Two conditions we deal with frequently are allergic conjunctivitis and dry eye. Each presents with a spectrum of symptomatology and, although treatments are available for both, there is also room for therapeutic improvement. A key area of unmet need is the intersection of these two conditions, with the growing awareness that as the prevalence of each condition rises, many patients experience both ocular allergy and dry eye.
Although population demographics suggest that there is likely to be a high degree of comorbidity between allergy and dry eye, there are few direct studies that address this issue. Two large-cohort, longitudinal studies do provide evidence that these are not simply two separate, independent conditions.
Ocular allergies, including both seasonal and perennial varieties, affect an estimated 60 million people in the United States and between 20 and 30 percent of individuals throughout the rest of the industrialized world.
While atopy continues its relentless march, the increased lifespan and the aging of populations worldwide are contributing to increased dry-eye prevalence. Like ocular allergy, dry eye is a disorder that ranges from a minor inconvenience to a pervasive, life-altering affl iction. It is a condition more common in women, and more common in patients over 50.5 Dry eye differs from ocular allergies, however, in that it has an extremely heterogeneous etiology that includes Sjögren’s syndrome, meibomian gland disorders and neural loop disorders that interfere with reflex tearing. Other causes include various dyslipidemias, mucin disorders (including cystic fi – brosis), Stevens-Johnson syndrome and the keratitis that can sometimes occur following refractive surgery.
Both ocular allergy and dry eye are aggravated by atmospheric pollutants such as ozone, automobile emissions and other byproducts of fossil fuel combustion. Ozone exposure can lead to elevated free radical damage to proteins and other cell constituents on the ocular surface. Other emission compounds can act as antigens, stimulate immune responses to other airborne allergens, or act as direct irritants to the ocular mucus membranes they contact, eliciting both lacrimation and immune responses. This is just one example of the close association between these two ocular disorders; the report of the International Dry-eye Workshop listed allergic conjunctivitis as a key “extrinsic factor” in dry-eye etiology.
One aspect of the comorbidity that does seem to be emerging is the reduced seasonality of the combined disorders. Dry-eye patients typically experience more severe symptoms in winter months when humidity is lower and people spend more time indoors. 5 The majority of patients with allergies are symptomatic in spring or fall, depending upon the specifi c allergens to which they respond.
The starting point for therapy of both conditions is likely to include the use of tear substitutes, which can flush allergens from the ocular surface while at the same time replenish a shortage of tear volume. Over-thecounter oral antihistamines might be an option for treating ocular allergies, but some of these come with a particularly troublesome side effect: The relief they provide from allergies is offset by their tendency to exacerbate symptoms of dry eye. A number of studies have shown that oral antihistamines such as loratadine or cetirizine can reduce aqueous tear production and worsen the ocular burning, grittiness and corneal staining in patients who suffer from dry eye.
Both allergic conjunctivitis and keratoconjunctivitis sicca are aggravated by pollutants in the atmosphere, including ozone, emissions from cars and trucks, and the various by-products of fossil-fuel combustion.
Beyond the use of artifi cial tears, treatment options for both conditions overlap with the use of topical or systemic anti-infl ammatories such as corticosteroids. In addition, several recent studies have suggested that some dual-action topical antihistamines, notably olopatadine and alcaftadine, may also exhibit some degree of anti-infl ammatory effects.9,10 When tested in preclinical models of dermal infl ammation, olopatadine inhibits cytokine levels while also inducing secretion of hyaluronic acid, a compound involved in epidermal healing.
Topical corticosteroids such as loteprednol are the last resort for both allergy and dry eye, and when used judiciously these agents can safely break the infl ammatory momentum that can result from either of these conditions, whether the condition is in isolation or exists in combination with the other. As long as the duration of steroid therapy is kept within a one- to two-week window the risks of increased intraocular pressure or ocular infection should not become significant. The other therapy used for dry eye, cyclosporine, is a drug with multiple actions that relieves dry eye by enhancing aqueous tear production in approximately 12 to 15 percent of patients.
While patients with ocular allergies experience an increased risk for dry eye, the converse is also true: Dry eye can exacerbate allergic signs and symptoms. In a recent paper we described a study that tested effects of exposure to an adverse environment designed to evoke dry eye (using the Ora Controlled Adverse Environment model) on the allergic responses of patients who report suffering from both allergic conjunctivitis and dry eye.
Confocal video microscopy provides images of the conjunctival surface before (left) and after (right) allergen challenge. The infi ltration of infl ammatory cells seen after the allergen challenge is characteristic of both late-phase allergy and dry-eye disease.
Two additional recent studies document damage to the conjunctival and corneal epithelium associated with prolonged allergen exposure
Historically, the stumbling block for dry-eye drug development has been the apparent disconnect between signs and symptoms of dry eye disease—dry-eye patients may be asymp tomatic with signifi cant corneal pathology, or may suffer from severe burning and ocular discomfort with little or no corneal staining in the clinic. The search for reliable biomarkers for ocular surface pathology is aimed at providing a reliable metric for drug discovery.
As we learn more about the pathology of the ocular surface, the commonalities between tear-fi lm dysfunction and allergic disease become more apparent. While the pathological processes underlying disease in each patient represent a complex amalgam of genetic, molecular and environmental factors, the end result seems to include a robust complement of signs and symptoms common to many patients with dry eye, allergy or both. The shared changes in the ocular surface include structural modifi cations in the epithelial cells, infl ammatory cell infi ltration and infl ammatory mediator release, as well as alterations in tear constituents. Each of these variations from the normal ocular surface homeostasis contributes to expression of the disease phenotype, and each represents a potential target for therapeutic intervention.
As with all new treatments, the key to addressing the needs of this growing population of patients is establishing viable metrics and effi cacy standards for therapeutic development. Ideally, new treatments will provide relief to sufferers of both dry eye and allergy, so symptoms of either disease need not be overlooked.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at the Schepens Eye Research Institute. Dr. McLaughlin is a medical writer at Ora Inc.
