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Future Trends in the Treatment of Dry Eye Disease

Dry eye was first recognized as a fundamental characteristic of Sjögren’s syndrome. Extensive investigations into the physiological and biochemical properties of tear fluid as well as research into the epidemiology and treatment of dry eye have subsequently provided important insight into this condition. Earlier chapters of this book have addressed the history and current status of dry eye as a medical entity. Despite the intense basic and clinical research activity over the past three decades, however, the diagnosis and effective treatment of dry eye remain problematic. Moreover, the number of individuals with dry eye has been increasing, with millions of people now affected worldwide. Given the relatively recent increase in life expectancy in many regions of the world and that tear secretion decreases with age, dry eye is likely to become an even more prevalent ophthalmic condition.

Dry eye is currently defined as a disorder of the tear film that is caused by a deficiency or excessive evaporation of tear fluid, results in damage to the interpalpebral ocular surface, and is associated with symptoms of ocular discomfort.1 In Japan, damage to the ocular surface is emphasized, and any pathological condition of the corneal epithelial surface caused by a reduction in the quantity or quality (or both) of tear fluid is considered to be dry eye. Dry eye is most frequently diagnosed on the basis of subjective symptoms that vary widely but often include blurred vision or the sensation of having a foreign body in the eye. The discomfort at the ocular surface can lead to psychological stress and disrupt the daily routine of life. It should be noted, however, that dry eye is different from ocular dryness. If a patient complains of such dryness, it is thus important to differentiate dry eye from other ophthalmic diseases or underlying pathological conditions that might be treated medically or surgically.

Dry eye is not a separate disease but is rather a manifestation of various underlying disorders. In an exploration of future trends in research into dry eye and the treatment of this condition, this chapter discusses in more detail the definition of dry eye, focusing on targets for treatment, as well as examines the physiological roles of tear fluid and the interactions between tear fluid and the corneal epithelium.

♦ Definition and Classification of Dry Eye Disease

Unlike other ophthalmic disorders of the anterior surface of the eye, such as infectious keratitis and genetic corneal dystrophies, the diagnosis of dry eye depends largely on subjective symptoms. Such a situation is obviously not desirable and can lead to an incorrect diagnosis. Establishment of a definition of dry eye that is based on objective criteria as well as subjective symptoms is thus important to facilitate the differentiation of dry eye from other underlying diseases with similar symptoms.

Dry eye is not a single disease entity. It is a syndrome caused by various factors that can act alone or combine to render the signs and symptoms more complex. Established modes of treatment are thus not necessarily effective for all types of dry eye. The categorization of dry eye is therefore another important goal in the development of new treatments for this condition. Dry eye can be classified clinically into three types, which are characterized by tear deficiency, tear evaporation, or mucin deficiency. The underlying pathological mechanisms differ among these categories, suggesting that the targets for treatment should be selected accordingly.

Tear fluid at the ocular surface comprises three layers, each of which has a specific physiological role. The mucous layer of tear fluid renders the surface of the corneal epithelium hydrophilic and maintains its affinity for the aqueous layer, which contains various water-soluble ions, metals, and proteins as well as cells. The oily layer prevents excessive evaporation of the aqueous layer. It is the components of the aqueous layer that maintain and regulate the physiological functions and structure of the corneal epithelium, but both the mucous and oily layers are required for maintenance of the aqueous layer. The current classification of dry eye thus appears relevant for the development of specific treatment regimens, but the problem of how to diagnose objectively the three categories of this condition remains.

Various diagnostic tests for tear physiology, such as measurement of the osmolarity of tear fluid and quantitation of lactoferrin, have been introduced relatively recently. Most ophthalmologists still rely on Schirmer’s 1 test and fluorescein staining for diagnosis of dry eye, however. Given the limited amount of tear fluid available, its collection under basal conditions in the clinical setting is difficult and may restrain the development and popularization of new diagnostic examinations for dry eye. The development of nanotechnology and analytic instruments that can measure the amounts of molecules at the nanomole, picomole, or even femtomole level may help to overcome this problem in the future.

♦ Tear Fluid and Dry Eye Disease

Tear fluid is an evolutionary adaptation to life on dry land that arose to prevent desiccation of the ocular surface. The lacrimal gland thus first appeared in amphibians during evolution² and has since served to protect humans from environmental changes, both natural and manufactured. As mentioned earlier, it is important to determine the cause of dry eye to select an appropriate mode of treatment. A flow chart for the diagnosis of dry eye disease has proved moderately effective in this regard.¹

The basic goal in the treatment of dry eye is to correct the underlying defect (be it quantitative or qualitative) in tear fluid as well as to ameliorate any associated disorders of the corneal epithelium, such as superficial punctate keratopathy and epithelial erosion. The mixture of the three principal components (oily, aqueous, and mucous) of tear fluid and their correct microstructure are required to maintain the surface of the corneal epithelium smooth and intact.³ These components are mixed by each blink and then reform into the three-layered structure. It is therefore important that each component be produced in sufficient amounts to maintain the structure of tear fluid, the oily layer derived from the meibomian glands, and the mucous layer produced by corneal and conjunctival epithelial cells4 as well as conjunctival goblet cells,⁵ which are especially important in this regard.

The quantity of tear fluid depends in large part on the function of the lacrimal glands. On the other hand, physical factors such as the frequency of blinking and the shape of the eyelids are determinants of the rate of evaporation of tear fluid. The excretion of tear fluid through the lacrimal duct also affects tear fluid structure. Such considerations of the dynamics of tear fluid have led to the recognition that conditions of the lacrimal and meibomian glands as well as eyelid shape should be taken into account in the diagnosis of dry eye disease and the selection of an appropriate treatment regimen.

If dry eye is caused by a deficiency of the oily layer of tear fluid, the target of treatment should be the meibomian gland. Lid hygiene, antibiotics, or steroids are often recommended for meibomian gland dysfunction caused by chronic infection such as meibomianitis or blepharitis. For dry eye caused by a deficiency of the aqueous layer, preservation of tear fluid by the application of ointment to prevent evaporation, occlusion of the lacrimal ducts with plugs, or administration of artificial tear fluid as eyedrops is indicated.

♦ Future Treatment of Dry Eye

Dry eye results from either a deficiency in or excessive evaporation of tear fluid, and the discomfort experienced by affected individuals relates to the condition of the ocular surface. Disturbances of the normal structure of the corneal or conjunctival epithelium lead to a wide variety of subjective complaints as well as objective signs. A loss of barrier function of the corneal epithelium may result in the activation of stromal keratocytes and an inflammatory reaction in the stroma. The loss or degeneration of superficial cells of the corneal epithelium can also result in stimulation of sensory nerves and thereby trigger an irritating stinging feeling.

Tear fluid serves not only to lubricate the eye and to retain moisture but also to maintain and regulate the structure and functions of the corneal and conjunctival epithelia by providing nutrients (such as glucose) and biologically active substances such as chemokines, cytokines, and growth factors (Table 18-1). Changes in the concentrations of these biologically active agents in individuals with dry eye can result in dysfunction of the ocular surface. These substances are supplied not only by the lacrimal glands but also by the conjunctiva, corneal epithelium, meibomian gland, and sensory nerve endings (Fig. 18-1).

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