EyeWorld Asia-Pacific June 2012 Issue

45 EWAP DEVICES June 2012 Recognizing that ocular surface diseases encom- pass more than just dry eye may help tailor treat- ments accordingly W hat used to be thought of as simply “dry eye” is now recognized to be several different diseases that all negatively affect the ocular surface in some way, and it’s becoming a bigger part of ophthalmic diagnoses. “Dysfunction in the ocular surface unit can lead to ocular surface disease; one of those symptoms and signs is the disease ‘dry eye’,” said Vincent P. de Luise, MD , assistant clinical professor of ophthalmology, Yale University School of Medicine, New Haven, Conn., USA. “But it is important to remember that dry eye is much more complex than just aqueous phase deficiency of tears.” Dr. de Luise said the ocular surface is “a complex biological and physiological unit of tissues comprising the corneal epithelium, limbal stem cells, bulbar and tarsal conjunctiva, the main lacrimal gland, and several crucial structures within the lid margin, specifically the meibomian glands, the accessory lacrimal glands of Krause and Wolfring, and the glands of Zeiss and Moll.” Ocular surface disease is a dysfunction of the ocular surface unit—usually the various lacrimal glands, conjunctival surface, and lid margin, he said. Damage can occur to the corneal and conjunctival surface as a result of genetics or inflammation, and “these increase tear osmolarity and exacerbate inflammation, causing irritation in the process and structural damage at the end stages,” he said. The role of inflammation in ocular surface diseases “is not clearly understood,” said Michael A. Lemp, MD , clinical professor of ophthalmology, Georgetown University and George Washington University, Washington, DC, USA, and chief medical officer, TearLab Corp., San Diego, Calif., USA. With the increased emphasis on dry eye and the meibomian gland (after reports on both topics were published), “we now have the capacity to tailor or target our therapy based on the actual problem,” Dr. de Luise said. For instance, if the issue is aqueous- based, physicians should consider non-preserved artificial tears, he said. The role of preservatives in topical treatments is being strongly evaluated now in glaucoma medications, Dr. Lemp said. “We’re at a point now where a lot of ophthalmologists recognize that ocular surface diseases impact a patient’s quality of life, including, most importantly, the quality of vision,” he said. Physicians may sometimes opt for a short course of topical steroids (such as loteprednol) to quickly improve the surface if the patient is expected to undergo surgery, Dr. de Luise said. Similarly, the patient may benefit from oral tetracycline derivatives (doxycycline, minocycline) or topical azithromycin for the treatment of meibomian gland dysfunction. He recommended considering topical cyclosporine 0.05% suspension, but holding off on placing punctal plugs until the inflammatory aspects of the surface have been addressed. Placing the plugs while the inflammatory aspects of ocular surface disease are active can paradoxically worsen a patient’s symptoms as the “inflamed tears” are still in the tear film. “However, topical cyclosporine 0.05% can take months to really be effective,” he said. “T-cells have a half life of 110 days, and topical cyclosporine only works on newly born T-cells.” Coming down the pike Several companies are developing pharmaceutical candidates that will address one or more ocular surface diseases. Some target a specific pathway; others are being revamped to eliminate preservatives; still others are being developed to work with or against a particular gene. For instance, Dr. Lemp said several companies are developing compounds that “look at better biomarkers for the study end points.” Additionally, he likes matrix metalloproteinase (MMP- 9) as a potential biomarker, even though it’s not specific for dry eye. “Measuring MMP-9 is an interesting test because it will probably give the physician useful information about the amount of inflammation in the eye,” Dr. Lemp said. While MMP-9 may not be the best marker in a clinical trial, it may lead researchers to discover the role of inflammation in surface diseases, he said. Biomolecules based on blocking interleukin (namely, IL-1) are also showing potential. “Schepens Eye Research Institute [Boston, Mass., USA] Expanding ‘dry eye’ definitions by Michelle Dalton EyeWorld Contributing Editor researchers are evaluating mucin levels and finding when we think we’re getting staining, it’s really a breakdown in the mucin coating of the cells,” Dr. Lemp said. “Changes in the MUC-16 profile associated with dry eye in general may lead us to a better understanding of the disease overall.” Dr. de Luise explained: “The conjunctival goblet cells elaborate the various mucins, some of which are soluble mucins and others of which are membrane- bound mucins. These latter membrane-bound mucins bind to the glycocalyx on the surface of the cornea, which adsorb the hydrophilic aqueous phase of tears to the hydrophobic cornea, and also serve to lower surface tension and help to spread the tear film.” What follows are some of the more promising pharmaceutical candidates for ocular surface disease. Anti-inflammatory drugs CF-101, in 0.1 and 1.0 mg doses (Can-Fite BioPharma, Petah-Tikva, Israel): An adenosine receptor agonist in Phase III studies for the treatment of aqueous- deficient dry eye (including Sjogren’s syndrome). The company estimated enrollment of 240 patients, randomized to one of three interventions (CF101 0.1 mg, CF101 1.0 mg, or placebo). Outcome measures include complete clearing of corneal staining by fluorescein staining. The study is expected to close in August. SAR 1118 (SARcode Bioscience, Brisbane, Calif., USA): A first- in-class small molecule integrin antagonist, SAR 1118 works to inhibit T-cell activation, adhesion, migration, proliferation, and cytokine release by blocking two continued on page 46