The Eyes of Texas: Advances in the Research of Ocular Allergy Agents

At a symposium held in conjunction with the American College of Allergy, Asthma, & Immunology Annual Meeting in San Antonio, Texas, four leaders in ophthalmology discussed recent developments in our under-standing of ocular allergies. The similarities and differences between ocular allergies and respiratory ailments were discussed to help clinicians diagnose and treat ocular allergies more effectively.

This program was supported by an unrestricted educationalgrant from Alcon Laboratories.

Introduction: Mast Cell Heterogeneity - Clinical Implications in the Management of Ocular Allergy

Gregg Berdy, MD, FACS, Clinical Instructor of Ophthalmology at the Department of Ophthalmology at Washington University in St. Louis, MO, began the symposium with a brief overview of the allergic response by saying “the allergic response is an allergen taken up by an antigen-presenting cell and that stimulates production of IgE by plasma cells which attaches to mast cells, and then upon re-exposure to the antigen the mast cell releases histamine and other mediators, which leads to ocular symptoms of itching, redness, chemosis, etc.” Therefore, “it is the mast cell that is really the sentinel cell in ocular allergic disease that we would like to target in our treatment,” said Dr. Berdy. Conjunctival mast cells contain the enzymes tryptase and chymase while lung mast cells do not contain chymase. This slight difference provides an excellent opportunity to develop medications that are specifically targeted to treat the lung or the eye. For example, drugs such as cromolyn and nedocromil that function well in the lung have limited effect on conjunctive mast cells while olopatadine, which is specific for conjunctive mast cell, is highly effective in treating ocular allergies.

The ocular allergic reaction can be divided into early and late phase reactions. In the early phase reaction, mast cell – histamine dependent reactions dominate leading to itching, vasodilation, redness, swelling, and chemosis. In contrast, late phase is largely dependent on eosinophils. Since most patients with seasonal allergies will remove themselves from the allergen before a late phase reaction can occur, the majority of late phase cases are chronic disease states such as atopic keratoconjunctivitis and vernal keratoconjunctivitis. In these patients, the mast cells secrete different cytokines and other mediators that recruit eosinophils, neutrophils and basophils which in turn lead to epithelial toxicity and tissue damage to the eye.

Dr. Berdy ended his introduction of ocular allergies by stating, “the mast cell is still the most important cell, the sentinel cell in ocular immune response and it’s responsible for releasing the mediators of both the early acute phase and late phase disease.” The ocular mast cells are different from lung mast cells and therapeutic measures should be directed specifically towards these cells.

Tips and Tricks in the Differential Diagnosis of Ocular Allergy

Mark Abelson, MD, Senior Clinical Scientist at the Schepens Eye Research Institute and Clinical Associate Professor at Harvard Medical School in Boston, MA used his 30 years’ experience to inform the audience of various tips and tricks for diagnosing and treating ocular allergy diseases.

Seasonal (Acute) AllergicConjunctivitis (SAC)
The first tip by Dr. Abelson was simply stated, “if it itches, it’s allergy.” The itching is due to histamine secretion from mast cells. Histamine binds to receptors on nerve endings to produce itching, and on blood vessels to produce redness and swelling. In experiments involving the introduction of various mediators into the eye (e.g., leukotrienes and prosta-glandins) only histamine produces itching. Common signs/symptoms of SAC include itching, hyperemia, chemosis, lid edema, mucous discharge, and tearing. SAC accounts for most (over 90%) of the ocular allergy seen in the United States, and perennial allergic conjunctivitis (PAN, due to dander and dust mite allergens) is similar in appearance.

Tricks for diagnosing SAC discussed by Dr. Abelson were:
• Ask the patient if and when they get itchy or red eyes. It should correspond to allergens in season, or exposure to dander or dust.
• It is important to have the patient distinguish between itching, and other sensations such as burning or foreign body sensation, as the latter may point to dry eye.
• Recognize that most patients are self-medicating their eye allergies with less effective over-the-counter eye drops.
Many times, a patient will not come to the office with eye allergy as their primary complaint. Integrating a question if their eyes itch and if they have eye allergy, including during the off season, will help identify if a patient can benefit from a prescription anti-allergic eye drop.

Atopic Keratoconjunctivitis (AKC)
AKC is a less common but more severe disease. AKC is often associated with atopic dermatitis. These patients are often genetically predisposed to this condition and it can be a perennial concern. Common signs/symptoms include itching, redness, photophobia, keratopathy, SPK/ulcers, keratoconus, anterior polar cataracts, stringy mucous discharge, and atopic blepharitis.
Tips:
• AKC is not just an ocular surface disease. It also affects the eye lids.
• Symptoms are severe with the most distinguishing feature being chronic ocular inflammation.
• A family history of allergy or AKC is common.

Tricks for diagnosing:
• Ask the patients if symptoms are perennial and worsen in the winter. This is a common characteristic of AKC.
• Eczema and/or asthma are common concomitant conditions.

Vernal Keratoconjunctivitis (VKC)
VKC occurs in patients genetically predisposed to this condition. VKC is a sustained hypersensitivity reaction. Elevated histamine levels are found in tears of VKC patients and it may be due to a decrease in the activity of histaminase, the enzyme usually present to degrade histamine upon release from the mast cell. Common signs include ptosis, ropy mucous discharge, photophobia, large, non-uniform cobblestone papillae, Tranta’s dots, limbal nodules, shield ulcers, and itching.

Tips:
• VKC (unlike AKC) is typically seasonal (spring to fall).
• VKC (like AKC) patients often have additional allergic conditions (eczema, asthma, rhinitis).
• More common in warm, tropical climates.
• Photophobia can be severe.

Tricks for diagnosing:
• Diagnosis is typically straightforward. Clinicians should use clinical signs for diagnosing VKC and not rely on family history or negative results with the allergic diagnostic tests.
• Flip the lid and look for two hallmark symptoms - upper tarsal giant papillae and gelatinous limbal infiltrates.

Drug-Induced Allergic Conjunctivitis (DIAC)
DIAC is due to medication use and common signs/symptoms include itching, redness, lid swelling, and dermatitis.

Tips:
• DIAC can occur immediately, or after months or years of drug use.
• Consider skin care products and cosmetics as a possible cause.
• Diffuse keratitis does not occur in DIAC and can be used to differentiate from a toxic non-allergic reaction.

Tricks for diagnosing:
• Examine the inside of the lower lids in comparison to the inside of upper lids. Upper lids are often normal looking while the lower lids and inferior conjunctiva are affected. As gravity pulls the drug to the inferior aspect of the eye and as drug is instilled, it may be spilled over onto the lower lids.
• To confirm if it is drug induced, remove the suspected agent and see if the signs and symptoms subside. If so, have the patient re-start the medication and see if it returns.

Differential Diagnosis of Other External Diseases
In addition to the above conditions, Dr. Abelson briefly discussed some of the external diseases that affect the eyes, which also produce redness and may be confused with allergy. These include dry eye, blepharitis, viral infection, contact dermatitis, chlamydia, pemphigoid, bacterial infection, contact lens related conditions, ocular rosacea, and medicamentosa. While a complete examination is necessary for each diagnosis, Dr. Abelson provided the audience with a few tips/tricks to aid in diagnosis. For example, if the patient complains of a burning sensation, it is most likely dry eye and “if it’s sticky in the morning, it’s bacterial conjunctivitis,” said Dr. Abelson.

The color of the redness can also give a clue. Redness that is “deep fire engine red” is usually associated with an ulcer, whereas a more pinkish red is seasonal allergies. Keep in mind, however, that these conditions can be seen concomitantly. Dry eye, which is a deficiency in the tear film in particular, can lead to an exacerbation of allergy as the tear film is essential in washing the eye, diluting the allergen, and acting as a barrier to the eye.

Concluding Remarks
Dr. Abelson summarized these basic diagnostic tips for assessing the most common ocular problems by stating: if it itches, it’s allergy; if it burns, it’s dry
eye; and if it sticks, it’s bacterial conjunctivitis.

Does The Eye Wheeze?

Ira Finegold, MD, Chief of the Division of Allergy at St. Luke’s-Roosevelt Hospital Center and Director of the RA Cook Institute of Allergy in New York, NY, began his presentation by stating there is a clear link between allergic rhinitis and asthma, as well as between rhinitis and conjunctivitis. “But is there a link between asthma and conjunctivitis?” asked Dr. Finegold, and spent the remainder of his presentation examining the evidence to support a connection
between eyes and lungs.

Epidemiology
In a recent Finnish study (Allergy 2001;56:377-384), a questionnaire answered by people with (n = 150) or without (n = 140) asthma found that within the asthmatic group, 61% had allergic rhinitis, with similar percentages for allergic conjunctivitis, indicating an epidemiological link between these three illnesses.

Anatomy
“Clearly there is an anatomic connection between the eyes and the nose: the nasal lacrimal duct,” stated Dr. Finegold. Treating the nose and improving eye symptoms is supported by a meta-analysis (BMJ 1998;317;1624-1629) that found 11 studies which favored intranasal steroids over systemic antihistamines. In another recent study (Clin Ther 2002;24:1161-1174) the conjunctive allergen challenge test was used to compare treatment options for allergic rhinoconjunctivitis. In this study, symptoms were reduced in patients given fluticasone + olopatadine versus fluticasone + fexofenadine. Interestingly, nasal symptom scores were also better in the fluticasone + olopatadine group further supporting the hypothesis that nasal and ocular systems are connected and respond best to targeted therapy.

Physiology and Pathology
Bronchial alveolar lavage (BAL) fluid composition and tears have many similarities. Both have increased IgE, histamine, and tryptase levels following a challenge. Mast cell degranulation is also similar in both the lung and the eye. Dr. Finegold provided the audience with several examples, including cytokines, nitric oxide, tryptase, and ICAM-1, that change during mast cell degranulation in both organs.

Therapy
Dr. Finegold focused on immunotherapy to illustrate how ‘global’ therapy may be a viable option in the future. For example, Varney et al. (Clin Exp Allergy 1997;27:860-867) found that 3 months of preventive immunotherapy significantly reduced cat allergy reactions. “Since the eyes and lungs are similar targets for the inflammatory cascade of mast cells, similar therapeutic interventions should be considered,” said
Dr. Finegold.

Concluding remarks
“The eye does not wheeze,” confessed Dr. Finegold, adding “but, it does participate in allergic mast cell and allergic reactions, and one should consider the global asthma, rhinitis, and conjunctivitis axis when treating these patients.”

Management of Allergic Ocular Diseases

Robert D. Gross, MD, FAAP, Clinical Associate Professor of Ophthalmology at the University of Texas Southwestern Medical Center briefly summarized the previous speakers’ presentations by stating that the most common ocular allergies are early phase diseases and neither threaten the visual acuity nor create tissue damage. In most cases, it is a mast cell/histamine effect and treatment should be directed accordingly. “On the other hand, more severe forms of ocular allergy can very definitely impact vision,” said Dr. Gross.

Treatment Options
The first category of medications discussed by Dr. Gross was vasoconstrictors (e.g., Visine, Naphcon). As the TV ad says, they ‘do get the red out’ but that is it’s only indication. “These drugs have no antiallergy effect,” said Dr. Gross, adding, “but in fact, they can make diagnosis much more challenging.” According to Dr. Gross these agents are drugs in search of an indication and patients with mild ocular allergies should use preservative-free tears.

Another treatment option is to pair a decongestant with a first-generation antihistamine such as Visine-A or Naphcon-A. These drugs do have some antiallergy effect but the decongestant component to these agents is the limiting factor. “These products are good for those situations where you have a nonallergic patient who encountered an allergen where you expect the treatment with a few doses will be sufficient to resolve the problem,” stated Dr. Gross.

Another group of medications occasionally used for ocular allergies are the NSAIDs. These drugs act by reducing prostaglandin production. Unfortunately, “prostaglandins in the eye do not have much to do with symptomatology,” said Dr. Gross, adding, “these drugs really don’t play much of a role for us in ophthalmology in managing clinical allergy.”

There are several antihistamines available, including levocabastine (Livostin) and emedastine (Emadine). All are excellent topical antihistamines but they all have one limiting factor: some patients will get a red eye due to toxicity after long-term use. Dr. Gross said, “these drugs are useful in my practice as a rescue medication for Naphcon-A or Vasocon-A, but they’re not a choice that I use for an entire allergy season.”

Another option is the topical corticosteroid, loteprednol (Alrex). This is a low-dose steroid given to avoid steroid-induced side effects such as increased intra-ocular pressure and cataracts. While loteprednol is relatively safe and effective, Dr. Gross warned the audience that in ophthalmology there is no safe steroid and treatment needs to be monitored regularly.

Mast cell stabilizers were also discussed. These drugs [i.e., cromolyn (Crolom), lodoxamide (Alomide), nedocromil (Alocril), and pemirolast (Alamast)] stabilize mast cells by inhibiting calcium influx and have two important features. First, they do not provide immediate relief but require several days to stabilize mast cells. Second, these drugs were designed for lung mast cells, not conjunctival mast cells.

Olopatadine (Patanol), ketotifen (Zaditor) and azelastine (Optivar) all have multiple mechanism of action indications. It should be noted that ketotifen and azelastine have been in existence for some time as systemic agents and have been historically classified as single action antihistamines.

The only dual action product specifically designed for conjunctival mast cells is olopatadine (Patanol). To illustrate the efficacy and safety of olopatadine, Dr. Gross discussed a study by Butrus et al. (Clin Ther 2001;22:1462-1472) who used the conjunctival antigen challenge model in patients randomly placed in one of three groups. The first group received nedocromil (one drop BID), for 14 days, and both the second and third groups received placebo (one drop BID) for 14 days. On the final visit, the first group received nedocromil (1 drop), the second group received olopatadine (1 drop), and the third group received placebo. The authors of this study concluded that one drop of olopatadine was clinically and statistically superior to 28 drops of nedocromil in reducing itching associated with allergic conjunctivitis. Furthermore, olopatadine was found to be significantly more comfortable. To illustrate the specificity of olopatadine for conjunctive mast cells, Dr. Gross mentioned studies by Yanni et al. (Arch Ophthalmol 1999;117:643-647, Ann Allergy Asthma Immunol 1997;79:541-545) who showed that most mast cell stabilizers are designed for lung mast cells and are poor stabilizers of conjunctival mast cells in comparison to olopatadine (Figure 1).

Dr. Gross ended his presentation by saying, “you’ve heard today about the many components of the allergic response and what I can tell you is that olopatadine perhaps more than any other agent we have out there today influences that allergic response at multiple levels,” adding, “and when we’re managing our patients, safety is key. This drug is safe even in children. When evaluating the red eye, keep allergy in mind and treat with the safest, most effective agent available.”

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