Thoughts on the Management of Ocular Allergy

ByRichard L. Lindstrom, MD

Ocular surface disease includes ocular allergic disease, dry eye, and blepharitis. Ocular surface disease is present in as many as 30% of patients encountered by ophthalmologists, yet an incorrect diagnosis is frequently made. For example, dry eye could be misdiagnosed as blepharitis, or ocular allergy could be misdiagnosed as dry eye. Treatments for the different aspects of ocular surface disease may vary, thus a correct diagnosis is critical to ensure the condition is properly managed. This requires knowledge of the clinical signs and symptoms accompanying each condition. An understanding of the underlying pathophysiology of each of these conditions is also important.

Ocular Allergic Disease

Ocular allergic disease refers to a group of hypersensitivity disorders that affect the ocular surface, most commonly the eyelids, conjunctiva, and cornea.¹ Also known as allergic conjunctivitis or ocular allergies, they are most commonly manifested as seasonal allergic conjunctivitis (SAC), although they can also occur perennially (PAC).² Other allergic diseases of the ocular surface include atopic and vernal keratoconjunctivitis, giant papillary conjunctivitis, and contact allergic conjunctivitis.³ While ocular allergy is placed in the category of ocular surface disease, along with blepharitis and dry eye, it has a different pathophysiology and thus should be treated differently. Ocular allergies are common, affecting more than 60 million Americans.^1,4 Approximately 30% of ophthalmology patients have inflammatory, allergic ocular surface disease that is not dry eye or blepharitis.

Pathophysiology of Ocular Surface Allergic Disease

The mast cell, which is filled with inflammatory mediators, is the key cell in the process that leads to ocular surface allergic disease. Pathophysiologically, chemical mediators released from mast cells as part of the inflammatory cascade play a key role in the ocular surface response (Figure 1).³ Whether events occur concurrently or in stages is controversial. A prominent opinion proposes that, in the early phase of the response, preformed mediators including histamines, slow reacting substance (SRS), and bradykinin, which are already active in the granules of the mast cell, are available for instant “attack” of target tissues when released. In the late phase, newly formed inflammatory mediators are continuously produced through activation of phospholipase A2, and there is a recruitment of inflammatory cells and further production of mediators.

Figure 1. The Inflammatory Cascade

Figure 1. The Inflammatory Cascade
Early and late phase mediators follow different inflammatory pathways.

Sources: Adapted from: Donnenfeld. Refract Eyecare. 2005;9(suppl):12-16; Slonim. Rev Ophthalmol. 2000:101-112.

Early and late phase mediators follow different inflammatory pathways (Figure 1). Early phase mediators, such as heparin and histamine, are released when the mast cell membrane is disrupted in response to exposure to antigen.³ Histamine is responsible for the itching, redness and swelling associated with ocular surface allergic disease.⁵ Other cytokines and inflammatory mediators released in the process include platelet activation factor and proteolytic enzymes such as tryptase and chymase.

Late phase mediators are produced when phospholipase A2 acts on mast cell membrane phospholipids, leading to the production of arachidonic acid. This compound is then transformed into inflammatory mediators.⁶ Other cells of the immune system, including eosinophils, neutrophils, basophils, and T lymphocytes also infiltrate the conjunctival mucosa and are activated to release additional mediators, including leukotrienes. They also trigger allergic symptoms including stuffy or runny nose, sneezing, itchy eyes, postnasal drip, or wheezing.

The Importance of Differential Diagnosis

It is important to differentiate among the conditions associated with the ocular surface to assure the proper approach to management is followed. SAC is characterized by a combination of clinical signs and symptoms that are the result of the inflammation. Symptoms that may include itching, burning, redness, tearing, lid swelling, epiphora and chemosis, and frequent allergic episodes can lead to chronically swollen, teary, red, and itchy eyes. ^1,3When taking the history from these patients, it is beneficial to determine the site of the itching. For example, if it is directly over the caruncle, which is a lymphoid structure, the cause is almost always allergic conjunctivitis. Gritty foreign body sensation is almost always dry eye, though it is experienced on rare occasions with SAC. Burning also occurs with blepharitis in response to the free fatty acids and diglycerides. Conjunctival chalasis with overlap of the conjunctiva is more common in dry eye, but chemosis of the conjunctiva occurs almost exclusively with allergic conjunctivitis. In addition, the surface of the eye looks wet; that is, this is not a dry eye condition.

Lid swelling is common in blepharitis, while in a typical eye with allergic conjunctivitis, lid margins may appear normal (Figure 2). However, the tear margin strip may have a large tear meniscus, particularly in younger patients. The tear meniscus is about 2 mm or less in a normal eye, and may be 3 mm to 4 mm with overflow tearing in allergic conjunctivitis. The tear meniscus is not filled with debris and foamy secretions, as commonly occurs in blepharitis.

Figure 2. Classic Signs of Seasonal Allergic Conjunctivitis

Figure 2. Classic Signs of Seasonal Allergic Conjunctivitis
Seasonal allergic conjunctivitis is characterized by a combination of symptoms such as itching, burning, and redness, that are the result of the inflammation. Lid margins appear normal, while the tear margin strip may have a large tear meniscus.

Source: Richard L. Lindstrom, MD.

Current Therapy for Allergic Conjunctivitis

The ideal treatment for ocular allergies would have the following characteristics:

Comprehensive coverage of all inflammatory mediators involved in the ocular allergic response
Resolution of most signs and symptoms of ocular allergies
Rapid onset of action
Targeted, site-specific activity
Effective and safe for long-term use
Favorable safety profile: minimal adverse events
Relief, providing soothing comfort

Although some patients with SAC respond to conservative treatment such as allergen avoidance, eye irrigation, and cold compresses, many patients may require prescription agents to resolve the signs and symptoms of SAC.²Several prescription therapies are available to treat SAC, including mast cell stabilizers, antihistamines and steroids.³ There are several mast cell stabilizer and antihistamine products that can be used either as monotherapy or in combination, which also have prophylactic usefulness. In some cases, corticosteroids are the only effective therapy for treating symptoms. Topical NSAIDs have questionable usefulness. The leukotriene effect results in recruitment of white cells; accordingly, exogenous prostaglandins can increase the leukotriene-mediated enhancement of the inflammatory response.

Clinically, a 2 phase response would have therapeutic implications. For example, if a patient knows he will be exposed to an allergen, he can prophylactically take a combination mast cell stabilizer/antihistamine. However, if the exposure cannot be predicted, and symptoms such as severe itching over the caruncle, chemosis, epiphora, and possibly lid edema have manifested, topical steroids such as loteprednol may be the only option that will provide relief.

Because most ocular surface disease is inflammatory, topical steroids provide the best treatment. By affecting multiple steps in both the early and late phase inflammatory cascade, they are a powerful therapy and provide the broadest spectrum of anti-inflammatory activity. Steroids stabilize intracellular and extracellular membranes, which is critical in preventing the initiation of early phase inflammatory reactions.⁵ In addition, they interrupt the activation of phospholipase A, preventing the release of arachidonic acid and thereby inhibiting the cyclooxygenase and lipoxygenase pathways that are responsible for persistent signs and symptoms.^1,5

The ideal ophthalmic corticosteroid therapy should be rapid, safe, and effective for prolonged use. Potential steroid side effects, including elevated IOP, formation or worsening of cataracts, and change in the normal eye flora resulting in selection of pathogens or exacerbation of infections, have caused some reluctance about their use.³ This hesitance, however, is largely because of the known side effects associated with ketone corticosteroids. In practice, the benefits of ophthalmic steroids in allergic ocular surface disease continue to outweigh the risks. If the entire inflammatory cascade is not addressed, persistent inflammation could result in more severe ocular allergic disease.^1,7

Although prednisolone acetate is often used in post-operative cataract and keratoplasty patients, in an allergic environment where the drug may be used repeatedly, long-term loteprednol is preferable. The primary complication of ophthalmic steroid use, elevation of IOP, is not as significant with loteprednol than it is with any of the prednisolone products, dexamethasone, or betamethasone. In typical cases, the 0.2% loteprednol solution is appropriate; however, severe episodes call for the stronger 0.5% solution.

Loteprednol Clinical Trials

Long-term safety

Although mild and infrequent increases in IOP have been reported following use of 0.5% loteprednol, there were no elevations of IOP in a retrospective multicenter study of 159 patients who used 120 to 3741 drops of 0.2% loteprednol solution per eye over intervals of up to 1 year.⁸ In addition, there was no cataract formation or exacerbation of infectious disease.

In 2 randomized, double-masked, controlled trials of the efficacy and safety of 0.2% loteprednol compared with placebo in 268 patients, 1 patient each in the loteprednol and placebo groups had mild (>10 mm Hg) elevation of IOP after 6 weeks of therapy.^9,10 Symptom resolution significantly favored loteprednol (P<.008). Placebo and loteprednol had similar safety profiles.

Although loteprednol may not be as powerful as prednisolone acetate, it has a preferable safety profile that, combined with its efficacy, warrants its use. It should provide an adequate comfort level in a relatively benign disease such as seasonal allergic conjunctivitis, which is not typically devastating to eyes. In summary, loteprednol is safe for long-term treatment of seasonal and perennial allergic conjunctivitis, providing the advantages of a steroid anti-inflammatory medication without the side effects of secondary glaucoma and cataract formation.

Final Recommendations

Seasonal allergic conjunctivitis presents frequently in ophthalmology practices. It presents with itching over the caruncle, with a wet eye that lacks the staining patterns of dry eye, and with normal appearing lids. If a patient has chemosis and significant symptoms, a topical steroid such as loteprednol may be initiated and administered as frequently as every 2 hours if warranted. A subsequent regimen of 4 times a day can be followed until control is achieved.

Patients who know they will be encountering antigens can prophylactically take a combination of a mast cell stabilizer and antihistamine before the exposure. If symptoms develop, loteprednol can be administered.

References

Abelson MB, Smith L, Chapin M. Ocular allergic disease: mechanisms, disease sub-types, treatment. The Ocular Surface. 2003 Jul;1(3):127-49.
Bhargava A, Jackson WB, El-Defrawy SR. Ocular allergic disease. Drugs of Today (Barc). 1998 Nov;34(11):957-71.
Slonim CB, Boone R. The ocular allergic response: A pharmacotherapeutic review. Formulary. 2004;39:213-222.
U.S. Census Bureau. Annual Estimates of the Resident Population for the United States, Regions, States, and Puerto Rico: April 1, 2000 to July 1, 2008 (NST-EST2008-01). Available at: http://www.census.gov/popest/states/NST-ann-est.html.
Slonim CB. The ocular response. Expert Review of Ophthalmology. 2000;7:101-112.
Donnenfeld ED. Refractive Eyecare. 2005;9(Suppl):12-16.
Abelson MB, Schaefer K. Conjunctivitis of allergic origin: immunologic mechanisms and current approaches to therapy. Survey of Ophthalmology. 1993 Jul-Aug;38 Suppl:115-32.
Ilyas H, Slonim CB, Braswell GR, Favetta JR, Schulman M. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye & Contact Lens. 2004 Jan;30(1):10-3.
Dell SJ, Lowry GM, Northcutt JA, Howes J, Novack GD, Hart K. A randomized, double-masked, placebo-controlled parallel study of 0.2% loteprednol etabonate in patients with seasonal allergic conjunctivitis. The Journal of Allergy and Clinical Immunology. 1998 Aug;102(2):251-5.
Shulman DG, Lothringer LL, Rubin JM, Briggs RB, Howes J, Novack GD, Hart K. A randomized, double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. Ophthalmology. 1999 Feb;106(2):362-9.