The Coming Revolution in Dry Eye Treatment
A better understanding of the causes of dry eye is leading to more accurate diagnosis -- and more effective treatment strategies.
By Mark B. Abelson, M.D., Katrina A. Wilcox, and George W. Ousler III

In recent years, both the prevalence and awareness of dry eye has increased significantly. It's estimated that 5% of the U.S. population has now been diagnosed with this condition. Moreover, the percentage of individuals who experience ocular discomfort as a result of situations they encounter in everyday living is much greater.

Traveling on an airplane, performing a visual task such as working on a personal computer, or using systemic medications like antihistamines that are known to cause drying can trigger ocular symptoms, or make existing symptoms temporarily worse. Fortunately, as the prevalence of dry eye has increased, so has our understanding of its various causes -- and our ability to develop effective treatments.

In this article, we'll describe how recent research into dry eye is giving us better diagnostic tools with which to develop more effective treatment strategies.

ILLUSTRATION: CHRIS VAN ES

Treatment evolves as knowledge grows

During the 1970s, researchers studying dry eye began to examine qualitative rather than quantitative changes in tear secretion. They thoroughly investigated the intimate relationship between tears and their contributory structures, such as the surface epithelium, lacrimal glands, meibomian glands, goblet cells, eyelids and the effects of blinking.

Over the past three decades, studies have identified numerous interrelationships among hormones, mucins, oils, growth factors, retinoids, cytokines and their sites of action found in various tissues (e.g. lacrimal, corneal, and conjunctival). To better understand such findings, many researchers began to conceptualize the ocular surface as a single-functioning and highly interactive unit. Consequently, therapeutic approaches have shifted toward the treatment of underlying disease processes associated with dry eye. Treatment strategies for dry eye and associated ocular surface diseases currently include polymer-based artificial tears, punctal occlusion, and patient avoidance of inciting causes.

In recent years, extensive basic and clinical research has led to a number of dry eye discoveries. One major finding is that dry eye isn't caused by a lack of tear volume alone, but by a deficiency in one or more of the tear components, resulting in epithelial pathology and inflammation of the ocular surface. In addition, we have been able to advance our knowledge in the following areas:

The lipid layer. The lipid layer is approximately 0.1 mm thick and is secreted primarily by the meibomian glands, as well as the glands of Zeiss and Moll. The function of this outmost layer of the tear film is to prevent tear evaporation from the ocular surface. Its polar and non-polar constituents consist of waxy, fatty lipids and cholesterol esters that are essential for maintaining the structural and refractive integrity of the tear film.

A landmark discovery related to evaporative dry eye syndromes noted the effect of sex steroid hormones on meibomian and lacrimal gland secretion, lipid profiling, and tear film break-up time. Human meibomian glands contain androgen receptor mRNA, androgen receptor proteins, and several enzymes that may convert testosterone or metabolized androgens into other androgenic forms. Studies have confirmed that androgens regulate meibomian gland dysfunction, control the quality and/or quantity of lipids produced by this tissue, and promote the formation of the lipid layer. It's the intricate relationship between different lipid classes, the length of fatty acids and alcohols, and hydrolyzation that maintains optimal barrier properties of the lipid layer.

Metaplastic changes to the lid margin epithelium can contribute to dry eye syndrome. Meibomian gland metaplasia impinges on the meibomian gland orifices, causing a decrease in the release of lipids and an increase in tear film evaporation.

The aqueous layer. The aqueous layer constitutes the middle layer of the tear film and is produced by the lacrimal gland and its accessory organs, the glands of Kraus and Wolfring. It's responsible for maintaining a healthy ocular surface by supplying it with essential components. These components include inorganic salts, glucose, urea, trace elements, lactoferrin, IgA, LDH, proteolytic inhibitors and oxygen. Many proteins found in the aqueous layer are part of the secretory immune system and are responsible for protecting the ocular surface from microbial agents and toxic compounds. Various lacrimal gland proteins, such as cytokines and growth factors, are synthesized in response to trauma or irritation of the ocular surface.

The mucin layer. The third layer of the tear film, the mucin layer, is produced mainly by goblet cells found in the conjunctiva and cornea. Although significantly thinner than the aqueous layer, the mucin layer is critical in providing a hydrophilic coating for the normally hydrophobic corneal epithelium. This layer lies adjacent to the ocular surface and its function is to promote continuity of the tear film by reducing the surface tension and insulating the aqueous layer from the polar cell membranes. Through its high molecular weight and greater carbohydrate-to-protein ratio, mucin enables the tears to completely wet the cornea.

In recent years, our understanding of ocular surface mucins and their role in dry eye disorders has improved significantly. It's been determined that this distinct family of glycoproteins prevents the penetration of pathogens, removes unwanted particulates, and maintains hydration at the ocular surface. Researchers have also identified 13 genetically distinct mucin species that are synthesized by several mucosal epithelial tissues -- including the cornea, conjunctiva, and lacrimal gland -- and suggest that each tissue secretes particular mucins that are coded for specific functions.

Ocular surface disease. Additional abnormalities identified in dry eye patients include immunological disorders, such as lymphocyte infiltration into the lacrimal gland and conjunctiva. It's thought that ocular distress from desiccation leads to cellular damage and the release of proinflammatory cytokines. Consequently, a cascading inflammatory response develops, resulting in exacerbated signs and symptoms of dry eye.

	Shortened tear film break-up time (TFBUT) or delayed blink cycle exacerbates the signs and symptoms of dry eye.

Today's treatment options are limited

Artificial tears are currently the only available treatment for dry eye symptoms and are the mainstay of existing therapy. Nearly all artificial tears are hypotonic or isotonic buffered solutions that contain electrolytes, surfactants, viscosity agents, and preservatives, as defined in the FDA's monograph on OTC products. The monograph lists all the pre-approved components and concentrations that may be used in ophthalmic products. One important ingredient in artificial tears is the viscosity agent, which is responsible for increasing residency time on the ocular surface. The ideal viscosity agent would increase tear film break-up time, reside on the ocular surface longer, and wouldn't cause blurred vision or caking.

Another critical ingredient in artificial tears is the preservative, usually found in multidose units. Many patients can use products containing preservatives successfully, particularly when the preservative is non-toxic and hypoallergenic. Newer preservatives, such as sodium perborate, which dissociates to water and oxygen, polyquad, and purite, are more comfortable and safe to use, resulting in better patient compliance. Other preservatives, however, can provoke allergic reactions or cellular toxicity, resulting in decreased comfort or compliance.

Think twice about recommending preserved products to patients who:

• have a history of previous allergic response to preserved ophthalmic products
• need to use the product more than six times a day
• wear contact lenses (preservatives can become concentrated under or in lenses and lead to epithelial damage).

For patients who can't tolerate preservatives, single unit-dose, preservative-free tear substitutes are an excellent alternative. However, because single-dose units tend to be costlier, patients attempt to "stretch" the tears in these vials for days, incurring the risk of contamination.

The primary goal when using tear substitutes is to prevent ocular surface damage before it occurs. By giving the patient different types of artificial tears, we let the patient determine what he is most comfortable with, which can help to increase patient compliance.

Better treatments are coming

Currently available artificial tears have succeeded in temporarily enhancing the comfort of patients, although no formulation has shown a significant improvement in the clinical parameters that determine dry eye. As we better understand the underlying causes of dry eye, we're able to develop therapies that treat rather than manage the condition. Such agents include anti-evaporatives, secretagogues (mucin and aqueous), mucomimetics, anti-inflammatories and improved polymers.

Anti-evaporatives. Potential therapies include the use of topical androgens to re-establish the normal activity of meibomian gland secretion. Androgens are known to "down-regulate" immune activity and positively influence epithelial cells by enhancing expression of certain genes, protein synthesis, and secretory processes. Treatment with topical androgens may alter the composition of meibomian gland secretions, stimulating the production of and release of meibomian gland fluid and improving evaporative dry eye.

Secretagogues. Researchers have shown that a deficiency in conjunctival mucin (e.g. MUC 4 and MUC5AC) exists among various dry eye disorders. Possible causes include a reduction in goblet cell count, alterations in mucin distribution or character, and lowered mucin mRNA expression. This suggests a potential therapeutic benefit of topically applied secretagogues that upregulate mucin gene expression at the ocular surface.

A compound known as 15(S)-HETE (hydroxy-eicosatetraenoic acid) is currently being investigated for its ability to stimulate human conjunctiva to secrete mucins. Rabbit models of desiccation-induced dry eye have shown that varying concentrations of 15(S)-HETE cause a rapid (5 minutes after instillation) increase in the thickness of a mucin-like layer of glycoproteins that may alleviate corneal injury and restore tear film integrity.

Evaluations of a synthetic P2Y2 receptor agonist (INS365) on fluid secretion also indicate promise in promoting many of the natural components of the tear film. It's believed that activating the P2Y2 receptors located on a variety of epithelial cells on the ocular surface (e.g. eyelids, cornea, and conjunctiva) stimulates the production of Cl-, fluid, and mucin. Recent studies have demonstrated that this key mediator of mucosal hydration and mucociliary clearance increases tear secretion in patients diagnosed with mild to moderate dry eye.

Secretagogues that stimulate the production of aqueous layer by the lacrimal glands are also being investigated as a potential dry eye therapy. A novel quinuclidine derivative of acetylchloride known as Cevimeline is currently approved to treat dry mouth associated with Sjogren's syndrome. This compound acts upon the muscarinic (M3) receptor, located on the lacrimal gland and salivary gland epithelium, and is responsible for upregulating tear secretions.

Mucomimetics. Mucin glycoproteins are responsible for the retention of water and other tear-fluid substances onto the ocular surface in the mucin layer of the tear film. Mucin has a high molecular weight and unique viscoelastic solution properties that aren't easily duplicated with simple synthetic polymer solutions. An artificial tear solution that closely mimics the composition of natural mucin may provide improved comfort and protection of the ocular surface. The product of MUC1 is a hydrophyllic, lubricious natural polymer that's expressed by the ocular surface epithelium and squamous cells of the conjunctiva. MUC5AC produces a gel-forming mucin that's secreted by the goblet cells. A treatment comprised of material that closely reproduces natural mucin may allow the tear film to spread and function in as natural a manner as possible, while lubricating and protecting the ocular surface.

Anti-inflammatories. The possibility of introducing a cytokine-blocking substance to the lacrimal glands and ocular surface to interrupt the inflammatory cycle associated with dry eye exists. Investigations of cyclosporine A (CsA) and its ability to suppress the cytolytic T lymphocyte are under way. These studies have shown that long-term treatment with topical CsA reduces inflammation in moderate to severe keratoconjunctivitis. Such compounds may be effective in reversing relevant inflammatory pathways that are believed to exist in the dry eye disease process.

Improved polymers. Natural tears serve to maintain the metabolism of ocular surface tissues, create a smooth surface to allow regular light refraction, and to lubricate the ocular surface to facilitate blinking. Artificial tears may not be able to exactly reproduce the natural components, but newer polymers may help to provide some relief in the treatment of the signs and symptoms of dry eye. Newer polymers aim to improve retention time and drop comfort, without blurring and lid caking. Viscous agents help to provide moisture to the ocular surface and act to prevent evaporation from occurring too quickly. Polymers with mild and moderate viscosity are effective lubricants, as their viscosity also prevents the mechanical removal of the tear film.

Toward individualized treatment

As the number of available treatment strategies for dry eye disorders increases, it's becoming more difficult for ophthalmologists to determine the potential value of a therapeutic approach. To successfully accomplish this task, it's necessary to develop more precise and clinically relevant tools with which to diagnose and classify the various dry eye states.

An established method by which dry eye patients can be categorized and future treatments evaluated is the Controlled Adverse Environment (CAE).

Developed by Wiley Chambers, M.D., of the FDA and Abelson et al., this model is able to exacerbate signs and symptoms associated with dry eye in a standardized manner by regulating humidity (less than 5%), temperature (76 ±6 (infinity)F), airflow (nonturbulent), visual tasking (television or personal computer use) and lighting. A method -- such as the CAE -- that consistently challenges the tear film and ocular surface is absolutely essential to properly study the progression of dry eye and determine treatment and concentration effect of its potential therapies.

One of the more exciting advancements involves a commonly used dry eye test known as tear film break-up time (TFBUT). Traditionally, TFBUT has been measured with large and varying amounts of sodium fluorescein (approximately 40 µL). With this technique, TFBUT was determined to be greater than 10 seconds in normals and less than 10 seconds in dry eye patients.

It's been shown that the accuracy and reproducibility of TFBUT measurements depend on the amount of fluorescein instilled into the tear film. When using amounts of sodium fluorescein that exceed the average tear volume (known to be 6 to 7 µL), it's thought that the tear film stability is influenced, resulting in an artificially lengthened TFBUT. To improve this technique, well controlled, microquantities of sodium fluorescein (5 µL) have been used to measure TFBUT. Consequently, more reliable and reproducible reference values have been established. With this improved technique, TFBUT was determined to be greater than 5 seconds in normals and less than 5 seconds in dry eye patients.

As a result of this precise clinical tool, a correlation between ocular discomfort and TFBUT was discovered. In a study that evaluated TFBUT in 33 subjects with a positive diagnosis of dry eye, 73% of the population (24 of 33 subjects) experienced ocular discomfort within 1 second of when the examiner reported TFBUT. This manifestation of ocular discomfort may be responsible for stimulating the eye to blink. Additionally, the data suggest a potentially simplified and non-invasive method of determining tear film stability.

After identifying this relationship between ocular discomfort and TFBUT, the impact of blink rate on the TFBUT system was recognized. Studies have shown that the average blink rate is approximately 12 times per minute or once every 5 seconds. In an ideal TFBUT system in which the ocular surface is continually protected, the time to tear film destabilization should match or exceed the time to the next complete blink. In contrast, when the TFBUT and blink rate don't coincide, the ocular surface is temporarily unprotected. This results in a sensation of ocular discomfort followed by the development of superficial punctate keratitis (SPK). This discordance between TFBUT and blink rate can be worsened by factors that shorten TFBUT (such as keratoconjunctivitis sicca and systemic medications that cause ocular drying) or by factors that decrease blink rate (such as fatigue and visual tasking). The diagram on page 54 depicts an unfavorable TFBUT system that results in an unprotected ocular surface and exacerbated signs and symptoms of dry eye.

When defining a clinically significant increase in TFBUT after treatment with a dry eye therapy, it's essential that this relationship be considered. For example, if a patient has a TFBUT of 3 seconds and blinks every 7 seconds, an agent must lengthen TFBUT by 4 seconds for the tear film to continually protect the ocular surface. Clinicians can also use this tool to properly evaluate the severity of a patient's condition according to the degree of discordance between his TFBUT and blink rate. Therefore, those who have minimal symptomatology due to habituation will blink less and be at greater risk for damage to the ocular surface.

The diagnosis of dry eye also relies on dyes that help assess the integrity of the ocular surface. Rose bengal has been a standard tool that selectively stains damaged cells of the cornea and conjunctiva. The use of lissamine green B has been proposed as an alternative dye with which to evaluate the ocular surface. Studies have demonstrated that lissamine green B and rose bengal exhibit similar staining patterns in individuals with dry eye syndrome, although lissamine green causes less irritation. Thus, lissamine green B may be a more tolerable, yet comparable, alternative for clinical evaluation of ocular surface damage in the assessment of dry eye syndrome.

Treatment will replace management

As we better understand the pathogenesis and diagnosis of dry eye, we also move toward an era in which this condition may be treated -- rather than managed through short-term symptomatic relief. A combination of these described therapeutic approaches will provide dramatic relief to chronic sufferers. In the meantime, researchers need to address the challenges associated with future therapies and pursue the complex interactions leading to dry eye.

Mark B. Abelson, M.D., an associate clinical professor of ophthalmology at Harvard Medical School, and a Senior Clinical Scientist at Schepens Eye Research Institute, consults on ophthalmic pharmaceuticals.

George W. Ousler III is senior clinical manager and Katrina A. Wilcox is a research associate of the dry eye department of Ophthalmic Research Associates.