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Management of Dry Eye

Supplements and Featured PublicationsManagement and Pharmacoeconomics of Dry Eye Disease: The Role of Cyclosporine
Volume 14
Issue 3 Suppl

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

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

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

Lacrimal outflow occlusion slows tear clearance, and is indicated in patients with aqueous-deficient DED.2 However, it is relatively contraindicated in the presence of clinically apparent inflammation. When inflammation is present, occlusion prolongs pocular surface exposure to abnormal tears containing proinflammatory cytokines; therefore, treatment of inflammation before plug insertion is usually recommended.2,32,33

Punctal plugs are the most commonly used means of occlusion, and have been shown to improve DED symptoms and signs in a number of clinical studies. There are 2 main types of punctal plugs: absorbable and nonabsorbable. Absorbable plugs are made of collagen or various polymers, and may last for days to months.2 Some newer absorbable materials may last as long as 6 months.33 Nonabsorbable plugs, often made of silicone or hydrophilic acrylic, are intended to be permanent.

A common complication of punctal plugs is epiphora (tear overflow). Mild epiphora has been reported in up to 36% of patients. Epiphora is usually well tolerated, but as many as 5% of patients request plug removal.33 Other AEs include infection2 and conjunctival irritation.33 Short-term absorbable plugs may be used initially to predict which patients are likely to tolerate nonabsorbable plugs; however, this test is not completely reliable.33

Spontaneous extrusion of plugs occurs in up to 50% of patients within 3 months, requiring replacement. In contrast, internal migration is uncommon but troublesome, because removal of a migrated plug may require surgery. If not removed, a migrated plug can cause complete occlusion, which may lead to epiphora, infection, or fistulas. Newer plug designs minimize the risk of spontaneous extrusion or migration.33

Intracanalicular plugs are an alternative to punctal plugs with less risk of extrusion or conjunctival irritation. However, canalicular inflammation or infection may occur. Furthermore, removal is more difficult than with punctal plugs, requiring more invasive procedures.33

Surgical occlusion (eg, using electrocautery, laser, or glue) is an option for patients who tolerate plugs but repeatedly extrude them. However, the wide choice of reversible devices currently available has decreased the need for occlusive surgery.33

Moisture spectacles/goggles reduce tear evaporation by increasing humidity around the eye. The patient’s glasses can be modified using commercially available top and side shields or swimming goggles can be used.34 However, evidence of efficacy is limited2 and adherence may be poor for cosmetic reasons.1

Therapeutic contact lenses (also called bandage contact lenses) may be used in severe DED, or when other therapy has failed, to help retain the tear film and/or promote ocular surface healing.35 For example, therapeutic contact lenses may be useful in the management of filamentary keratitis.35-37 However, because contact lenses can also exacerbate DED, patients using them for DED must be monitored closely.35

Silicone hydrogel lenses have been recommended for use in DED because of their high oxygen permeability and relatively low water content. The low water content makes them less likely to dehydrate35 in the presence of a hyperosmolar tear film.

The Boston scleral lens is a therapeutic contact lens that is custom-manufactured using a computerassisted design program.38,39 It is a rigid gas-permeable lens that vaults the cornea and rests entirely on the sclera, creating a fluid-filled precorneal space.38,40 In this way, it provides a “liquid bandage” for the corneal surface, reducing or eliminating desiccation, hyperosmolarity, and friction with the eyelids.39 It is also fluid-ventilated—designed with channels that allow tears to flow into the precorneal space, avoiding the development of negative pressure.38,40

The Boston scleral lens is indicated for management of severe, refractory ocular surface disease, for example, to relieve disabling pain and photophobia or treat persistent epithelial defects.38-40 It is also used to improve visual acuity when conventional lenses are inadequate or are not tolerated.38 Successful use has been reported in DED, including DED with filamentary keratitis38,40 and severe DED secondary to graft-versus-host disease,38,39 Sjögren syndrome,38 or radiation.38 Additional information about the Boston scleral lens can be obtained from the Boston Foundation for Sight at http://www. bostonsight.org or (781) 726-7337.

Tarsorrhaphy (closure of the eyelids) is reserved for severe or refractory DED.1,34 Methods include:

• Short-term tarsorrhaphy using, for example, tape, adhesive glue (lasts a few days), or botulinum toxin (lasts an average of 16 days).41

• “Permanent” tarsorrhaphy. The lid margins are excised and sutured so that they heal together. The procedure can be reversed later.41

In most cases, only the lateral portions of the lids are closed to narrow the palpebral aperture, decreasing evaporation.34,41 A partially open eye allows partial vision, administration of drops, and corneal examination; it also allows more oxygen to reach the cornea.41 However, if partial closure fails, complete closure may be indicated.34

In a retrospective review of 77 tarsorrhaphy patients, complications included trichiasis (ingrown eyelashes) in 18.2%; adhesion of the upper and lower lids after tarsorrhaphy removal in 2.6%; pyogenic granuloma in 1.3%; and keloid formation in 1.3%. All of these complications occurred in patients with permanent tarsorrhaphies. Other reported complications have included lid margin deformities, suture granulomas, focal cellulitis, skin breakdown, and distichiasis.41

Tear stimulation: secretagogues

Topical corticosteroids are approved by the FDA for corticosteroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior globe. This indication can be interpreted as including DED.2

Several randomized trials have demonstrated that short-term topical corticosteroid use (as long as 4 weeks) improves signs and symptoms of DED2:

• In a single-blind trial,32 DED patients were randomly assigned to 30 days of treatment with either a topical corticosteroid, fluorometholone; a topical nonsteroidal antiinflammatory drug (NSAID), flurbiprofen; or artificial tears alone. (All patients received artificial tears, but these were used QID in the artificial tears–only group, and as many as 8 times daily in the corticosteroid and NSAID groups.) The corticosteroid group had significantly improved symptom scores on days 15 and 30, compared with the other groups. Corneal staining and goblet cell numbers were also improved with topical corticosteroid treatment compared with the other 2 treatments.50

• In a double-blind trial involving 35 patients with ocular rosacea, oral oxytetracycline significantly improved nonspecific clinical signs compared with placebo.57

Essential fatty acids (EFAs) may, theoretically, benefit DED in 2 ways: by reducing inflammation and by altering the composition of meibomian lipids.72 There are at least 2 EFA nutritional supplements marketed specifically for DED: one containing omega-3 fatty acids from flaxseed and fish oil,73 and another containing a blend of omega-3 and omega-6 fatty acids (docosahexaenoic acid/eicosapentaenoic acid [DHA/EPA] from cod liver oil and gamma-linolenic acid [GLA] from black currant seed oil, respectively).74 However, evidence for EFA efficacy is limited and conflicting.

Epidemiologic data from the Women’s Health Study (WHS) showed an association between higher dietary omega-3 fatty acid intake and a lower risk of DED. Omega-6 fatty acid intake was not independently associated with DED; however, a higher omega-6:omega-3 ratio was associated with significantly greater DED risk.75 Several small clinical trials of EFA nutritional supplements have also been conducted (described below).

Omega-3 fatty acids. In a randomized, doubleblind, placebo-controlled trial involving 41 patients with Sjögren syndrome, an omega-3 supplement improved DED symptoms more than placebo; however, the difference did not reach statistical significance (P = .082).76

Omega-6 fatty acids. The WHS data suggest that omega-6 fatty acid supplementation should not improve DED; however, small clinical trials have given conflicting results:

• Two randomized trials of omega-6 fatty acids in Sjögren syndrome patients (N = 28 and N = 90) showed no significant improvement in DED signs or symptoms compared with placebo. 77,78 In one of the trials, however, the active treatment group had significant improvement versus baseline, whereas improvement in the placebo group versus baseline did not reach statistical significance.77

• A randomized trial of prophylactic LA plus GLA versus no omega-6 treatment was conducted in 60 patients undergoing photorefractive keratectomy. Significant postoperative differences were found in DED symptoms and some objective signs, in favor of LA plus GLA.81

Topical acetylcysteine was mentioned in the literature as a DED treatment as early as the 1960s,82 and is still sometimes used in DED patients with dense mucus accumulation,83 for example, in filamentary keratitis.37,84 Acetylcysteine is not commercially available as a topical ophthalmic agent.83 Inhalational acetylcysteine (FDA approved for use as a bronchial mucolytic) has been diluted for offlabel use as a topical ophthalmic agent.

Topical vitamin A (retinol)

Previous practice guidelines have used an etiology-oriented approach to DED.1,34 However, commonly used etiologic classifications (eg, aqueous-deficient vs evaporative, Sjögren vs non-Sjögren) often are not helpful in establishing a treatment plan.32

Table 1

International Task Force (ITF) guidelines, published in 2006, propose a classification of DED severity based on clinical signs and symptoms. The ITF also developed treatment algorithms according to severity classification and the presence or absence of lid margin disease.32 In 2007 the Management and Therapy Subcommittee of the International Dry Eye WorkShop (DEWS) adopted a modified form of the ITF severity grading, as shown in .2 The DEWS treatment recommendations were based on the modified severity grading.

Cyclosporine versus other anti-inflammatory agents

Table 2

In the ITF algorithm for treatment of DED without lid margin disease (), topical cyclosporine is recommended as a treatment option for DED at level 2 severity (but only in the presence of clinically evident inflammation), whereas punctal plugs are recommended at level 3 severity (after control of inflammation).32 In contrast, the DEWS recommendations list both cyclosporine and punctal plugs as level 2 options, without specifying the presence or absence of clinical inflammation.2 Thus, there appears to be no clear consensus regarding the relative roles of cyclosporine versus punctal plugs.

In a small comparative trial, 30 patients with moderate DED were randomized to 6 months of treatment with either cyclosporine 0.05% or lowerlid punctal plugs, or both. Outcome measures included rose bengal staining, Schirmer scores without anesthesia, and artificial tear use.88

• At 1 and 3 months, both of the plug-containing regimens significantly improved Schirmer scores compared with baseline and with cyclosporine alone. Cyclosporine alone produced no initial Schirmer score response; however, by 6 months, all 3 groups had significant improvement compared with baseline, with no significant between-group differences.88

• In contrast, both of the cyclosporine-containing regimens significantly improved rose bengal staining at 3 and 6 months compared with baseline; there was no statistical difference between cyclosporine with versus without plugs. Plugs alone did not improve staining scores at any time point compared with baseline.88

Pharmacologic and nonpharmacologic approaches to management of DED include:

• Avoidance of exacerbating factors such as low humidity, wind or drafts, dust or smoke, prolonged visual tasks, exacerbating medications.

• Tear supplementation—for example, artificial tears, autologous serum tears.

• Tear stimulation—for example, oral cholinergic agents such as pilocarpine or cevimeline (used off-label for aqueous-deficient DED).

• Other therapies—for example, nutritional supplements (essential fatty acids); mucolytics (topical acetylcysteine, used off-label in DED with filamentary keratitis); and topical vitamin A (off-label and controversial, but possibly useful in severe DED with squamous metaplasia or ocular surface keratinization).

Artificial tears are the mainstay of DED therapy. Most tear supplements act as lubricants; other actions may include replacement of deficient tear constituents, dilution of proinflammatory substances, reduction of tear osmolarity, and protection against osmotic stress. A wide variety of OTC artificial tear products are available, which differ with respect to a number of variables that include:

• Electrolyte composition. Potassium and bicarbonate appear to be the most important.

• Viscosity. Higher viscosity increases tear retention time and may help protect the ocular surface, but is more likely to cause visual blurring. Viscosity agents used in artificial tears include CMC, HP-guar, and lipids such as those that make up castor oil or mineral oil. Lipid-containing products are intended to decrease tear evaporation by restoring the lipid layer of the tear film. HP-guar is believed to form a bioadhesive gel, mimicking the mucous layer of the tear film.

• Compatible solutes. These are small nonionic molecules (eg, glycerin) that are taken up by ocular surface epithelial cells. Because they increase intracellular osmolarity without disrupting cellular metabolism, they may protect against osmotic stress.

Although artificial tears can improve DED symptoms and objective findings, there is no evidence that they can resolve the inflammation that accompanies DED. Therefore, anti-inflammatory therapy may be indicated, including:

• Topical corticosteroids. Although effective, these agents are generally recommended only for short-term use because prolonged use may result in AEs including ocular infection, glaucoma, and cataracts.

• Topical cyclosporine. Topical cyclosporine is currently the only pharmacologic treatment that is FDA approved specifically for DED. Although its onset of action is relatively slow, it is safe for long-term use and appears to be disease-modifying rather than merely palliative. The most common AE is transient burning or stinging. Because blood levels are negligible even after long-term use, the risk of systemic toxicity is minimal.

Topical NSAIDs have been used off-label in DED; however, their use is controversial because they can promote corneal melting in patients with a compromised ocular surface. Some experts feel that they have no role in DED therapy.

Treatment selection is guided primarily by DED severity. ITF guidelines, published in 2006, proposed a DED severity classification based on clinical signs and symptoms. The ITF also developed a treatment algorithm according to severity grading and the presence or absence of lid margin disease. In 2007 the DEWS Management and Therapy Subcommittee published treatment recommendations based on a modified form of the ITF severity classification.

Author Affiliations: From Georgetown and George Washington Universities, and OcuSense, Inc, Washington, DC.

Funding Sources: The research and manuscript were funded by Allergan, Inc.

Author Disclosures: The author reports being a consultant for Alcon, Allergan, Novagali Pharma, OcuSense, Inc, and SARcode; and being a major stock shareholder for OcuSense, Inc.

Authorship Information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Address Correspondence to: Michael A. Lemp, MD, 4000 Cathedral Avenue, NW #828B, Washington, DC 20016. E-mail: malemp@lempdc.com.

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