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Only recently have most eye care providers come to recognize dry eye as a disease. Thanks to years of research and dedication by the Tear Film and Ocular Surface

Society (TFOS), industry members, and other groups and individuals, providers have begun to realize the complexity of this chronic, inflammatory, progressive condition. New ways of diagnosing and treating dry eye disease (DED) have been developed as a result of that realization. This article provides an update on relevant topical ocular therapeutics that are avail-able or in the pipeline.

CYCLOSPORINECyclosporine was initially isolated in

1971 from the fungus Tolypocladium inflatum Gams.1 Cyclosporine A is a calci-neurin inhibitor that inhibits the inflam-matory cycle by decreasing key cytokines involved in T-cell recruitment, activation, and amplification.2 Cyclosporine A also inhibits apoptosis by blocking the open-ing of the mitochondrial permeability transition pore, and the molecule has been shown to increase the density of conjunctival goblet cells.2,3 Goblet cells have important mucin production and immunoregulatory capabilities.

Until 2 years ago, cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) was the only commercially avail-able ophthalmic formulation of cyclo-sporine. Approved in 2003, it is the most

prescribed branded eye drop in the United States, with 6.4 million patients treated, according to the manufacturer. Restasis is available in two forms. The original pre-servative-free vial is labeled to be used for a single instillation of the drops and then discarded. A newer option is a multidose bottle of the drug that is currently the only FDA-approved ophthalmic bottle for dispensing a preservative-free oph-thalmic medication (Figure 1). According to Allergan, manufacturing of the single-use vials will continue at this time, so both delivery options are available for your patients.

Restasis is labeled for twice-daily dosing and is indicated to increase the production of tears in patients whose tear production is presumed to be suppressed by inflam-mation associated with keratoconjuncti-vitis sicca. The most frequent side effects of the drug are mild and include burning

Figure 1. Restasis.

WHAT’S YOUR DRY EYE ACUMEN?

Dry eye therapeutics that every optometrist should know about. BY JERRY L. ROBBEN, OD

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� COVER FOCUS THE LOWDOWN ON OCULAR THERAPEUTICS

upon instillation, discharge, hyperemia, and foreign body sensation. Most of these side effects typically subside after a short period of use of the drug. Although Restasis’ indication is for tear production only, research has suggested that cyclosporine has mul-tiple mechanisms of action. In clinical trials of Restasis, a significant increase in goblet cell density was observed 6 months after drug initiation, and a reduction in corneal staining (Figure 2) starting at 1 month after drug initia-tion was observed.4,5

Another option for an ophthalmic formulation of cyclosporine A is chondroitin sulfate/cyclosporine 0.1%, (Klarity-C, ImprimisRx; Figure 3). ImprimisRx operates as a 503B out-sourcing facility, which means it is

FDA-registered and required to meet Current Good Manufacturing Practice regulations to safeguard the quality and safety of compounded medications.

Klarity-C is available in a 5.5-mL bottle and delivers twice the concentration of cyclosporine A as Restasis in a preservative-free vehicle. After a physician prescribes Klarity-C via the company website, phone, or fax, someone at ImprimisRx contacts the patient to arrange payment and direct delivery by mail. Medical insur-ance is not used.

A third cyclosporine product (Cequa, Sun Pharma) will likely become available later this year. Like Restasis, Cequa is indicated to increase tear production in patients with kera-toconjunctivitis sicca, but Sun Pharma has suggested that its product’s higher concentration of cyclosporine (0.09%) may reduce the time it takes for the drug to take effect. Cequa uses an innovative nanomicellar vehicle that reportedly enhances drug delivery to the ocular surface. According to Sun, its product packages cyclosporine A within tiny micelles that are both hydrophobic and hydrophilic, allowing the active drug to penetrate through the tear layer and into corneal and

conjunctival tissues more effectively. The end result is reportedly a drug with a higher initial concentration and higher penetration into ocular tissue. FDA clinical trials showed primary endpoint improvement compared to vehicle at 12 weeks. Secondary end-points improved at 1 month.6

LIFITEGRASTXiidra (lifitegrast ophthalmic solution

5%, Takeda Pharmaceutical, formerly Shire; Figure 4) is the only drug indicated for the treatment of both signs and symptoms of DED. It differs from the immunomodulatory drug cyclosporine A in that it is an engineered immunoan-tagonist. It is classified as a lymphocyte function associated antigen-1 (LFA-1) antagonist, and it is the only medication with this novel classification.

Lifitegrast’s proposed mechanism of action is to block T-cell activation by adhering to the LFA-1 site on T-cells, inhibiting those T-cell sites from binding to the protein intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule that is expressed on the ocular surface and overex-pressed in patients with DED.7-9 When a T-cell’s LFA-1 receptor is allowed to bind to ICAM, the result is T-cell migration and activation and cyto-kine release. These events increase inflammation, ICAM expression on the cell surface, and T-cells, exacerbat-ing DED’s effects. Blocking this molec-ular “handshake” binding of the T-cell with ICAM improves DED signs and symptoms.9 In clinical trials, lifitegrast improved DED symptoms in as little as 2 to 6 weeks and signs in 12 weeks.

Side effects are similar to those reported for cyclosporine, except

Figure 2. Lissamine green allows visualization of dead and devitalized cells on the ocular surface. Here, mild to moderate conjunctival staining is seen.

Photo

court

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Figure 3. Klarity-C. Figure 4. Xiidra.

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for the addition of dysgeusia, which a minority of patients experience.10 This side effect is generally mild and is alleviated by drinking fluids or by dosing at bedtime. According to the manufacturer, Xiidra has been pre-scribed to 2 million people to date.

AUTOLOGOUS SERUM Autologous serum tears have been

used widely in specialty clinics for years to manage severe DED. Made from a patient’s own blood, autologous serum eye drops provide growth factors that, when instilled onto the ocular surface, promote epithelial healing and possibly maintain the health of an ocular surface prone to breakdown.11 A drawback to autologous serum eye drops has been that patients were required to visit a lab-oratory to have blood drawn. The blood is then sent to a specialized compound-ing pharmacy that makes the tears. Such pharmacies are not always locally avail-able, and the process is expensive.

Vital Tears is a nationwide com-pany that can provide autologous serum drops (Figure 5) by mail order. Patients may visit a local laboratory to have blood drawn and shipped to Vital Tears, which prepares and ships the serum drops. The prescribing phy-sician places the initial order and refill approvals, and Vital Tears coordinates billing and shipping directly with the patient. In some cases, the company can even arrange for a mobile phle-botomist to draw the patient’s blood at his or her home. Improving access and reducing cost may increase the use of this treatment option. TAILORED TREATMENT

Therapeutic options for DED are expanding. This growth, combined with the complexity and multifac-torial nature of the disease, means that eye care providers must tailor treatment to the individual patient. A useful approach is to consider short- and long-term goals.

Because lifitegrast begins to improve the signs and symptoms of DED relatively quickly, it can be a good first choice for patients with significant symptoms or for those

who will require ocular surgery soon. Cyclosporine A is generally thought of as a broader-spectrum option with a slower onset of action. It may there-fore be a more suitable alternative for patients who can wait longer for therapeutic effect or who can initially be given a steroid cycle pulsed dose.

Despite the expanding options described here, DED remains undertreated. Based on data from the 2013 National Health and Wellness Survey, Farrand et al estimated that 6 million people have experienced DED symptoms but have not been diagnosed with DED.12 This statistic would be unacceptable for any other eye disease, and it should be unaccept-able for DED as well. n

1. Borel JF. History of the discovery of cyclosporine and of itsearly pharmaco-logical development. Wien Klin Wochenschr. 2002;114(12):433-437.2. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. 2002;120(3):330-337.3. Kymionis GD, Bouzoukis DI, Diakonis VF, Siganos C. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol. 2008;2(4):829-836. 4. Pflugfelder SC, De Paiva CS, Villarreal AL, Stern ME. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008;27(1):64-69.5. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic solution in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000;107(4):631-639.6. Tauber J, Schechter BA, Bacharach J, et al. A phase II/III, randomized, double-masked, vehicle-controlled, dose ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 2018;12:1921-1929.7. Anderson ME, SiahaanTJ. Targeting ICAM-1/LFA-1 interaction for control-ling autoimmune diseases: designing peptide and small molecule inhibi-tors. Peptides. 2003;24(3):487-501.8. Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopula-tions in Sjögren’s and non-Sjögren’spatients with dry eye. Invest Ophthalmol Vis Sci. 2002;43(8):2609-2614.9. Zhong M, Gadek TR2, Bui M, et al. Discovery and development of po-tent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treat-ing dry eye. ACS Med Chem Lett. 2012;3(3):203-206. 10. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of lifitegrast ophthalmic solution 5.0% in patients with dry eye disease: a 1-year, multi-center, randomized, placebo-controlled study. Cornea. 2016;35(6):741-774.11. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59(2 Suppl):21-26.12. Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol. 2017;182:90-98.

JERRY L. ROBBEN, ODn Chief Optometrist and Director of Clinical

Research, Bowden Eye & Associates, Jacksonville, Florida

n Founding Member and Contributor, Dry Eye University

n Clinical Director, Dry Eye Accessn jrobben@bowdeneye.comn Financial disclosure: Speaker (Allergan, Shire)

Use of certain medications, including antihistamines, decongestants, antidepressants, birth control pills, and hormone replacement therapy

Dry eye is more common in those older than 50 years

Autoimmune disorders (eg, Sjögren syndrome, lupus, scleroderma, rheumatoid arthritis) and other diseases, such as diabetes and thyroid disorders

Women are more likely to develop dry eye than men (and also have an increased risk for autoimmune disorders)

Windy, smoky, or dry environments

Prolonged screen time

Seasonal allergies

Laser eye surgery

Source: Facts about dry eye. National Eye Institute. https://nei.nih.gov/health/dryeye/dryeye. Accessed March 1, 2019.

COMMON CAUSES OF DRY EYE

Figure 5. Vital Tears serum drops.

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