Anti-Inflammatory Therapy in the Treatment of Dry Eye

Emsel L. Bowling  OD, MS, FAAO, Dipl

 There is increasing evidence that dry eye is an inflammatory disease. Dry eye disease (DED) is related to inflammation of the ocular surface, based on the patient’s immune response and induced by many cytokines.1-4 The presence of these inflammatory mediators on the eye likely accounts for at least some of the burning and itching experienced by the patients. Disease or dysfunction of the tear secretory glands leads to changes in tear composition, such as hyperosmolarity, that stimulate the production of inflammatory mediators on the ocular surface.5 There are numerous factors that may contribute to the formation of ocular surface inflammation such as desiccating stress,6 hyperosmolarity,7 proinflammatory cytokines released from the lacrimal glands,8 and blinking abnormalities.9 A vicious cycle of inflammation may develop on the ocular surface in dry eye, which will ultimately lead to ocular surface disease. As a result of inflammation, some patients may continue to complain of eye irritation despite adequate aqueous enhancement therapies.

Topical Steroids
Clinical evidence indicates that therapies inhibiting inflammatory mediators reduce the signs and symptoms of DED.10 Topical corticosteroids are approved by the FDA and prescribed for corticosteroid-responsive inflammatory conditions of the conjunctiva, cornea and anterior globe—including DED.11

There are a variety of steroids available in eye care. The two traditional groups of agents are the ketone steroids (prednisolone, dexamethasone, fluorometholone, medrysone and rimexolone) and the ester steroid (loteprednol). A randomized, double-masked, placebo-controlled study of loteprednol etabonate showed that a subset of patients with the most severe inflammatory signs at entry—treated topically with loteprednol—showed a significantly greater decrease in central corneal fluorescein staining scores when compared to its vehicle (31% vs. 0%, respectively). There was also a 25% decrease in inferior bulbar conjunctival hyperemia in the loteprenol-treated group compared to a 33% increase in the vehicle-treated group. There was no change in intraocular pressure in the steroid treated group. The study showed that patients with at least moderate clinical inflammation were more likely to show significant benefits with loteprednol.12

Although topical corticosteroids are effective, they are generally recommended only for short-term use because prolonged use may result in adverse events including ocular infection, glaucoma, and cataracts.13 However, corticosteroids may differ in their propensity to cause these complications. For example, dexamethasone is very potent steroid, but doesn’t penetrate ocular tissues well and has a strong side effect profile. In contrast, prednisolone is almost as potent and penetrates ocular tissues well. Other steroids, like loteprednol etabonate and fluorometholone, are less potent and have better safety profiles.

The most worrisome steroid side effects are intraocular pressure (IOP) spikes and cataract formation. Compared to dexamethasone and prednisolone, loteprednol and fluorometholone have lower rates of these complications. In a summation of randomized studies, treatment with loteprednol etabonate (0.5% concentration) for greater than 28 days resulted in a 2% incidence of elevated intraocular pressure, compared with a 7% incidence with prednisolone acetate (1% concentration) and 0.5% incidence with placebo.14

Cyclosporine
An alternative to steroids, or as an adjunctive therapy, topical cyclosporine can also be used to control inflammation in dry eye disease. While cyclosporine does not demonstrate the rapid anti-inflammatory effect of steroids, it carries fewer risks and is safe for long-term use.

Because of their complementary efficacy and safety profiles, many practitioners often begin dry eye treatment by prescribing both topical steroids and cyclosporine. Following the recommendation of the Asclepius Panel, the use of combination therapy is instituted with the topical corticosteroid, Lotemax (loteprednol etabonate ophthalmic suspension 0.5%, Bausch + Lomb) and Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan).15 The Asclepius Panel recommends practitioners begin early treatment with an anti-inflammatory agent (such as Lotemax) four times a day to improve symptoms and to prevent disease progression. After two weeks, the frequency of the corticosteroid is reduced to twice daily and supplemented with Restasis twice a day.

Lotemax may increase patient adherence to the regimen by alleviating the stinging that accompanies Restasis. In one study, pretreatment with Lotemax reduced the stinging associated with Restasis by 75%.16 Treatment with loteprednol was stopped after day 60, while cyclosporine treatment is continued. Thereafter, patients should continue this therapy and increase Lotemax dosage during acute flare-ups.17 In this way, the patient gains an immediate anti-inflammatory effect from the steroid and long-term control of inflammation from the cyclosporine. Combined immunomodulation using cyclosporine and loteprednol, which act on different steps in the inflammation cascade, should work faster and more effectively than use of the drugs separately as monotherapy and makes the two medications an effective therapeutic option.

Doxycycline
Oral doxycycline, a tetracycline derivative, is also used in managing ocular surface diseases and is likely effective due to its anti-inflammatory properties. Tetracyclines are used in DED primarily for their anti-inflammatory rather than antibacterial actions. Mechanisms may include decreased matrix metalloproteinase activity, and decreased production of proinflammatory cytokines.18

Dry eye is related to inflammation of the ocular surface, and immune-mediated inflammation plays an important pathogenic role. Anti-inflammatory therapies can rapidly and effectively relieve the symptoms and signs of moderate or severe dry eye.

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