biopsies are suggestive of then it is. So back to our patient, you discuss with him a few treatment options namely pp dietary restrictions, topical corticosteroids and biologics, the latter and the context of clinical trials. So he chose the PP. You started him on pent up, resolve 40 mg twice a day and re evaluated him after eight weeks. So the question for you is what's the chance of him responding to the PP 25% 50% 75% Or 100%. I'll give you a few seconds here to think about it. So it's a high dose BP. And a patient with the The correct answer is 50%. And this is illustrated here by a systematic review and meta analysis that was done by Alfredo loose Endo and his colleagues and published in 2016 showing you the combined histological remission rate using high dose PP. I. Um Of 50% and interestingly it's not much different in Children, adults, Children having 54% response rate and adults having 50% response rate. So if you're patient response to the PPE, what do you do next patient is now on a high dose pp this is a chronic disease. If you stop the PPE, the disease will relapse so long term treatment is needed. And the goal always with any of the medical therapies including with PPE is to go to the lowest dose of treatment or of medication that will maintain remission. To illustrate my point. I'm referring you here to a retrospective multi center study Conducted by Molina Infantry and colleagues and published in 2015 Where they took 75 adults with who were responsive to a high dose PP. And then they started them on a low dose PP. After a mean follow up of 26 months, There was maintenance of histological remission in 73% of patients. So the vast majority of patients maintain remission on the lower dose of PPE back to our patient after eight weeks. He remains symptomatic and his upper endoscopy with biopsy reveals no change unfortunately. So this time he asks you for a dietary elimination. So in addition to already avoiding peanuts, which he avoids because of an egg mediated food allergy which would be the most optimal dietary option for this patient. A avoidance of all dairy products or milk elimination diet. Be avoidance of all foods that test positive by allergy testing, that skin tests and or blood tests and that's what we call the allergy test based elimination diet option c avoidance of milk, wheat, egg, soy all nuts and all seafoods. And as you can see this is the six food elimination diet which is the most common form of the emp eric elimination diets for Joey. An option D an exclusive feeding with an amino acid based formula also known as the elemental diet where all foods are removed and the patient is fed in non allergenic asset based formula. Not here that all the options are correct and our potential options for this patient. So what I'm asking for is what do you think is the most optimal dietary option for this patient? The most optimal option is avoidance of milk, wheat, eggs, soy walnuts and all seafood. Also known as the six food elimination diet. Mhm. So let me show you the data to support this choice. Dietary therapies in general Can be grouped into three types based on what has been published in the medical literature so far. One the elemental diet which as I mentioned consists of removing of all foods from the patient's diet and exclusively feeding with an amino acid based formula which is non allergenic. And this is a very Efficacious Diet where the response rate is more than 90%. However it's very difficult to follow by patients therefore rendering it not optimal. The second option is the allergy test directed elimination diet and that is a diet that were foods that test positive either by prick skin testing or a to p patch testing is followed and sometimes hero I. G. Levels to foods are done and foods are removed when they are positive. This this diet is not optimal since E. Is not an I. G. Mediated allergy to food. So foods cause you? Re not V. A. I. G. Mechanism, but by a non I. G. T. Cell mediated mechanism. Therefore the efficacy rate for this diet has not been great as you will see in a minute and then the third option or the third type of diet that is commonly published, is the empirical elimination diet. And that consists of empirically removing. Without any testing, common foods such as milk, wheat, egg, soy, all nuts and all seafood and that is the six ft elimination diet. Now let's do a comparative efficacy of diets here, which I'm showing you on this slide starting from the bottom all the way up. Dark blue bars represent Children. Dark pink bars represent adults. Let's focus on the adults as you can see here. The elemental diet is highly effective in patients with E, followed by the empirical elimination diets. So as I mentioned, six food elimination diet consists of removal of milk, wheat, egg, soy or nuts and all seafood since it is still a difficult diet to perform other studies followed, removing fewer foods. Now the choice of these foods was based on those that are eventually figured out to be the most common. So the four food elimination diet for example removes milk, wheat, eggs soy which are the most common for foods triggering a OE and that results in about 50% efficacy rate. The two food elimination diet consists of removal of milk and wheat from the diet, which are the two most common food triggers studied in. That results in about 40% efficacy rate. And adults. You see here on the graph the allergy test directed elimination diet where it falls Right behind the empirical elimination diets and finally at the top of the graph here, you see milk elimination diet consisting of removing removal of all dairy, which is the simplest form of empirical elimination diet where indirect data have shown an efficacy rate of about 20% sincerely is a chronic disease. If you stop the diet in a patient that responds to the diet, the disease will relapse. But at the same time you cannot keep the patient avoiding all six foods. And When you choose a six food elimination diet for example. So what happens is following that induction phase where you would remove all six foods, allowing the patient to eat other table foods and you perform an upper endoscopy with biopsy showing disease remission. Now you would go into the reintroduction phase where foods are added one at a time, followed by clinical and histological assessment. If the food added creates yuri relapse, then we know that food is a trigger and it will have to be removed again from the diet if the food added does not result in relapse. So we still have a continued yo era mission then we know that that food was always safe and is not a trigger for that patients. Therefore it can stay in the diet and additions of foods are done. What at the time that way either removing the food again or keeping the food until a maintenance phase is achieved where now the patient is on a diet which is not as unrestricted as when they started but also not as super restricted as when they were when they followed initially the induction phase and that is their maintenance dietary treatment. So back to our patient, he went on an empirical six ft elimination diet with good adherence with the help of a dietician. His symptoms did not improve and his endoscopy and biopsies showed persistent eerie. Unfortunately. So this patient so far has not responded to A PP. And now has not responded to a diet. So he decided to switch to another medication. So the question for you is what's the best option for this patient? A renaissance B. Political zone and held spray to swallow C. And histamine and the Kremlin. So again, what do you think? An oral steroid, topical steroid apply to the esophagus histamine or cromelin? The correct answer. Care is B floating zone and held spray to swallow. Let's go over the topical corticosteroids as one of the treatment options for you. Unfortunately none of them are yet FDA approved for use. However, two formulations are commonly used off label. One is the flitting zone HF a inhaler to swallow. So the flight tickets on HF inhaler is used for asthma. But instead of asking the patient to puff and inhale, we tell them to puff and swallow so that the mist now coats the esophagus as opposed to going into the lungs. And a typical induction dose in adults is 8 80 micrograms twice daily. And then the other formulation that's commonly used is the viscous by destiny to swallow. So for that the Bds Sinead vials which are used also for asthma. These are the vials that are opened into the nebulizer for nebulizer used in patients with asthma instead of being opened and placed in a nebulizer chamber. What we do is we take them and we thicken them with a sugar substitute or maple syrup or other thickeners so that the viscosity can increase. So when they are swallowed by the patient, they will coat the esophagus and not slide down quickly to the stomach. And a typical induction dose in adults using medicine, it is one mg twice daily. The efficacy rate using these topical cortical steroids based on eight randomized control trials around 65%. Now again, just like we went over with every other treatment is a chronic disease. If you stop the steroids you will get you a relapse. Therefore chronically the best is to try to reduce the dose to the lowest those chronically that will maintain remission in the patient progress is being made. However, using topical corticosteroids as several studies are currently in progress. One is using medicinal oral suspension. Currently in a Phase three trial with an extension and teenagers and adults. Preliminary data have shown some promising results both clinically as well as histological. E. Another drug Being studied is political zone orally disintegrating tablets. And that's in Phase two with an extension and adults. And a third drug being used is badass in it or disperse herbal tablets. That study is not conducted in the us but rather in Europe Phase three trial with an extension and adults results of which were published and the medication was recently approved by the european medicines agency which is the equivalent of the FDA in the United States. So we'll have to see where these trials would lead us. And to see if we can get an FDA approved medication using topical corticosteroids. What about biologics? Biologics are an attractive option since the since the disease E. Is a non IgG mediated but rather a T cell mediated disease where the food allergens trigger E In A.T. helper type two mechanism. So an allergic phenotype is seen in the U. E. So if one looks at the esophagus of patients with the OE one would see up regulation of th two cytokines, aisle four, aisle five and I'll 13, many of which are really important in the eventual survival and recruitment of sniffles to the esophagus. A few phase two trials have been done so far. Initially monoclonal antibodies were used to aisle five or against IR five using two drugs. In two different studies, Maple is a mob and realism mob. Both showed histological improvement of E. But no significant clinical improvement. Therefore these studies were stopped for E. Or they were no longer pursued for E. Another monoclonal antibody targeting interleukin 13 was used in two different trials. One using the drug QA X 5 76 the other one using RPc 40 46 and both showed histological improvement and the trend in clinical improvement. Further studies using these drugs are awaited And more recently a monoclonal antibody against ill four receptor alpha which would abrogate the secretion of both aisle four and I'll 13 was used. The drug was jupiler mob. And this trial was recently published revealing a Both histological and clinical improvement. Therefore a Phase three trial is currently in progress biologics sometimes are an option for patients that have a topic comorbidities that are refractory to standard of care treatment or where treatment for all these comorbidities are showing several side effects for these patients. And since these biologics do affect the allergic path of physiology which is very common with other allergic comorbidities. Then they can be an option for patients. Once FDA approved other biologics that are currently in clinical trials include Ben realism mob which is in phase three trial. This is an antibody against the I. R. Five receptor alpha. I'll five receptor is present on the surface of your cinephiles and basic skills. Ben release a mob reduces Rosenfels and basic skills through antibody dependent cell mediated site of toxicity. Another trial is using layer until a mob which is currently a phase two slash three trial. And this is an antibody against cyclic eight Cyclic eight is present on the surface of your sniffles and mast cells. It reduces ear cinephiles through antibody dependent cell media site of toxicity and inhibits mass selves. Key takeaways from the talk. Oh is a chronic disease with potential long term complications. Therefore when you decide on a treatment for patients please plan and discuss with patients long term treatment options. It's important to balance efficacy with side effects of therapies. We did not discuss side effects and details today but it's important to really balance for every treatment. We choose whether it's medication or diet, the efficacy and the side effects for the individual patients. Before a shared decision is made and finally consider the age and comorbidities of the patient with the O. E. When deciding on a specific therapy. If you're still not sure what therapy option to choose. I'm closing by sharing with you here as a table the summary of the A. G. A. Institute and the joint task force on energy immunology practice parameters. Guideline recommendations on the management of E. The table in front of you lists all therapies historically considered for, with the Joint Task Force recommendation provided and the quality of evidence ranking for each. Thank you for your attention.