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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
Utilization Characteristics of Topical Cycolsporine and Punctal Plugs in a Managed Care Database
Richard G. Fiscella, BS Pharm, MPH; Jeffrey T. Lee, PharmD, FCCP; John G. Walt, MBA; and Todd D. Killian, MBA, MS
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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
Nutritional supplements
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
• In contrast, 2 other randomized trials (N = 26 and N = 40) demonstrated significant improvement of DED symptoms and some objective signs with the omega-6 fatty acids linoleic acid (LA) plus GLA, compared with placebo.79,80
• 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
• A randomized trial of LA plus GLA versus lid hygiene versus both treatments in 57 patients with MGD demonstrated that combined treatment was more effective than either treatment alone.72

The positive clinical trials of omega-6 fatty acids were all conducted in Italy, whereas the negative trials were conducted in North America, the United Kingdom, and Scandinavia. In light of the WHS findings described above, one may speculate that the conflicting results could be explained by differences in dietary omega-6:omega-3 fatty acid ratios among these countries. Differences in study design, as well as limitations caused by small study size, may also account for the discrepant results.

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)
Vitamin A deficiency is a known cause of xerophthalmia; however, most DED patients are not vitamin A–deficient. Because retinol is present in tears, it has been hypothesized that DED may be associated with local retinol deficiency at the ocular surface.83 Based on this hypothesis, topical retinol has been used to treat various forms of DED, with variable results.83 Limited data suggest a possible role in reversing squamous metaplasia and keratinization of the ocular surface in severe DED, for example, in cicatrizing conjunctivitis or graft-versus- host  disease.83,85-87 However, the use of topical retinol in DED remains controversial.83

Guidelines and treatment selection
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

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 Table 1.2 The DEWS treatment recommendations were based on the modified severity grading.

Cyclosporine versus other anti-inflammatory agents
As discussed above under Treatment options, topical cyclosporine has demonstrated long-term efficacy and safety in the treatment of DED. In contrast, topical corticosteroids are effective but are not recommended for long-term use because of their AEs. Oral tetracyclines have been used for their anti-inflammatory activity, primarily in DED associated with ocular rosacea; however, this use is offlabel and is based on limited evidence. Topical NSAIDs have also been used off-label, but whether they have any role in DED has been questioned because of reports of serious AEs in patients with a compromised ocular surface.

Cyclosporine versus punctal plugs
In the ITF algorithm for treatment of DED without lid margin disease (Table 2), 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
• Artificial tear use declined significantly in all 3 groups compared with baseline, at all time points except in the cyclosporine-only group at 1 month. At 6 months there was no statistical difference between combination treatment and cyclosporine alone; however, combination treatment was significantly superior to plugs alone.88

The investigators concluded that all 3 treatments were effective, but that plugs were more beneficial for immediate relief of dryness, whereas cyclosporine improved ocular surface health over time. The combination of the 2 treatments produced the greatest overall improvement.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.
• Eyelid hygiene (particularly in patients with MGD).
• Tear supplementation—for example, artificial tears, autologous serum tears.
• Tear retention—for example, punctal plugs, moisture spectacles/goggles, therapeutic contact lenses, tarsorrhaphy.
• Tear stimulation—for example, oral cholinergic agents such as pilocarpine or cevimeline (used off-label for aqueous-deficient DED).
• Anti-inflammatory agents—for example, topical corticosteroids, oral tetracyclines, topical cyclosporine.
• 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.
Osmolarity/osmolality. Some studies suggest that artificial tears should ideally mimic the osmolarity of normal tears; however, others suggest that hypo-osmolar artificial tears are optimal.
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.
Preservatives. There are 2 main types of preservatives: detergent (eg, benzalkonium chloride) and oxidative (eg, stabilized oxychloro complex). Detergents can irritate or damage the ocular surface with frequent use; oxidative preservatives are less likely to do so. Preserved tears are usually well tolerated in mild DED when used no more than 4 to 6 times daily. If more frequent application is required, unpreserved tears should be used.
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.

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