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Welcome to “Allergic Rhinitis Navigating Options for Individualized Patient Care.”

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The faculty members for this activity are Jonathan Corren, MD, a Clinical Associate Professor of Medicine and Pediatrics at the University of California, Los Angeles Private Practice in Allergy and Clinical Immunology at Allergy Medical Clinic and Medical Director, Allergy Research Foundation, Inc. in Los Angeles, California. Denis Yoshii, DO, Allergy and Asthma Institute Medical Center of Southern California and Assistant Professor at the University of California, Irvine in Costa Mesa, California and Carman Ciervo, DO, Chair and Associate Professor of Family Medicine School of Osteopathic Medicine at the University of Medicine andMedicine School of Osteopathic Medicine at the University of Medicine and Dentistry of New Jersey in Stratford, New Jersey.

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The learning objectives for this activity are:Define the epidemiology, pathophysiology, clinical presentation, and diagnosis of allergic rhinitis Explain the impact of allergic rhinitis on patients’ quality of life and variations between physician awareness and patient-perceived treatment outcomesAnalyze and apply recent evidence-based pharmacologic treatment for individual management of patients with allergic rhinitismanagement of patients with allergic rhinitis

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This activity is sponsored by the American College of Osteopathic Family Physicians (ACOFP) The activity is supported by an educational grant from UCB Inc. and sanofi-aventis US, LLC.

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Disclosure of Financial Relationships and Discussion of Off-label UsesDr. Ciervo has indicated that he or an immediate family member has a financial relationship or interest with a proprietary entity producing health care goods or services through speakers’ bureaus for sanofi-aventis. He has indicated that he will not discuss unapproved or investigational uses of products or services.Dr. Corren has indicated that he or an immediate family member has a financial relationship or interest with a proprietary entity producing health care goods or services through research grants from AstraZeneca Pharmaceuticals LP speakers’ bureaus forresearch grants from AstraZeneca Pharmaceuticals LP, speakers bureaus for GlaxoSmithKline, Schering-Plough Corporation, AstraZeneca Pharmaceuticals LP, and Amgen, and consultant fees for AstraZeneca Pharmaceuticals LP. He has indicated that he will not discuss unapproved or investigational uses of products or services.Dr. Yoshii has indicated that neither he nor any member of his immediate family has a financial relationship or interest with any proprietary entity producing health care goods or service. He has indicated that he will discuss unapproved or investigational uses of products or devices specifically saline lavage for treatment of allergic rhinitis combinationproducts or devices, specifically saline lavage for treatment of allergic rhinitis, combination therapy of fluticasone and azelastine, and the use of topical budesonide for allergic rhinitis.The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Innovia, the ACOFP, CECity, UCB or sanofi aventis US LLC. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity

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matter before relying solely upon the information contained within this educational activity.Thank you for participating in this activity.

Dr. Jonathan Corren: Thank you for that very kind introduction and welcome everybody. I know it’s a hard choice between outside and inside, so thank you for being here. We are going to try to take the last 20 years of research in the field that I specialize in allergy immunology and compress it into the next 20 minutes. So having said that, this will be a challenge so hold onto your seats because this is going to be a rollercoaster ride through really a lot of condensed basic science information that we have accumulated over the past couple of decades and what I am going to be talking about in this introductory lecture is really what makes allergyam going to be talking about in this introductory lecture is really what makes allergy tick.

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So what we are going to do is get start off with an appreciation for really what is the impact of what is seemingly a trivial disease on both individual as well as society at large? We are going to go through some of the major environmental factors that actually contribute to the development of what we know as allergy. And then finally, we are going to highlight some of the pathogenetic events and here we are going to get into the actual roles of the mediators and the cells and paint this picture in such broad strokes that you will be able to leave here today with an understanding of why we use the drugs that we use to treat allergic rhinitiswe use the drugs that we use to treat allergic rhinitis.

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Now before we understand how a disease works, we have to have some appreciation for what is the disease and here we will start up with an identification of rhinitis and rhinitis is really a syndrome there is non allergic rhinitis there is allergicwill start up with an identification of rhinitis and rhinitis is really a syndrome, there is non-allergic rhinitis, there is allergic rhinitis. We will be getting into some of that differential diagnosis with the coming lectures, but we will start with the idea that there are certain cardinal symptoms such as nasal congestion, postnasal drip, watery rhinorrhea, sneezing, itching, all these sorts of things that if you have any one of these symptoms on a consistent basis, you can claim that this patient does in fact have chronic rhinitis. Now what we have learned over the past 10 years is that about half of the patients with rhinitis claim that a stuffy nose is their most bothersome complaint. A nasal congestion turns out to be one of the more difficult symptoms to treat. There are some other things that go along with this constellation, particularly in allergic rhinitis. With all the nasal things that are going on, we can have itching not only of the nasal structure, but of the eyes, the ears and the palate. And I think this itching that we see in many of the patients with allergic rhinitis is probably the best hallmark that the patient is allergic rather than some other undifferentiated cause of their rhinitis. Along with th di l t th th h th t h ld thi k b t b th ti l thithese cardinal symptoms, there are some other phenomena that we should think about, because these particular things can very strongly affect the quality of life of patients, who have allergic rhinitis and this would include things such as the sense of smell, this is much more affected in nasal polyposis, but it can be affected in allergic rhinitis as well and once smell is gone, so goes the taste. Headaches occur in about half of the patients, who have chronic allergy and are probably more common in allergic rhinitis and they are even being in sinusitis. And then finally, this issue of facial pressure and the issue of cough, and the cough which is due to postnasal drip primarily again can mimic other problems like chronic sinus disease and even bronchial asthma.

Dykewicz MS, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998;81:478-518.Lerrick AJ. A prospective, open-label evaluation of azelastine (Astelin®) nasal spray for the treatment of seasonal allergic rhinitis and perennial nonallergic (vasomotor) rhinitis. Today’s Therapeutic Trends. 2003;21:215-226.Lieberman PL, Kaliner MA, Wheeler WJ. Open-label evaluation of azelastine nasal spray in patients with seasonal allergic rhinitis and nonallergic vasomotor rhinitis. Curr Med Res Opin. [in press].

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Now the epidemiology of allergic rhinitis has literally exploded over the past couple of decades and we are going to be talking about that in more detail when we get into some of these issues of why allergy prevalence has increased so much over the past decade or two. But we know always that it affects a large number of people probably about 20% of adult patients, upwards of 30% of children, talking about tens of millions of people. And the prevalence as it is increased has affected literally every segment of the population and here we are looking at the actual statistics as to which distribution affects which age group We can see that it tends to come onto which distribution affects which age group. We can see that it tends to come on around age 3 to 5 very often, takes 3 or 4 seasons of exposure to allergy for the immune system to begin to react. But then we see that we continue to have proportion of people that are affected in every single quadrant of age even in people who are over 65 years of age and most of those people have developed allergy in an earlier time in life, but even in people of 60s and 70s you will see the novel allergy developed for the very first time, which is unusual, but it’s something that we should always look for in people who present with new onset postnasal drip and cough and other sort of nasal symptoms.

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Now, as if it wasn’t enough to have a cold that never goes away which is tantamount to what allergic hi iti i th b f i t t biditi hi h ff t th b t ti l ti frhinitis is, there are number of very important comorbidities, which affect the substantial portion of

patients who have allergy and this starts with bronchial asthma. About 90% of patients with asthma have concomitant nasal allergy and if you flip the coin over, about 25% to 50% of patients with allergic rhinitis have concomitant asthma, so it's a cofactor in that disease. In otitis media, any child who continues to have ear infections after the age of 3 should be suspected of having possible allergy and about 50% of those patients will have a component of allergy in the recurrent otitis media or otitis media with effusion. Both chronic sinusitis as well as recurrent acute sinusitis are very heavily contributed to by allergy and it's again about 50% of patients where allergy plays a significant role. Now something we often don’t think about but it is a child who ultimately goes on to develop braces, orthodontic appliances and it's these maxillofacial abnormalities that are very heavily weighed upon by a child who has to constantly breathe through their mouth at night and it's that pattern of air flow, which causes a high-arched palate, a recessed mandible and ultimately the need to straighten the teeth particularly if there is an overbite or underbite because of the influence of allergy. And then finally, we are left with something that we often don’t think about and that is the impact psychologically that both allergic as well as non-allergic rhinitis can have upon patients. And this starts with something like fatigue, people are tired because they don’t sleep well at night, they may wake up multiple times at night, what we call microarousals or they may full blown sleep apnea by virtue of having allergic rhinitis. It turns out that somewhere, there is an odds ratio of 1.5 to 2-fold increase for both anxiety and depression in patients who have concomitant allergy. We previously believed, well it must have been the Diphenhydramine that made them feel lousy, but now we know that there are chemicals released during allergic reactions, particularly tumor necrosis factor-alpha interleukin-6 amongst others that make people or cause them to feel certain ways such as anxious or depressed. Then finally something that’s important and again we don’t think about often is what is the impact of this upon a child in school who is learning or for that matter an adult who is in a setting

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p p g gwhere they constantly need to assimilate new information. And I think this is again an issue, where allergy has been shown to play a very important role.

Now if we take all of these conditions both of those related to the direct symptoms of allergies as well some of these comorbidities, it turns out that there is a huge impact on quality of life. What we are looking at here, our quality of life domain using a standard SF-36 Quality of Life Questionnaire. We are comparing patients with allergy and call it fuchsia versus normal patients, who have no chronic condition in yellow. And what we find out is that many of the domains, particularly a sense of feeling chronically ill is very heavily affected by the appearances of nasal allergy and if you compare patients with rhinitis versus bronchial asthmatics it turnsallergy and if you compare patients with rhinitis versus bronchial asthmatics, it turns out that the detriments to quality of life are actually worse in patients with nasal allergy than those who have full blown asthma, so this is a disease with heavy impact and heavy effects on life.

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If you take all of these issues and add them up financially and this is an area certainly that insurers think about particularly when we are looking at things like Pay for Performance, it turns out that about $3 billion are spent annually to treat this disease and this combines both medications and doctor’s visits. If you then go in and you take the comorbid conditions, you add another component in the billions of dollars. And then when you look at the actual indirect effects of the disease, which would be things like absenteeism, it turns out that nearly 4 million days of worker loss per year a similar number for school But we don’t leave it at that because itloss per year, a similar number for school. But we don t leave it at that because it turns out that not only is absenteeism an issue for patients who have a chronic stuffy nose due to the rhinitis, but presenteeism and this is a concept that deals with the productivity of the worker in the workplace due to a concomitant medical condition. And because of the distractions that are brought upon by this disease, where people are constantly touching their nose and blowing their nose and feel sleepy from the disease, they maybe at work, but they don’t function as well and their productivity consequently drops significantly. So we can roll all of these up and if we were to speak to the people at Medicare administration, I was just alluded to by one of our introducers that certainly, I think this substantiates cause for concern on a national level because of this allergic condition.

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Now, I promised you that we would take 20 years of research into pathophysiology and we would try to wrap it up into a nice clean bundle, so that you would leave today with some understandings of what is the immunology of allergic rhinitis. And if we go up into that far left-hand corner, we start off with the first event that must take place in order for an individual to develop all these symptoms with subsequent allergy exposure and that is a phase called sensitization which is the development of IgE, which binds to mast cells and triggers a reaction. Now with subsequent exposures that are transient we end up with what we would call an acuteexposures that are transient, we end up with what we would call an acute inflammatory event, which is largely due to the release of mediators. We are going to explore all of these events individually and understand them better. And then finally, we go from the acute inflammatory event, which is following a transient exposure to chronic inflammatory disease of the nose, which is akin to the actual disease itself and this is much more due to the presence of inflammatory cells that are ingressed into the membrane and now reside there and cause this list of problems that we have been talking about.

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Sensitization, which is the first step in this entire process, requires that the B cells in the blood and the lymph nodes and in the local tissue to start to churn out an IgE molecule that is specific for a certain allergic trigger. So if you walk into a room where there are three cats, the trigger is Felis Domesticus, one of the major cat allergen or if you go into a room a typical room where a premedical student might live, there is lots of Dermatophagoidesfarinae, which is one of the dust mite allergens. So the body has the ability to make this IgEas a consequence of certain things that must be met, prior to sensitization, this begins at the level of the genotype. We know there are somewhere between 10 and 20 genes

h ll f th diff t l i ti diff t f t f th i fl tperhaps more, all of these different loci creating different facets of the inflammatory reaction. If one parent is allergic maybe a 30% to 40% chance that the child will be, if you have two allergic parents, it goes upwards to 50% to 60% and we know that genes are important to this. But there are early life events that regulate our immunologic balance and this is one of the things I am going to expand upon and talk about momentarily of how exposure to things like viral infections and endotoxins are so important. Certainly, you can't become allergic to dust mite allergen or cat allergen or any other allergen for that matter without enough exposure early in life It turns out that if you have exposure from the firstwithout enough exposure early in life. It turns out that if you have exposure from the first day of life, this may actually help bring about tolerance but exposure after 6 to 12 months of age is probably the more critical period and this is something we have learned from looking at studies of animal allergy. Dietary factors, I believe are very important and if we look at this epidemic of allergy and asthma that’s occurred throughout the world, we see certain patterns where populations that are deficient particularly in Vitamin C, D and E maybe more prone to the development of allergy. And then finally, this discussion would not be complete if I didn’t mention the role of air pollution and this is one of the other areas that I am going to

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if I didn t mention the role of air pollution and this is one of the other areas that I am going to expand upon in the coming minutes.

Now what are these events that occur early in life? When we are born if you were to take a sample of cord blood from that infant, you would find that there are two different types of CD4 Helper Lymphocytes that are present. There are Th1 cells which are instrumental to delayed-type hypersensitivity for just fighting microbacterial infections and to viral immunity. And we find that there are certain cytokine characteristics of those cells and you are looking 3 GM-CSF, interferon-gamma in contradistinction to Th2 cells, which we believe are important in history for the fighting off parasitic infections and perhaps still in certain parts of world thatfor the fighting off parasitic infections and perhaps still in certain parts of world that is true, but they seem to play their biggest role in causing allergy. And when you look at what happens during the first few months of life, if children encounter endotoxin or viral infections, they will shift away from a CD4 Th2 predominant pattern to a CD4 Th1 pattern.

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And if we look at what that looks like in a very simplistic cartoon, we find that Th2 cells predominate and if children are around particularly gram-negative bacterial products, as many people are in the developing world, where there are large livestock nearby the house, manures used as fuel, there is a lot of endotoxin, viral infections are more prevalent and we shift it over to Th1, but in children who get lots of antibiotics and grow up in the proverbial bubble, as we tend to do in more westernized societies, where there are not large families children may not be in daycare And we see a persistence of this Th2 type subtype along with thedaycare. And we see a persistence of this Th2 type, subtype along with the development of Th1, so these people are not Th1 deficient but they are Th2 surplus, which leads to development of allergy.

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Air pollution is an issue, when you go back into the 1950s in Japan, which was the cusp of their allergy epidemic, it turns out that you didn’t find much atopic dermatitis, asthma or rhinitis. And if you go back through the previous decades in the medical literature in Japan, it was not until the introduction of diesel fuel in their buses that you began to see this outcropping, large amounts of patients beginning to develop atopic dermatitis and other allergic diseases. And some work from a laboratory near my office, Andy Saxon’s lab at UCLA has shown that air pollutants maybe very instrumental in switching on the allergic geneinstrumental in switching on the allergic gene.

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And let’s go into Dr. Saxon’s lab and look at a nose, just a nose, no body attached to the nose that was exposed to nasal allergen challenge and if you do it with the allergen alone and this isn’t people who are not sensitized to the allergen being challenged with, that you end up making an IgG type protein, which will not bind the mast cells and will not trigger an allergic reaction, but if you add diesel to that, mix in a few diesel particles, put it into the atomizer, within a few weeks you will develop IgE protein and it’s these IgE molecules that subsequently are responsible for the allergic reactionsallergic reactions.

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So we have sensitization, let's take that patient who now has IgE, spray a bit of allergen into their nose or simply put them into a room where there is a lot of cat allergen.

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In that mast cell, which is now on with IgE molecules will bind nicely to this little yellow allergenic epitopes. And we have two things that go on in quick succession, we have it immediate within minutes to granulation of the mast cell, where you are getting both histamine as well as other preformed mediators such as heparin and within about 10 to 15 minutes, we begin to get preformed or excuse me, you will get newly synthesized mediators from the lipid membrane and these are things like cysteinyl-leukotrienes and prostaglandins and platelet-activating factor.

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Now if we look at the mediators in allergic rhinitis, the first thing we always think about is histamine and histamine is critical because it does a couple of things. It does cause vascular leak, which causes edema of the airway immediately, but it also causes triggering of neuronal reflexes and those are responsible for the sneezing and itching that bothered people within minutes of allergenic exposure. Most of the histamine comes from the mast cell or the basophil which comes in later, I am going to swing over here as we look at some of these things. And if we then move down to the cysteinyl-leukotrienes which are these synthesizedthen move down to the cysteinyl-leukotrienes, which are these synthesized mediators, the major source are the mast cells as well as the eosinophils that come in much later, these mediators primarily cause edema, but may also cause perpetuation of the allergic reaction by bringing eosinophils in subsequently. And then finally, something we often don’t think about is being part of allergy the prostaglandins, predominantly prostaglandin D2, which also causes edema and is released from mast cells.

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If we look at the late-phase nasal allergic response, we have now elaborated and elicited all of these factors, but some of these including leukotrienes and platelet-activating factor and eotaxin, we are over the insulin hours bringing lots of inflammatory cells. And this is all in your handout, we have eosinophils, we have basophils and we have lymphocytes and you can see that there are number of very important mediators. The eosinophils releasing both cationic proteins like ECP as well as leukotrienes, we have basophils primarily histamine and cysteinyl-leukotrienes and then very interestingly the lymphocytes which are really theleukotrienes and then very interestingly the lymphocytes, which are really the orchestrators of the subsequent chronic disease that develops in these patients.

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So the actions of the late-phase mediators, once all of those cell populations are in the nasal tissue, are very responsible for releasing something called cytokines and these cytokines I think are very unique to both the late-phase reaction as well as development chronic inflammatory nasal disease. With Interleukin-4, what I want you to remember about Interleukin-4 is it does have acute inflammatory consequences. It increases something called an adhesion molecule VCAM-1 which allows the eosinophils to get back into the tissue and rest there for longer periods of time It also is very instrumental in causing IgE production We have got Interleukin-time. It also is very instrumental in causing IgE production. We have got Interleukin-5, which is renowned for bringing eosinophils from the bone marrow into the systemic circulation and then into the nose. And then finally Interleukin-13, very much like Interleukin-4 and the reason this is a unique cytokine is because it maybe one of the instrumental cytokines regulating airway remodeling in both the upper and lower airway.

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Chronic tissue inflammation is the ultimate consequence of these events. What makes it different from just the late-phase response, you have epithelial damage. We used to think the epithelium is sloughed and died and run away, but in fact it becomes an active immunologic organ releasing a number of mediators like TNF as well as other cytokines that keep the tissue inflamed. You end up with this sort of vicious cycle, the more epithelial damage there is, the more inflammatory cells will keep coming back in and you end up with truly persistent disease.

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And what this chronic disease ultimately leads to is what we call non-specific nasal hyperreactivity. Now what does that mean to you and your patients? It means once you have inflammatory disease, let's say due to ragweed exposure in the fall that you are now developing non-specific type of responsiveness that somebody walks into a perfume counter in Macy's and those little volatile organic compounds will cause the nose to become very easily irritated, sneeze, itch and become congested. And this non-specific reactivity gives people the illusion that they are now “allergic” to everythingto everything.

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How can we summarize, what we have talked about in these first few minutes, certainly allergic rhinitis is an increasingly common disease, unfortunately due to a whole host of factors ranging from what we eat to what we are exposed to in the air that there are environmental factors that we must keep in mind not only from the point of view of how we treat patients, but ultimately perhaps as public policy issues because we are literally creating an allergic population across the developed world. And finally thank goodness to very good research over the past decade or two we now understand much of why this happens thank younow understand much of why this happens, thank you.

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Thank you so much Dr. Corren that was an absolute excellent concise presentation of lot of complex mediators that occur with allergic rhinitis. We are going to move right along with Dr. Yoshii moving along to a case presentation, Dr. Denis Yoshii.

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Good morning, so our case presentation begins with a 23-year-old college student, who presents to your practice with a runny nose that just won’t stop. He has tried several over-the-counter antihistamines and medications with no success. He is looking to try a prescription medication and hopes that he will find some relief. History, there is no history of asthma. Has a history of severe allergies as a child and already knows that he is sensitive to ragweed and tree pollen. Past medical history, has tried several over-the-counters including diphenhydramine and inhaled oxymetazoline And then in the symptoms symptoms are exacerbated during springoxymetazoline. And then in the symptoms, symptoms are exacerbated during spring and cold weather and his runny nose often keeps him awake at night.

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So your question, how would you classify JW’s rhinitis, go ahead.

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The way I think about allergies and rhinitis in particular, especially when we are talking about allergic rhinitis, think of it in terms of structure and function, just like they brought you all through med school thinking about. So the structure of the nose, it drains the eyes, it drains the ears, it drains the sinuses. So the eyes drain through the nasolacrimal duct. The nose drains in the posterior portion of the nasal pharynx and then the sinuses drain through the osteomeatal complex, which is underneath the middle turbinate. What's that mean? When the nose is stuffy and congested it will block off all these three drains and that goes along with yourcongested, it will block off all these three drains and that goes along with your symptoms. So if the nose is stuffy and congested, it backs up the sinuses and they have sinus pressure or the development of the sinusitis. If they block off the nasolacrimal ducts, they start tearing instead of draining down through the nose like they are supposed to they will tear. And then finally, if the eustachian tubes are blocked, they are going to either have you know they are either going to have fluid inside their middle ear or they can even develop an otitis media.

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The function of the nose, the function of the nose, the base-base function, humidify the air and filter the air, so again if the nose is stuffy and congested and you are not breathing through the nose anymore and you are breathing through the mouth, what happens the nose is supposed to filter the air and humidify the air as soon as you switch the mouth breathing, you breathe all the dry junky air straight into the lungs, you are more prone to cough, you are more prone to trigger off your asthma. And if you think of it that way, now you understand what's going on for your patients and that’s the take-home messagethat s the take-home message.

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The most bothersome symptoms reported by allergic rhinitis, the stuffy nose is probably the most common that people will walk into and when most people walk into your office saying, I have allergies, it's not I have an IgE-mediated allergic Rhinitis, what they are saying is my nose is stuffy, I have a headache, I have postnasal drip and this actually reflects that the nose is stuffy, they do have headache, they do have postnasal drip, and those are the most top common three symptoms that people will complain about.

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Again the way we think about it, we have our two big classifications. We have allergic rhinitis and non-allergic rhinitis. Allergic rhinitis is what we thrive on it's the IgE-mediated rhinitis, but non-allergic rhinitis as you will see is extraordinarily common in people with rhinitis and even in our case, non-allergic rhinitis plays in. Non-allergic rhinitis changes in weather, changes in temperature, lack of humidity, strong odors, cigarette smoke, and now irritants, this general classification of irritants, I want to make sure that we at least think that reflux and laryngopharyngeal reflux will cause more rhinitis as well This will cause the nasal congestion Viralreflux will cause more rhinitis as well. This will cause the nasal congestion. Viral infections, viral infection is common cause of rhinitis, foreign bodies and rhinosinusitis. One of the other things, we know that VCAM-1 is up regulated during rhinitis, ICAM-1 is also up-regulated in rhinitis and that’s CD21 which is an important entryway for rhinovirus. So people with rhinitis are a little more prone to develop viral infections as well.

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So allergic rhinitis, how do we find out what's going on, we skin test and this is a little girl and if you look at her back, she is allergic and that’s why allergy is so nice, it’s easy. There is another way of doing the testing; if you don’t have an allergist available to you, there is Radioallergosorbent Testing, RAST, which is the blood test. Commonly asked for me, which one is more sensitive or which ones a better way, the skin testing of course is more sensitive in picking up the allergies except for a couple of the foods; RAST is better for milk and peanut.

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Six-month old with a four-year-old sibling has purulent nasal discharge for one month, no family history of allergies and often this will actually come out and this is a foreign body, this actually was a LEGO. But what's the most common thing that we pull out of nose is peas and of course it’s the sibling that puts the foreign body up the nose.

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Gastroesophageal reflux disease, we see it in our practices all the times, the lower esophageal sphincter isn’t holding the food down in the stomach as well and it’s a common complaint. Although, we always tell people that avoid fatty foods, spicy food, caffeine, alcohols, cigarettes because that makes the reflux worse, spicy foods don’t seem to be as big of a deal. And of course, there is mechanics involved with reflux, if you eat a large meal and then lie down, you have more pressure on the lower esophageal sphincter, which means more of the reflux is going to come up And the way to think about it is you have this very low pH stuff sitting in theup. And the way to think about it is, you have this very low pH stuff sitting in the stomach and if it comes up and if it hits the nose, the nose is going to swell up and make tons of drippies trying to wash itself off because that’s the only thing the nose knows how to do, is that it swells up and makes drippy, when it’s trying to humidify the air, it swells up, it makes mucus.

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Typically, we talked about heartburn and we just asked patients do you have heartburn, but I think we actually need to go just a couple more steps in depth, especially when we are talking about refractory rhinitis or even refractory asthma, because this ends up being such a common issue. Are the patients getting typical classic heartburn or the acid regurge is probably what I hear more commonly. And I actually just ask the patients, do you get yucky tasting burps or bad tasting burps and that’s something that everyone understands. Water brash is something that I wasn’t asking and I was missing a lot of my patients who had reflux that waswasn t asking and I was missing a lot of my patients who had reflux that was actually making their rhinitis and even their asthma worse. Water brash is the sensation where the stomach feels hot and then all of a sudden their mouth starts watering after that, that’s actually reflux. Dysphagia, the common symptom is that feels like there is a lump or a ball in the throat and that’s also reflux. And then the extraesophageal manifestations of reflux, asthma, laryngitis, chronic cough. When we look at chronic cough, there is a nice article that came out, 74% of people with chronic cough actually have reflux and silent reflux as its underlying mechanism.

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Less common forms of rhinitis, we have our occupational rhinitis, anytime you are working in a dirty area or a harsher area, you are potential for rhinitis. Aspirin and vasodilators can do it, pregnancy can also cause rhinitis. The gustatory rhinitises are the people who eat the spicy foods and all of a sudden their nose starts running. Skiers nose, which is also considered a vasomotor rhinitis which is what our case presentation had and then atrophic rhinitis, the nose actually well it becomes, it atrophies as you become older.

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Conditions that mimic rhinitis, cystic fibrosis, if you are seeing, because the cystic fibrosis because the secretions are thickened, if you are seeing nasal polyps in a patient less than 18 years old, at least run that through your mind that it’s potential for cystic fibrosis. Mucociliary defects that’s important because the cilia especially inside the sinuses and the nose are moving all these fluids out, anatomical abnormalities foreign bodies which we saw, tumors and granuloma, sarcoid, Wegener’s and midline granulomas just to keep in differential.

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The symptoms of allergic rhinitis, you see in the office all the time, it’s the people who, actually with you guys out here, I hear you sneezing. So the people who are sneezing, the people who have the nasal congestion, the watery nasal discharge, itchy watery eyes, and postnasal drip, it’s not in practice. I usually think if a person has postnasal drip, I am thinking more sinus and if it’s rhinitis, where the drippies are coming out at the front of their nose that’s more of a rhinitis or allergic rhinitis. It’s just something that helps me distinguish what I am looking at in the patient clinicallyme distinguish what I am looking at in the patient clinically.

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Risk factors for rhinitis, just like what you have heard and we will actually show in other slide. If you have 80%, 90% of the people actually it’s 85.7% of people with asthma have allergies, have allergic rhinitis. If you are treating the asthma and you are not treating the rhinitis, you are not going to be taking care of your patient as effectively as you can. Atopic dermatitis, atopic dermatitis, the patient, the children who develop atopic dermatitis, 80% of them go on to develop allergic rhinitis, in some place between 20% and 30% of those people go on to to develop asthma So as soon as you see atopicof those people go on to to develop asthma. So as soon as you see atopic dermatitis, that’s a big road sign that these people are going to have the allergic disease; that they are going to move onto allergic rhinitis. The early treatment of atopic dermatitis, aggressive treatment of atopic dermatitis and you might disrupt that progression that march, the allergic march. The family history of allergies, if mom has allergies because pregnancy is a Th2 state, if mom has allergies 50% of those children will have allergies, if dad has allergies it ends up being about a 30% chance of developing allergies and if both parents have allergies then it ends up being 80% chance. So right from the family history, just on statistics you know okay, both parents have allergies, chances are the child can have allergies as well. Rhinitis for daycare centers, it’s more of the viral, right. Little Johnny goes, he wipes his nose and then he goes and plays with the toys and wipes it onto the next child and that goes all along with the viral infection. Occupational exposures,

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child and that goes all along with the viral infection. Occupational exposures, it’s like construction workers that have the most rhinitis and after our heavy rains here in California, the surfers end up with sinusitis and rhinitis and it’s just because all the stuff gets washed into the ocean.

Physical changes with allergic rhinitis, when you are looking into the nose, what are we looking for, we see this pale blue turbinates, not commonly, it doesn’t, pale blue is the classic, but it doesn’t, but red is a very common color, we see in the nose and for the turbinates. Clear, watery nasal discharge, the allergic salute, which we will see, lymphoid hyperplasia and you can actually see the lymphoid hyperplasia, the easiest place is actually in the conjunctiva, in the lower conjunctival sac and you will actually see what's called Trantas’ dots which are this little white hyperplasia of lymphoidwhat s called Trantas dots, which are this little white hyperplasia of lymphoid tissue, itchy, watery eyes.

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This is our classic nasal salute, so what's happening the patient has allergies, it’s itchy, she is rubbing her nose straight up and what you are going to see on physical exam is that she will have a crease right here. And so when the people walk in and they already have a crease across their nose, you know their nose is itchy, it’s going to be allergic rhinitis.

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This is the other nasal allergic salute and growing up, I remember my brother doing this, because his nose was constantly runny, he would just shove tissue up there to prevent it and it’s the common fix.

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Dennie’s lines is another thing that you can look for which is these extra lines that you see forming underneath the eye and of course we know the nose is stuffy because she has already got a tear, which means that the nasolacrimal ducts are blocked off. The Dennie’s lines form actually what we suspect is we have more lymphoid hyperplasia, so we actually see kind of creasing inside the skin underneath that.

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This is actually the high-arched palate that we are talking about, and this medieval device that’s here is palatal expander, but why are we seeing, what is going on in terms of development that we are seeing with the high-arched palates. The grow spurt for the jaw occurs between the ages of 6 and 8, for the jaw to grow you actually need to sleep with your mouth closed, if you are a mouth breather, if you are a snorer during the ages of 6 to 8, what happens is there is no stimulus for the jaw to grow, so the jaw stays a little bit short and the palate instead of spreading actually collapses on itself And so if we make our impact in allergic rhinitis and getactually collapses on itself. And so if we make our impact in allergic rhinitis and get these children sleeping with their mouth closed, we might make an impact on the number of orthodontics that we need and the use of the palatal expanders, but it is this timeframe of 6 to 8, where you want to make the impact on the allergic rhinitis.

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Classifications of rhinitis, allergic rhinitis impact on asthma, they actually made a nice delineation for the classification of rhinitis, seasonal versus perennial, I am going to go through this kind of fast.

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Intermittent versus persistent and because what you are going to find and then mild, moderate or severe.

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The reason they wanted to find the rhinitis and most of your patients are going to actually able to tell you, my rhinitis is all the time, I am always stuffy and so they will actually already have their own classification.

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But it actually helps us target our use of medications for our patients.

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And this is why I sped through it because most of the patients who come in they have non-allergic rhinitis, 23% of people have allergic rhinitis but a lot of people actually have mixed both allergic and non-allergic rhinitis just like our case presentation. JW knew that it was ragweed that triggered off the allergies but also went he was skiing.

Settipane RA Demographics and epidemiology of allergic and nonallergic rhinitis AllergySettipane RA. Demographics and epidemiology of allergic and nonallergic rhinitis. Allergy Asthma Proc. 2001;22:185-189.

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And then is it seasonal or is it perennial most people actually complain that their rhinitis symptoms are year long. So 56% of people will complain that their rhinitis is all the time.

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Allergic rhinitis and concomitant diseases are frequently seen in these patients.

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The management of allergic rhinitis may decrease the exacerbations of sinusitis, asthma and the otitis media because of the structure of the nose. Early immunotherapy for allergic rhinitis have shown to decrease the development of asthma because you are stopping the allergic march, making impact on the allergies early and you might be able to prevent the development of other allergic diseases. So the portion of people with allergic rhinitis who have these other things, chronic sinusitis happens in 67% of the people with allergic rhinitis and that goes along with structure and function asthma So if you have allergic rhinitis 21% of the populationstructure and function, asthma. So if you have allergic rhinitis 21% of the population actually has asthma and so when the people are coming in with the cough associated with rhinitis, at least again think about could this be an asthma, could this be a mild intermittent asthma that’s happening.

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And then on if you flip it, if you have asthma here is that 85.7% or 90% of people with asthma have allergic rhinitis and again so if you have your asthmatics and you are doing good medical therapy with them, don’t miss these components, don’t miss the allergic rhinitis or non-allergic rhinitis. People with sinus problems, how many of them have allergic rhinitis, 65% and then the otitis media in some place between 50% and 23% of people with the otitis media have allergic rhinitis. This ends up being important because if you use your first set of Pneumoeustachian Tubes, right if you just look at the number of people who get those PE Tubes 24% of themif you just look at the number of people who get those PE Tubes, 24% of them actually have allergies as the underlying trigger.

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Nasal allergies can make the asthma worse, yes.

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In the evaluation of rhinitis, the history and physical ends up being important. If you are worried about the sinuses, you can’t transilluminate even using your otoscopes, direct visualizations is of course is our classic diagnosis rhinoscopy if you have it available to you. Nasal smear is not done as often but we are looking for eosinophils. Skin testing is the gold standard for their diagnosis and you can RAST test as well.

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Imaging for persistent disease, physical exam again dark circles underneath the eyes, the Dennie’s Lines which we have the picture of, when you look into a person’s ear and you see the effusion, you already know that the nose is stuffy because the posterior nasopharynx is where the Eustachian Tubes are draining, the mouth breathing and then are they wheezing.

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X-ray, CTs see go with a CT if you are really suspicious but you are not making a diagnosis of sinusitis with your CT, you are looking for anatomical abnormalities that are making these patients more predisposed to having their sinusitis.

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And then patient’s satisfaction, yes this specialist we have a 4%, 100% satisfaction not very high.

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This is actually what I want to spend a lot of my time on fixing the nose because one of my favorite things to do in the office is actually use saline, just use regular old saline this is the recipe and you have it in your packets.

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But this is one of the pictures of, one of the devices that people are using for their noses, they fill this pot with normal saline, quarter teaspoon salt, half teaspoon baking soda and 8 ounces of water and they drip it through the nose.

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In the offices though we actually have these mechanical devices that do something similar and so the water actually goes up the nose over to the other side and out the other nostril.

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And I know everyone is going eew, but it is a billable event. So if you actually teach patients how to do this, how to do a sinus lavage in the office using a mechanized device that is specifically for sinuses, for sinuses.

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And this is one of the brands that I know for sure. This is the Grossman Hydro Pulse. If you do, if you teach it then there was a CPT code that you can use which is the 31000 but you have to use a modifier 52 because modifier 52 means you are using a down coded service because, otherwise 31000 is actually a surgical procedure.

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So the people who do this sinus wash what are the patients saying. And they are saying that they feel empowered, that they feel that it’s this wonderful opportunity to be healthy that it is so simple you can do it whenever you want. And then you don’t have to run to the doctor’s office every few months to get antibiotics because your sinuses are acting up. So anytime they start getting the sneezing, anytime they start getting the postnasal drip they jump on doing the sinus lavage and they feel better.

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Why won’t people do the sinus wash because it’s uncomfortable, because it’s strange and this is probably one of the most common complaints, I mean you are putting salt water up your nose.

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And then what was the most helpful thing at getting people to do the sinus wash at home and it’s learning it in the office. And this hands-on part was critical. So what do we do with our sinus wash? So we have got this wand looking thing we put that up to the nose we make a tight seal, we have the patients pant, just slightly what that does is it drops the pallet and allows the water to go over because if the patients clinch down then what’s going to happen is the water is going to go on to the Eustachian Tubes. You always start on the stuffy side of the nose because you can always push the water pass the stuffy side but if you go in towards the stuffy sidealways push the water, pass the stuffy side, but if you go in towards the stuffy side then the water is going to get into the Eustachian Tubes, the patients are going to feel miserable. If both sides are stuffy then you don’t do it because you are just going to end up with more problems, make up for your salt water at some place, bring it in, run the machine and clear out these tubes that there is no cold water in it. Because of course if you get cold water up into the nose, you get the ice-cream headaches it’s how the patients describe it. And then always keep it on low, don’t turn it, you don’t need the high setting.

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Thank you very much Dr. Yoshii, too bad it wasn’t a lunch time lecture that would have maybe we have run over a little while. We are going to go through a case presentation, a case presentation that’s going to be a little bit more detailed on purpose and it really what it does at listening to Dr. Corren’s lecture it really translate those early phase reactions and late phase reactions and how impactful it can be on someone’s life.

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So my case presentation is Mrs. C is a 56-year-old white female with the history of seasonal allergic rhinitis during most of her life beginning in her early school age. However, over the last several years, she has noticed perennial symptoms worsening with perfumes and odors. Her past history is unremarkable for illness and surgeries just except for hospitalization for an uncomplicated child birth. She has been a homemaker and very active in community service & activities. She does not smoke and occasionally will drink wine.

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She has tried several over-the-counter medications which I am sure many of you hear in your practices that’s where a big part of where patients will reach first before they come to the physician or healthcare provider. But she stopped them due to their lack of efficacy. She is adamantly against any form of steroid medication and I think this is also another part of the educational process that we have to do for our patients to let them know the safety of topical nasal steroids. Recently she found some congestion relief with the over-the-counter spray however the benefit is waning and unfortunately that spray may have been something like Afrinwaning and unfortunately that spray may have been something like Afrin, Oxymetazoline which we know can actually cause a problem in and of itself which is Rhinitis Medicamentosa.

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She said she can no longer tolerate her favorite boutique due to its fragrances. She has a diminished sense of smell and appetite. She used to really enjoy cooking as a significant hobby and now she says it just causes her more congestion. She has had more colds recently which she attributes to being around her grandchildren which certainly could be the case there much more common to carry viral infections and pass them on especially with touch. But her grandkids are always teasing her about having to carry around tissues.

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She says her quality of sleep has diminished and she is losing interest in her Bridge Club. Her husband says she is increasingly just more lethargic and doesn’t have the energy or the spunk that she used to and then recently of significant concern are these episodes of wheezing and shortness of breath that she is having with her colds. She has had some difficulty concentrating and recently nearly missed having an auto accident when she was out due to inattentiveness. She presents today getting to the final end of this case because she is concerned now that she may have asthma and she is worrying about potential dementia So when you think thathave asthma and she is worrying about potential dementia. So when you think that a runny nose is just something very simplistic and patients aren’t adversely affected through many components of their life you can see how from an early situation, early on in her childhood this may have been something that was again just seasonal, treated and she was okay to the point where the late phase reactants that come into play that Dr. Corren talked about how they can translate into rhinitis that transcends the course of one’s life and then becomes very, very impactful. Whatever the cause may be, whatever the underlying immunologic pathophysiology, I think what’s important is that we, as primary care practitioners, have to address the rhinitis and treat it.

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So how do we translate the evidence and the well-well thought out lectures that you have heard and being given regarding the pathophysiology and the classification and the treatment and translate that into patient management as well as compliance.

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Well I think that our previous speakers did a wonderful job talking about how allergic rhinitis impacts many other disease processes and many other disease processes impact allergic rhinitis and hence this Venn Diagram here that I present to you.

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Okay again what are some of the things that we can do to treat allergic rhinitis? Well, initially we want to affect the environment. Avoid the factors that cause the symptoms. Sometimes this is possible, sometimes this isn’t. Sometimes it maybe something as simple that a particular perfume may trigger an event of rhinitis in an individual well that’s something that’s more easy to avoid than someone actually having to walk out and right now on the East Coast where it’s ragweed season you have got to go outside. Then of course we have therapies that we use both palliative therapies as well as pharmacotherapy which we are going to get into topalliative therapies as well as pharmacotherapy which we are going to get into to help treat both the underlying etiology as well as the symptoms. Allergen Immunotherapy a very, very important component as primary care practitioners I think it’s very incumbent upon us to educate our patients about the appropriateness along many different avenues and spectrum of their disease process and very, very important to refer them to the allergist and immunologist when needed to be able to put them through this if they are going to be compliant and their allergic rhinitis is actually very, very impactful on their life. I recently had a 17 year old gentleman who started dating and his rhinitis was so significant that prior to that we were using pharmacotherapy and it just was not controlling it and we discussed allergen immunotherapy because he is committed to long term that this isn’t something that he wants to deal with because it’s embarrassing to him and then certainly patient education, educating the patient about the disease process and the importance of follow up.

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follow up.

Smoke, we certainly want to discourage patients from smoking and minimize the use of smoke that’s associated wood burning fire places which can be certainly a trigger, you saw the evidence about diesel fumes as well as other air pollutants. Pet dander it’s very unreasonable to say you have to get rid of your cat or your dog. Patients just won’t do it I think the slide that Dr. Yoshii had with the children actually on the doghouse was basically more likely what would be to happen so therefore let’s come to our reasonable accommodation. Let’s keep the pet out of the bedroom If at all possible let’s keep the floors as allergen friendly if possible woodbedroom. If at all possible let s keep the floors as allergen friendly, if possible wood floors as opposed to carpets and blankets and other things that are just going to harbor that dander. Washing the pets, using a HEPAtype filter is even more effective than an electrostatic filter. Dust mites, again trying to wash bedding and wash it at a temperature that’s actually going to kill or decrease some of the dust mites so to speak. Reducing the humidity to prevent mould spores and then certainly keeping trash where it needs to be and avoiding the potential allergens that can come from that.

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You know individuals that enjoy gardening, you need to talk to them about if they are using composts and they are using other raking leaves and other things like that, that can potentially trigger allergens and again lowering humidity inside the house to prevent that and then when the pollen season is really bad and it’s right now on the East Coast you know we had a very significant ragweed season because it was so dry you know not opening the windows for that “fresh air” but actually using air conditioning so that at least you decrease the amount of allergens that are therethat are there.

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This just looks like a very complicated treatment algorithm. It’s actually very practical and it’s by Nassif and we are going to go through it step-by-step.

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If you get a patient history and you have heard all the symptoms of allergic rhinitis and you are hearing an itchy watery nose, itchy eyes, you want us to if you are doing a physical examination. Dr. Yoshii went through some of the physical examination, signs that you would see with the patient that has allergic rhinitis. You are then going to go to a major subtype and look at that subtype to help to find how you are going to treat and if we see the subtypes here we have got mixed rhinitis. Then there is rhinosinusitis, an infectious process, important to treat rhinosinusitis and one of the differentiating things that we use here is really the length ofand one of the differentiating things that we use here is really the length of symptoms that individuals have. Certainly younger patients are much more likely to come in, in the first one to two to three days if they have symptoms and they need an antibiotic. I need an antibiotic I am sick and they will even tell you sometimes what antibiotic they need. Unfortunately that’s not what we want to do. We want to see number 1 whether it’s either viral or allergic and try to differentiate that and then treat that appropriately and then predominantly those individuals who have the itchy watery eyes, the runny nose where it’s allergic we are going to take a whole another avenue.

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Depending on which particular avenue or which diagnosis we make whether it’s mixed rhinitis, rhinosinusitis or predominantly allergic rhinitis the treatment recommendations are going to be different, okay. The options are going to vary. If we have somebody with a mixed rhinitis certainly topical nasal sprays are going to be more appropriate, topical Atrovent is going to be appropriate and people are even going to be using mixed H1 blockers with a decongestant. If somebody has rhinosinusitis, yeah you maybe using a mixed agent with an H1 blocker and a decongestant but it’s also going to be important in that particular situation todecongestant but it s also going to be important in that particular situation to prescribe an antibiotic to treat their acute rhinosinusitis and I am also a believer in using topical nasal steroids if the patient has significant symptoms and their rhinitis as opposed to their allergic rhinosinusitis develops and keeping them on that for a period of time to kind of decrease the mucosal edema and then finally with allergic rhinitis you are going to be using a topical intranasal steroid. You are going to be using things like Azelastine which is a topical H1 blocker. There is a component of H1 blockers that are both oral. You may want to even if somebody comes in with very, very significant symptoms using oral steroids for a very short course period of time. Most practitioners have gotten away from an injection of steroid for a short course of period of time because obviously steroids are something that should be used very judiciously.

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And then of course it’s important to follow up and see how the patient did. Did they adhere to the therapy? Did they respond to the therapy that is going to help you decide what is the next course of action that you need to take and you also have to rethink your evaluation, did I in fact made the right diagnosis, is this maybe not just allergic rhinitis but perhaps this is mixed rhinitis and if the patient doesn’t get better and you have prescribed an antibiotic, well was this a resistant organism such as a resistant pneumococcus or did I in fact just make the diagnosis of a bacterial rhinosinusitis when in fact this was viral So keeping in mind those symptoms suchrhinosinusitis when in fact this was viral. So keeping in mind those symptoms such as perversion of taste, perversion of smell, maxillary or whatever sinus it is, tenderness, fever you know looking at the criteria that are going to make you lean more towards that it is bacterial versus viral and this is very important when prescribing antibiotic.

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So when we look at the therapies that are out there it’s both palliative and pharmacotherapy and you certainly got a very, very well thought out and illustrated vision of using nasal lavage that Dr. Yoshii explained and how you can do that and that is very important. I find that inhalation of warm mist is also very, very helpful. Again you may define the nasal area and help decreasing some of the inflammation that way and then when it comes to pharmacotherapy we have a whole panoply of things that we can do to help treat patients which include the intraoculars, antihistamines corticosteroids decongestants mixed antihistamine decongestantsantihistamines, corticosteroids, decongestants, mixed antihistamine decongestants, hormones, anticholinergics and also the leukotriene receptor antagonist are not up there but we also mentioned them in a little bit.

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Dr. Yoshii went through the guidelines that help us define the symptomatology is it less than 4 weeks, is it less than 4 days. Out of the week in other words it’s intermittent. Is it greater than 4 days per week? Is it greater than 4 weeks is it persistent and then is it mild? It’s not having any effect on their daily activity, their sleep, their ability to concentrate, their ability to work or is it moderate to severe and then in fact it is having an effect on one of those particular areas. Very, very important to get this part of history because it’s going to help you define and decide how you treathow you treat.

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This is basically a really nice diagram that looks at people that may have just mild intermittent disease you are certainly going to educate about allergen avoidance that’s always going to be important. You may want to use an intranasal decongestant. This is something that even though the guidelines will say less than ten days, I actually prefer and I think it’s more prudent to use this less than three days because if not you can develop a rhinitis medicamentosa, oral or topical antihistamines, topical being intranasal azelastine or an oral H1 blocker which we will talk about When we get toazelastine or an oral H1 blocker which we will talk about. When we get to moderate to severe intermittent intranasal corticosteroids, cromolyn sodium and then still doing these other issues and I actually this is where I think it’s very, very important to at least broach the topic with the patient. Again getting a sense of what the patient wants and where they want to guide their therapy to at least talk about immunotherapy and it’s not necessarily if all other therapies fail even though this is what the ARIA guidelines say. It really is if it has having an impactful component on that patient’s life and that patient’s ability to function and again like I described the 17-year-old who is now very, very concerned about and being embarrassed with dating and constantly having this rhinitis. Mild persistent and moderate to severe persistent again taking all those areas into consideration.

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So years ago and they are still out there and we have the first generation antihistamines. The issues with the first generation antihistamines we are going to talk about I don’t know too many of you are probably out there using promethazine, hydroxyzine better known as Phenergan or Atarax.

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They are highly lipophilic. They cross the blood-brain barrier. They have a lot f id ff d i d h l k h i k b fi i i h hof side effect sedation and when you look at the risk benefit ratio with these

particular agents I think the risk far outweigh the benefits and the patient’s quality of life is pretty poor with these agents. They can affect an elderly man, their ability to urinate, cause urinary retention so for the most part I don’t see a lot of appropriateness for these particular agents.

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Now we have second generation antihistamines very importantly which I think do play an important role in controlling the symptomatology of rhinitis and they are azelastine, cetirizine, desloratadine, fexofenadine, loratadine and now levocetirizine, for some of you who were like oh I wish this guy would give us the other names. Azelastine since I will be fair and balanced as Astelin. Cetirizine is Zyrtec, desloratadine is Clarinex, fexofenadine is Allegra, loratadine is Claritin and levocetirizine recently new and I believe it may even have been launched already is XyzalXyzal.

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Okay second generation antihistamines why do we use them? They have l d i f i Th h l i i f h H1longer duration of action. They have greater selectivity for the H1 receptor and there is little or no central nervous system penetration except for other side effects that occur with one in particular which we are going to talk about and studies show them to be much more efficacious than the first generation antihistamines as far as when you are looking at treatments of symptoms as well as patients reported scores on their quality of life.

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So what are they? Of course we have fexofenadine and the indications you d f lf h h I i l i d f f Wcan read for yourself they are there. It comes in a multitude of forms. We

also now have the Fexofenadine or Allegra oral suspension which makes it nice for treatment in children particularly. It’s non-sedating fexofenadine and even at higher than recommended doses studies have gone all the way up to 720 milligrams and it is still a non-sedating oral antihistamine. Cetirizine on the other hand has more indications in fact so it comes in a 5, 10 milligram tablet. Also it comes in an oral suspension that is 1 milligram per mlmilligram tablet. Also it comes in an oral suspension that is 1 milligram per ml and the problem with Cetirizine I think for most of you have probably used it clinically there is an associated sedation that occurs with Cetirizine or Zyrtec and so therefore patients will find that it works pretty well for their allergic rhinitis but it also causes a degree of sedation and then there does have to be some dosage adjustments.

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Loratadine which is obviously now a OTC it’s non-sedating but it is not in fact ff i b i d bi d ll h H1as effective because it does not bind as well to the H1 receptor as

desloratadine which has the indications as you can see for seasonal allergic rhinitis, chronic allergic rhinitis as well as Chronic Idiopathic Urticaria and each of them come in their respective tablet formulations as well as we have a syrup for desloratadine and again as I mentioned desloratadine does bind to the H1 receptor more aggressively, so therefore symptomatology reduced.

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Some of the newer therapies levocetirizine which is an isomer of cetirizine what’s nice about this particular enantiomer and isomer is that it takes away the sedation that occurs with cetirizine so you still have the marked blockade of the H1 receptor but you don’t have the sedation that has occurred with this and there has been numerous studies to show this. Primarily these studies were done not in this country South Africa. This study shows that levocetirizine is actually more effective than desloratadine, loratadine and fexofenadine so it’s kind of like a new improved version of cetirizine because I think most of you would agree that cetirizine worksversion of cetirizine because I think most of you would agree that cetirizine works effectively in H1 blockade for the most part and controlling symptoms but the sedation can be rather problematic.

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And levocetirizine was shown to be effective. This is again a study by Potter in children as you can see that both in week 1 it was statistically significant and at week 2 there was just statistical significance.

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Azelastine is our intranasal topical antihistamine. It is indicated for seasonal ll i hi i i ll i hi i i I ’ b i dallergic rhinitis, non-allergic vasomotor rhinitis. It’s one to two sprays b.i.d.

Probably the biggest complaint that you are clinically about this particular medication is that when you apply it there is associated burning that occurs with this. It works in the same manner as the systemic antihistamines except that it’s direct approach to the nasal mucosa. It down regulates intercellular adhesion, molecular expression. It inhibits cytokine expression all the things that the previous speakers talked about so it does have that immunologicthat the previous speakers talked about so it does have that immunologic effect but again probably the biggest complaint here is the side effect.

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Currently available decongestants that we have that are often in combination with some of the H1 blockers are Pseudoephedrine which is found in most of the cold remedies that you will see over-the-counter and at lower dosage than what we see involved with our H1 Blockers on a prescription level and then Phenylephrine. Phenylephrine is really not a good agent, it’s much less effective than Pseudoephedrine, it has extensive first past metabolism so we see less of this used. And then of course we have a topical decongestant which is oxymetazoline which is also over-the-counter and again you have to be careful with this it has towhich is also over-the-counter and again you have to be careful with this, it has to be used for a very short interval of time not that one creates a dependency and a rhinitis medicamentosa situation.

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Again, I talked about the antihistamine decongestant combination di i f d f i d hi i i d h f hmedications often used for mixed rhinitis and there are many of them out

there in combination. The decongestant is obviously for the most part different in varying dosages of Pseudoephedrine. The Antihistamine helps the itchy, watery eyes, the sneezing and the decongestant again works on the nasal congestion by narrowing the blood vessels in the nose.

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The intranasal corticosteroids are a very important component of what we used to treat and have revolutionized our treatment of allergic and mixed rhinitis and we have beclomethasone, budesonide, flunisolide, fluticasone propionate, Furoate, Mometasone Furoate, Triamcinolone. Ciclosonide is a drug that actually is probably not going to be launched in this country but for a period of time it was thought that it was, so therefore even though it is particularly FDA approved, actually it’s being used in Europe but not currently in this country.

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Intranasal corticosteroids again interfere with the allergic inflammation at l diff i i h d h D C lki b dseveral different points in the cascade that Dr. Corren was talking about and

in long term have significant ability to control symptomatology in both the early and the late phase responses. They exert their effect through vasoconstriction, reduction of mucosal edema, inhibit expression of cytokines and other mediators that are going to make the rhinitis worse. Their onset of action is from several hours to days and really their maximal effect is usually seen after a couple of weeks of usage although patients willeffect is usually seen after a couple of weeks of usage although patients will report to you that they may see individual side effects decrease in a very short period of time.

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We certainly have this study that was well corroborated here that shows the efficacy of fluticasone and its ability to be well tolerated and it compared placebo against fluticasone furoate at the 110 microgram dosage and nasal and ocular symptoms were significantly improved, the majority of the study patients were compliant. Probably the one constant recurrent theme that we get on patients that are using intranasal steroids is that there can be associated epistaxis with these agents and it’s pretty much across the board with regard to this. Most of these agents are of a isotonic component the aqueous component in them is isotonic Interestinglyisotonic component, the aqueous component in them is isotonic. Interestingly enough, there is some thought process that perhaps the isotonicity may affect ciliary ability to move secretions both in the nose and posterior pharynx and perhaps a hypotonic solution would be a better medium to actually introduce these steroids.

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Patients preference for intranasal steroids will really vary according to patient d I hi k i ’ h i d i h id h l h kand I think it’s the patient education that we provide them to let them know

this is not steroids that individuals who are body builders and are in any way using those kinds of steroids, these are different form of steroids that for the most part they do not affect systemic regulation of glucocorticoids or mineralocorticoids. If nasal obstruction or congestion persist, steroids can be used in conjunction with topical antihistamines and decongestants. Again local side effects, I talked about previously, an epistaxis being probably thelocal side effects, I talked about previously, an epistaxis being probably the most common. Again with effective intranasal steroid usage and availability and treatment of rhinitis, really the systemic steroid should really be reserved for a short course period of time in which someone who is really suffering needs control.

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Intranasal Cromolyn, Cromolyn Sodium which as you know is over-the-h bi d i i h hi i l di i i h i hcounter, the biggest detriment with this particular medication is that it has to

be used so frequently. It does stabilize mast cells, it prevents degranulation so it prevents the premeditators or newly formed mediators but the problem with this again is the dosage formulation is q.i.d. for it really to be effective and so that can be both cumbersome for the patient as well as it can lead into an expense.

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Intranasal anticholinergics what we have out there is Ipratropium Bromide, hi d h bl d b i b i i i i ll di ib d ithis does not cross the blood-brain barrier, it is not systemically distributed, it

does provide relief from rhinorrhea only. Again the problem with this particular agent, it can cause excessive drying in the nose and therefore you can have associated epistaxis with that and again this is a medication that’s going to be administered 2 to 3 times daily. And what you find is patients don’t like to take medications at work very often and so therefore once a day or b.i.d. usually has a much higher compliance.or b.i.d. usually has a much higher compliance.

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We have the leukotriene antagonists of which Montelukast being an LDT4 receptor antagonist other name for this being Singulair was approved and studies have shown significant benefit with the use of Montelukast with regard to the treatment of allergic rhinitis. We also know that this drug is used for mild asthma.

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Immunotherapy, I think this is an important component to present to patients, to educate them about the way that it works again reduces specific IgE synthesis, the induction of a specific allergen-specific IgG blocking antibodies, it decreases target organ reactivity all the particular areas that doctor Dr. Corren went through, it really works on that long term. And so if you have a patient that you know is going to be compliant with this, wants to really get to the underlying etiology if they have allergic rhinitis and control that rhinitis over the long term, this is something that is important to present to them as an option Then again it’s carefully selecting the patientto present to them as an option. Then again, it s carefully selecting the patient.

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It may not necessarily be that they had poor or no response to environmental controls or pharmacotherapy, it may be that their symptoms are so bothersome and they are willing to put in the time and effort that goes into immunologically modulating so that the individual will not have symptoms associated with chronic rhinitis.

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An outstanding Q&A, I would really like to thank everybody. I think we almost got a question from everyone in the audience and it was a pleasure. I hope you enjoyed the program and thank you very much for your kind attention.

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