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Symposium: Treatment Options for Ocular Allergies
A global perspective
Jose Güell, MD: Red eye is one of the most common conditions observed by ophthalmologists and primary care physicians (Figure 1). Ocular allergy is a major cause of red eye.
It is a worldwide problem and affects many quality of life aspects, including social interaction, work productivity, ability to sleep and general well-being.
The primary objectives of treatment center on resolution of clinical signs and symptoms. The choice of the treatment will be based on a medication’s efficacy in treating signs and symptoms of the types of allergic conjunctivitis, as well as dosing convenience and comfort.
Diagnosis of ocular allergy
Güell: What are the clinical signs and symptoms of red eye?
Mark B. Abelson, MD, CM, FRCS: Red eye in and of itself is not descriptive because many types of redness exist. For example, a deep red is usually more significant in endophthalmitis or severe uveitis.
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A light pink color generally indicates seasonal allergy. The pattern of redness in seasonal allergic conjunctivitis, although it may affect the circumlimbal area, is generally diffuse and associated with a pink type of fluid. The fluid is probably a mixture of transudate, exudate and cells in the subconjunctival space producing a mild chemosis.
Güell: What tests or characteristics are important for an ophthalmologist to diagnose red eye as ocular allergy?
Alejandro J. Aguilar, MD: Ophthalmologists may decide to perform laboratory tests when signs and symptoms are not clear.1 In patients with allergy, immunoglobulin E (IgE) is elevated in tears. IgE may not be elevated in other ocular conditions such as dry eye.
Metaplasia will not be associated with allergy, but ophthalmologists may detect an increase in the number of mast cells that produce mucus.
Abelson: When making a differential diagnosis, ophthalmologists must examine the distribution and caliber of vessels and determine whether they are deep vessels of the sclera or superficial vessels of the conjunctiva. They must also classify vessel location as conjunctival, palpebral or perilimbal.
Ophthalmologists should also examine the conjunctiva under the surface of the upper and lower lids for evidence of a papillary reaction.
Ophthalmologists should characterize mucus present in the eye. Thick, gelatinous and purulent mucus may signal bacterial conjunctivitis. Thin, translucent and stringy mucus is common with dry eye. Globular mucus is common with certain types of allergic conjunctivitis. Seasonal allergic conjunctivitis, however, is not particularly a mucus-producing condition.
Differential diagnosis
Abelson: Are there any particular criteria of the red eye that help ophthalmologists reach a differential diagnosis of ocular allergy?
Panayotis Zafirakis, MD: Differential diagnosis is the foundation of treatment, and appropriate treatment of each patient relies on correct diagnosis (Figure 2). Differential diagnosis can be done accurately yet quickly in most cases, keeping in mind the golden rules: If the eye is itchy, it may be allergy; if the eye is sticky, it may be bacterial conjunctivitis; and if the eye burns, it may be dry eye.
For a differential diagnosis, if the red eye has pain with blurred vision, an ophthalmologist must be able to rule out iritis, uveitis, acute glaucoma and keratitis.
| Source: Leonardi A. |
If the red eye has discharge, the ophthalmologist must determine what kind of discharge. If the discharge is purulent, bacterial conjunctivitis may be the correct diagnosis. If the discharge is watery, viral or allergic disease may be the correct diagnosis, and if the discharge is watery with itching, the patient most probably has allergic conjunctivitis.
Jesús Merayo-Lloves, MD, PhD, MBA, DO: Differential diagnosis should be conducted from the basic level. Most patients with allergy complain of itching. Pain, pupil abnormalities and corneal injury are not related to allergies.
In a differential diagnosis of ocular allergic disorders, the No. 1 consideration is dry eye. Patients with dry eye will complain of burning, sandy eyes. If the ocular surface is not protected appropriately, the patient eventually could develop an allergic reaction.
Andrea Leonardi, MD: The most common diseases that are part of the differential diagnosis with ocular allergy are dry eye, toxic and mechanical conjunctivitis, blepharitis and chronic infection such as chlamydia.
Seasonal allergic conjunctivitis can be easily diagnosed through patient history and the type of allergen exposure. Additional tests are not necessary to determine whether the patient is experiencing an allergic reaction.
Allergic tests, however, can provide insight into the specific allergen and offer an opportunity to prevent or minimize exposure; thus, skin-prick tests are recommended.
Chronic diseases such as perennial allergic conjunctivitis are the most difficult to diagnose. Aside from taking history and allergen exposure information, cytology is helpful to determine the type of inflammatory cells present. If eosinophils are not found in tears or in conjunctiva scraping, the condition may not be allergy. If eosinophils are present, ophthalmologists should consider a skin test. If no cells are found in the cytology and the patient is in an active phase of the disease, it is most likely not an allergic condition and other diseases should be considered.
Dry eye and blepharitis
Abelson: What role do dry eye and blepharitis play in allergy?
Kyoung Yul Seo, MD, PhD: All atopic patients have some degree of dry eye and blepharitis, in my experience. Tear-deficient-type dry eye is combined with blepharitis, as in Sjögren’s syndrome. In Sjögren’s syndrome, even though the major pathology is reduced tear volume, decreased emulsification of lipid from the eyelid will be present.
Patients with a long history of atopy have decreased tears and some component of meibomian gland dysfunction. A reduction in the number of goblet cells in allergic patients contributes to a breakdown of mucin layer, eventually aggravating dry eye.2,3
Abelson: Dry eye and allergy are two common conditions. Up to 25% of people have allergic conjunctivitis, and between 7% and 15% of people will experience a degree of dry eye associated with a disease such as Sjögren’s syndrome or based on medication, dehydration or environmental factors.4
As tear film decreases, a barrier of protection is lost. The concentration of pollen able to penetrate through the conjunctiva will be higher and more likely to cause an allergic response.
Leonardi: The symptoms of dry eye are different from those of allergic conjunctivitis, but the two conditions may overlap. For example, a patient allergic to mites may also have dry eyes.
Another common condition associated with allergy is blepharitis, either seborrhea or meibomitis. Conversely, blepharitis may simulate an allergic condition.
For these reasons, ophthalmologists should carefully examine the eyelid dynamic, the eyelid margin, eyelashes and the eyelid glands in addition to the ocular surface.
The patient’s history and signs and symptoms of which the patient complains can draw the ophthalmologist toward a correct diagnosis.
A persistent conjunctival follicular reaction is likely associated with different conditions such as toxic conjunctivitis; drug-induced conjunctivitis, also called medicamentosa; or chronic infections, especially chlamydia.
In these cases, there may still be an allergic association, but performing an exact test, such as polymerase chain reaction assays for chlamydia or an accurate history of use or abuse of topical drugs, and the potential exposure to irritants may help ophthalmologists reach a diagnosis.
Dominique Brémond-Gignac, MD, PhD: In blepharitis in children, dry eye could be the first symptom after conjunctival allergy. It can be observed as first-time lid edema and then again as conjunctival allergy.
Abelson: Aside from the atopic blepharitis, is there an allergic blepharitis?
Güell: Different types of allergic blepharitis exist, but the most common is the contact type of blepharitis among patients who are allergic to metals, perfumes or chemicals that might come in contact with the skin of the eyelids. Most of the time, the conjunctiva is not involved.
The conjunctiva might be more involved in other types of blepharitis. Those are cases in which the patient can be allergic to mites, for example.
Pollens can be allergenic triggers in other types of blepharitis, not with an IgE direct type of reaction but rather with a contact-type cell-mediated reaction. Those types of blepharitis are less common and less easy to distinguish from allergic conjunctivitis, but the conjunctiva is usually more involved.
Merayo-Lloves: Atopic blepharitis can be seen in the context of atopic eczema in other areas of the skin; however, eczema in the lids or the lids margin is sometimes the only visible manifestation of atopic blepharitis.
It is not type-1 hypersensitivity, but can be put in the context of allergy or atopic keratoconjunctivitis. The first manifestation may be lid inflammation and eczema. Other types of blepharitis involve ocular rosacea or a reaction to a toxin from staphylococcal infection.
| Source: Leonardi A. |
Güell: Are ophthalmologists likely to see more early-phase or late-phase allergic reactions?
Leonardi: Most patients experience only an early-phase reaction, characterized by peaks of itching, redness and lid swelling.
Ophthalmologists must remember, however, that patients with seasonal allergies may have continuous exposure to allergens over the course of their daily activities.
A clinical late-phase reaction is characterized by persistent redness and swelling, and is related to the release of several mediators that induce the recruitment and activation of inflammatory cells in the conjunctiva (Figure 3).
Güell: Is the number of new diagnoses for seasonal and perennial allergic conjunctivitis increasing?
Abelson: Vernal allergies have become rare. The incidence of seasonal and panseasonal allergies, however, continues to rise in industrialized countries.
Zuguo Liu, MD, PhD: We investigated the clinical characteristics of 241 patients with allergic conjunctivitis in China and found that 99% of patients have itching, and 80.8% have foreign body sensation.5 The two symptoms were most common in allergic conjunctivitis.
The three most common signs include hyperemia, with an incidence of 93.7%; upper tarsus papilla, with an incidence of 88.1%; and follicle, with an incidence of 78.4%.
Those common symptoms and signs should be helpful in the diagnosis of allergic conjunctivitis.
Pediatric ocular allergy
Güell: Are there particular considerations at the time of diagnosis for pediatric patients with ocular allergies?
Brémond-Gignac: Allergy in children requires special considerations on the part of an ophthalmologist. Ophthalmologists must be cautious with pediatric red eye.
Children often do not elaborate on their symptoms. Questioning family members about daily symptoms is important.
Frequent eye rubbing may be caused by itching, which would suggest ocular allergy. Laboratory examinations such as conjunctival impression cytology could be helpful for follow-up on suspicious symptoms.6
Family history is also important because some studies have shown an effect of heredity. When one parent presents with any allergy, the risk of offspring developing the same allergy is 30% to 40%. The risk without an allergic parent is 15% to 20%. With an identical allergy in both parents, the risk increases by 70% to 80% for the same allergy among their offspring. If the mother is allergic, the risk is increased from two times to 10 times.7,8
Treatment goals and strategies
Güell: The goal of treatment for seasonal allergic conjunctivitis is to effectively resolve clinical signs and symptoms, and improve quality of life.
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How does targeting the mast cell and histamine help ophthalmologists achieve that goal?
Aguilar: One of the most important aspects of treatment is maintaining stabilization of mast cells. If mast cell activity is not blocked, symptoms such as itching and red eye will continue.
Ophthalmologists must know that conjunctival mast cells are specific mast cells (Figure 4).
Leonardi: Histamine is the main mediator in the allergic response. Histamine is responsible for ocular itching, redness, tearing and lid swelling – signs and symptoms typical in ocular allergy.
Zafirakis: Ophthalmologists know that histamine is the principal mediator of allergic conjunctivitis responsible for itching and vasodilation.
Ophthalmologists also know that mast cell stabilizers do not exhibit an immediate effect because itching will continue until all tear-film histamine is neutralized. If ophthalmologists improve the signs and symptoms of allergic conjunctivitis, they indirectly improve a patient’s quality of life.
Abelson: How do the dual targets of mast cells and histamine affect treatment decisions for seasonal allergic conjunctivitis?
 | Figure 4. This image captures a human conjunctival mast cell undergoing degranulation (area within yellow boundary) with histamine-containing granules spilling out of the cell. To acquire this image, human conjunctival tissue samples were collected from adult subjects with a documented history of allergic conjunctivitis. Samples were fixed in half-strength Karnovsky fixative immediately following sample procurement and were processed and imaged at the Schepens Eye Research Institute, Boston, using confocal technique. Source: Abelson MB |
Leonardi: Dual-acting drugs that combine histamine-receptor antagonism and mast-cell stabilization are important to block histamine-related symptoms and as prevention to inhibit mast-cell degranulation.
Aguilar: I prefer to treat an acute-phase patient with dual-action pharmaceuticals that function as mast cell stabilizers and antihistaminic drugs. My first option is to use a mast cell stabilizer together with an antihistaminic for seasonal and perennial allergies.
Zafirakis: Using a dual-action medication from the beginning of treatment offers two advantages.
First, the patient will use the same medication throughout treatment. Second, the patient will comply better with the regimen that calls for one medication instead of two medications.
Güell: What consideration should ophthalmologists give quality of life when making treatment decisions?
Brémond-Gignac: Quality of life is often the most important treatment goal for a patient although it may not be the same for every patient.9
Sometimes it is preferable to see if patients can avoid allergens. Sometimes it is difficult for patients to manage daily treatments. The quality-of-life goals should determine the treatment.
Zafirakis: Patients must be educated that an allergy is never cured. Ophthalmologists cure symptoms, not the disease. The first goal is to improve quality of life.
Allergies can have a negative effect on quality of life by causing physical impairment and by influencing social interactions.
Symptoms such as itching, sneezing and congested or runny nose can significantly affect sleep, visual tasks or productivity at work or school.
Ocular redness can be socially stigmatizing, as people with red eyes appear as if they did not get enough sleep, are drinking or have been crying. Lid swelling makes people look older or as if they have been crying or have not had enough sleep.
Treatment of ocular allergies, therefore, is aimed at improvement of both physical well-being and physical appearance.
Güell: How should ophthalmologists approach treatment for seasonal allergic conjunctivitis?
Zafirakis: Treating seasonal allergic conjunctivitis requires several steps. When pharmacological treatment is considered, the first choice should be a dual-action medication such as olopatadine (Opatanol [Europe]/Patanol solution, Alcon Inc.).
In addition to pharmacological treatment, ophthalmologists may wish to consider nonpharmacologic treatment.
This can include avoidance of allergens, which may be difficult for some patients. Cold compresses may relieve symptoms.
Another option is tear substitutes; they are an important line of defense. Tear substitutes dilute allergen and mediators in tears and flush allergen and mediators out of the eye.
Peter McCluskey, MD, FRANZCO, FRACS: I have moderately used artificial lubricating eye drops in patients with allergic eye disease because many patients do not have aqueous tear deficiency with this disease.
They have an unstable tear film with a pro-inflammatory tear film composition that needs to be normalized.
Liu: In China, severe industrial pollution leads to dry eye and allergen in about 20% of patients.
Ophthalmologists typically treat these patients with anti-allergy medication and artificial tears. For patients with less severe allergies, ophthalmologists generally do not use artificial tears.
Merayo-Lloves: Among nonpharmacologic options, my first approach in the treatment of seasonal allergic conjunctivitis is patient education. The second is physical therapy, such as cold compresses.
The third is artificial tears, preferably a product that offers long-term stability in the ocular surface that does not interfere with vision. After this initial step, most patients need anti-allergy eye drops such as olopatadine.
I limit the use of steroids. The administration of steroids should be monitored closely and controlled by the ophthalmologist.
I prefer to use custom-made, preservative-free eye drops that are provided by a local pharmacy for specific patients.
Treatment categories
Güell: The available treatments for seasonal allergic conjunctivitis include over-the-counter decongestants/vasoconstrictors, antihistamines, mast cell stabilizers, steroids and multiaction compounds.
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Do systemic antihistamines offer treatment value for seasonal allergic conjunctivitis?
Abelson: Systemic antihistamines, even new ones that are nonsedating, are drying and can decrease tear production by at least 50%.10 Even among patients with normal tear production, tear production can decrease dramatically. Patients can be elevated into a more severe dry eye condition.
Although the antihistamine may help systemically, it can actually worsen ocular allergy. That may be more evident in people who face environmental challenges.
Aguilar: One of the most dangerous adverse effects of systemic antihistamines is an anticholinergic effect that can produce dryness and, in few patients, can produce glaucoma.
Güell: What problems do ophthalmologists encounter with common treatment modalities?
Zafirakis: Vasoconstrictors can produce dryness, which increases the allergic symptoms.
Abelson: Available vasoconstrictors – phenylephrine, oxymetazoline and naphazoline – have limited vasoconstriction ability that does not last 90 minutes, yet they should not be used more than four times a day. The same is true of 0.25% pheniramine maleate, which is a common over-the-counter antihistamine available worldwide. These antihistamines last fewer than 2 hours but cannot be used more than four times a day.
The regimen does not provide the full coverage patients need. They go without relief for a long period or overuse the medications and face the possibility of medicamentosa. The more patients use them, the less the medications will decrease the redness.
Merayo-Lloves: Nonsteroidal anti-inflammatory drugs, in my opinion, are not effective in ocular allergy because cells such as eosinophils do not respond to the metabolic target of NSAIDs.
Abelson: Avoidance of allergens and non-pharmacologic approaches such as cold compresses can be effective but usually only for a brief period.
Patients are aware of these temporary solutions, as well as over-the-counter drops that act as eye washes or vasodilators and have minimal placebo effect.
Güell: Is there a role for oral antihistamines to treat allergic conjunctivitis without other manifestations of atopy?
Abelson: There is not a role for oral antihistamines in allergic conjunctivitis. Furthermore, there is probably less of a role and maybe no role for oral antihistamines in rhinoconjunctivitis.
An allergic, itchy, red swollen eye is best treated topically. A stuffy, red, nasal, swollen epithelium with sneezing and itching of the nose is best treated nasally with topical steroids or topical antihistamines.
Several studies addressed this issue and found a combination of a steroid nasal drop and olopatadine was superior to systemic antihistamines for rhinoconjunctivitis.11,12 The medication is delivered directly to the diseased tissue with little to no drying. Patients receive a more targeted effect of the therapeutic agent.
Güell: Is there any role for topical antihistamines or mast cell stabilizers alone?
Zafirakis: Both histamine and mast cells are important targets of ocular allergy treatment.
Histamine is the most important mediator to relieve the signs and symptoms of allergic conjunctivitis. A mast cell stabilizer is important for homeostasis of the disease.
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A mast cell stabilizer or antihistamine alone may not be effective. Olopatadine should be used for acute-phase allergies for the antihistamine action and for long-term stabilization of the mast cell.
Güell: Is there any indication for topical or systemic steroids?
Leonardi: Corticosteroids should be avoided in most patients with seasonal or chronic allergies.
General practitioners, however, frequently prescribe topical steroids for seasonal allergy, and patients often treat themselves with these drugs.
In Italy, pharmacists frequently give steroids directly to the patients without a prescription. Educating those involved in patient management is important to avoid adverse effects and to choose an effective and safe treatment.
Ophthalmologists should remember, however, that corticosteroids are the most effective drugs for the treatment of ocular surface inflammation and that ophthalmologists must use them when necessary.
Ophthalmologists must consider a topical steroid treatment when a patient presents with severe inflammatory, noninfective ocular surface disease, especially in vernal or atopic keratoconjunctivitis, to quickly reduce inflammation and yield an appropriate anti-allergy treatment.
Systemic steroids can be considered only in severe ocular allergic reactions involving the cornea or in extremely severe allergic blepharitis.
Dual-action clinical efficacy
Güell: How does olopatadine, a dual-action histamine and mast cell stabilizer, compare with other treatments for seasonal allergic conjunctivitis?
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Abelson: A study compared loteprednol etabonate 0.2% (Alrex, Bausch & Lomb) with olopatadine 0.1%.13 Although loteprednol is the optimal steroid for treating ocular inflammation, because of the nature of the acute insult in seasonal allergic conjunctivitis, it was theorized that a mast cell stabilizer-antihistamine would be more effective.
Researchers found olopatadine was more effective at inhibiting itching and redness, even allowing a 2-week load for loteprednol in a seasonal allergic model.
A study by Katelaris and colleagues compared cromolyn sodium 2% with olopatadine and found olopatadine was superior to that pure mast cell stabilizer.14
Both of these studies were well-designed — that is, both were randomized, masked, placebo-controlled and properly powered.
Arriving at the conclusion that one treatment is superior over the other requires that investigators find clinically relevant and statistically significant differences for appropriate, verified, primary endpoints.
Güell: How does olopatadine compare with epinastine in terms of symptom control?
Abelson: Lanier and colleagues performed a comparative study of olopatadine and epinastine (Elestat, Allergan).15 Olopatadine was significantly more effective in controlling itching, redness and chemosis.
In comparative studies of olopatadine and currently marketed products available worldwide,13-20 olopatadine has the broadest range of effectiveness and the greatest amount of efficacy in each of the symptom-relief categories, particularly the most important one of itching (Figure 5).
In the United States, olopatadine is the only therapeutic agent approved to treat redness. A series of attributive studies21-23 demonstrated olopatadine’s significant effect in reducing chemosis compared with other agents and its significant effect in reducing lid swelling, improving quality of life and decreasing the rhino component of rhinoconjunctivitis.
Güell: What have other clinical studies shown about olopatadine’s efficacy?
Leonardi: Preclinical studies of olopatadine showed it to be effective as a mast cell stabilizer in vitro and as a potent anti-H1-receptors antagonist.24,25
To prove the stabilizing effect of olopatadine on conjunctival mast cells in vivo, we recently performed an allergen challenge study comparing the effect of olopatadine with placebo.26
After 1 week of treatment, histamine levels were measured in tears before and after challenge. Significantly lower levels of histamine in tears occurred in the eyes pretreated with olopatadine, compared with eyes pretreated with placebo.
Histamine tear levels in placebo-treated eyes were as high as they were after challenge without any pretreatment, while olopatadine significantly reduced histamine release.
Abelson: In a study by Berger and colleagues, more than 90% of 200 patients with allergic rhinitis also had allergic symptoms.27
Olopatadine significantly improved ocular allergy and overall quality of life.
Maintaining or improving quality of life requires an agent that is comfortable, safe, rapid and long-acting, and relieves all signs and symptoms.
An agent that could accomplish these goals would be optimal.
How does ketotifen (Zaditor, Novartis) compare with olopatadine?
Aguilar: We compared the clinical activity of olopatadine 0.1% and ketotifen 0.05% in patients with seasonal and perennial allergies.28
The results were favorable for olopatadine against ketotifen, and patients tolerated olopatadine better than ketotifen.
Few adverse reactions occurred with olopatadine: about 4% vs. about 22.5% with ketotifen.
Leonardi: In a study conducted by Dr. Zafirakis and me, patients were asked how they reacted to olopatadine 0.1% or ketotifen 0.025% treatment.29 We treated 100 patients: 50 in Athens and 50 in Padua, Italy.
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All patients had active symptoms of seasonal allergic conjunctivitis when each patient received two bottles of eye drops in a double-masked fashion.
Patients treated themselves for 1 month with one or the other bottle, twice a day, based on which of the two bottles they preferred.
Zafirakis: Eighty percent of Italian patients and 82% of patients from Greece said olopatadine was the medication they preferred to use more often.
Olopatadine was the better medication for relief of allergy signs and symptoms among 78% of Italian patients and 82% of Greek patients (Figure 6).
The percentages were the same when patients were asked which bottle they would request from their ophthalmologists.
The majority of patients — 70% from Italy, 82% from Greece — determined their preferences based on efficacy and comfort.
Eighty percent of all patients responded that they were satisfied with olopatadine compared with previous medications that they had taken from the pharmacy.
Güell: How does olopatadine compare with levocabastine?
Leonardi: Olopatadine has several advantages compared with levocabastine,30 which is still a good antihistamine (H1-receptor antagonist).
Olopatadine is effective not only as an antihistamine but also as a mast cell stabilizer and thus has both a symptomatic and a preventive effect.
Olopatadine has a longer effect on the ocular surface compared with levocabastine, and thus can be prescribed twice daily compared with four times a day for levocabastine.
Olopatadine is more comfortable and better tolerated than levocabastine. Because levocabastine is a suspension, which is generally less tolerated, patients need to shake the bottle before application.
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All these factors explain the better compliance and better clinical results for olopatadine compared with levocabastine.
Treatments around the world
Abelson: What are global differences in the primary therapy choice for seasonal allergic conjunctivitis?
Aguilar: My first treatment choice in Argentina is mast cell stabilizer and antihistamine drugs in dual action and in the acute phase of the allergy response.
Leonardi: My first choice in Italy is dual-action drugs, such as olopatadine. I am satisfied with it, and I recommend olopatadine during the allergy season.
I do not recommend tear substitutes in seasonal allergy. I prefer to use an eye drop that is pharmacologically active, safe and comfortable.
For patients with vernal keratoconjunctivitis, I prefer to use a combination of drugs, usually lodoxamide (Alomide solution, Alcon Inc.) and olopatadine. Lodoxamide is effective in vernal patients. It not only is a mild mast cell stabilizer, but also has an effect on eosinophils.
When steroids are required in vernal or atopic conjunctivitis, I use them as a pulse therapy for a few days without stopping the mast cell stabilizer and the antihistamine treatment.
McCluskey: My treatment regimen in Australia now begins with a combination of a mast cell stabilizer and a topical antihistamine. A majority of ophthalmologists now would use that as their first choice. It is a superior class of drugs.
We try to reserve the use of topical steroids for severe cases. I also recommend ocular lubricants.
Liu: China does not have as many pharmacologic options as other countries. Antihistamines and mast cell stabilizers are available commercially, but an agent combining antihistamine and mast-cell-stabilization activity is not available.
For allergic patients, I treat first with an antihistamine and may add a mast cell stabilizer. If the treatment is not effective, I prescribe a low-concentration steroid, increasing the concentration as needed.
Patients who do not respond well to an initial steroid typically have dry eye, and artificial tears can be beneficial.
Güell: One of the standard ways to treat patients with vernal allergies in my practice in Barcelona has been systemic steroids at the lowest possible dose, instead of topical steroids. Olopatadine can reduce the systemic dose of steroids.
Zafirakis: When olopatadine became available in Greece, it was more effective for treating seasonal or vernal allergic conjunctivitis for two reasons.
First, olopatadine blocks specific H1 histaminic receptors, stopping the action of histamine. Second, the medication does not have a biphasic effect on the mast cell, as other dual-action medications do.
These other medications stabilize mast cells at low subtherapeutic levels but then lose that effect and may potentiate mast-cell degranulation once therapeutic drug levels are achieved.
For vernal keratoconjunctivitis and atopic keratoconjunctivitis, I use a combination of olopatadine and lodoxamide because lodoxamide has an anti-eosinophilic effect blocking the actions of basic major protein and eosinophilic cationic protein: two proteolytic enzymes that affect the cornea structure.
Steroids may have a role in severe conditions. I use steroids aggressively for a short period to avoid the adverse effects that they may produce after long-term treatment.
Brémond-Gignac: In France, ophthalmologists combine antihistamine and a mast cell stabilizer as a first-line treatment. I use dual-action medications in my practice.
For children, I also recommend a washing treatment because it is important to eliminate the maximum possible amount of allergen.
Seo: Korea is different from other countries because of a problem with an over-the-counter vasoconstrictor and topical steroid combination. The use of these eye drops caused cataracts and glaucoma. As a result, most of the vasoconstrictors and vasoconstrictor-steroid combinations are available only by prescription.
Ophthalmologists are now moving to combinations of olopatadine and other medications. In the past, ophthalmologists used antihistamines as first-line drugs.
Ophthalmologists used mast-cell stabilizing agents with antihistamines as second-line treatments and added topical steroid drops only in severe disease.
Recently, new antihistamines with mast-cell stabilizing action and second-generation mast cell stabilizers have become available and are the current trend in Korea.
Merayo-Lloves: In Madrid, ophthalmologists use olopatadine when the patient is symptomatic.
When the eye is not the only target of the allergic reaction and rhinitis is present, ophthalmologists use a systemic drug possibly with topical nasal therapy.
Abelson: It appears that despite some geographical differences in allergic patterns and treatment availability, a dual-action molecule that provides most mast cell stabilization and antihistamine activity is the preferred treatment for seasonal allergic conjunctivitis worldwide.
I would like to thank Ocular Surgery News and Alcon Inc. for organizing this panel. I would also like to thank our faculty for participating in an excellent discussion of allergic conjunctivitis in terms of its basic and clinical science, and pharmacology and epidemiology.
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- Welch D, Ousler GW 3rd, Nally LA, et al. Ocular drying associated with oral antihistamine (loratadine) in the normal population-an evaluation of exaggerated dose effect. Adv Exp Med Biol. 2002;506:1051-1055.
- Spangler DL, Abelson MB, Ober A, Gomes PJ. Randomized, double-masked comparison of olopatadine ophthalmic solution, mometasone furoate monohydrate nasal spray and fexofenadine hydrochloride tablets using the conjunctival and nasal allergen challenge models. Clin Ther. 2003;25:2245-2267.
- Lanier BQ, Abelson BM, Berger WE, et al. Comparison of the efficacy of combined fluticasone propionate and olopatadine versus combined fluticasone propionate and fexofenadine for the treatment of allergic rhinoconjunctivitis induced by conjunctival allergen challenge. Clin Ther. 2002;24:1161-1174.
- Berdy GJ, Stoppel JO, Epstein AB. Comparison of the clinical efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension in the conjunctival allergen challenge model. Clin Ther. 2002;24(9):1477-1478.
- Katelaris CH, Ciprandi G, Missotten L, et al. A comparison of the efficacy and tolerability of olopatadine hydrochloride 0.1% ophthalmic solution and cromolyn sodium 2% ophthalmic solution in seasonal allergic conjunctivitis. Clin Ther. 2002;24(10):1561-1575.
- Lanier BQ, Finegold I, D’Arienzo P, et al. Clinical efficacy of olopatadine vs epinastine ophthalmic solution in the conjunctival allergen challenge model. Curr Med Res Opin. 2004;20(8):1227-1233.
- Butrus S, Greiner JV, Discepola M, Finegold I. Comparison of the clinical efficacy and comfort of olopatadine hydrochloride 0.1% ophthalmic solution and nedocromil sodium 2% ophthalmic solution in the human conjunctival allergen challenge model. Clin Ther. 2000;22:1462-1472.
- Ciprandi G, Turner D, Gross RD. Double-masked, randomized, parallel-group study comparing olopatadine 0.1% ophthalmic solution with cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in children with seasonal allergic conjunctivitis. Curr Ther Res. 2004;65:189-199.
- Deschenes J, Discepola M, Abelson MB. Comparative evaluation of olopatadine ophthalmic solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using the provocative antigen challenge model. Acta Ophthalmolo Scand Suppl. 1999;228:47-52.
- Berdy GJ, Spangler DL, Bensch G, et al. A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther. 2000;22:826-833.
- Spangler DL, Bensch G, Berdy GJ. Evaluation of the efficacy of olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochloride 0.5% ophthalmic solution in the conjunctival allergen challenge model. Clin Ther. 2001;23:1272-1280.
- Abelson MB, Spitalny L. Combined analysis of two studies using the conjunctival allergen challenge model to evaluate olopatadine hydrochloride, a new ophthalmic antiallergic agent with dual activity. Am J Ophthalmol. 1998;125:797-804.
- Abelson MB, Gomes PJ, Vogelson CT, et al. Effects of a new formulation of olopatadine ophthalmic solution on nasal symptoms relative to placebo in two studies involving subjects with allergic conjunctivitis or rhinoconjunctivitis. Curr Med Res Opin. 2005;21:683-691.
- Abelson MB, Gomes PJ, Vogelson CT, et al. Clinical efficacy of olopatadine hydrochloride solution 0.2% compared with placebo in patients with allergic conjunctivitis or rhinoconjunctivitis: a randomized, double-masked environmental study. Clin Ther. 2004;26:1237-1248.
- Yanni JM, Miller ST, Gamache DA, et al. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol. 1997;79:541-545.
- Brockman HL, Momsen MM, Knudtson JR, et al. Interactions of olopatadine and selected antihistamines with model and natural membranes. Ocul Immunol Inflamm. 2003;11:247-268.
- Leonardi A, Abelson MB. Double-masked, randomized, placebo-controlled clinical study of the mast cell-stabilizing effects of treatment with olopatadine in the conjunctival allergen challenge model in humans. Clin Ther. 2003;25:2539-2552.
- Berger W, Abelson MB, Gomes PJ, et al. Effects 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 Immunol. 2005;95:361-371.
- Aguilar A. Comparative study of clinical efficacy and tolerance in seasonal allergic conjunctivitis management with 0.1% olopatadine hydrochloride versus 0.05% ketotifen fumarate. Acta Ophthalmol Scand Suppl. 2000;230:52-55.
- Leonardi A, Zafirakis P. Efficacy and comfort of olopatadine versus ketotifen ophthalmic solutions: a double-masked, environmental study of patient preference. Curr Med Res Opin. 2004;20(8):1167-1173.
- Abelson MB, Greiner JV. Comparative efficacy of olopatadine 0.1% ophthalmic solution versus levocabastine 0.05% ophthalmic suspension using the conjunctival allergen challenge model. Curr Med Res Opin. 2004;20:1953-1958.
Geographic differences in allergens set apart allergies around the globe
Mark B. Abelson, MD, CM, FRCS: The symptoms of seasonal allergic conjunctivitis — redness and itching — may be universal, but the triggers for the allergic reaction can differ significantly by geography. Allergens that can trigger seasonal allergic conjunctivitis range from dust mites to pollen and pet dander. Some allergens are more prevalent and may contribute more to patterns of ocular allergy in specific areas.
What are the most common allergens encountered in different countries? What are the geographical patterns of ocular allergy?
Zuguo Liu, MD, PhD: The most common allergen in urban China is pollution, which is severe in the cities. Seasonal allergic conjunctivitis accounted for 28.6% and perennial conjunctivitis accounted for 43.2% of allergic conjunctivitis cases in a study I performed in China.1 Patients with severe disease that interferes with their daily lives will consult an ophthalmologist.
Because China is a large country, allergy patterns differ between the north and south. Perennial conjunctivitis is more common in north China, where pollution is more common. Seasonal conjunctivitis is more common in the south, where there are more trees. Vernal conjunctivitis is not as common in China as it is in other countries. Dry eye is also common in China, as is ocular allergy.
Peter McCluskey, MD, FRANZCO, FRACS: In Australia, the most common allergens observed on skin testing are house dust mites. Grasses are also common allergens. The New South Wales emblem is the wattle, and many people are allergic to that. In Sydney, the most common problem with ocular surface disorders is that ophthalmologists underscore the blepharitis, particularly in men. For an adult woman, many ophthalmologists will assume a red eye is dry eye. For an adult man, they will think this is more likely to be allergic and particularly overlook rosacea and blepharitis.
Panayotis Zafirakis, MD: In Greece, the highest counts of airborne pollen grains are from March to June. Regarding patient sensitization, the sensitivity is to grasses, olive, goosefoot, wall pellitory, mugwort, plantain, cypress, hazel, pine, poplar and plane. The most common ocular allergy conditions are seasonal allergic conjunctivitis and perennial conjunctivitis. Atopic and vernal keratoconjunctivitis, which are the most severe cases, are not as common in Greece.
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Kyoung Yul Seo, MD, PhD: In Korea, the skin test shows few pollens as allergens. The most common allergen is the dust mite, which accounts for 70% to 80% of allergies in Korea, and the frequency is increasing. As more people moved into apartments, changes in lifestyle also contributed significantly to the rise of the house dust mite as an allergen. The increase is likely due to the relatively constant temperature and humidity in apartments. This may also explain a similar increase for the role of the dust mite in other countries such as China, Taiwan and Japan.
Andrea Leonardi, MD: Allergen seasons in Italy start with tree pollens at the end of February and March, and are followed by the grass season in April, May and June. In August, alternaria, a common potent allergenic mold, becomes a problem, which can last until the end of October. Mites are present all year. Seasonal allergic conjunctivitis is common in Italy.
Abelson: In North America, there are seasonal variations in allergens. It can begin in January in the South with trees and sweep north so that allergens become prevalent in the Northeast by the beginning of April. Following that is a wave of grasses, meadow fescue and other allergens before a period of relief and then another wave of ragweed in the early fall. As the weather cools, people spend more time indoors where they are subject to dust mites and dryness, which can trigger dry eye.
Dominique Brémond-Gignac, MD, PhD: The prevalence of ocular allergies in Paris among children is probably two-thirds for seasonal allergic conjunctivitis and one-third for perennial conjunctivitis. In the south of France, seasonal allergies are also more common. Reaching a diagnosis of allergy can be difficult in children. Skin tests are not positive in children early. Sometimes ophthalmologists have to wait to know exactly what allergen is responsible. The skin test may not always reflect the real conjunctival allergy.
Alejandro J. Aguilar, MD: The most common allergy in my practice in San Isidro, Buenos Aires, is seasonal. Pollen is the most common allergen in my practice. Domestic animals also contribute to allergic disease.
Jesús Merayo-Lloves, MD, PhD, MBA, DO: Most patients in Spain present with seasonal allergic conjunctivitis, caused mainly by tree pollen followed by grass pollen. There is a reduced number of patients, mostly children from the south, who develop vernal keratoconjunctivitis also with seasonal exacerbations.
Reference
- Liu Z, Yao Y, Sun B, et al. The clinical characteristics of allergic conjunctivitis. Chin J Pract Ophthalmol. 2004;22:684-697.
Successful ocular allergy treatment depends on understanding allergic pathway
Jose Güell, MD: An ideal treatment for seasonal allergic conjunctivitis would not only relieve symptoms but also would interrupt the allergic cascade to prevent further ocular allergy development.
Understanding the allergic pathway is key to understanding and treating seasonal allergic conjunctivitis and other ocular allergies.
Allergic pathway and mast cells
Güell: One component of the allergic pathway is the mast cell. Describe its importance.
Mark B. Abelson, MD, CM, FRCS: About 50 million mast cells are present in the conjunctiva, more medially than laterally. Mast cells increase in number as the severity of the allergic reaction increases. The cells move to the surface of the conjunctiva with prolonged allergenic exposure and in sensitized individuals.
The final common pathway is cross-linking of immunoglobulin E (IgE) and the alteration of the mast cell membrane. Tonofibrils are activated and cause the release of preformed mediators and stimulate the release of mediators and the mast cell.
One cannot determine the inciting antigen except by history, skin test, provocative test or seasonality. The presence of free radicals can be stimulated either by antigens or by irritants that can exacerbate the reaction even to pollen that may not have had as much of an effect.1
The ability of mast cells to increase their numbers when stimulated with colony-stimulating factors is well-known.2 Specific IgE from the specific plasma cells binds to the mast cell in the primary exposure.
The sensitized cells persist for years, ready to respond when their IgE is cross-linked by exposure to allergens. The mast cell plays a role in allergy, but the mast cell also plays a role in homeostasis, and slight amounts of histamine released on an ongoing basis modulate the capillary networks.
Panayotis Zafirakis, MD: The mast cell plays a major role in the cascade of allergic reaction, but there are two types of mast cells: tryptase positive and tryptase/chymase positive. Tryptase mast cells are found in the lungs and intestines. Tryptase/chymase mast cells are found in the human conjunctiva and skin.
Tryptase/chymase mast cell stabilizers such as olopatadine are effective for managing diseases involving human conjunctival mast cells.
Other cells also play a role in the cascade of mast cells. The antigen-presenting cells that transport allergen to the T cells are necessary for T-cell activation of B cells that produce the IgE specific to the allergen.
Normal conjunctiva does not have mast cells in the epithelium. In atopic or vernal keratoconjunctivitis, however, mast cells can be found in the epithelium, and this can help ophthalmologists diagnose those conditions.
Kyoung Yul Seo, MD, PhD: The load of the mast cells in late phase was recently shown by researchers from Stanford University in California.3 They found the mast cell acts not only on acute-phase disease like a switch, but also continuously acts on other inflammation-related cells: Th2, eosinophils and fibroblasts.
In that model, the researchers proved mast cells are important throughout the allergic reaction. Membrane stabilization can be effective to minimize inflammation and to inhibit the structural change in the late phase. Long-term use of anti-allergy agents with mast cell stabilizing activity with minimal complications is expected to be beneficial to patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis.
Abelson: From the perspective of uveitis and chronic inflammation, what role does the mast cell play in allergy?
Peter McCluskey, MD, FRANZCO, FRACS: The striking thing is the dichotomy between the T-cell infiltrate and the structural changes in the severe forms of allergic disease, vernal keratoconjunctivitis and acute keratoconjunctivitis, compared with seasonal and perennial allergic conjunctivitis.
An extra step drives and perpetuates the reaction of severe disease. The reaction is T-cell driven as it is in most other chronic forms of inflammation.
Abelson: How do mast cells interact with fibroblasts?
Andrea Leonardi, MD: Factors released from mast cells are involved in the conjunctival, post-inflammatory fibrotic reaction. Several cytokines and mediators released from mast cells can activate fibroblasts.
Histamine also stimulates fibroblast growth and production. Growth factors, such as fibroblast growth factors and transforming growth factor beta, are other important factors involved in fibroblast activation. We found both these factors increased in tears of chronic ocular severe allergic conditions and localized in conjunctival mast cells.4,5
The role of histamine
Güell: Histamine is another key component of the allergic pathway. What role does it play in seasonal allergic conjunctivitis?
Abelson: Seasonal allergic conjunctivitis is a contained condition in which a mediator histamine accounts for much of the condition.
Other mediators – leukotrienes, prostaglandins, growth factors and chemokines – form a cocktail that, when placed in the conjunctiva, either individually or together, produces subcomponents of seasonal allergic conjunctivitis. When the proper cocktail is added to the eye, it produces signs and symptoms of allergic conjunctivitis.
Güell: What are key differences between the roles of histamine and mast cell in ocular allergy?
Abelson: When researchers first identified histamine in the eye in the late 1960s/early 1970s, it was in patients with severe vernal ocular allergies.6 The high levels of histamine found at the 100-ng level were distinct from those found in healthy eyes.
Histamine is released and peaks about 3 minutes after mast-cell challenge. By 7 to 8 minutes, histamine returns to normal. This is the normal allergic seasonal conjunctivitis. In vernal conjunctivitis, histamine will reach up to 80 ng to 100 ng, but only for about 30 seconds, and then histaminase starts to work.
The other mediators released by the mast cells, as well as chemokines, cellular infiltration, the late-phase kickoff effect and the structural changes subsequently seen in vernal and atopic allergies, make this distinct from temporary seasonal and panseasonal allergies. Some recent evidence shows that certain antigens have the ability to induce reactive oxygen species and free radicals.2 Free radicals may add to the potential for surface damage in the presence of certain allergens.
The mast cell does not always seem to produce the same cocktail. It has about 90 known mediators, preformed and formed, that it appears to release in different ratios, depending on patterns of stimulation. IgE stimulation probably produces a different pattern than what is seen with mast cell activity in wound healing.
Other mediators
Güell: What other mediators are integral to the allergic pathway?
Leonardi: In an IgE-mediated reaction, mast cells are the first cells to be activated. Histamine is the primary mediator released and causes itching, redness and swelling. Many other mediators, such as prostaglandins and leukotrienes, cytokines and enzymes, are also immediately released (see table above).
One of the most important is tumor necrosis factor (TNF) alpha. TNF-alpha is a potent pro-inflammatory cytokine involved in the expression and production of chemokines, such as eotaxin, by conjunctival cells.
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TNF-alpha is also involved in the expression of adhesion molecules on vascular endothelial cells. This causes the adhesion of inflammatory cells on the vessel wall, a mechanism necessary for cell migration into the tissues. TNF-alpha increases the adhesion molecules’ expression also on epithelial cells and fibroblasts, which increases the persistence of inflammatory cells within the tissue.
The exact reason why epithelial cells express adhesion molecules and produce chemokines is unclear as to whether this is a defense mechanism to clear inflammatory cells out of the tissue or it is only a consequence of the pro-inflammatory cascade.
One of the consequences, however, is the activation of inflammatory cells, especially eosinophils, on the ocular surface and the release of toxic mediators that cause corneal epithelial damage and corneal ulcers in atopic and vernal keratoconjunctivitis.
Abelson: Prostaglandins and leukotrienes have lower concentrations, compared with higher concentrations of a number of mediators with opposite effects on various tissues.
One of the critical things to highlight is that it is not just the mast cell, but epithelial cells and fibroblasts that participate in allergic reaction, mostly in the more severe forms of disease, the panseasonal, the atopics and the seasonal.
The fascinating thing about seasonal allergic conjunctivitis is the absence of any particular structural changes and the reversibility of it.
Chronic swelling of the eyelid probably produces tissue changes through collagen stretching and damage over many years. As patients rub the eyelid, the skin may loosen and may lead to baggy lids or blepharochalasis later in life.
The conjunctiva itself, however, seems to resolve from any of the acute changes without structural residue, as there would be in a vernal or an atopic with the scarring or with the ground substance changes.
References
- Basci A, Dharajiya N, Choudhury BK, et al. Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis. J Allergy Clin Immunol. 2005;116:836-843.
- Solomon A, Puxeddu I, Levi-Schaffer F. Fibrosis in ocular allergic inflammation: recent concepts in the pathogenesis of ocular allergy. Curr Opin Allergy Clin Immunol. 2003;3:389-393.
- Tsai M, Grimbaldeston MA, Yu M, et al. Using mast cell knock-in mice to analyze the roles of mast cells in allergic responses in vivo. Chem Immunol Allergy. 2005;87:179-197.
- Leonardi A, Radice M, Fregona IA, et al. Histamine effects on conjunctival fibroblasts from patients with vernal conjunctivitis. Exp Eye Res. 1999;68:739-746.
- Leonardi A, Brun P, Tavolato M, et al. Growth factors and collagen distribution in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2000;41:4175-7183.
- Abelson MB, Soter NA, Simon MA, et al. Histamine in human tears. Am J Ophthalmol. 1977;83:417-418.