New Strategies in the Diagnosis and Management of Ocular Allergy

Ocular allergy accounts for a large number of patients' visits to ophthalmologists. Although the disorder may have an impact on the skin and periocular tissue, the conjunctiva is more commonly affected. Ocular allergy encompasses a spectrum of diseases characterized by antigen-specific immunoglobulin E (IgE) and T-helper type 2 lymphocytemediated hypersensitivity. Allergic disorders may have overlapping signs and symptoms, but each has its own pathognomonic characteristics that are useful in determining the specific diagnosis. By understanding the pathophysiology of allergic conjunctivitis, physicians can choose the appropriate therapy by which to control their patients' allergic responses (Figure) and accompanying symptoms and signs of disease.

Pathophysiology

Seasonal allergic conjunctivitis is the prototype of ocular allergy, and it begins as an antigen-IgE antibody interaction on the surface of conjunctival mast cells.1 Exposure of airborne allergens to sensitized IgE-coated mast cells is the initiating stimulus.

The exogenous allergen binds two separate IgE molecules, creating a dimer formation.^2,3 This bridging of IgE molecules induces the activation of mast cell membraneassociated enzymes, leading to the initiation of a biochemical cascade that ultimately causes a release of granules into the extracellular space.^4-10

The sentinel role of histamine in the acute allergic response has been well established.^11,12 The identification of histamine receptors (both histamine 1 and 2)13,14 has permitted investigators and clinicians to better understand its role in human allergic diseases. The conjunctival epithelial surface contains both receptor subtypes, with each receptor's controlling a specific response to histamine. Stimulation of the H1 receptor causes ocular itching,^15,16 whereas stimulation of the H2 receptor produces vasodilation of conjunctival vessels.¹⁷ Histamine is only one of several mediators of inflammation that are implicated in the etiology of allergic disease.

Epidemiology

According to a survey of the National Family Opinion, Inc., database of 200,000 American households, 31.5% of the population (approximately 79.5 million Americans) has ocular/nasal symptoms seven or more times per year.¹⁸ The survey also reported that approximately 14.5 million Americans have physician-diagnosed seasonal allergic rhinitis/conjunctivitis. In studies of patients with pollen allergy, ocular symptoms occur in approximately 75% of patients with rhinitis.¹⁹

According to a nationwide random sample of Americans with rhinoconjunctivitis (N = 312) who completed the Rhinoconjunctivitis Quality of Life Questionnaire, the condition leads to a significant decline in the general health status of sufferers compared with healthy controls (n = 96).²⁰ Another survey included 481 random American households containing a person afflicted with rhinoconjunctivitis. It revealed that 19% of the respondents who were being treated by a physician for ocular/nasal symptoms stopped seeing him or her because they believed that “effective treatments are not available.”²¹

Ocular Allergic Disease

Patients with seasonal allergic conjunctivitis (SAC) or perennial allergic conjunctivitis (PAC) present with complaints of red, itching, tearing, and burning eyes.^22,23 These symptoms are nonspecific for diagnosis; therefore, to make a differential diagnosis, the clinician must examine the entire patient. SAC and PAC are often accompanied by symptoms of allergic rhinitis: a runny and itchy nose, scratchy and itchy soft palate, and itchy ear canal. These symptoms of rhinitis often accompany symptoms of allergic conjunctivitis, because the allergens and the pathophysiology of the diseases are similar.²⁴

Ocular symptoms may have a seasonal onset (ie, SAC), occurring in the spring when the levels of grass and tree pollen peak or in the fall when the levels of weed pollen peak. PAC is chronically manifested and may be caused by an allergy to dust mites, feathers, or animal dander. Upon examination, the patients' eyelids usually appear edematous and erythematous, and the conjunctiva has mild to moderate chemosis with injection of the bulbar and tarsal conjunctiva. A ropey, mucosal discharge may be apparent. Itching is the most important symptom for a differential diagnosis.

If the eye does not itch, then the problem is not ocular allergy. It should be noted that itching can be a sign of dry eye disease, but that condition is not accompanied by other seasonal symptoms and has a different ocular corneal staining pattern with vital dyes than allergic conjunctivitis.²⁵

SAC and PAC are characterized by an antigen-specific IgE mast cell-mediated response.²⁶ In a sensitized individual, the allergen binds to IgE-coated mast cells in the conjunctiva, causing mast cell degranulation and a release of inflammatory mediators. Together, these mediators produce itching, redness, and chemosis of the conjunctiva—the so-called triple response to allergen exposure. Recent studies have demonstrated the role of certain conjunctival dendritic cells (antigenpresenting cells) in the pathophysiology of ocular allergy. ^27-30 Nonetheless, the histamine response continues to be an important contributor to the early phase of the allergic reaction, as mentioned previously.

Choices for Treatment

A variety of nonprescription and prescription therapies are available. Identifying the allergen and teaching patients how to avoid or reduce their exposure via control of their environment can be a beneficial first step. Application of topical artificial tears can dilute the antigen load and prevent the allergens from interacting with the mast cells in the conjunctiva. Cold compresses can be used as an adjunct to decrease itching. Allergenspecific immunotherapy may be effective, and novel methods of administration are being developed to improve safety and compliance.^31-33 Prescription pharmaceuticals are the mainstay of treatment, and topical ophthalmic medications give optimal symptomatic control.

During the past 4 years, three prescription products in the antihistamine-mast cell stabilizer class have been introduced. They are olopatadine 0.2% ophthalmic solution (Pataday; Alcon Laboratories, Inc.), bepotastine besilate 1.5% ophthalmic solution (Bepreve; Ista Pharmaceuticals, Inc.), and alcaftadine 0.25% ophthalmic solution (Lastacaft; Allergan, Inc.).

Olopatadine is a useful adjunct for the treatment of allergic conjunctivitis in adults and children 3 years of age and older. The results from clinical trials of up to 12 weeks' duration demonstrate that this agent effectively relieves ocular itching with once-daily use.³⁴ In one study, olopatadine was significantly more effective than placebo at reducing ocular itching at all time points for both the onset of action and the 16-hour allergen challenge. The drug was also significantly more effective than placebo in the reduction of conjunctival redness, chemosis, and eyelid swelling.³⁵ In results from two patient-reported outcome studies, significantly more individuals reported being very satisfied with olopatadine's speed of relief and comfort than with azelastine 0.05% (Optivar; Meda Pharmaceuticals, Inc.).³⁶

Bepotastine besilate has been available for the past 2 years and is indicated for twice-daily dosing in adults and children 2 years of age and older. This antihistamine-mast cell stabilizer has a high specificity for the histamine 1 receptor.^37-39 In two well-controlled conjunctival allergen challenge studies, bepotastine demonstrated rapid and sustained reductions in ocular itching, the primary endpoint.^40,41 These decreases were clinically and statistically significant at a majority of time points.⁴² Also of interest was the observation that the drug produced statistically and clinically significant reductions in a prespecified secondary endpoint, the Non-Ocular Composite Symptom score, incorporating nasal congestion, rhinorrhea, ear/palate itching, and nasal itching.⁴³

Alcaftadine is the newest entry onto the market for the treatment of allergic conjunctivitis, and the drug offers multiple mechanisms of action (data on file with Allergan, Inc.). In the agent's pivotal FDA clinical trials, 97% of subjects treated with alcaftadine reported minimal itching 3 minutes after the product's instillation, and 87% reported minimal itching 16 hours after instillation. ⁴⁴ With its rapid onset of action and extended duration of itching control through 16 hours with one drop, alcaftadine addresses patients' needs for effective relief of symptoms. The drug has an excellent safety profile, with less than 4% of treated subjects in the pivotal trials reporting adverse ocular events. Alcaftadine is the only once-daily allergy drop to be both pregnancy category B and approved for use in pediatric patients as young as 2 years of age.

Conclusion

With 4.7 million prescriptions filled annually in the United States for allergic conjunctivitis medications⁴⁵ and undoubtedly some multiple of that purchased as over-the-counter treatments, ocular allergy affects a large number of patients. Although effective treatments have been available for some time, there has always been a trade-off between efficacy, duration of action, and convenience. The unique clinical profile of the drugs that combine an antihistamine and a mast cell stabilizer helps to address shortcomings of older treatments.

The question of which ophthalmic allergy drop is most effective and truly provides patients with the best full-day itching control is an important one. In the next few months, several clinical studies will be released, including the results of a randomized, masked, controlled trial evaluating these drugs in a head-to-head protocol.

Gregg J. Berdy, MD, is in practice with Ophthalmology Associates and is an assistant professor of clinical ophthalmology in the Department of Ophthalmology and Visual Science at Washington University School of Medicine, both in St. Louis. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Berdy may be reached at gregg.berdy@youreyedoc.com.

1. Allansmith MR, Abelson M. Ocular allergies. In: Smolin G, Thoft RA, eds. The Cornea. Boston, MA: Little, Brown & Co.; 1983:231-243.
2. Ishizaka T, Ishizaka K. Biology of immunoglobulin E: molecular basis of reaginic hypersensitivity. Prog Allergy. 1975;19:60-121.
3. Siraganian RP, Hook WA, Levine BB. Specific in vitro histamine release from basophils by bivalent haptens: evidence for activation by simple bridging of membrane bound antibody. Immunochemistry. 1975;12:149.
4. Foreman FC, Hallett MB, Mangar J. The relationship between histamine secretion and 45calcium uptake by mast cells. J Physiol. 1977;271:193-214.
5. Irani AM, Butrus SI, Tabbara KF, Schwartz LB. Human conjunctival mast cells; distribution of MCT and MCTC in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clinl Immunol. 1990;86:34-40.
6. Flowers RJ, Blackwell GJ. The importance of phospholipase A2 in prostaglandin biosynthesis. Biochem Pharmacol. 1976;25:285-291.
7. Warner JA, Peters SP, Lichtenstein LM, MacGlashan DW Jr. 3H arachidonic acid incorporation and metabolism in purified human basophils. Fed Proc. 1986;45:735.
8. Hanahan DJ, Demopoulos CA, Liehr J, Pinckard RN. Identification of naturally occurring platelet activating factor as acetyl-glyceryl-ether-phosphorylcholine (AGEPC). J Biol Chem. 1980;255:5514-5516.
9. Chilton FH, Ellis JM, Olson SC, Wykle RL. 1-O-alkyl- 2-arachidonoyl-sn-glycero-3-phosphocholine: a common source of platelet activating factor and arachidonate in human polymorphonuclear leukocytes. J Biol Chem. 1984;259:12014-12019.
10. Barnes PJ. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol. 1989;83:1013.
11. Schwartz LB, Austen KF. Structure and function of the chemical mediators of mast cells. Prog Allergy. 1984;34:271-321.
12. Snyder SH, Axelrod J. Tissue metabolism of histamine -C14 in vivo. Fed Proc. 1965;24:774- 776.
13. Ash ASF, Schild HO. Receptors mediating some actions of histamine. Br J Pharmacol Chemother. 1966;27:427.
14. Black JW, Duncan WAM, Durant GJ, et al. Definition and antagonism of histamine H2- receptors. Nature. 1972;236:385-390.
15. Owen DA, Poy E, Woodward DF. Evaluation of the role of histamine H1- and H2-receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation. Br J Pharmacol. 1980;69:615-623.
16. Robertson I, Greaves MW: Responses of human skin blood vessels to synthetic histamine analogues. Br J Clin Pharmacol. 1978;5:319.
17. Harvey RP, Schocket AL. The effect of H1 and H2 blockade on cutaneous histamine response in man. J Allergy Clin Immunol. 1980;65:136-139.
18. Nathan RA, Meltzr EO, Selner JC, Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99:S808-S814.
19. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(suppl 86):8-160.
20. Meltzer EO, Nathan RA, Selner JC, Storms W. Quality of life and rhinitic symptoms: results of a nationwide survey with the SF-36 and RQLQ questionnaires. J Allergy Clin Immunol. 1997;99:S815-S819.
21. Storms W, Meltzer EO, Nathan RA, Selner JC. Allergic rhinitis: the patient's perspective. J Allergy Clin Immunol. 1997;99:S825-S828.
22. Berdy GJ, Berdy SS. Ocular allergic disorders: disease entities and differential diagnoses. Curr Allergy Asthma Rep. 2009;9:297-303.
23. Granet D. Allergic rhinoconjunctivitis and differential diagnosis of the red eye. Allergy Asthma Proc. 2008;29(6):565-574.
24. Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J Allergy Clin Immunol. 2005;115(1):118-122.
25. Berdy GJ. Treatment stategies for ocular allergy. Advanced Ocular Care. March 2010;1(2):39- 41.
26. Berdy GJ, Leonardi A, Abelson MB. Antihistamines and mast cell stabilizers in allergic ocular disease. In: Albert DM, Miller JW, Azar DT, Blodi BA, eds. Albert & Jakobiec's Principles and Practice of Ophthalmology. Philaldelphia, PA: Saunders Elsevier, Inc.
27. Nakamura T, Ohbayashi M, Toda M, et al. A specific CCR3 chemokine receptor antagonist inhibits both early and late phase allergic inflammation in the conjunctiva. Immunol Res. 2005;33(3):213-221.
28. Ohbayashi M, Manzouri B, Flynn T, et al. Dynamic changes in conjunctival dendritic cell numbers, anatomical position and phenotype during experimental allergic conjunctivitis. Exp Mol Pathol. 2007;83(2):216-223.
29. Tominaga T, Miyazaki D, Sasaki S, et al. Blocking mast cell-mediated type I hypersensitivity in experimental allergic conjunctivitis by monocyte chemoattractant protein-1/CCR2. Invest Ophthalmol Vis Sci. 2009;50(11):5181-5188.
30. Bundoc VG, Keane-Myers A. IL-10 confers protection from mast cell degranulation in a mouse model of allergic conjunctivitis. Exp Eye Res. 2007;85(4):575-579.
31. Jutel M, Jaeger L, Suck R, et al. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005;116(3):608-613.
32. Roder E, Berger MY, de Groot H, van Wijk RG. Immunotherapy in children and adolescents with allergic rhinoconjunctivitis: a systematic review. Pediatr Allergy Immunol. 2008;19(3):197- 207.
33. Werfel T. Epicutaneous allergen administration: a novel approach for allergen-specific immunotherapy? J Allergy Clin Immunol. 2009;124(5):1003-1004.
34. Pataday [package insert]. Fort Worth, TX; Alcon, Inc.; 2006.
35. Abelson MB, Gomes PJ, Pasquine T, et al. Efficacy of olopatadine ophthalmic solution 0.2% in reducing signs and symptoms of allergic conjunctivitis. Allergy Asthma Proc. 2007;28(4):427- 433.
36. Epstein AB, Van Hoven PT, Kaufman A, et al. Management of allergic conjunctivitis: an evaluation of the perceived comfort and therapeutic efficacy of olopatadine 0.2% and azelastine 0.05% from two prospective studies. Clin Ophthalmol. 2009;3:329-336.
37. Kato M, Nishida A, Aga Y, et al. Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent bepotastine besilate. Arzneimittelforschung. 1997;47(10):1116-1124.
38. Kaminuma O, Ogawa K, Kikkawa H, et al. A novel anti-allergic drug, bepotastine besilate, suppresses interleukin-5 production by human peripheral blood mononuclear cells. Biol Pharm Bull. 1998;21(4):411-413.
39. Andoh T, Kuraishi Y. Suppression by bepotastine besilate of substance P-induced itchassociated responses through the inhibition of the leukotriene B4 action in mice. Eur J Pharmacol. 2006;547(1-3):59-64.
40. Abelson AB, Torkildsen GL, Williams JI, et al. Time to onset and duration of action of the antihistamine bepotastine besilate ophthalmic solutions 1.0% and 1.5% in allergic conjunctivitis: a phase III, single-center, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge assessment in adults and children. Clin Ther. 2009;31:1908-1921.
41. Macejko TT, McLaurin EB, Kurata FK, et al. Bepotastine besilate ophthalmic solution 1.5% reduces ocular itching following dosing in the conjunctival allergen challenge (CAC) model of acute allergic conjunctivitis. Invest Ophthalmol Vis Sci. 2009:50, E-Abstract 6328.
42. Bergmann MT, Gomes PJ, Williams JI, et al. Bepotastine besilate ophthalmic solution 1.5% reduces ocular itching in a multisite clinical model of allergic conjunctivitis. Poster presented at: 2009 American Society of Cataract and Refractive Surgery (ASCRS) Symposium and Congress; April 3-8, 2009: San Francisco, CA.
43. Macejko TT, Meier EJ, Bergmann MT, et al. Bepotastine besilate ophthalmic solution 1.5% for up to 8 hours following dosing reduces total non-ocular symptoms, rhinorrhea, and tearing in a multi-site clinical model of allergic conjunctivitis. Poster presented at: 2009 American Academy of Allergy Asthma and Immunology (AAAAI) Annual Meeting; March 3-17, 2009: Washington, DC.
44. Torkildsen G, Shedden A. The safety and efficacy of alcaftadine 0.25% ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. Curr Med Res Opin. 2011;27(3):623-631.
45. SDI Health LLC. Vector One National. November 2011 MAT. http://www.sdihealth.com/ vector_one/national.aspx.