New insights advance diagnosis, treatment of dry eye

In 2007, the International Dry Eye WorkShop, sponsored by the Tear Film and Ocular Surface Society, provided the ophthalmic and scientific communities with a new definition of dry eye:

“Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface,” Pierre-Jean Pisella, MD, said.

“The key point of this new definition was the recognition that ocular surface inflammation is always present in the dry eye. It was a paradigm shift, as dry eye ceased to be just a lack of water and became a complex disease involving inflammation. Therapy radically changed with the need of introducing anti-inflammatory drugs,” he said.

The definition summarized the conclusions of a critical review of all current knowledge on dry eye disease by an international panel of experts that worked on the issue for more than 3 years. It sparked the interest of researchers and gave dry eye full recognition as a disease with specific characteristics, a well-defined pathophysiological mechanism and evidence-based strategies for diagnosis and treatment.

Tear film hyperosmolarity, which may arise from either insufficient tear secretion or excessive evaporation, was also recognized as a core mechanism of dry eye, correlated to inflammation in a bidirectional vicious circle: A dysfunctional tear film triggers a cascade of inflammatory events, but on the other hand, a dysfunctional tear film can be the result of an acute or chronic state of inflammation.

Within this circle, inflammation tends to self-perpetuate and self-maintain, which explains why dry eye has an inherent tendency to become chronic.

According to Edward J. Holland, MD, OSN U.S. Edition Cornea/External Disease Board Member, the inflammatory cascade plays different roles in aqueous-deficient dry eye and evaporative dry eye.

“We certainly can understand that inflammation plays an important role in the etiology of aqueous-deficient dry eye. In evaporative dry eye, inflammation probably isn’t the primary underlying etiology but develops secondarily. We know that the patient with meibomian gland dysfunction with abnormal lipid layers develops secondary inflammation in response to the abnormal tear film,” he said.

Pathogenesis and progression

Dry eye may be caused by a number of conditions. It may be related to systemic, autoimmune pathologies, such as Sjögren’s syndrome; diseases that affect lid structures and dynamics, such as meibomian gland dysfunction (MGD); or environmental or lifestyle-related factors. Other factors may include age-related hormonal changes, the aggressive action of toxic eye drop components such as preservatives, contact lens wear and corneal refractive surgery.

“These multiple causes account for the increasing incidence of dry eye in our times,” Dr. Pisella said.

In France, 25% of general practitioners’ consultations are for some form of ocular surface disease.

“The aging of the population, but also environmental and lifestyle-related factors like the prolonged exposure to light from computer monitors or TV, air conditioning, pollution and possibly a high-calorie diet, may all be correlated with increased risk of dry eye,” Dr. Pisella said.

Intense sports activities are a less well-known but frequent cause of dry eye from contamination of the tear film by intense perspiration, according to Piergiorgio Neri, MD, PhD.

Other potential risk factors, such as cigarette smoke, alcohol, contraceptive pills and botulinum toxin, have not been proven but are likely to have a contributing role, he said.

Some patients may present with a combinations of causative factors. One such case could be a patient with seborrheic dermatitis who lives in an unfavorable environment, Dr. Neri explained.

“Individual etiologies often cause dry eye by several interacting mechanisms, but whatever the cause, the process that is eventually triggered is always what we call the vicious circle of dry eye,” he said.

Damage and consequences

High tear osmolarity and inflammation adversely affect the corneal epithelium, Stephen C. Pflugfelder, MD, said.

“High osmolarity stresses the epithelium and causes the epithelial cells to produce inflammatory mediators such as MMP-9, a proteolytic enzyme that degrades the tight junctions between cells,” he said.

“Increased MMP-9 activity accelerates detachment of apical corneal epithelium, exposing less mature subapical epithelial cells and nociceptors, which signal discomfort from the ocular surface. It also allows inflammatory mediators and T-cells to percolate down through the epithelium,” he said.

T-cells that infiltrate the conjunctival and corneal stroma and epithelium produce two types of cytokines: interferon gamma and interleukin-17 (IL-17), Dr. Pflugfelder explained.

Interferon gamma promotes cell apoptosis of the epithelium and causes the cells to produce a cornified envelope, a component of the skin’s epidermis that is impervious to water.

“This cell envelope doesn’t belong to the natural structure of healthy corneal epithelial cells, but interferon gamma promotes the cells in the eye to start producing cornified envelope precursors,” Dr. Pflugfelder said. “That’s why in very severe dry eye conditions, like Stevens-Johnson syndrome, the surface of the eye might start showing a skin-like appearance.”

“IL-17 has been reported to upregulate the expression of MMP-9, which accelerates detachment of ocular surface epithelial cells, leading to barrier disruption and influx of inflammatory cells and mediators from the tears. We are well inside the vicious cycle,” Dr. Pflugfelder said.

Tear film instability profoundly affects visual quality.

“The air-tear interface is the principal refracting surface on the eye, accounting for approximately 65% of its optical power. A stable tear layer is essential to maintain a smooth surface and high-quality vision,” he explained. “When there is dry eye or an unstable tear film, or the corneal epithelium is irregular and doesn’t hold the overlying tears, then that optical surface becomes irregular and starts affecting quality of vision.”

Patients with dry eye typically have diminished visual acuity in low-contrast conditions.

“They also present severe symptoms of ocular irritation and discomfort that can significantly impact quality of life and productivity,” Dr. Pflugfelder said.

A study by Schiffman and colleagues, presented at the American Academy of Ophthalmology meeting in 2001 and published in Ophthalmology in 2003, showed by utility assessment questionnaires that the impact of the most severe forms of dry eye on quality of life is equivalent to unstable angina.

Diagnostic tools

Current means to diagnose dry eye include slit lamp analysis, corneal staining with fluorescein, conjunctival staining with lissamine green, Schirmer’s test and evaluation of tear breakup time. New diagnostic methods involve digital imaging of the ocular surface, identification of inflammatory markers and measurement of tear osmolarity, a key marker of dry eye.

According to Dr. Pisella, Schirmer’s test, which has been largely abandoned since the introduction of vital dyes, remains a fundamental tool in diagnosing aqueous-deficient dry eye.

“It is the only test that gives true information about the production of water by the lacrimal glands,” he said.

More advanced tools include the Keeler Tearscope, which evaluates the appearance, volume and stability of the tear film, and the TearLab Osmolarity System, which measures tear film osmolarity.

The latter, Dr. Neri said, is an important new frontier in dry eye disease management because osmolarity plays a crucial role in the pathogenesis of the condition.

“The TearLab analyzes the composition of a tear fluid sample and converts it into numeric data that help understanding disease level and monitoring the patient’s response to treatment,” he said.

However, cost issues limit the use of the technology for routine testing.

“I have it in my office, but only use it for clinical trials. The cost of the test is around €20, and there is no reimbursement for it,” Dr. Pisella said.

The RPS InflammaDry Detector is designed to test for matrix metalloproteinase-9 (MMP-9), the inflammatory marker that has been shown to be elevated in the tears of patients with dry eye disease.

Another effective way of evaluating the presence of inflammation is impression cytology, Dr. Neri said.

If a rheumatic disease is suspected, specific tests for anti-SSA and SSB antibodies, which are found in the circulation of patients with Sjögren’s syndrome, should be performed, he said.

“And never forget the eyelids, which are critical to detect dermatological comorbidities,” Dr. Neri said.

Dry eye treatment

Dry eye management hinges on patients’ understanding of the multifaceted and chronic nature of the disease and their compliance to a regimen of strict surveillance and long-term treatment.

Physicians, on the other hand, need to establish personalized strategies that account for individual etiologies and response to treatment.

Tear substitutes have been the mainstay in the treatment of dry eye symptoms for many years. Although no longer considered as a standalone therapy, they nevertheless remain an important component in a more complex treatment strategy.

Recent advances in the understanding of tear film physiology and pathology have allowed the formulation of a variety of tear substitutes capable of addressing specific deficiencies of tear components.

“In the old days, substitutes were only meant to mimic the volume of human tears. In the early ’80s, we used sodium chloride, and not much more was available,” Dr. Neri explained. “A few years later, and up to 2000, mucomimetic polymers were introduced, aiming at re-establishing not only the quantity but also the quality of tears. Substitutes containing hyaluronic acid, polyvinyl alcohol, carbomer-based lipids and [tamarind seed polysaccharide] were developed. But the true revolution was after 2000, when the outermost oil layer of the tears, which was thought to be irreplaceable, was recreated by novel tear substitutes.”

The choice of artificial tears is made according to the clinical signs and etiology of dry eye, Dr. Pisella said.

Tear film instability and hyper-evaporation associated with MGD require gel-form tear substitutes to replace the mucin layers, while aqueous-deficient dry eye needs to be treated by preservative-free, water-based tear substitutes.

“In patients with associated Sjögren’s syndrome and MGD, and therefore suffering from both lack of water production and hyper-evaporation, a combination of tear substitutes, as well as warm compresses, should be applied,” Dr. Pisella said.

In most patients, artificial tears only are not sufficient. Anti-inflammatory therapy is mandatory to target the inflammatory component of the syndrome.

Topical steroids and cyclosporine are the two agents available today for the reduction of dry eye-related inflammation. While approved and marketed in the U.S. as Restasis (Allergan), cyclosporine is not available for topical ophthalmic use in Europe.

“We can order it only through hospital prescription, and it will be delivered by the National Drug Agency for a nominative prescription. The other way of using it in France is a local preparation in hospital pharmacy,” Dr. Pisella said.

Despite these limitations, topical cyclosporine is widely used in Europe.

“We talked about topical cyclosporine at a European symposium held during the meeting of the French Society of Ophthalmology this year, and most specialists from all countries said they use it routinely,” he said.

A combination of short-term steroids and long-term cyclosporine is the favorite treatment strategy of U.S. specialists and is also widely used in Europe. Steroids have the most rapid onset of action and are extremely effective in the acute phase of inflammation while cyclosporine, which has a lower onset of action, begins to work. However, the development of high safety profile steroids such as Lotemax (loteprednol etabonate, Bausch + Lomb) has encouraged physicians to extend the use of these medications for longer periods.

“I was a great user and advocate of cyclosporine, but since loteprednol has entered our armamentarium, I have considerably reduced its use, and now I prescribe it only in rare cases of steroid-resistant/dependent dry eye,” Dr. Neri said.

According to Dr. Holland, a paradigm shift has occurred in recent years in the management of dry eye.

Earlier treatments proved ineffective because they tended to address the symptoms rather than the cause of dry eye, mainly using tear substitutes. Today’s approaches are more effective because they address the underlying immune-based inflammation. This can help restore neuronal control and the normal composition of tears.

Due to its efficacy and safety parameters, loteprednol etabonate is the best choice for dry eye patients, Dr. Holland said. It is a potent steroid but has the best safety with respect to IOP rise and risk of cataract.

“It gives us a steroid that we can use with confidence. This is important for our patients, since steroids are in general much more effective than nonsteroidal anti-inflammatory drugs or other agents that we would have to use for patients unable to tolerate long-term steroid administration,” he said.

As a new treatment paradigm with dry eye patients, Dr. Holland recommends initial therapy with loteprednol to reduce the inflammation and maintenance therapy with loteprednol and cyclosporine for long-term control.

This has led to improved quality of life for patients with dry eye, with a significant reduction in the use of artificial tears, he said. Loteprednol has an immediate effect on inflammation and, with appropriate tapering, can be administered for long-term maintenance therapy.

In addition, loteprednol should be used on an as-needed basis for a few days for episodes of breakthrough inflammation, he said.

The weak point of loteprednol is that it contains preservatives. Dr. Pisella prefers using preservative-free steroids in single doses because he does not like to expose patients with ocular surface problems to the additional toxic effect of preservatives.

“Dexamethasone (Dexafree, Théa Pharma) is my first choice for these patients. It is a high-power steroid, and I use it only for a short period, typically 9 days in the acute stage. I follow the rule of three, ie, three drops a day for 3 days, then two drops a day for 3 days and finally one drop a day for 3 days,” he said. “I also prescribe cyclosporine, but since it takes about 8 days to 10 days to have the drug available, steroids cover exactly that time span.”

Novel therapies

Ongoing research is aimed at achieving more detailed knowledge of inflammatory pathways and targeting various types of inflammatory mediators in dry eye patients.

Dr. Pflugfelder has been involved in experimental studies evaluating the regulatory aspects of interleukin 1 (IL-1) on ocular surface epithelial inflammation and the potential benefits of IL-1 receptor antagonists.

He also investigated the role of endogenous resolvin E1 and resolvin analogues in the treatment of dry eye.

“Resolvins are compounds made from omega-3 fatty acids. They’re like super fish oils,” Dr. Pflugfelder said. “Fish oils, taken by mouth, have been found in clinical trials to improve signs and early symptoms of dry eye. The resolvins are 10,000 times more potent than fish oil.

In the preliminary studies, they’ve been used topically.”

Selective glucocorticoid receptor agonists are another class of experimental drugs that bind to steroid receptors but have none of the side effects associated with steroids.

SAR 1118 (SARcode Bioscience) is an integrin antagonist that inhibits the binding of lymphocyte function-associated antigen-1 to intercellular adhesion molecule-1, blocking T-cell mediated inflammation. SAR 1118 has entered phase 3 U.S. Food and Drug Administration clinical trials.

“The early studies show that it potentially is going to work faster than topical cyclosporine and potentially be more effective. As we know, topical cyclosporine has a delayed onset of several months,” Dr. Holland said.

A study in Cornea discussed the safety and efficacy of T-Clair SPHP700-3 (Sinclair Pharmaceuticals), a preservative-free formulation of linseed extract and polyvinylpyrrolidone. SPHP700-3, an over-the-counter product, is approved in the European Union, but in the U.S., its status as a prescription or over-the-counter drug is under review by the FDA.

The study reported that SPHP700-3 improved tear film stability, ocular surface lubrication and overall dry eye symptoms.

Novel treatments for MGD include the LipiFlow Thermal Pulsation System (TearScience), a device that applies heat and pressure to the meibomian gland to liquefy and evacuate obstructions. The second-generation product allows physicians to treat both eyes simultaneously.

“In the FDA clinical trials, about 85% of patients had improved signs and symptoms after one LipiFlow treatment,” Dr. Holland said. “That’s an in-office procedure that’s applied to the upper and lower lids of both eyes in patients with MGD. I think that’s quite exciting.”

For severe dry eye-related corneal epitheliopathy, prosthetic replacement of the ocular surface ecosystem, or PROSE, has proven to be a good option.

The device is a transparent dome that fits under the eyelids, vaulting the damaged cornea and resting on the sclera. Filled by artificial tears, it provides constant lubrication while maintaining the necessary oxygen supply to the inflamed eye.

“The fluid-filled reservoir shields the cornea from blink trauma, noxious environmental stimuli and inflammatory mediators in the tears. The body-temperature saline reservoir also prevents corneal cooling and nerve firing that occurs in the inter-blink intervals. Patients may experience almost immediate relief in photophobia and irritation symptoms after placing the device on the cornea,” Dr. Pflugfelder said. – by Michela Cimberle and Matt Hasson