New Perspectives on Allergy Management: Ophthalmologists and Allergists Weigh in on Key Issues
by the Review of Opthalmology and the National Retina Institute.
Supported by an unrestricted educational grant from Alcon.
This activity has been designed to meet the educational needs of ophthalmologists involved in the care of patients suffering from allergies.
Statement of Need:
Ocular allergy is a prevalent condition affecting millions of individuals worldwide. Allergy is a systemic condition with a high percentage of individuals experiencing ocular symptoms. It is estimated that more than 50 million people in the United States are affected by allergies and that allergic rhinitis affects as many as 20 percent of all adults and 40 percent of children.
Although practicing in different specialties, ophthalmologists and allergists often encounter patients with overlapping signs and symptoms related to allergies. For example, ocular allergens may come in contact with the ocular surface via direct routes or indirectly via the nasolacrimal duct with inhaled allergens. The concept of “one airway” in systemic allergy may extend to the ocular surface. Thus, it is important for eyecare providers and systemic allergists to understand and communicate evolving concepts to provide optimal patient management.
After completing this educational activity, participants should be better able to:
- Identify the epidemiologic trends of allergy as they relate to the eye
- Expand collaborations between allergists and ophthalmologists to better recognize and manage all symptoms.
- Interpret the “one airway” concept in systemic allergy as it relates to the eye.
- Recognize newer treatment options in allergy to provide optimal relief of all symptoms.
William Berger, MD,
University of California College of Medicine,
Department of Pediatrics, Division of Allergy and Immunology,
Graduate School of Management
Bradley Chipps, MD,
Cystic Fibrosis Center,
Capital Allergy & Respiratory Disease Center,
Sleep Laboratory of Sutter Community Hospitals
Francis S. Mah, MD,
University of Pittsburgh School of Medicine (UPMC),The Charles T.
Campbell Ophthalmic Microbiology Laboratory at the UPMC Eye Center.
Terrence P. O’Brien, MD,
Charlotte Breyer Rodgers Distinguished Chair in Ophthalmology;
Bascom Palmer Eye Institute at Palm Beach Gardens;
Director, Refractive Surgery Services
Michael B. Raizman, MD,
Tufts University School of Medicine,
Cornea and Cataract Service at the New England Eye Center.
The Bert M. Glaser National Retina Institute designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.
Disclosure of Conflict of Interest:
NRI requires that all continuing medical education (CME) information is based on the application of research findings and the implementation of evidence-based medicine. NRI promotes balance, objectivity and absence of bias in its content. All persons in position to control the content of this activity must disclose any conflict of interest. NRI has mechanisms in place to resolve all conflicts of interest prior to an educational activity being delivered to the learners.
NRI is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest.
The faculty have all had financial relationships within the last 12 months; however, their apparent conflicts are resolved. They reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Dr. Berger—Consulting fees: Alcon, Altana, AstraZeneca, Meda, Sanofi- Aventis, Sepracor, GlaxoSmithKline (GSK), Schering- Plough, Genentech, Novartis, Apieron, Verus , Dey. Fees for non-CME services received directly from a commercial interest or their agents(s) : Alcon, Altana, AstraZeneca, Meda, Sanofi- Aventis, Sepracor, GSK, Schering- Plough, Genentech, Novartis, Apieron, Verus, Dey. Contracted research: Alcon, Altana, AstraZeneca, Meda, Sanofi- Aventis, Sepracor, GSK, Schering- Plough, Genentech, Novartis, Apieron, Verus , Dey.
Dr. Chipps—Grants for clinical research: Aventis, Genentech, AstraZeneca, GSK, Novartis, Schering- Plough, Sepracor, Merck. Grants for educational activates : Alcon, Aventis, Genentech, AstraZeneca, GSK, Novartis. Advisor for consult: Alcon, Aventis, Genentech, AstraZeneca, GSK, MedPoint, Novartis, Schering- Plough, Sepracor, Merck. Speakers bureau: Alcon, Aventis, Genentech, AstraZeneca, Boehringer, GSK, MedPoint, Novartis, Pfizer, Schering- Plough, Sepracor, Merck.
Dr. Mah— Consulting fees: Alcon, Allergan, Inspire. Contracted research: Alcon, Allergan, Inspire.
Dr. O’Brien—Consulting fees: Alcon, Allergan, AMO/ VISX, Ista, Inspire, Bausch & Lomb.
Dr. Raizman—Consulting fees: Alcon, Allergan, Inspire; Fees for non-CME services received directly from a commercial interest or their agents : Alcon, Allergan, Inspire; Contracted research: Alcon, Allergan, Inspire.
The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interest related to the content of this CME activity:
Bert M. Glaser, MD, The National Retina Institute has no real or apparent conflicts of interest to report.
Ruth A. Zeller, The National Retina Institute, has no real or apparent conflicts of interest to report.
Karen Rodemich, Review of Ophthalmology, has no real or apparent conflicts of interest to report.
Alicia Cairns, Review of Ophthalmology, has no real or apparent conflicts of interest to report.
Method of Participation:
There are no fees for participating and receiving Continuing Medical Education credit for this activity. During the period of April 2008, through April 30, 2009, participants must:
- read the learning objectives and faculty disclosures;
- study the educational activity;
- complete the post-test by recording the best answer to each question
A statement of credit will issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better. Online test takers will be issued a printer-friendly, real-time certificate.
Disclosure of UnLabeled Use:
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. NRI, Review of Ophthalmology and Alcon do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of NRI, Review of Ophthalmology and Alcon. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
IN JANUARY, TWO SEPARATE, but major meetings took place in Hawaii for ophthalmologists and allergists. Internationally recognized ophthalmologist Terrence P. O’Brien interviewed four leading ophthalmologists and allergists during these events, and asked these physicians pointed questions regarding approaches to treating allergies, how the two medical professions can better work together and more. Following are the highlights of these interviews.
THE BIGGER PICTURE
Terrance P. O’Brien, MD: In general ophthalmology, the average clinical practitioner has an extensive systemic medical background knowledge, yet principally diagnoses and treats the eye. When you see and treat ocular allergies, what systemic comorbid conditions concern you and how do you approach therapeutic management? I think sometimes ophthalmologists may have a tendency to focus on the eye and lessen emphasis on extraocular systemic features.
Francis S. Mah, MD: Many times, people don’t know they have ocular allergies or allergic conjunctivitis, so when a patient presents with a chief complaint of irritation, itching or redness, I try to delve into more of the past medical history (eg, I’ll ask more about the actual medications that patients are taking). Especially with patients who come in with mild swelling, some injection of their eyes and itching-type symptoms, we need to ask about nasal symptoms such as nasal rhinitis, an asthma history, a history of eczema or atopic dermatitis and whether they have some history of seasonal allergies. These are obviously pointed questions to determine whether patients have a history of an atopic type of phenomena with an immune system that might be at higher risk for allergic or atopic ocular conditions as well as their systemic disease.
Some patients say they have no problems, but when you ask about medications, they provide you with a list. It is up to you to try to decipher whether any of these medications may help you identify some of the clues to the patient’s current complaints. Look not only for p rescription medications, which are much more readily given up by the patients, but also for over- the - counter (OTC) medications, which patients sometimes overlook. Asking about the use of medications that have become OTC (eg, loratadine [Claritin, Schering-Plough]), can also provide clues and identify some comorbid conditions.
Dr. O’Brien: As ophthalmologists, we are so technologically oriented that we can, for the most part, via direct observation of the ocular tissues utilizing instruments with high magnification and resolution, sort through the clinical signs to come up with a specific diagnosis. However, clinical history is equally, if not perhaps more important, for uncovering the source of the ocular irritation , especially the symptoms of itching distinguished from other irritations that may mimic itching. You made the very valid point about direct inquiry to obtain a complete medication history. Too often, patients will overlook the OTC medications that may be significantly linked to their comorbid condition or actually exacerbate their ocular disease. What other symptoms do you try to elicit from patients with allergy in addition to the ocular symptoms when you’re focusing in on the airway and systemic attributes?
Dr. Mah: The more easily thought of conditions that we as ophthalmologists try to identify are of the dry eye type of symptoms. We are also more focused on issues with contact lenses. Some key clues to help identify cause are to characterize when they have their symptoms of redness, swelling or itching; obviously, seasonality is also a huge clue. As we know, any type of inflammation can be a trigger for dry eyes, so it’s wise to back up and ask yourself whether something else could actually be causing the inflammatory trigger to cause dry eyes? When I hear itching as a symptom, I try to get a comprehensive history and identify some factors that may help target allergy as the primary condition causing the secondary dry eyes.
Dr. O’Brien: Historically, ophthalmologists perhaps do not collaborate as closely with allergists as may optimally benefit our patients. In which instances should allergists refer to ophthalmologists? What are the conditions that you as an ophthalmologist worry about, say with red eye that might be a warning sign that a patient should be referred sooner rather than later?
Dr. Mah: I know that in my own personal experience, when patients get collaboration between specialties, it seems that the care is more efficient and there is more rapid resolution of the ocular issues. I think there are a couple of key times when there may be more of an urgency toward the allergistreferring to the ophthalmologist. A key time is when there is any doubt regarding an infectious etiology, specifically viral, as a cause of the symptoms. Oftentimes, adenovirusor, more concerning, herpes virus can cause a nonspecific irritation (itching, a watery tearing); the nonspecific swelling and injection could all be caused by either allergy or a viral etiology and if, for example, the impulse is to treat with steroids — even mild steroids—this may actually be putting gasoline on the fire, especially if it is herpes. The initial impulse could cause a potentially devastating visual problem. Heavy disc h a rge without itching, as well as any significant visual changes are scenarios in which you have to consider a more rapid referral .
Dr. O’Brien: Certainly any red eye that presents with decreased vision, pain or photophobia should be referred promptly without delay and not be given a therapeutic trial of a topical corticsteroid. Not only is there concern of potentiating Herpes simplex viral infection with devastating consequences, but also exacerbating the contact lens patient who might actually have an infection from either severe bacteria, fungal disease or even Acanthamoeba. Putting a topical corticosteroid on a Gram-negative bacteria, fungus or Herpes simplex is likely to rapidly deteriorate the condition. Topical corticosteroids are used widely, but what other concerns exist with their use, especially with achronic disease such as allergic conjunctivitis, that is relapsing and remitting?
Dr. Mah: there are several critical issues. Obviously, the chance of infection increases . More specifically for ophthalmologists, we’re concerned about cataract formation. Posterior subcapsular cataracts are strongly linked with steroid use, not only systemically, but also topically. Even a mild steroid can be associated with posterior sub-capsular cataracts, this has to be a suspicion especially in a patient who has decreasing vision over time.
Dr. O’Brien: Especially in pediatric patients, where there may be a cumulative effect over time if corticosteroids are used repeatedly.
Dr. Mah: Exactly. And although this is a visually disturbing issue, it’s a potentially reversible issue with surgery. The more devastating problem is glaucoma and intraocular pressure (IOP) increases with prolonged steroid use because this may cause permanent vision loss.1 According to some case reports, even nasal steroids cause increased intraocular pressure and glaucoma.
Dr. O’Brien: Cases occur all too frequently where a patient has perhaps a genetic p redisposition to develop asteroid-induced elevation of eye pressure contributing to development of irreversible damage to the optic nerve over time. Many of these patients typically have connections to the medical field, where a relative, friend or even the friendly neighborhood pharmacist might unwittingly refill steroid medications, thus leading to chronic abuse of the medication.
The danger is certainly that corticosteroids are effective acutely and non-specifically with some of the acute phase reactants, so there is an immediate gratification that is potentially addictive to patients with this chronic disease. With the availability of agents that have combined mast cell stabilization and antihistaminic properties that can be applied topically, where do you limit the use of topical corticosteroids in patients with allergy?
Dr. Mah: I have limited the amount of steroids that I use topically because of the advent of so many excellent combination products that have not only mass cell stabilizing characteristics, but also strong antihistaminic properties. I limit steroids to the severe allergic, visually impactful conditions (atopic keratoconjunctivitis and vernal keratoconjunctivitis), where I will initiate steroid therapy with an intensive dosing regimen, but rapidly taper as the patient responds. Besides these more severe, visually impactful conditions, I’ve really limited my steroid use. Even the so-called synthetic, soft or nonpenetrating steroids have been lowered on my list of therapeutic options due to the advent of other excellent, safer medications.
Dr. O’Brien: I agree. We should try to spare the use of any topical corticosteroid, however “soft” they may be because even those can lead to elevations in pressure in select predisposed individuals. And again, because of the potential for the addictive behavior once topical corticosteroids have been used, when other available alternative effective agents are well tolerated and safe, we probably want to reserve steroid use for only in the most severe refractory cases. What features do you look for in a compound to p rovide optimal relief of the symptoms most commonly associated with ocular allergy?
Dr. Mah: there are some important characteristics that we would ideally want in any p roduct that we would consider. With any medication, you want immediate effects. Therefore, we want an agent that, when placed in the eye, is going to eliminate the symptoms of itching, re dness, as well as the mild swelling that can occur with allergic conjunctivitis as quickly as possible.
Another key issue is longlasting effects. Therefore, we want something that is going to be able to be used once a day to encourage patient compliance. Finally, with any medical therapy, we want something that is non-toxic and comfortable when used. More specifically for ocular allergies, not only do you want the rapid antihistamine properties to relieve the itching and redness that occurs acutely, but you also want the mass cell stabilizing capabilities so patients will be able to avoid those symptoms altogether. For example, if a patient is going to visit grandma who has a cat they’re allergic to, they can put drops in that have mass cell stabilizing capabilities so they stay comfortable during the visit.
Dr. O’Brien: I think biocompatibility is especially important for those of us in the eyec a re field. Whenever we’re applying an agent topically to the ocular surface, we want to be assured that in addition to efficacy, we are pre serving comfort and not adding insult to an already inflamed eye.
Sometimes we get so sub-specialized in medicine that ophthalmologists and allergists don’t have as much interaction as might be beneficial for our patients who suffer from diseases such as allergy that overlap different systems. Dr. Bradley Chipps will explore this topic, focusing particularly on the unified allergic airway, ocular symptoms in allergy sufferers and the future of Anti-IgE therapy.
MAKING THE CONNECTION
Dr. O’Brien, MD: Although ophthalmologists and allergists have traditionally not communicated as frequently or extensively as perhaps optimal, we are nevertheless connected at least anatomically, if you will, by the nasolacrimal duct and also perhaps through the airway. Dr. Chipps, perhaps you could discuss for those of us in ophthalmology this emerging concept of “one airway” as it relates to allergy?
Bradley Chipps, MD: As we look at the respiratory epithelium from the nose to the most peripheral bronchi, we basically have a continuous epithelial surface. The corneal surface, of course, although anatomically separate, has the highest collection of mast cells of any organ in the body, so is clearly part of the unified allergic airway and a major player in the morbidity and burden of illness that patients with allergic disease have—especially seasonal allergic rhinitis, where the ocular symptoms can be debilitating and keep people from their regular activities. So as we then look at allergic rhinitis and the protean manifestations that ocular disease is occurs, we have to figure out what the best treatments are to decrease this significant problem that causes our patients to have significant functional disabilities, quality of life and also ability to work and go to school.
Dr. O’Brien: You make some valid points and this emerging concept of the “one airway” is crucial for both ophthalmologists and allergists to recognize that we cannot avoid one area by concentrating too much on another in terms of our treatment strategies. Clearly, some patients have principally ocular findings of allergy and in others, the symptoms are centered more exclusively in the nose. However, I think that there is a significant proportion who suffer from both rhinitis and allergic conjunctivitis. Thus, the term allergic rhinoconjunctivitis remains valid.
Dr. Chipps: I would put that proportion at least at two-thirds . We have a significant comorbid problem with nasal airway disease and one that often is underappreciated and then implicit to that of course invites lack of specific treatment.
Dr. O’Brien: Exactly. I think there’s a general underappreciation of how many patients with systemic allergy have ocular symptoms. As you point out, the studies indicate that greater than 80 percent of patients suffering with allergy are also suffering with ocular symptoms. With this unified airway concept, how can we best treat all symptoms—that is the nasal, the airway and the ocular disease?
Dr. Chipps: We’re particularly taken with the notion of being able to treat both the nose and the eye with the same pharmacologic preparation . With the advent of olopatadine HCl 0.1% (Patanol, Alcon) being available as a nasal preparation, an inverse histamine agonist, a mast cell stabilizer with multiple targets that are positively effected, we have the ability to avoid the use of a corticosteroid to treat both the eyes and the nose in a very safe and effective way and will give a whole new perspective to our patients to be able to address this.
Dr. O’Brien: I think you are so correct to emphasize the safety aspect of treatment, especially with a chronic disease where there is a cumulative potentially damaging effect of corticosteroid therapy to the ocular tissues as well as other tissues of the body. As an allergist, when do you treat and when to refer? It’s been my feeling that we should collaborate more directly as complimentary subspecialists with our patients. Where do you see the synergies where allergists can work closely together with eyecare providers?
Dr. Chipps: Clearly, when there’s unilateral disease, loss of visual acuity and eye pain, we have to involve you folks. We need your expertise on slit lamp evaluation, corneal staining, etc. This especially holds true for unilateral disease and for refractory bilateral disease, when itching is not a major component.
Dr. O’Brien: I think, for the allergist, when you have patients who present with a red eye accompanied by the triad of pain, decreased vision and photophobia, these are the warning signs as you appropriately pointed out, that would mandate referral to an eyecare specialist.
As we work more closely together, we can better serve our patients by recognizing when there ’s an acute pro blem and vice versa on the ophthalmic side when a patient is suffering systemically. Perhaps we as eyecare providers have been focusing more intently on the eye and avoiding some of the other systemic comorbidities that patients are suffering from . What are some areas of development in the allergy - related phar maceutical industry that are particularly interesting to you as an allergist ?
Dr. Chipps: One of the things that strikes me is the whole notion of patients’ acceptance of these drugs , which is inextricably bound to the comfort that the drug provides to the eye when it’s placed on the conjunctival membrane. And we know that since ketotifen fumarate 0.025% (Zaditor, Novartis) is now an over- the - counter (OTC) preparation, we have a lot of pressure from insurance companies and pharmacy benefit managers to push patients to use an OTC preparation as opposed to a prescription preparation. It is important to keep in mind that if a patient isn’t able to accept a drug because of discomfort , they’re not going to use it, and will obviously not get the clinical benefit we would hope they would.
Dr. O’Brien: Dr. Warner Carr’s preference study (presented at the Western Society of allergy, Asthma and Immunology meeting in Hawaii in January) reassures us that a pharmaceutical agent is more likely to be not only effective, but safer and better tolerated by the patients than perhaps an OTC, lesser effective agent that has a greater adverse drug reaction profile.2 What are some of the challenges also faced with this managed care environment where nasal spray usage has perhaps not been optimized?
Dr. Chipps: Cetirizine HCl ( Z y rtec, McNeil-PPC) has recently been released as an OTC product and more and more insurance companies and pharmacy benefit managers are pushing patients to use an OTC preparations. As you know, the only nasal preparation we have is NasalChrom (cromolyn sodium), which is dosed t.i.d. or q.i.d., so it’s not very practical to use that. So we’re left then with nasal steroid and then the nasal antihistamine preparations as our choices as a prescription product. In my practice, I try to use a nonsteroidal compound if it has equal or better efficacy than a steroid compound at every juncture. So, again, as the two nonsteroidal nasal sprays became available, we want to make sure that the provider community is informed re g a rding the efficacy, the indications and the fact that it is a very rational alternative strategy to nasal steroid, which of course has been dramatically underused compared to nasal H1 inverse agonists, the oral second generation antihistamines.
Dr. O’Brien: Over the years, there have been a lot of hopes for anti-IgE therapy for allergy sufferers. Where do we stand with anti-IgE currently and what is on the recent horizon in this promising area?
Dr. Chipps: Anti-IgE therapy (omalizumab [Xolair, Genentech /Novartis]) is a novel biologic product that is quite expensive. It is, however, extremely effective in patients who have allergically mediated asthma that is not well controlled by the expert panel III, step IV guidelines (medium does of inhaled steroid and a long-acting beta agonist with or without an leukotrine-modifying agent). The drug has been shown to decrease exacerbations, improve quality of life, decrease courses of oral prednisone and have a modest improvement in lung function. We need to continue to expand the indications for omalizumab.
One potential indication is the treatment of allergic rhinitis, both as primary therapy, and also in a study that Dr. Tom Casale and the Immunotherapy Treatment Network published that showed that when omalizumab is used concurrently with immunotherapy, a dramatic decrease in reaction rate occurred .3 The reaction rate went from 12 percent basically to 0 percent, so we’re able then to treat patients more effectively with immunotherapy, get them to maintenance quicker and also treat patients who were having reactions before and that’s hopefully going to allow them to use immunotherapy to decrease the burden of their illness and as a disease-modifying strategy.
Additionally, omalizumab is being investigated in other areas: patients with latex sensitivity, patients with multiple drug sensitivity, patients with refractory urticaria, patients with eczema—again these are areas that a FDA-approved indication is not currently available, but are being investigated and the children’s study has been completed. I’ve participated in that. We’ll begin to see analyses of these data once the database is locked and hopefully will lead it then at some point in time to an indication for omalizumab for children 6 to 12 years of age realizing the indication now is 12 years of age and above.
Dr. O’Brien: The future certainly looks bright for both pediatric and adult sufferers . You mentioned quality of life and clearly, with millions of people suffering from allergy, the impact of chronic disease on their quality of life is not to be underestimated. You’ve had a long track record of using olopatadine 0.1% on a b.i.d. basis for patients suffering fro m seasonal and perennial allergic conjunctivitis. What’s been the impact of your experience with the olopatadine HCl 0.2% ( Pataday, Alcon) once daily in terms of patient compliance and their quality of life?
Dr. Chipps: Patients seem to like it better because it’s once a day and they found the efficacy to be equal to the previous 0.1% formulation, realizing that we’ve not gone though a spring allergy season yet where I practice with the 0.1 and the 0.2 both available to compare them head to head. We’ll do that this spring, so we’ll have a better idea then. But at least for the perennial patients they love having just one drop once a day—that’s it and it works for 24 hours and they’re extremely happy with that.
Dr. O’Brien: Certainly in ophthalmology and glaucoma we’ve realized for many years that compliance is an issue— especially when we request that our patients take multiple agents multiple times a day. It’s challenging for busy people— especially for working mothers and fathers caring for the pediatric group—to administer drugs so frequently, so the once a day can definitely improve compliance. We mentioned the nasolacrimal duct and the “one airway”. Clearly, an eye dro p applied to the surface of the eye can migrate into the nasal tissues and have some efficacy as has been shown previously.
Dr. Chipps: I think the story is more complicated than just the nasolacrimal duct. There is surely some systemic trafficking molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM), the eotaxin that are down-regulated by this molecule and also when we use this molecule in the nose, the nasal ocular reflex arc can be blocked too, so I think there a re clearly multiple sites where the drug has a high probability of having a positive impact and as a result, I think we’re going to see that we can use the same drug in the eye and nose and it’s not a steroid. We have a fantastic opportunity to control symptoms in a safe manner.
Dr. O’Brien: Is there anything else you’d like to share about the combination of systemic and ocular allergy?
Dr. Chipps: An article from the Annals of Allergy Proceedings looked at olopatadine nasal spray with seasonal allergic rhinitis showing a pristine safety profile, but also a significant improvement in not only total nasal symptoms, but quality of life and work production activity Index all show-ing positive results and as a result consequently, a better functionality and a significantly improved quality of life.4 That’s really where the battle is won or lost with allergic rhinitis . You have to improve a patient’s quality of life and the two things that drive the patient in are their eye symptoms and nasal congestion and both are the major problems with that realizing of course then the comorbidities associated with allergic rhinitis, perinasal sinus disease, ear disease, obstructive sleep apnea, asthma—all a re very important and all can be improved with appropriate treatment of the nasal airway.
Dr. O’Brien: On the topic of the most appropriate treatment for ocular allergy, Dr. Michael Raizman will discuss available options (eg, combination products and once-a-day formulations) as well as patient preference when it comes to the treatment of their condition.
FOCUS ON TREATMENTS
Dr. O’Brien, MD: Dr. Raizman, can you share with us some of the features that you view as being particularly well suited for mast cell stabilizer/antihistamine combination products and which have you employed in your practice to most effectively benefit your patients suffering from ocular allergy?
Michael B. Raizman: I’ve had the most experience with olopatadine 0.1%, olopatadine 0.2%, epinastine HCl 0.05% (Elestat, Allergan) and azelastine HCl (Optivar, MedPointe). they're all good, safe and effective products and patients benefit from them. I tend not to use azelastine because patients find it to be less comfortable on their eye and some complain about the taste of the product in their throat after instillation in the eye.
Epinastine is well tolerated and I think it and olopatadine 0.1% have similar, excellent characteristics. If patients like these products, I have them continue to use them. With the advent of olopatadine 0.2%, we have an even more effective formulation of olopatadine and in my year or so experience using this new, higher concentration formulation, I think my patients really like the new product and seem to get even better efficacy than they got with olopatadine 0.1%.
Dr. O’Brien: You’ve made some excellent points about the products that are available and I think we all have evolved toward a preference for combination products. We’ve realized that not only is the antihistaminic effect important, but so is the mast cell stabilization. We can draw some corollaries with glaucoma and we know that our glaucoma patients, who are sometimes taking multiple medications multiple times a day, become rapidly fatigued both physically, emotionally and even financially, with the burden of taking so many drops. Clearly, a once-aday preparation is desirable if it has the same efficacy, comfort and other profile as the b.i.d. product. What do you think the future of once-a-day coverage will provide ?
Dr. Raizman: As you’ve mentioned across the board in ophthalmology at least, we’re seeing a lot of products being designed to last longer and be administered less often, whether it’s a topical nonsteroidal, a pressure -lowering agent or an agent to treat allergy. Patients definitely appreciate drops that allow less frequent administration and as a result, we’re seeing better compliance.
Dr. O’Brien: Is there anything you do by way of historic inquiry to determine the optimal time for administration of the once-a-day agent? Is there a subset of patients who are actually more prone to nocturnal allergy from their sleeping environment (eg, pillows, dust mites under the bed)?
Dr. Raizman: there definitely are patients who experience more itching at different times of the day. A lot of my patients who have dust mite allergies tend to have more itching in the morning when they first get out of bed, so those patients often benefit from putting drops in the night before. It depends on when their symptoms are greatest . Some patients only really have symptoms when they’re outside playing golf or mowing the lawn. For this group, I suggest instilling a quick-working drop maybe 15 to 30 minutes before they’re going to be exposed outdoors. You have to be flexible and talk to patients about their options.
Dr. O’Brien: Despite the popularity of refractive surgery, we still have approximately 30 million individuals using contact lenses of one type or another. What’s been your experience with the use of combination products for patients suffering from contact lensmediated allergic syndromes?
Dr. Raizman: Patients who have a condition such as giant papillary conjunctivitis (GPC) will often get good relief from the use of an antihistamine/ mass cell stabilizer combination. However, in these patients, it’s most important to address the primary problem, which is generally related to the lens coating and materials.
Occasionally, I’ll see a patient whose symptoms are relatively mild and they’ll be able to continue wearing their lenses in the same manner they did before simply by adding an antihistamine/mass cell stabilizer drop . However, in most instances, I can find ways to improve their comfort by modifying the type of lens they’re wearing, their cleaning regiments, and the solutions that they use to clean it or by switching them to more frequent disposal of the lenses. A daily disposable lens is really ideal for a patient who has allergy - related contact lens issues
Dr. O’Brien: So while the pharmacotherapy is beneficial, you also have to address mechanical issues that are underlying and contributing to the genesis of the condition?
Dr. Raizman: And I actually prefer to address those points first, rather than relying on a pharmacologic approach.
Dr. O’Brien: Certainly we know that the environment plays a role in allergy and that some patients are more genetically predisposed than others, however, the environment adds to the genetic predisposition. What do we know about seasonal allergic conjunctivitis and fluctuations in antigen load and how products can still be beneficial for relieving itching and redness?
Dr. Raizman: there ’s no question that through the allergy season, the amount of pollen t hat’s in the air varies from day to day and even from one time of day to another. Therefore , patients will have trouble predicting when they’re going to have the most symptoms. So if you have an effective product that a patient uses every day, that will work for them whether it’s a light pollen day, a heavy pollen day or regardless of their activities on those days.
Dr. O’Brien: As you pointed out earlier, the general preference for agents that have a sustained duration of action in addition to acute efficacy is an evolving trend in ophthalmology certainly with regard to allergy, but also, as you mention, in other therapies for inflammatory conditions as with the nonsteroidal agents as well.
Dr. Raizman: If I have patients who are fairly symptomatic during allergy season, it’s easier to tell them to use the d rop every day rather than trying to guess what day they’re going to have problems with it. So through however many weeks of the allergy season, if they can put a drop with sustained efficacy in once a day, it’s a simple way for them to manage their symptoms.
Dr. O’Brien: Sometimes when ophthalmologists are focusing in biomicroscopically at high magnification on the ocular tissues, they may momentarily overlook that the eye is connected to the rest of the body. Vice versa, allergists , when dealing with important symptoms that involve the nose and airway, may disregard factors about the eye. Dr. William Berger will examine the use of nasal sprays, the addition of topical ocular agents to a treatment regimen and the role of histamine receptors in the ocular allergic response .
Dr. O’Brien, MD: Dr. Berger, based on your extensive clinical experience, how effective are nasal sprays at treating ocular symptoms of allergy?
William Berger, MD: Many of the studies that were conducted to bring these medications to market use what we refer to as the rhinoconjunctivitis quality of life. And not only were nasal symptoms assessed through a nasal symptoms score that included nasal congestion, post-nasal drip, sneezing and itchy nose, but also in looking at eye symptoms such as itchy, red eyes, tearing and patient discomfort and, as a result, many of the nasal sprays not only helped improve the scoring system of nasal symptoms, but they also improved eye symptoms.
However, these studies were conducted with the nasal spray versus placebo, not with the nasal spray, for example, compared to an ocular product, so the improvement in the eye symptoms, many believe, is due to the fact that there is some reflex where relief of nasal symptoms will also improve eye symptoms, but it is not a direct effect of the nasal spray on the eye .5 In fact, the makers of nasal corticosteroids are quick to point out that it’s not the corticosteroid, for example, going up the nasal lacrimal duct and getting into the eye because they don’t want to create a concern about cataract fomation or glaucoma. And they certainly wouldn’t want to give the impression that this is a systemic effect, so they propose a theory that has not been well documented, but might explain the ocular improvement with the nasal steroid sprays.
Dr. O’Brien: We have a spectrum of disease and, yes, while some patients have principally conjunctivitis of an allergicetiology, and others have purely rhinitis, the majority of patients fall somewhere in between, where they suffer variably from rhinoconjunctivitis. Tell us about your experience with topical ocular medications being applied to the eye, then helping the rhinitis?
Dr. Berger: Many of us know that, for example, if you have a pungent odor or irritation to the nose, and your nose runs, your eyes might also be affected and very often, you’ll get tearing. But we also know that if there is an injury to the eye, very often, your nose runs even though there’s not a direct irritant to the nose. So we’re aware that patients who have an improvement in their eye symptoms will tell us that their nasal symptoms improve and vice versa.
But it’s important for practitioners to know that some very good studies have shown that even with optimal therapy of allergic rhinitis with either nasal steroids or systemic oral antihistamines, the addition of a topical eye preparation to the eye significantly improved eye symptomatology over and above just using the oral antihistamine or the nasal steroid alone.6
Dr. O’Brien: Carr and colleagues presented a paper summarizing a study demonstrating the shortcomings of treating the ocular symptoms with just a nasal spray alone.7 Can you discuss the pivotal findings from these studies?
Dr. Berger: Basically, patients were put into studies where they were either on a oral antihistamine such as fexofenadine HCl (Allegra, Sanofi Aventis) or loratadine or on a nasal steroid (usually one of the topical nasal corticosteroids). It was shown that using not only a rhinoconjunctivitis quality of life tool, but also a specific conjunctivitis quality of life tool, that there was a significant improvement in patients who had an ocular preparation added to their regimen as opposed to a placebo. There was also a very large difference between those who had been treated with an oral antihistamine or nasal steroid alone versus those who had the addition of an eye product. In this case, olopatadine (Patanol, Alcon) was the medication being tested and there was a statistically significant improvement in patients who had been previously thought to be optimally treated by adding this medication.
Dr. O’Brien: As a systemic allergist, clearly you’ve had an appreciation for the role of the mast cell in the cascade of events that occur in allergy and the eye is unique— especially the conjunctiva of having a high number of mast cells of a unique type. Given that, with your understanding, can you discuss your preference for a combination agent that has both mast cell stabilization properties as well as antihistaminic properties over either medication alone in the management of your patients with allergic rhinoconjunctivitis?
Dr. Berger : People normally think of allergies as only affecting the nose, yet according to the Gallup survey of allergy taken in 2005, more than 50 percent, and in some studies up to 90 percent of patients who have nasal allergies also have eye allergies, but most patients and many doctors don’t clearly understand the mechanism by which this occurs.
We can become sensitized to certain allergens, and this process is genetically determined. And that genetic tendency to develop allergy causes you to produce IgE, which is the allergy antibody that circulates in the bloodstream and is in excess or elevated amounts in patients who have allergies. The IgE circulates in the bloodstream and binds to mast cells in the respiratory tract and the conjunctiva. When you come in contact with something to which you are allergic (pollen, animal dander, dust mite), there is cross-linking on the mast cell surface of the antigen with cell-bound IgE, literally a key and lock mechanism where it unlocks the cell and activates the mast cell, releasing many mediators. Some mediators are pre-formed and others are newly synthesized, which help to maintain or sustain that inflammatory reaction.
The idea of having a medication that has a dual mechanism certainly is attractive in that it can stabilize the mast cell so that it does not release these mediators that cause inflammatory reaction and also that it blocks the receptors on the cell surface that are mediated by histamine, which can cause the allergic reaction. And the chemical histamine causes the vasodilation, itching, runny nose and eyes that patients often complain about. So to be able to have a medication that works on two different significant mechanisms of the inflammatory process would be preferable to a medication that only worked at only one stage.
Dr. O’Brien: You’ve emphasized the importance of histamine as the principal mediator in this cascade, and over the years, we’ve learned more about the histamine receptors and we’ve recognized that there may be more than one type involved. Can you discuss what we know about histamine 1 (H1) and histamine 2 (H2) receptors and their role in the ocular allergic response?
Dr. Berger: The biology of histamine receptors is interesting in that many people are aware of the fact of H1 receptor antagonist being referred to as “antihistamines”. People know about loratadine, fexofe-nadine and chlorpheniramine (various), and these usually are associated with nasal allergies and have not been all that effective systemically for ocular allergies, but a lot of people aren’t aware of the fact that there are H2 receptors, which are often involved in the gastrointestinal tract (we use H2 receptor antagonists to treat people, for example, who have gastric acid secretion).
Evidence even points to the fact that both H1 and H2 receptor antagonists exist in the skin and sometimes allergists will actually treat urticaria , chronic urticaria (hives) and even angioedema with a combination of both H1 and H2 receptors such as using hydro xyzine (Atarax, Vistaril) together with cimetidine (Tagamet , GlaxoSmithKline ) .8 Controversy does exist, however, about whether the H2 receptors play an important role in the eye in t erms of the redness that’s associated with eye symptoms. The predominant receptor certainly, is the H1 receptor, but the jury ’s still out about H2 receptor antagonist activity.
Dr. O’Brien: Are there also other histamine receptors that we need to be aware of?
Dr. Berger : there have been a description of both H3 and H4 receptors, but at the present time, they’re of academic interest only because we don’t have any specific H3 and H4 re c e ptor antagonist that we can treat.
Dr. O’Brien: Are there any recent findings that are particularly exciting to you that may have impact for your patients suffering from ocular allergy as well as rhinitis?
Dr. Berger: From purely a clinical point of view as an allergist, if I could give some advice, patients will complain bitterly of their nasal allergies and it isn’t until you actually ask them when they start to describe their eye symptoms. So very often, allergists, who are I guess focused on the nose, don’t really ask about the eye, so often, they’re just treated with nasal topical steroids or possibly systemic oral antihistamines, when in fact, clearly the most effective and safest therapy is what doctors in my field are looking to, which is topical targeted therapy. So the mass cell stabilizer antihistamine eye drops are much more effective than giving a tablet throughout the body. And from the other point of view, we want the ophthalmologists to know that there is a body below the eyes.
In patients who have allergic eye disease, it is rare for them to have isolated allergic eye disease. In the vast majority of cases, they also have allergic nasal disease and if it’s not something that they’re prepared to handle, then they might provide tremendous benefit to their patients to get an allergy consultation.
Dr. O’Brien: I think certainly we are all at times guilty of perhaps excessive sub-specialization. We can collectively work in closer collaboration as allergists and ophthalmologists on behalf of our patients with two eyes and one body suffering with allergy.
- Spiliotopoulos C, Mastronikolis NS,
Petropoulos IK, et al. The effect of nasal steroid
administration on intraocular pressure. Ear Nose
Throat J. 2007;86(7):394–395.
- Carr study re: pharmaceutical agent vs. OTC
- Casale TB, Busse WW, Kline JN, et al.
Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweedinduced seasonal allergic rhinitis. J Allergy Clin
- Fairchild CJ, Meltzer EO, Roland PS, et al. Comprehensive report of the efficacy, safety,
quality of life, and work impact of olopatadine
0.6% and olopatadine 0.4% treatment in patients
with seasonal allergic rhinitis. Allergy and
Asthma Proceedings. 2007;28(6):716–723.
- Kaiser HB, Naclerio RM, Given J, et al.
Fluticasone furoate nasal spray: a single tre a tment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol. 2007 ; 119 ( 6 ) : 1430 – 1437 .
- Berger W, Abelson MB, Gomes PJ, et al. E ffects of adjuvant therapy with 0.1% olopatadine hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using
systemic or nasal therapy. Ann Allergy Asthma
- Carr. Poster presentation: Optimal treatment
of allergic conjunctivitis in patients with allergic
rhinitis. Western Society of Allergy, Asthma and
Immunology. Kailua-Kona, Hawaii, January
- Greaves MW, Davies MG. Histamine receptors in human skin: indirect evidence. Br J Dermatol . 1982 ; 107 (Suppl ) 23:101 – 105.