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Supplements Management and Pharmacoeconomics of Dry Eye Disease: The Role of Cyclosporine
Prevalence, Burden, and Pharmacoeconomics of Dry Eye Disease
Stephen C. Pflugfelder, MD
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Management of Dry Eye
Michael A. Lemp, MD
Dry Eye Disease: Pathophysiology, Classification, and Diagnosis
Henry D. Perry, MD

Management of Dry Eye

Michael A. Lemp, MD

The management of dry eye disease (DED) encompasses both pharmacologic and nonpharmacologic approaches, including avoidance of exacerbating factors, eyelid hygiene, tear supplementation, tear retention, tear stimulation, and  anti-inflammatory agents. Artificial tears are the mainstay of DED therapy but, although they improve symptoms and objective findings, there is no evidence that they can resolve the underlying inflammation in DED. Topical corticosteroids are effective anti-inflammatory agents, but are not recommended for long-term use because of their adverse-effect profiles. Topical cyclosporine—currently the only pharmacologic treatment approved by the US Food and Drug Administration specifically for DED—is safe for longterm use and is disease-modifying rather than merely palliative. Treatment selection is guided primarily by DED severity. Recently published guidelines propose a severity classification based on clinical signs and symptoms, with treatment recommendations according to severity level.

(Am J Manag Care. 2008;14:S88-S101)

Treatment options
There is a wide variety of pharmacologic and nonpharmacologic approaches to the management of dry eye disease (DED). These approaches are best described within categories that include avoidance of exacerbating factors, eyelid hygiene, tear supplementation, tear retention, tear stimulation, and anti-inflammatory agents.

Avoidance of exacerbating factors
Environmental modifications such as humidification, avoidance of wind or drafts, and avoidance of dusty or smoky environments may ameliorate DED symptoms. Lifestyle or workplace modifications may be helpful, for example, taking regular breaks from reading or computer use, and lowering the computer monitor below eye level so that the gaze is directed downward.1-4 Increasing blink frequency1 or fast blinking exercises4 have also been recommended. If feasible, medications that exacerbate DED should be discontinued.1 In an accompanying article in this supplement, Perry discusses modifiable risk factors for DED, including exacerbating medications.5

Eyelid hygiene
Washing the eyelid margin with a gentle soap decreases bacterial colonization. Bacterial colonization is believed to inhibit conjunctival goblet cell proliferation6 and may also increase the breakdown of meibomian lipid.2 Reducing colonization, therefore, may improve both the mucous and lipid layers of the tear film. Warm compresses may reduce evaporative loss by temporarily thickening the lipid layer.6 Manual expression of the meibomian glands has been shown to increase lipid layer thickness and tear film stability in normal subjects.7

In a small nonrandomized study of patients with meibomian gland dysfunction (MGD), a daily regimen of eyelid scrubbing and warm compresses, plus meibomian gland expression performed as an office procedure every 6 weeks, resulted in less-solidified meibomian secretions and significantly increased lipid layer thickness. Patients also reported improvement of DED symptoms.8

Tear supplementation
Artificial tears are the mainstay of DED treatment. They are used in all stages of DED, either alone (in mild to moderate disease) or in combination with other treatments (in moderate to severe disease).9  Most tear supplements act as lubricants; other actions may include replacement of deficient tear constituents, dilution of proinflammatory substances, reduction of tear osmolarity,2,9 and protection against osmotic stress.10

A wide variety of over-the-counter (OTC) artificial tear products is available. These products differ with respect to a number of variables that include electrolyte composition, osmolarity/osmolality, viscosity, the presence or absence of preservatives,2 and the presence or absence of compatible solutes.10

Electrolyte composition. Products that mimic the electrolyte composition of natural tears are available. Of the electrolytes, potassium and bicarbonate appear to be the most important.2
Osmolarity/osmolality. DED patients have higher-than-normal tear film osmolarity (ie, crystalloid osmolarity, which relates to the concentration of small dissolved particles, such as ions). Although some studies suggest that artificial tears ideally should mimic the osmolarity of normal tears, others suggest that hypo-osmolar artificial tears are optimal.9 Products with varying degrees of hypo-osmolarity have been developed.2

Colloid osmolality (which relates to macromolecule concentration) also varies among artificial tear products, and may be important because it influences water transport across the ocular surface epithelium. Theoretically, high colloid osmolality may be beneficial in reducing swelling of damaged epithelial cells.2

Viscosity. Higher artificial tear viscosity increases tear retention time and may help protect the ocular surface. Viscosity agents used in artificial tears include carboxymethylcellulose (CMC), polyvinyl alcohol, polyethylene glycol, propylene glycol, hydroxypropyl-guar (HP-guar), and lipids such as those that make up castor oil or mineral oil.2

Lipid-containing artificial tear products such as Refresh Endura (with castor oil) and Soothe XP (with mineral oil) are intended to decrease tear evaporation by restoring the lipid layer of the tear film2,11-13; this may be particularly useful in patients with MGD.11 HP-guar (in products such as Systane) is believed to form a bioadhesive gel when exposed to ocular pH, increasing aqueous retention and protecting the ocular surface by mimicking the mucous layer of the tear film.14,15

Hyaluronic acid is a naturally occurring viscoelastic substance16 that may also have antiinflammatory activity.17 In small randomized trials, artificial tears containing sodium hyaluronate (SH) have demonstrated greater improvement of DED signs and/or symptoms compared with normal saline18 and with other viscosity agents such as CMC19 or hydroxypropyl-methylcellulose/dextran.16 However, in another report, an SH-containing tear supplement was significantly less effective than topical cyclosporine in improving tear film stability and goblet cell density.17 SH-containing artificial tear products are commercially available in some countries, but have not been approved by the US Food and Drug Administration (FDA) for use  in the United States.2

High-viscosity agents tend to cause visual blurring; therefore, lower-viscosity agents are generally preferred for mild to moderate DED. However, in more severe cases, high-viscosity agents may be needed for symptom control.9 Ophthalmic gels and ointments have higher viscosity than liquids; they are also associated with more visual blurring than liquids and, therefore, are usually reserved for overnight use.9 Gels containing carbomers cause less blurring than petrolatum-based ointments,2 perhaps because carbomer viscosity decreases rapidly on exposure to tear salts.20

Preservatives. Preservatives are added to artificial tears to reduce the risk of bacterial contamination in multidose containers, and to prolong shelf life. There are 2 main types of preservatives: detergent and oxidative.9

Detergent preservatives act by altering bacterial cell membrane permeability.9 Detergents have toxic effects on the ocular surface epithelium and, with frequent use, can cause epithelial irritation and damage. Patients with a compromised tear film are at higher risk. Benzalkonium chloride, the most widely used preservative in topical ophthalmic preparations, is an example of a detergent preservative.2,9

Oxidative preservatives penetrate the bacterial cell membrane and act by interfering with intracellular processes. They are sometimes referred to as “vanishing” preservatives because they dissipate on contact with the eye and, therefore, are less likely than detergents to cause ocular damage.9 However, they may not always dissipate completely in DED patients because of decreased tear volume.2 Stabilized oxychloro complex is an example of an oxidative preservative.

Preserved tears are usually well tolerated in mild DED, when used no more than 4 to 6 times daily.2 (Exposure to preservatives in other topical ophthalmic agents [eg, glaucoma medications] must also be taken into account.) If more frequent use is necessary, unpreserved tears are recommended.2,9 Until recently, the FDA required unpreserved tears to be packaged in single-dose vials to avoid bacterial contamination; this makes them more expensive and less convenient to use.2 However, an unpreserved product (Visine Pure-Tears) is now available in a multidose vial with a dispensing system designed to prevent contamination.2,9

Compatible solutes. Osmotic stress occurs when the concentration of molecules and/or ions inside a cell differs from that outside the cell— as is the case in DED, in which the corneal epithelium is exposed to hyperosmolar tears. Under osmotic stress, the corneal epithelial cells tend to lose water, and may compensate by increasing their internal electrolyte concentration to stabilize their volume. However, elevated electrolyte concentrations can eventually lead to cellular damage.10,21

Compatible solutes are small nonionic molecules (eg, glycerin) that can be taken up by cells, increasing intracellular osmolarity without disrupting cellular metabolism. Artificial tears containing compatible solutes may thus provide protection against osmotic stress.10,21 Products containing compatible solutes include Optive and Refresh Endura (with 0.9% and 1% glycerin, respectively).

Large, randomized, masked comparative trials of different artificial tear products have not been performed.2 However, limited data suggest that there may be differences in product efficacy, for example:

• In small, randomized, comparative trials, a product containing polyethylene glycol, propylene glycol, and HP-guar, with the detergent preservative polyquaternium-1 (Systane), was significantly more effective than a CMC product preserved with stabilized oxychloro complex (Refresh Tears) in improving symptoms,22,23 ocular surface staining,22,23 and tear breakup time (TBUT).24 Systane also improved TBUT significantly more than an unpreserved product containing glycerin, polysorbate 80, and castor oil (Refresh Endura).24
• A randomized, internally paired study compared a mineral oil–containing product (Soothe) versus Systane. Forty patients received a single drop of Soothe in one eye and a single drop of Systane in the other eye (the eye in which each treatment was used was randomly assigned). Both treatments significantly increased tear film lipid layer thickness, but the increase was significantly greater with Soothe than with Systane.25 In a similarly designed trial (N = 41), Soothe increased lipid layer thickness significantly more than Refresh Dry Eye Therapy (a product similar to Refresh Endura, but preserved with stabilized oxychloro complex).26

Although artificial tears can improve symptoms and objective findings, there is no evidence that they can resolve the inflammation that accompanies DED.2

Autologous serum tears, produced from the patient’s serum, have been used in severe DED. Autologous serum tears have biochemical and mechanical properties similar, but not identical, to those of normal aqueous tears.27 They are unpreserved but can be stored frozen for 3 to 6 months,27,28 so that blood donation is required 2 to 4 times a year.

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