Dry Eye Today

The latest on what's important, what will work and what's to come.

BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

While dry eye disease is undoubtedly as old as the eye itself, it began generating significant medical and media attention in the early 1990s, when research brought new insights. Much has changed since then, from how dry eye is characterized to how clinicians understand the causes and approach treatment. This article will explore the latest on insights and therapeutic options from experts in the field.

Categorizing Dry Eye Patients

Though dry eye has myriad causes, clinicians recently have offered differing evaluations on how to categorize those causes, and even whether they are important. Traditionally, categories have included post-menopausal women, contact lens wearers, those with autoimmune disease, congenital and trauma-induced dry eye (including LASIK patients). Other experts argue that the older classification of evaporative vs. aqueous-deficient dry eye is still relevant. Still another clinician points out that whatever the entry point for the disease, the expression is the same; treatment, he says, focuses more on severity than cause.

Post-menopausal women indeed make up a large group of dry eye sufferers, but according to Robert Latkany, M.D., director of the Dry Eye Center of New York, this group is really a subset of a category that would be more accurately termed the "abnormal hormone group." Some recent research suggests that primary deficiency in dry eye may be androgens rather than (just) estrogen. Androgens decline in both men and women as they age.

"You have to keep men in the abnormal hormone group," says Dr. Latkany. "It's not just post-menopausal women." Additionally, he points out that women with polycystical ovarian disease, who are not post-menopausal, are prone to dry eye.

Dr. Latkany says he does not like the term "chronic dry eye sufferers" because it fails to indicate the important causes behind dry eye. The physicians interviewed for this article generally divide patients who suffer from dry eye into the following groups by cause: allergy/rosacea; autoimmune disease (including Sjogren syndrome, rheumatoid arthritis and thyroid); contact lens wearers; lacrimal gland dysfunction and lid disease; and post-trauma (patients who have had infections such as herpes or shingles, those who have undergone radiation therapy, or vision correction surgery).

The post-trauma group includes patients who have undergone LASIK. According to Michael A. Lemp, M.D., professor of ophthalmology at Georgetown and George Washington Universities in Washington, D.C., more than 50% of these patients have some degree of dry eye postoperatively.

Gary Foulks, M.D., professor of ophthalmology at the University of Louisville, however, contends that the older classification of evaporative dry eye vs. aqueous-deficient dry eye is still useful.

"Because the management for both categories, although similar, is a little bit different," Dr. Foulks says.

The evaporative vs. aqueous-deficient classification was reaffirmed by the Dry Eye Workshop Study (DEWS) last year, he says. While it is possible for a patient to have both conditions at once, categorization can help the physician find the proper therapy.

"If you look at the aqueous-deficient category, the presence or absence of Sjogren syndrome is often helpful in making therapeutic decisions, just because you know the likelihood of the severity of the disease," says Dr. Foulks. For evaporative dry eye, on the other hand, the most common cause is meibomian gland dysfunction, or lid margin disease (Figure 1). "That's an important feature to recognize because it has management implications," he says.

Figure 1. Meibomian inspissation — one form of meibomian gland dysfunction.

Dr. Lemp, however, states that while the entry point for dry eye disease may vary, the expression is the same, with the same signs and symptoms occurring on the ocular surface (the case of graft vs. host reaction is a possible exception). "There's the relationship between the tears and the cornea and the conjunctival surface," he notes. "You have an instability of the tear film and an increase in the salt concentration of the tears, or in other words, osmolarity is elevated."

These common pathogenetic mechanisms on the ocular surface mean that the treatment for each of the causes of dry eye will be similar. Recent research (including the Delphi Panel Report and DEWS) suggests focusing not on the cause or causes, but on the degree of severity. "As dry eye disease progresses in severity, it is typical for the conjunctiva to first show staining with rose bengal or lissamine green stain (Figure 2) in the interpalpebral area," says Dr. Foulks. "Corneal staining with fluorescein (Figure 3) is a subsequent finding and typically begins in the infero-nasal area with extension to the central and temporal sectors, but a wide spectrum of staining is possible in the later stages of the disease." Although he acknowledges the shift in management focus, he also contends that identifying the cause is important. "You need to know which aspects of the dry eye problem you're treating," Dr. Foulks says.

Dr. Latkany claims that understanding the cause behind an individual patient's dry eye is important in providing proper counseling to the patient, which can improve morale and compliance with a treatment regimen. For the abnormal hormone group, for example, he says, "I cannot overemphasize how important it is to explain to the patient why he or she has dry eye. They understand that they can't reverse the hormonal changes and that currently there is no hormonal treatment."

He tells these patients that clinical trials are addressing the problem and there are many new drops to try. "My message is, be patient, help is around the corner, and I'll keep you comfortable until then," Dr. Latkany says. Counseling each patient individually, he asserts, is the key to getting them involved in treatment.

Taking Dry Eye Seriously

One of the most significant changes that has occurred in dry eye treatment over the past 15 years is that it is not a "syndrome" as it was originally characterized, but a disease. Steven Wilson, M.D., professor and chair, Department of Ophthalmology, University of Washington, Seattle, recalls that when he was a resident, many doctors did not think of dry eye as a disease. He says the new recognition has been important. "You can imagine going through every day — immediately upon waking until the time you were fortunate enough to fall asleep — thinking about the sandy, gritty irritation in your eyes," Dr. Wilson says.

"It's an honest-to-goodness disease," agrees Dr. Lemp. "It has all the characteristics of a disease, and to use a term like 'syndrome' trivializes what can be the very severe nature of the problem."

Not least trivial are the quality-of-life issues it brings. Blurry vision is typically the most common symptom, followed by dryness, burning, foreign-body sensation, redness, swelling, pain, tearing and itchiness.

Dr. Wilson, who sees many refractive patients, says that dry eye in this group is usually expressed in significant fluctuations in vision. "This bothers them in everything they do," he says. "I often hear complaints, especially in the first 6 months after a patient has had LASIK, if they have dry eye and it hasn't been treated yet, that they have trouble working on the computer and other tasks where they tend not to blink as much."

Also supporting the effect of dry eye on quality of life is a 2003 study by Schiffman et al.,¹ in which participants ranked dry eye approximately equal to angina as a life stressor.

Dr. Lemp reports that recent research also links dry eye to the complaints of ocular fatigue that many patients express. Patients would complain of not wanting to read as much, yet, he says, when their vision was tested on standard acuity charts, their reading was satisfactory. "We now know that the tear film, which is unstable, is breaking up between blinks," he says.

While most patients could momentarily form a tear film by blinking and then read the eye chart, staring continuously for just a few seconds longer would cause tears to break up. "Their vision would go from 20/20 down to 20/40, 20/50, 20/60," Dr. Lemp says. "Some recent studies in Japanese literature in particular have shown that if you can measure that visual acuity between blinks, by the time you get part of the way down to between the next blink, that patient would not be given a driver's license."

Figure 2. Lissamine green staining of the cornea.

This explains the ocular fatigue, Dr. Lemp explains, because people unconsciously attempt to blink more when they cannot see well. The effort, however, soon makes them tired, so they avoid activities that require focusing, which affects their quality of life.

Because patients with dry eye also have weakened ocular surface defense mechanisms, they are also prone to secondary problems, including, in some circumstances, microbial infections.

The Cyclosporine Revolution

Another critical change, of course, has been the recognition of inflammation's role in dry eye disease. In the early 1990s, Dr. Lemp reports, research began to show there was evidence of inflammation apart from what was evident upon clinical examination.² The understanding led to the development of cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan), which remains the only FDA-approved drug approved to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.

Dr. Wilson reports that approximately 85% of his dry eye patients respond to cyclosporine A, showing at least an improvement in their signs and symptoms. Additionally, he says, many of his patients taking the medication report not requiring artificial tears as often. And because the presence of significant dry eye can provoke inflammation, Dr. Wilson often prescribes Restasis to treat forms of dry eye that are not, or do not appear to be, inflammation based. Surgically-induced dry eye patients are an example.

"Some might say that the surgical patients are going to be fine in the end and just treat them with artificial tears and ointments," says Dr. Wilson. "While dry eye may resolve on its own after 6 to 8 months go by and the nerves regenerate, I tend to think of those patients in a different way now."

Figure 3. Fluorescein staining of the cornea in dry eye.

He suspects that patients often have an underlying inflammatory dry eye condition that is subclinical — until refractive surgery exacerbates it. "Although dry eye will probably get better if you wait 6 to 8 months, I tend to advise those patients that they should undergo a 6 to 8-month regimen of anti-inflammatory treatment," he says. "This way we can impact their underlying chronic dry eye condition and hopefully prevent it from progressing."

He says he is liberal in his use of cyclosporine, noting that some data, including a study of his own, suggest that among patients who respond to anti-inflammatory treatments, progress of dry eye disease may even be halted. Even for patients who have traditional dry eye but have not had surgery, he recommends the 6-to-8-month course of cyclosporine. Afterward, if symptoms return, he advises that they remain on the drug chronically.

"It's funny," says Dr. Wilson, "you can ask a group of ophthalmologists, 'do you think dry eye is a progressive disease?' and most will raise their hands. But what always amazes me are the ones who don't raise their hands, because you see these really severe patients. Do they think these patients just woke up that way one morning and never had anything pre-existing? That just doesn't make sense to me."

Thus it is critical, he contends, to control the inflammation. Dr. Wilson also recommends the cyclosporine regimen for post-menopausal women. "Most of those women do get hormonal treatment, and that may or may not be helpful for their dry eye condition," he notes.

Some patients, of course, have found cyclosporine uncomfortable, so much so that they soon discontinue use.

Some of Dr. Latkany's patients do not tolerate cyclosporine A well. "I have patients who say, "I tried it for 3 weeks, it did nothing, it always burns,'" he says. "But you have to let them know that it might take 4 to 6 weeks to work, and then effects peak at 4 to 6 months — so did the drug truly fail them?" He tells patients that he can give them something to ease the burning sensation, and prescribes loteprednol etabonate in conjunction with cyclosporine.

Dr. Lemp reports that many clinicians also prescribe topical steroids for short-term use when they start patients on cyclosporine to provide some immediate relief and get them "over the hump." The steroids are tapered off as the cyclosporine begins to take effect. Another trick doctors have discovered to make cyclosporine more comfortable, he says, is refrigeration, which reduces the sting.

The Place of Plugs

Though clinicians agree that cyclosporine has revolutionized the treatment of dry eye, experts also agree that punctal plugs still have an important role to play. There are, however, some caveats.

Dr. Foulks reports that he will not use plugs until any inflammatory component in a patient's dry eye disease has been controlled, because he has had experiences when the symptoms get worse after punctal plugging. With patients who have early, mild dry eye that aggravates their contact lens wear, however, he will insert punctal plugs in order to retain more tears and keep patients in their lenses.

Dr. Wilson uses plugs in patients with moderate to severe dry eye following a course of cyclosporine and steroids if they are not responding 1 to 3 months later.

"I want their tear film and the inflammatory status of their eyes to be the best they can be, so we're not just keeping in the 'bad humors,' so to speak," he says. After eliminating debris in the eye, he will keep the plugs in as long as possible. However, Dr. Wilson points out that plugs often extrude and some patients simply do not like the feeling.

For Dr. Latkany's practice, plugs are often a perfect fit. "I get the Manhattan crowd," he explains. "They are not the type to use a drop every hour and ointment at night. They typically want the quick fix."

Given the challenges involved in getting patients to be compliant with medication, he finds that plugs are often a wise choice. "The physician inserts the plug and it works immediately," says Dr. Latkany. "We must consider each patient's needs. Lifestyle is as important as severity."

Artificial Tears Improve

Manufacturers' improvements to artificial tears since the early 1990s mean that they now do more than just replace volumes of tears. Recent formulations are much more effective than in the past. The polymers some contain, for example, make the tears become gel-like when they contact the eye's surface, which tends to stabilize the tear film, Dr. Lemp points out. "Others have lipids, like natural tears do, and they tend to retard evaporative tear loss," he says.

Dr. Foulks' criteria for selecting artificial tears is whether the patient's dry eye is evaporative or aqueous deficient. Patients with predominantly evaporative dry eye associated with meibomian gland dysfunction are instructed to use lipid-containing tear stabilizing drops, such as Refresh Endura (Allergan) or Soothe (Alimera), in addition to an oral regimen.

"If the patient has predominantly surface–disease-based evaporative dry eye from epitheliopathy, then I'm more likely to recommend the use of Systane (Alcon), not only because of its tear stabilization, but also because of its protective effect on the ocular surface," Dr. Foulks says.

He advises his aqueous-deficient patients to try Optive (Allergan) or Systane to protect the surface against hyperosmolarity. Dr. Foulks uses the artificial tears for patients with a mild form of the disease, but suggests their continued use when and if he prescribes cyclosporine. "You also get the protective effect from the advanced lubricant drops," he says.

Supplements Are Worthwhile

Nutritional supplements such as omega-3 fatty acids may still lack the clinical trials that would prove their purported benefits in fighting dry eye disease. However, these experts agreed that anecdotal evidence certainly exists and further, that many patients swear by them.

"They [omega-3 fatty acids] have little downside. They may have some systemic benefit beyond dry eye, so there's no reason not to use them at this point," Dr. Lemp says.

The controlled, large-scale studies these "neutraceuticals" need are difficult to perform, he explains, because the supplements are almost never used alone, so it is difficult to isolate any effects they may have from other substances being used in the eye.

Roy S. Chuck, M.D., director of refractive surgery at the Wilmer Eye Institute, Baltimore likes to use omega-3 fatty acids in conjunction with plugs, doxycycline/minocycline and topical steroids when Restasis fails, he says.

Dr. Latkany has such faith in omega-3s that he makes his own fish oil/flaxseed oil combination. Yet he has reservations about neutraceuticals' scope. "I don't think I have too many patients for whom this alone is all that's needed and they're cured, but I think they definitely contribute to the therapy," he says.

Therapies on the Horizon

Though no new therapeutics have been approved since cyclosporine, several are currently in clinical trials. The most frequently mentioned is the topical secretagogue class of drugs. One, diquafosol tetrasodium ophthalmic solution 2% (Prolacria), is being developed by Inspire Pharmaceuticals. Currently in Phase 3 trials, its mechanism of action is to stimulate the release of the three natural tear components that play a role in tear secretion: mucin, lipids and fluid.

"My enthusiasm for them [secretagogues] is not because there is necessarily always a dramatic response," Dr. Foulks explains, "but they are well-tolerated and you do see a definitive response." While the response can be highly patient-specific, he believes secretagogues will have an important role in managing dry eye.

Dr. Latkany is particularly interested in hormone treatments, but he cautions that combinations have not been determined. He notes that most of his dry-eye patients are women older than 40 years, underscoring the likelihood of a hormonal component to the disease. However, more clinical data are required to determine the value of hormones.

Finally, says Dr. Chuck, "Most, if not all dry eye, has a common denominator in causing immune-mediated ocular surface compromise." He says that immune mediators are currently being explored at the molecular level to find further intelligent design of targeted dry eye therapies.

Though these developmental therapies for now remain out of clinicians' reach, their eventual availability is sure to cause a dramatic change in the treatment of dry eye.

"Doctors are going to have to make choices," says Dr. Lemp. "Instead of the one therapeutic on the market, clinicians will have to ask themselves some questions, such as 'What is the basis for determining treatment?'"

Dr. Lemp predicts that severity of disease will probably be the determining factor, but notes that some of the drugs will likely treat different aspects of the disease, rather than inflammation. "Some will probably work in conjunction with Restasis," he says. "Doctors are going to have to find reasons and assess severity to find the best treatment. That will change the whole management in the office setting." OM

References

1. Schiffman RM, Walt JG, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology. 2003;110:1412-1419.

2. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584-589.