Two Docs Talk Allergies and Asthma

[Narrator] Welcome to MedEvidence where we help you navigate the truth behind medical research with unbiased, evidence-proven facts powered by ENCORE Research Group and hosted by cardiologist and top medical researcher Dr. Michael Koren.
[Dr. Koren] Hello I'm Dr. Michael Koren, returning for our next episode of MedEvidence, where we discover the Truth Behind the Data. Again, I have the great pleasure of being with my guest Dr. Sunil Joshi who is an allergist-immunologist and who is also a very well-known person in our community because of his work at the Duval County Medical Society and the foundation. We do appreciate that work very much.
[Dr. Joshi] Thank you, thank you!
[Dr. Koren] Terrific stuff! He's involved in organized medicine and also involved in clinical research. For all these reasons we have a great connection and we're having this really fabulous discussion about pollen and allergies. During our last segment, I talked about this “theoretical patient” who turns out to be me! This was somebody that had no problem with allergies as a teenager - in fact, he thought his friends were making up stories about allergies. Then during residency, while attending a graduation in Massachusetts, he developed symptoms for the first time: watery eyes, running nose, facial swelling, and saying “What the heck is going on here?” and not really feeling sick. We're going to start with that. Now, I admitted that this was me, so let's go back to my 26 or 27 year old self and I show up in your office and how do you help me?
[Dr. Joshi] Well, number one: if those symptoms were just a one-time thing we talk about other potential things that triggered it. But if it became a chronic illness for you then of course we're going to start looking into potential causes for your allergy symptoms. The way we do that is through allergy testing. Allergy testing is actually not as difficult as people make it out to be.
[Dr. Koren] It sounds very complicated.
[Dr. Joshi] (laughing) It's something we call skin testing. What we do with the skin testing is we take the allergen. For instance, the things that are outdoors that you may be allergic to - the different tree pollen and the protein that's associated with that tree pollen - comes from an extract company. It’s basically mixed with nothing but salt water.
[Dr. Koren] How many allergens are you testing?
[Dr. Joshi] For trees we have about 14 in Northeast Florida that can cause allergies. They're very prevalent in this area. Keep in mind that the whole Western panhandle of Florida is nothing but trees, it still really isn't developed. A lot of that pollen is coming into the Jacksonville area that's where all the fronts come from and the wind comes that way as well.
[Dr. Koren] We're here in Northeast Florida as we speak; for those listening to us from outside of our area.
[Dr. Joshi] That's right! We do have pollen from a lot of different parts of the country that come down here. So we will test for those, and the way we test is that a little bit of fluid is in a vial with a toothpick, basically. It's what we call technically a Derma pick but it looks like a toothpick. We pull out the toothpick - it has some of that fluid attached to it - and we drop that on the person's forearm. Then we use that same toothpick and scratch the skin with it. We wait for 15 minutes. A positive test is a hive like a mosquito bite and a negative test, nothing happens. That's what we call prick testing for environmental allergies. Very easy! Within 15 minutes we have an answer in terms of whether you're allergic to Oak Tree Pollen or not.
[Dr. Koren] Interesting! Now again, you obviously didn't do the testing on me back then, but given my story what would you anticipate to find?
[Dr. Joshi] Yeah so in Massachusetts at that time of the year, and since that was really kind of an isolated incident, I would expect to see a potential combination of tree pollen and grass pollen. Grass starts to pollinate in the summer so depending on what kind of season they were having you could start to expect to see grass pollinating in that June/July time period. Late May might have had a little crossover there. If it was an outdoor graduation and you're outside in grass pollen, you can expect that as well. I would have expected to see something in that tree/grass realm.
[Dr. Koren] Interesting. Any particular species of trees?
[Dr. Joshi] Up in the Northeast birch tree pollen is a very common one that causes allergies up there. They also have pine trees and oak trees, but Birch is probably the most common.
[Dr. Koren] Does that really matter from a practical standpoint?
[Dr. Joshi]  It matters in the sense of how you treat it. Of course, there are medications to treat allergies, and they can treat all kinds of allergies with antihistamines and topical nasal sprays. But if you were going to do targeted immunotherapy, then we do need to know exactly what you're allergic to because each of those proteins are different. If we're going to get you to the point where you are no longer allergic or significantly less allergic or desensitized, we would need to know if it's a birch tree versus an oak tree versus a pine tree. This is so we get the right tree pollen in there in the mix.
[Dr. Koren] Makes sense. Talk a little bit more about this desensitization process.
[Dr. Joshi] Okay! To be desensitized basically… I think there's a misnomer. People think if you're desensitized, you're no longer allergic to something. That's the ultimate goal; to develop tolerance so that you no longer react to oak trees. The reality is that what we're trying to do is minimize your symptoms, improve your quality of life, and decrease your need for medication. This is so that you can be outside during the spring pollen season and not suffer. First, we’d find out what you're allergic to: it could be your dog or cat or other things in the environment. Then we would start treatment. If you're doing allergy shots, for instance, you'd be introduced to a very small amount of that allergen mixed with salt water. It's very natural, to be honest. It starts off with such a low dose it's almost like you're getting a placebo injection initially. Each time you come in you get a little bit more of what you're allergic to until you get up to a dose that's high enough to turn off your allergies but not so high to cause an allergic reaction. If we do that in weekly increments, in our practice, it takes about 24 to 25 weeks to get up to your top dose. It takes about six months of the year, so there's a little time commitment. Once you get up to your top dose, then you don't come once a week anymore. You ultimately just come once a month for your shot and we leave the dose the same. The goal, of course, is to see how you're doing the NEXT pollen season, and then pollen season after that. It's a five-year course typically. That's not because it takes five years for the patient to feel better; instead, it takes five years for us to get as close to tolerance as possible. Anything more than that doesn't necessarily give you any more chance of tolerance, so we typically stop at five years. At that point, 85 percent of the patients are able to go forward without shots, need less medications, and have less quality of life issues.
[Dr. Koren] For life?
[Dr. Joshi] At least for the next five to ten years. These studies don't go on for too long but we know that for an extended period after stopping shots, they're able to tolerate that environment.
[Dr. Koren] So getting back to our hypothetical patients um how would you treat me?
[Dr. Joshi] In that particular case it was a one-time episode and maybe if it was persistent…
[Dr. Koren] We didn't get the whole history! It did happen periodically after that. Very seasonally and in very specific circumstances. So again, it always seemed to be in May and always during outdoor events that happened to be in bucolic grassy places.
[Dr. Joshi] Okay, got it. So this is someone, in your case you, who's suffering with late spring pollinosis or allergies. In this particular case obviously, we'd give you some information about common sense ways to avoid the allergen: taking showers when you come home, washing your hair, putting on a new pair of clothes, that type of thing. If we were looking at medications (what most of our patients want a prevention strategy) and we know that this is something that's typically going to happen to you in that May/June/July time period, we would want to pre-treat you. We would preempt your symptoms and get you on a preventative plan, in particular with topical nasal steroid spray. Some are available over the counter and some are prescription. They can be used to prevent symptoms before they start. The worst thing people do with allergies is they wait till their symptoms begin. It's much easier for us to prevent symptoms than it is for us to treat symptoms.
[Dr. Koren] It's a great point, a very very important point.
[Dr. Joshi] In all of medicine, right? In cardiology, it’s much better to prevent heart disease and treat heart disease and an allergy is the same thing. Once the proverbial cat is out of the bag (that's an allergy term, cat out of the bag)..
[Dr. Koren] (laughing)
[Dr. Joshi] Right, so once the cat is out of the bag, it's very hard to get it back in. So our goal is always when we're seeing our patients, if this is clearly a seasonal allergy sufferer, we want to get in front of the story. We want to get him controlled so that during the season they have a good quality of life. That's what my plan for you would be: to say “let's do a topical nasal steroid before the season and then have an antihistamine to use as needed kind of as your rescue through that season, and let's see how we do.”
[Dr. Koren] Yeah! I'm going to reiterate that point about early and preventative treatment because it's so important throughout medicine. There's a Chinese proverb from traditional Chinese medicine that states that a weak physician waits until the end stage of the disease before the physician treats the patient, a good physician treats people in the early stages of disease, but the BEST physicians treat people before they have the disease.
[Dr. Joshi] Absolutely, absolutely!
[Dr. Koren] I think that's a really key point. One of the crazy theories I had back then, and I love your comments on this, is that because I never had any problems whatsoever until I was a medical resident, I wondered if there was some exposure that I had during my medical training that led me to develop allergies. In particular, as a medical student or as an intern or resident you got pricked by a needle that was in a patient or got exposed to people with various diseases and you might just wonder if that was what predisposed me to this problem and why I developed it later in life. I’d be curious about your perspective.
[Dr. Joshi] It's a really good question actually and it actually gets down to the Immunology of how we fight off infections or fight off allergies. Actually, what happens a lot to us in in residency or in medical schools is that we get exposed to communicable diseases, right? Viruses, bacterial diseases, things of that sort. What happens is that our immune system develops a reaction to it, just like when you get a vaccine or you get the flu. Your immune system reacts in such a way to protect you and to protect you from the next time you get infected by that. That's what it's supposed to do, so theoretically what would happen is that if you're getting exposed to these viruses or other substances, you should actually be less likely to develop allergies because our immune system as it's developing has a fork in the road. That fork is to go forward into fighting off viruses and to developing that protective part of our immune system, or if they're not seeing viruses - like if our society is too clean and we're not exposed to viruses or parasites - then it doesn't have anything to fight here. In that case, it starts to push more towards the direction in which we fight off things that are ubiquitous in the environment; that are normally there such as dust mites, such as dog allergens, such as oak tree pollen, or even peanut allergen. Now you're starting to develop more allergies to these proteins that you're getting exposed to because you're not getting exposed to the others. The Hygiene Hypothesis states that if you are getting exposed to viruses at certain times in your life then you're less likely to develop allergies. You may have allergy symptoms because your nose runs and your eyes itch and water, but you're pushed away from that allergy phenotype.
[Dr. Koren] Wow, that is fascinating stuff! We're going to really dig into that, but one of the things I want to talk about before we dig into that is defining what an eosinophil is and where that particular cell fits into this whole hypothesis
[Dr. Joshi] The eosinophil through our training here in the United States is considered the allergy cell. Eosinophils actually through most of the world and through evolution fight off parasitic infections, in particular in developing countries. We just don't see parasites here. Eosinophils are produced in the bone marrow. They come out into the bloodstream and then they get into tissue. Here in the westernized world as they get into tissue, they release certain mediators inside of the cells that cause scar tissue to form and also bring other immune cells into the environment. This can either help heal a process or destroy the tissue. It depends on why it's there for it to have its effect. If you fall off your bike and you have scar tissue in your and you're open here (indicates arm) and you need scar tissue to form and the eosinophils come in there at that point that's doing a good thing. It's protecting you. But if it's coming into your lungs after you got exposed to diesel exhaust fumes or cigarette smoke or an allergen and it puts down scar tissue that's a bad thing. It really depends on where they're going and what they're doing in terms of whether they're positive or negative.
[Dr. Koren] Interesting! Eosinophils have this interesting way of bringing different specialists together. Here in our clinical research center, we've done studies in eosinophilic esophagitis. As a cardiologist, I've seen patients that have eosinophilic heart disease. We think that asthma is often driven by eosinophils. All these different organs are affected by eosinophils, so I really want to explore this hypothesis with you in the next segment and also how docs can work together on these things
[Dr. Joshi] Absolutely!
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[Narrator] Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts. Powered by ENCORE Research Group and hosted by cardiologist and top medical researcher Dr. Michael Koren.

[Dr. Koren] I'm Dr. Michael Koren here to host another episode of MedEvidence! I have a tremendous guest today; Dr. Sunil Joshi is joining me. He's an allergist, an immunologist, and somebody involved in organized medicine as a past president of the Duval County Medical Society and Foundation. We also have a shared passion in clinical research and have had some great discussions already about some really interesting things including the hygiene hypothesis of allergies. We're going to jump into that. We left it off in the last session talking about eosinophils.

[Dr. Joshi]  Yes.

[Dr. Koren] We were talking about the fact that they're an immune cell. They can do good or bad things and are perhaps a mediator of different allergic issues that can affect multiple different tissues. These include the GI tract - we're doing studies as we speak in eosinophilic esophagitis. It can affect the heart; it's going to feel like myocarditis. It can certainly cause asthma. Since asthma is your bailiwick let's talk a little bit about that.  Let's talk about the role of eosinophils and asthma and then some of the interesting hypotheses about who's at risk for these things.

[Dr. Joshi] So definitely eosinophils play a role in asthma. The higher the eosinophil count is in the bloodstream - if somebody gets a blood test where they just get their screening blood work done - if their eosinophils are above 300, those patients who have asthma typically have more severe asthma. Our entire population of severe asthmatics makes up about five to ten percent of all of the asthma patients that are out there. Allergists of course see a skewed population and see a lot more of all the severe asthmatics. Between 70% and 90% of them have high eosinophils in their bloodstream, so we feel that the eosinophils drive their asthma to the point where they have to be on very high doses of inhaled steroids or other combination medicines just to control their asthma, or they need to be an oral steroids / systemic steroids to manage their asthma. The eosinophils are a marker of severe asthmatics.

[Dr. Koren] Interesting. You mentioned steroids and we are running clinical trials as we speak in eosinophilic asthma. So talk just a little bit about steroids versus some of the newer ideas for treating this. Then we'll get into that a little bit more down the road, but I want you to set that up for a reason I'll get to in a second.

[Dr. Joshi] Okay! One of the things with asthma, since the more severe it is the more likely it is to be an eosinophilic disease, is we've learned through the years that steroids - whether they're topical steroids or oral steroids - do have a tendency to decrease the eosinophils. If you put eosinophils in a vat and put a drop of steroids in there they would die. So the treatment of choice to manage yeast milk asthma is topical inhaled steroids. These are steroids that go directly into the lungs, get into the tissue, and then then kind of suppress the eosinophils that are in there so that you have less disease. You have less scar tissue being laid down, less remodeling. Those tend to work. When they're not working then we have to go to oral steroids / systemic steroids. We know that if patients who have severe eosinophilic asthma go on oral steroids their eosinophils in the bloodstream drop at the same time that their symptoms improve. The steroids decrease the eosinophils in their bloodstream as well. The problem of course is that steroids are not safe. If you're on oral steroids at least two times a year or more you have a three times increased risk of having a bone fracture or a blood clot or even having sepsis - bloodstream infections. Let’s also mention the long-term consequences of diabetes, osteoporosis, glaucoma, and cataracts that can be associated with steroids. The topical steroids are much less likely to do that. In fact, when using the recommended doses correctly, it would take somebody five years of using an inhaled steroid to equal one five-day course of an oral steroid. But if the inhaled steroids aren't working that's where we're left with “what do we do now?” and we typically have had to do oral steroids.

[Dr. Koren] Explain a little bit more the difference between eosinophilic asthma and other forms of asthma and the use of steroids or other medications.

[Dr. Joshi] Eosinophilic asthma makes up the majority of severe asthmatics, almost up to 90 percent of them. The steroids (inhaled steroids and topical steroids) do have a tendency to work a lot better in these folks. In folks in which their asthma is not driven by eosinophils, they're typically then driven by what we call neutrophils which are other forms of white blood cells. In these patients, the inhaled steroids and oral steroids don't work nearly as well. They almost have more of a picture of a COPD patient or maybe a smoker - but in this case, they don't smoke and they happen to have asthma. We're still using topical steroids but in their cases, we're going to use more bronchodilators and more of what we call muscarinic antagonists. These actually prevent the bronchial areas from producing phlegm and mucus which also complicates these patients' symptoms. We call this triple therapy for these folks. These are going to be more likely to be effective than higher doses of inhaled steroids. Those are even more difficult to treat because we don't necessarily have great treatment for the neutrophilic asthmatics.

[Dr. Koren] Do we have ways of going at the eosinophils more directly than steroids?

[Dr. Joshi] Absolutely we do! That's one of the great things you know with the advances in medicine and in particular in immunology. We understand what the mediators are that drive eosinophils to come out of the bone marrow, survive when they're out of the bone marrow, and then go from the blood into the tissue. We could target a bunch of different areas to prevent that. There are specific targets to specific receptors that can help kill eosinophils, stop their survival and production in the bone marrow, and also some that prevent them from getting from the bloodstream into the tissue as well.

[Dr. Koren] Are any of these on the market?

[Dr. Joshi] Yeah, they are out there on the market and we use them routinely in our patients who qualify for them. There are some that block a certain inflammatory mediator that brings eosinophils out of the bone marrow, called IL-5. It blocks it directly and it also can block that receptor on the cell. Then there are some that actually block the ability of the eosinophils to get into the tissue by decreasing certain proteins that come onto the cell that drive it into the tissue. There's some out there that decrease the eosinophils without us having to use oral steroids.

[Dr. Koren] Interesting, interesting. Are these types of drugs equally good at treating eosinophilic asthma and other eosinophilic diseases? Do we know that yet?

[Dr. Joshi] Well and that's where the clinical trials come into play! 

[Dr. Koren] I knew they would come into play at some point.

[Dr. Joshi] Yeah! They come into play. Obviously, the ones that are on the market for asthma do help to decrease exacerbation rates and some of them help to decrease the need for oral steroids as well in these patients. There are some that also work for chronic sinusitis that have eosinophils disease which is called nasal polyps. There are a few that are approved for that as well. But there are other disease processes we have to look at. You were mentioning the eosinophils in the esophagus, but even just high levels of eosinophils in the bloodstream are not good for the body because they can start to attack these other organs such as the heart, the skin, the lungs, and the kidney. There's some agents that just can reduce the eosinophils in the bloodstream as well.

[Dr. Koren] Interesting. In your opinion, is the future of dealing with these issues going directly at the bone marrow, or more tissue basis, or somewhere in between?

[Dr. Joshi] Well, where do the eosinophils cause the problem? They cause the problem in the tissue. So ultimately the goal for the patient is to be better no matter what the case is. But the goal is for us to try to diminish the adverse effects of the eosinophils. Where do they have their adverse effects? In the tissue. Whether that's in the sinus cavity, in the lungs, in the heart, or on the skin, that's where they do their damage. If we were able to develop treatment options that could prevent the eosinophils from getting into the tissue or them while they're in the tissue, then we're winning the game.

[Dr. Koren] Gotcha. For these types of eosinophilic therapies are they pills or injections and how frequently do you get them?

[Dr. Joshi] Typically the ones that are on the market right now are injection therapies. There are some that target the eosinophils directly and are taken every month and there's one of the agents that's done every other month. We typically ask these people to come to our office to receive these injections, but they can do them at home as well; the FDA has approved that. There's also an agent that actually blocks the eosinophils directly from coming into the tissue that's done every two weeks. These are subcutaneous injections so they're not IV and they're not going into the muscle. They're just going into the subcutaneous fat; almost like a diabetic needle.

[Dr. Koren] You mentioned interleukins and things that block interleukins. I'm not an allergy or immunologist but I can explain that those are our protein signals that amplify the immune system, such as eosinophils in this case. Can you comment a little bit more on how that works in terms of therapies? Are we doing direct poisons to the eosinophils or are we blocking the mechanisms to amplify their numbers or their effects?

[Dr. Joshi] We're doing both! One of the interleukins is IL-5 and this molecule is important for the eosinophils to develop in the bone marrow, come out of the bone marrow, and come into tissue. There's an agent that blocks IL-5 directly. As it blocks IL-5 directly it can reduce eosinophils in the peripheral bloodstream by 75% within two days. 

[Dr. Koren] Wow!

[Dr. Joshi] A significant decrease! There's another agent that actually blocks the receptor for IL-5 which is found on the eosinophil itself. As it blocks that receptor IL-5 the body recognizes it and kills the eosinophils.

[Dr. Koren] Oh wow!

[Dr. Joshi] So these eosinophils come out of the bone marrow but then are killed because of this particular agent. You target the IL-5 directly, which is important for eosinophil survival, or you target the receptor for IL-5 so the IL-5 can't do anything for the eosinophils and the body recognizes to kill it. Two different ways to reduce eosinophil count.

[Dr. Koren] Fascinating! How long does that treatment last? Is it recurrent? Give us a little insight into that.

[Dr. Joshi] You do need to do the treatment once a month if you're blocking IL-5 directly. If you're actually killing the eosinophils that particular agent is used every two months.

[Dr. Koren] Is this something that people are committed to for life? How long is a typical course?

[Dr. Joshi] That's a good question. We don't modify the progression of the disease with these agents. When you stop it, theoretically, the symptoms should come back. We hate to tell people that they're going to be on something lifelong. Each doctor is different and, anecdotally speaking, my patients want to come off of drugs once they're better. We come to an agreement that will do this for a year or maybe two to get you really well controlled. Then we can try to slowly back off of the agent, understanding that each patient is different. Not every patient fits what we see in the studies and there may be some patients who, instead of needing it once a month, might be able to get away with it once every three months. Maybe some could even stop it completely. Their eosinophils count may come back up, but if we're able to manage their disease (remember we're treating the patient) and they're better, then maybe they don't need the agent anymore!

[Dr. Koren] Interesting, interesting. We are, as you mentioned, doing clinical trials in this area and using these types of products. Are there any snippets that you can share? For example, people who were being treated for the eosinophilic disease in one realm seem to get benefits in another realm? Give us a little sense about this crossover phenomenon.

[Dr. Joshi] That's a great question. Obviously, we medical professionals are to use drugs for what they're intended to be used for. But sometimes we have hopes that it'll help with something else, right?

[Dr. Koren] Exactly!

[Dr. Joshi]  So we see that! Absolutely, I've seen that in my patients. The very first patient that I put on an anti-IL-5 drug was a lady who had severe eosinophilic asthma, but also had chronic sinus disease and had eosinophilic esophagitis. 

[Dr. Koren] Interesting.

[Dr. Joshi] We really needed to help her asthma out. She was requiring oral steroids very frequently, she was interested in something that was not steroid-based and we got the drug approved for her. We reduced her eosinophil count very quickly. Her asthma got better, but suddenly she was swallowing better too! She was having much less acid reflux and much less heartburn. Then about a year into treatment she went to go see her GI for her regular upper endoscopy and the eosinophils were gone!

[Dr. Koren] Wow!

[Dr. Joshi] Now her asthma is really well controlled and I haven't had her on steroids in about three years. I'm thinking about backing off on the agent but she doesn't want to stop it because it's helped her heartburn. Her eosinophilic esophagitis has gotten better and she's like “no I don't want to stop it!” That's just an anecdotal example but there are other people with similar things with their sinuses and their skin as well.

[Dr. Koren] That's fabulous! I love that anecdote and we're gonna go into this concept of cross fertilization of different disease processes in our next segment.

[Narrator] Thanks for joining the MedEvidence podcast. To learn more head over to medevidence.com or subscribe to our podcast on your favorite podcast platform.

[Narrator] Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts. Powered by ENCORE Research Group and hosted by cardiologist and top medical researcher, Dr. Michael Koren.
[Dr. Koren] Hello, I'm Dr. Michael Koren here hosting another episode of MedEvidence where we discuss the Truth Behind The Data. It's been a pleasure. We’ve had multiple sessions and a great conversation so far. This is Dr. Sunil Joshi. He’s an allergy immunologist and is also very involved in organized medicine. Thank you for your service as past president of the Duval County Medical Society and Foundation.
[Dr. Joshi] Thank you.
[Dr. Koren] We do appreciate that, on behalf of all Physicians. Dr. Joshi is a community leader and somebody that's interested in clinical research so he’s a soul mate in that area. We've been having a really fabulous discussion about allergy and Immunology new drugs, the evil eosinophil, and how we calm that evil eosinophil, and also alluded to some of the clinical research that we're doing. We actually left off our last session talking about how eosinophils can have effects in different organ systems. You shared with us a great case of somebody that you were treating for eosinophilic asthma who also got tremendous benefits from her eosinophilic esophagitis.
[Dr. Joshi]  That's right!
[Dr. Koren] What a cool case.
[Dr. Joshi] Yeah and there's so many more like that too. That one stands out because I wasn't even sure it would work. She was the first patient I was using one of these agents on and it worked in multiple areas.
[Dr. Koren] So more broadly this gets the idea of the immune system and its impact on different diseases that we don't necessarily consider immune diseases, but maybe they are. We were just talking about diabetes. Type 1 diabetes is probably autoimmune based.
[Dr. Joshi] Oh it is absolutely autoimmune based.
[Dr. Koren] What's interesting is that there's some theories that get into your hygiene theory that you're talking about that suggest that people that are more exposed to pathogens and viruses, including southern people, are less likely to have type 1 diabetes than people who grew up in the north. Do you want to comment?
[Dr. Joshi] That's the perfect example. As we talk about a hygiene hypothesis, some autoimmune diseases are actually driven by the part of the immune system that fights off viruses and bacteria, but type 1 diabetes is actually not. It's actually down that same path similar to allergies and igG4 processes. It makes perfect sense that people who are exposed to more viruses in warmer climates, who may even have some parasitic infections in the mountain regions, versus folks who are not as exposed in the colder regions (at least traditionally before climate change) would see that difference in overall disease processes. This includes autoimmune diseases such as type 1 diabetes.
[Dr. Koren] In my area of cardiology there's a lot of talk about inflammatory cells and how they affect atherosclerosis. It's believed at this point in the atherosclerosis hypothesis that macrophages in particular and other inflammatory cells are very very important in terms of progression of a coronary heart disease and other forms of atherosclerosis.
[Dr. Joshi] Oh, absolutely. It makes sense, too. That's why in cardiology you guys now have markers of inflammation that help you determine somebody's risk of heart disease like the CRP and things like that. Again it all comes back down to inflammation in the immune system.
[Dr. Koren] We know for example that folks that have rheumatoid arthritis have a higher risk for cardiovascular disease and other things where your immune system and your inflammatory system are revved up over extended periods of time.
[Dr. Joshi] The overdrive of the immune system. We probably don't even know half of what it is doing to our bodies.
[Dr. Koren] We're just really in the infancy of this. The other thing you mentioned in the previous segment that I thought was fascinating is that we actually have a fair number of drugs already out there that target the eosinophil and other elements of the whole inflammatory cascade. There are drugs that will tame that eosinophil. I'm very curious, with a lot of these new drugs they're very expensive and I'm sure there's some sort of prior authorization process. Tell me how you decide to go from sort of standard antihistamine steroids to these more sophisticated therapies and then go into a little bit of the process.
[Dr. Joshi] Okay, great question! When the standard therapies have been working for 30 or 40 years why do we jump to biologics? We don't jump to biologics! If a patient is doing well with a standard of care that we would typically do for an asthmatic; if they're able to have a good quality of life, if they're not having exacerbations two or more times a year; or they're not needing systemic steroids, there would be no reason to jump to a biologic. It's when they're not doing well with that standard of care and continuing to fail that we start thinking about biologics. Based on certain biomarkers, certain biologics would be more likely to be the ones that we would go after. Those biomarkers might be the eosinophil count, something that we measure called exhale nitric oxide in a breathing test, or even an allergy antibody level. These help us decide what biologic agent we choose. There is definitely prioritization needed for all of this. In our office, we have a full-time employee whose only job is to try to get these medications approved for these patients. The reason for that, and you can't blame the insurance companies, is that these medications are in the three to four thousand dollars a month range - maybe even higher than that for some of the newer agents. It's very very expensive, so they want to have proof as to why the patient needs the drug. We have to provide that proof to them and then they approve it. Further, just because the insurance company approves it doesn't mean the patient doesn't have to pay for it. The patient may have a high copay, they may have a high coinsurance or they might be a Medicare patient who's now in their donut hole. So suddenly patients, even with a 20% coinsurance, are paying $800 a month for this drug.
[Dr. Koren] Wow.
[Dr. Joshi] It becomes cost prohibitive. Then we have to go through all of the processes to see if we can have them qualify for some rebates from the drug company, etc. to make it more cost effective.
[Dr. Koren] So it's become complicated to get these new sophisticated, wonderful drugs. They do things that we couldn't even imagine a few years ago, but they are very costly. There's been a lot of research and development of course that has to be recaptured by the companies that develop them and it's tough on some patients.
[Dr. Joshi] It is, and it's tough on us as providers too because we know we've got this potential treatment option. It takes us time to have that discussion with a patient to the point where they're now ready to do a biologic. It takes a while to convince them they need to take that step, but then after that the cost comes in and it's another battle we have to fight, unfortunately.
[Dr. Koren] Right, right. That actually gets into one of the rationales for participating in clinical research. There are a lot of reasons why people like clinical trials. One of my favorite things to quote is if you ask the random person on the street whether or not they'd be interested in a clinical trial 40% say yes, both in North America and Europe. That's the general sense of being supportive of clinical trials if they've had no exposure. Once they've been exposed - if you've been in a clinical trial - and you ask the patient “would you do another one,” the positive rate is 97 to 99.
[Dr. Joshi] Wow!
[Dr. Koren] So there's something about the process that people really enjoy, that makes them feel fulfilled.
[Dr. Joshi] Yeah, yeah. 
[Dr. Koren] Part of that could be getting access to medicines that they wouldn't have access to otherwise. This could be either because they're not exactly available for them, because they don't quote “meet the indication” for that medicine,  or because they can't afford it. I'm sure you've had that experience in the clinical research realm.
[Dr. Joshi] Oh, absolutely! I think there are multiple factors. I definitely thought that it would be lower than 40%, to be honest with you.
[Dr. Koren] Europeans are actually a little bit lower than Americans.
[Dr. Joshi] Okay, very interesting!
[Dr. Koren] Americans tend to be a little bit more optimistic.
[Dr. Joshi] That's good, that's good! When people actually enroll into a trial I think they realize how easy it is. Number one: they just show up. Number two: in most of these trials just because they're actually interacting with a nurse or healthcare provider or professional about health in general, they focus on their own health a little bit more. So the placebo effect of these trials is pretty high just by the fact that they are interacting with someone who's now talking to them about their health and they don't have to pay for it. Not having to pay for a drug that could cost up to three thousand dollars a month also would make me want to be part of that clinical trial network as well. There's that percentage of patients who want to contribute to science of course on top of that. If you could do all of that, get that benefit and feel better at the end of the day, of course that would be a great way.
[Dr. Koren] Legacy is a big issue also. A lot of people do it because they don’t want their kids to have to deal with the same thing. There's probably some genetic components to some of the things that you deal with.
[Dr. Joshi] Yes there are. So if patients can help us understand what treatments and diagnostic factors can make a difference then it does help other people coming behind them; in particular their offspring.
[Dr. Koren] Absolutely, absolutely. Talk to us a little bit about the clinical trial that's going on here in Northeast Florida using an oral agent to knock off those evil eosinophils. tell us a little bit about it.
[Dr. Joshi] We've been talking about agents to treat eosinophils that are injection therapies. Most patients would want something simple, something oral. There's a drug that has been studied for ALS amyotrophic lateral sclerosis, otherwise known as Lou Gehrig's Disease. It’s a horrible disease and there's so much research looking for ways to prevent progression of that disease. There was a drug that was out there aimed at it and unfortunately, it didn't work for ALS. But what they noticed as they were checking blood on these folks is their eosinophil accounts were dropping 
[Dr. Koren] Interesting.
[Dr. Joshi] This is without very many other side effects of note. The eosinophil counts were dropping. So here we have disease processes where we're targeting eosinophils with injection therapies and now there's this potential drug that decreases eosinophils too. The question is, if we are able to decrease the eosinophils in the bloodstream, will that help them with their asthma? It's helping them with these other biologic agents, but if it's an oral agent it certainly would be more convenient for the patient. It’d be something they could do at home with a relatively low side effect profile. Wouldn't that be amazing! One study led to another that might help us with another debilitating disease.
[Dr. Koren] That's interesting. When it was first being proposed as a treatment for a neurological disease was it through the eosinophilic mechanism?
[Dr. Joshi] No! I think it was through a mechanism to reduce a certain protein that's involved with ALS and the eosinophils somehow got implicated as something that was dropping as a result of this drug. We don't 100% understand the mechanism of how this drug reduces eosinophilia like we do with these other agents (when talking about IL-5, etc.) we just know that it does. So we’ll see what the outcomes are.
[Dr. Koren] Interesting. That's one of my favorite parts of clinical research when you discover something you had no idea that you would discover.
[Dr. Joshi] Right! 
[Dr. Koren] You're going down one road and if you keep your eyes open you'll find something that may help people in another area.
[Dr. Joshi] That's what makes research fascinating.
[Dr. Koren] One of you know one of the classic examples of that is Viagra.
[Dr. Joshi] Yes!
[Dr. Koren] Viagra was developed as a treatment for coronary artery disease, and with the concept that it was a phosphodiesterase inhibitor and it helped dilate arteries and all this sort of thing. It didn't work very well for angina, but they couldn't get the study drug back from the men that were in the trial. They tried to figure out “what the heck is going on here?” One thing led to another and they found out their sexual function got better. It went from a possible cardiac drug to a drug for erectile dysfunction.
[Dr. Joshi] Amazing.
[Dr. Koren] So you never know how things will twist and turn.
[Dr. Joshi] That's right! Then you have to go down that road if it can help people. You go down that road, it's all about quality life, and in this case it may be about disease progression too.
[Dr. Koren] Yeah. Well Sunil, I've learned so much from you. Thank you very much for being here, thank you for being a guest on MedEvidence and it's fascinating. We'll definitely have you back on another topic and thank you for sharing your wisdom with our audience.
[Dr. Joshi] My pleasure, I love talking about allergic diseases! Like I said, I could talk about this for two or three days straight.
[Dr. Koren] Absolutely. That will be our marathon session, stay tuned.
[Dr. Joshi] (laughing) 
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