New insights advance diagnosis, treatment of inflammatory dry eye

Inflammation is ubiquitous in ocular surface disease. Recognized as both a cause and consequence of dry eye, inflammation is a primary target in assessment and clinical treatment.

Left partially or completely unresolved, inflammatory dry eye can progress and lead to epithelial damage and vision loss. Dry eye also increases the risk of poor outcomes and complications after surgery.

The inflammatory cascade plays different roles in aqueous-deficient dry eye and evaporative dry eye, Edward J. Holland, MD, OSN Cornea/External Disease Board Member, said.

“We certainly can understand that inflammation plays an important role, first in the etiology of aqueous deficient dry eye,” Dr. Holland said. “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.”

Marguerite B. McDonald, MD, OSN Refractive Surgery Board Member, characterized ocular surface inflammation as “a vicious cycle … a sort of a chicken-and-egg thing,” in which inflammation is self-perpetuating.

Quality of vision is best when the air-tear interface is smooth, according to Stephen C. Pflugfelder, MD. Image: Doyle MA

“There is significant overlap between my preferred treatments for aqueous deficient and evaporative dry eye because most patients have a component of both. But there are some differences,” Dr. McDonald said.

In a report published in Investigative Ophthalmology and Visual Science, the International Workshop on Meibomian Gland Dysfunction standardized the definition and etiology of meibomian gland dysfunction (MGD).

“It’s been called posterior blepharitis, meibomian gland disease, meibomitis,” Dr. Holland said. “We had multiple names, and when you have multiple names, you get confusion. So this report from the workshop is a very good piece of literature that’s going to help with the definition of what MGD is, grading the severity and trying to match a treatment paradigm to the severity.”

New diagnostic and therapeutic methods promise to help ophthalmologists identify pathologic pathways of inflammatory dry eye and tailor treatment accordingly.

Pathogenesis and progression

Eric D. Donnenfeld

Inflammation in aqueous-deficient dry eye is primarily T-cell mediated. T-cells infiltrate and damage the lacrimal gland, creating fibrosis and inflammatory components in the tear film, Eric D. Donnenfeld, MD, OSN Cornea/External Disease Board Member, said.

“Instead of having a normal tear film, which is supportive of the ocular surface, pro-inflammatory cytokines and inflammatory markers are secreted by the lacrimal gland, which further damage the ocular surface and start an inflammatory cascade that cycles, creating a worsening of the ocular surface and results in corneal anesthesia,” he said. “The inflammatory markers on the ocular surface damage the epithelial cells and cause further inflammation and reduce goblet cell density so that the mucin component of the ocular surface is damaged as well.”

Inflammation of the lacrimal gland leads to diminished tear production and a propagation of inflammatory mediators on the ocular surface, Dr. Holland said.

In evaporative dry eye, inflammation is largely attributed to a metabolic breakdown of lipids in the meibomian glands, with fatty acids obstructing the glands and hindering their function.

“The lipid metabolism is changed in meibomian gland disease from unsaturated fats to saturated fats that clog the meibomian glands,” Dr. Donnenfeld said. “The meibomian gland orifices eventually become clogged and lose the ability to function, resulting in permanent scarring of the meibomian glands.”

MGD involves a variety of changes that can lead to superficial punctate keratitis and Salzmann’s nodular dystrophy, Dr. McDonald said.

“The meibum is altered from its normal, clear fluid state to a pasty, yellow-white material that is highly inflammatory and toxic to the ocular surface,” she said. “In susceptible patients, this results in elevated white scars on the cornea that can decrease vision and lead to corneal ulceration, neovascularization, a host of things. Then, without the proper meibum to protect the tear layer, there is evaporative loss of the tears, which become hyperosmolar. Hyperosmolar tears are very damaging to the ocular surface, so things just keep spiraling downhill.”

Common comorbidities in aqueous-deficient dry eye include rheumatoid diseases. Comorbidities in MGD/evaporative dry eye include lipid metabolism disorders such as rosacea and omega-3 deficiency, Dr. Donnenfeld said, noting that surgical trauma and corneal anesthesia can lead to neurotrophic dry eye, which may also involve inflammation.

Damage and visual effects

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 proteolytic enzymes that degrade the junctions between cells, he said.

“When that happens, the cells start to detach prematurely, exposing the underlying younger cells,” Dr. Pflugfelder said. “It also allows inflammatory mediators and even white blood cells to percolate down through the epithelium.”

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

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.

“The eye doesn’t normally have that, but interferon gamma promotes the cells in the eye to start producing this cornified envelope,” Dr. Pflugfelder said. “That’s why in very severe dry eye conditions, like Stevens-Johnson syndrome, the surface of the eye will start to look like skin.”

IL-17 is commonly found in mucosal autoimmune diseases, such as inflammatory bowel disease, Dr. Pflugfelder said.

“Proteases accelerate detachment of ocular surface epithelial cells, leading to barrier disruption and influx of inflammatory cells and mediators from the tears. This creates a vicious cycle,” he said.

Tear film instability profoundly affects visual quality, Dr. Pflugfelder said.

“The air-tear interface is the principal refracting surface on the eye. The most power to bend light in the eye is at that interface. It needs to really be smooth,” he said. “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, Dr. Pflugfelder said.

Diagnostic testing tools

Marguerite B. McDonald

Before testing for dry eye, the physician should scrutinize the patient’s medical history, Dr. McDonald said.

“A summary of the patient’s medical history is still really important,” she said. “A well-trained technician can take a good one for you, so that it takes only a moment to peruse.”

Objective methods of identifying and assessing dry eye include slit lamp analysis, corneal staining with fluorescein, conjunctival staining with lissamine green, Schirmer testing and evaluation of tear breakup time. The ocular surface disease index, a questionnaire, is used to record subjective dry eye symptoms.

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.

A study published in Investigative Ophthalmology and Visual Science suggested that tear osmolarity may be the best single test for dry eye.

The InflammaDry Detector (RPS) is designed to test for matrix metalloproteinase-9 (MMP-9), an inflammatory marker for dry eye, Dr. Donnenfeld said.

“That marker can now be measured for the first time with a new point-of-service test that allows clinicians to diagnose the inflammatory component of dry eye on a routine basis and allows you to see if it’s inflammation causing the dry eye or if it’s due to other causes,” he said. This test is especially important in patients who undergo LASIK and cataract surgery and allows clinicians to begin anti-inflammatory therapy.

Dr. McDonald said the InflammaDry Detector renders definitive results.

“It’s a different sort of test because it detects an important marker for inflammation. It’s like a pregnancy test: positive or negative,” she said. “You either have elevated MMP-9 in your tear film or you don’t. I consider the detection of elevated MMP-9 in the tears to be complementary to tear osmolarity testing; it tells you if there is inflammation or not. If the osmolarity test indicates that the patient does not have dry eye but the patient has an elevated MMP-9 level, then the ophthalmologist should look for other sources of inflammation: allergic conjunctivitis, MGD, etc.”

The TearLab Osmolarity System (TearLab) is an objective and quantitative test for diagnosing and treating dry eye. The test requires 50 nL of tear film to diagnose dry eye.

“It’s quick and easy. I test patients who are 40 or older because the incidence of dry eye spikes at 40. I also test patients with a prior history of dry eye, complaints that sound like dry eye/ocular surface disease and all preoperative patients,” Dr. McDonald said. “It’s very helpful in diagnosing the mild to moderate cases that might not have significant complaints. It’s also great for encouraging compliance. Patients are more likely to be compliant when they hear that their osmolarity scores are getting better. More importantly, tear osmolarity scores help the ophthalmologist track the patient’s response to treatment.”

A study published in Cornea reported that the TearLab system identified elevated tear film osmolarity in moderate to severe keratoconjunctivitis sicca with 87% sensitivity and 81% specificity.

The LipiView Ocular Surface Interferometer (TearScience) allows physicians to obtain digital images of the tear film and grade it within about 3 minutes.

A study in the American Journal of Ophthalmology said the measurement of ocular surface temperature is a rapid, noninvasive and reliable method of screening for dry eye.

Treatment strategies

Dry eye management hinges on patients understanding that dry eye is a multifaceted and chronic condition that requires strict surveillance and long-term treatment.

“I tell patients that this is a chronic problem they will probably have for years and that therapy should be changes in dietary habits, the routine use of hot compresses and the treatment regimen that’s been recommended for them,” Dr. Donnenfeld said.

Dr. Donnenfeld recommended that clinicians treat inflammation, not just dry eye symptoms.

“The key to treatment is to treat the pathogenesis of the disease and not treat the sequelae. Don’t treat the symptoms — treat the disease process itself. That means anti-inflammatory therapy,” he said.

Dr. Donnenfeld said that his preferred first-line treatment for aqueous deficient dry eye begins with Restasis (cyclosporine ophthalmic solution 0.05%, Allergan) accompanied by a topical steroid such as loteprednol. Nutritional supplements also play a key role in treating inflammation.

“It works very well,” he said. “Nutritional supplements containing omega-3, flaxseed and fish oil combinations have anti-inflammatory effects and are very important. Sometimes for people with significant dry eye, oral doxycycline can play a role there as well, which has an anti-inflammatory effect in addition to the antibiotic effect.”

For aqueous-deficient dry eye, Dr. McDonald said she prefers cyclosporine twice daily combined with Lotemax (loteprednol etabonate, Bausch + Lomb) four times daily for 2 weeks and twice daily for 2 weeks.

“The Lotemax does a few things,” Dr. McDonald said. “It masks the stinging that sometimes accompanies the induction of Restasis therapy. It breaks the cycle of inflammation quickly. And it gives instant relief to the patient because cyclosporine emulsion, as safe and powerful as it is, takes about a month to kick in before the patient notices any difference at all. They get discouraged and stop therapy just before they get the big payoff.”

Lotemax is the best choice for a topical steroid for Restasis induction, Dr. Holland said.

“Lotemax is a potent steroid but has the best safety with respect to IOP rise and risk of cataract,” he said. “I recommend the aqueous-deficient dry eye patient use Lotemax for induction therapy and then taper over 2 months. In addition, Lotemax should be used on an as-needed basis for a few days for episodes of breakthrough inflammation.”

Bottled tears are suitable for patients with mild to moderate dry eye; unpreserved tears are best for patients with moderate to severe dry eye, Dr. McDonald said.

For evaporative dry eye, Dr. McDonald said she directs patients to use soaks and scrubs twice daily with over-the-counter lid cleansing pads such as those from OCuSOFT. At level 2 and up, she has patients use topical azithromycin solution rubbed into the lids twice daily, just after the hot soaks and scrubs, and often prescribes oral doxycycline 20 mg daily.

“I caution people not to take [doxycycline] plus or minus 1 hour of a meal that contains dairy because dairy inactivates it,” Dr. McDonald said. “I also tell them that doxycycline makes them slightly more sun sensitive. So, they should wear a shirt, hat and sunblock outside.”

Loteprednol ointment on the lid margins, an antibiotic-steroid combination such as TobraDex ST (tobramycin/dexamethasone ophthalmic suspension 0.3/0.05%, Alcon), oral doxycycline and Durezol (difluprednate ophthalmic solution 0.05%, Alcon) in severe cases are useful in treating ocular surface inflammation, Dr. Donnenfeld said.

Punctal plugs are effective but only in specific clinical circumstances.

“Punctal plugs play an important role, but the problem is that most patients are given punctal plugs before the inflammatory component is treated,” Dr. Donnenfeld said. “You need to treat them first for the underlying process and then place the plug once the tear film has been optimized.”

Dr. McDonald said that punctal plugs are suitable for patients with aqueous-deficient dry eye and some patients with evaporative dry eye due to MGD, but only after the inflammatory process is under good control.

“When I put people on cyclosporine emulsion, I have them come back in 4 to 6 weeks,” she said. “If they’re improved but not perfect, I insert punctal plugs. I usually put four in all at once because I have a referral practice with fairly severe dry eyes. If there is any question at all, however, I put in the lower plugs and bring them back in another 4 to 6 weeks to see if they need the upper plugs.”

Cauterization is a viable option in cases in which puncta are too small for plugs, Dr. McDonald said.

Novel therapies

The LipiFlow Thermal Pulsation System (TearScience) applies heat and pressure to the meibomian glands.

“If the patient qualifies, they can have the LipiFlow treatment with a disposable attachment that gives pulsating warmth to the lids and helps express the altered meibum,” Dr. McDonald said.

The U.S. Food and Drug Administration recently approved a second-generation LipiFlow Thermal Pulsation System. The updated device allows the physician to treat both eyes at once and includes an upgraded graphic interface.

“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.”

SAR 1118 (SARcode Bioscience) is an integrin antagonist that inhibits the binding of lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1. This helps to prevent T-cell mediated inflammation.

SAR 118 has entered phase 3 FDA clinical trials. According to a SARcode news release, about 588 patients will be randomized to undergo treatment with SAR 1118 5% ophthalmic solution or placebo twice daily for 12 weeks. Outcome measures will include fluorescein staining, visual function, safety and tolerability.

“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.

In a phase 2 clinical trial, SAR 1118 significantly improved dry eye signs and symptoms at 2 weeks, was well tolerated and was associated with only mild and transient adverse events, the SARcode release 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.

Other treatments in development include resolvins, which 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 drugs that bind to steroid receptors but have none of the side effects associated with steroids.

PROSE, which stands for prosthetic replacement of the ocular ecosystem and was developed at the Boston Foundation for Sight, is a system with a reservoir that gradually dispenses medication.

“It’s a remarkable device for moderate to severe dry eye because it actually smooths out the corneal surface, but you can use it as a vehicle that will deliver drugs,” Dr. Pflugfelder said. – by Matt Hasson

References:

• Jacobi C, Jacobi A, Kruse FE, Cursiefen C. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea. 2011;30(12):1289-1292.
• Kamao TK, Yamaguchi M, Kawasaki S, Mizoue S, Shiraishi A, Ohashi Y. Screening for dry eye with newly developed ocular surface thermographer. Am J Ophthalmol. 2011;151(5):782-791.
• Khanal S, Tomlinson A, McFadyen A, Diaper C, Ramaesh K. Dry eye diagnosis. Invest Ophthalmol Vis Sci. 2008;49(4):1407-1414.
• Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci. 2011;52(4):1994-2005.
• Su MY, Perry HD, Barsam A, et al. The effect of decreasing the dosage of cyclosporine A 0.05% on dry eye disease after 1 year of twice-daily therapy. Cornea. 2011;30(10):1098-1104.
• Villani E, Laganovska G, Viola F, et al. A multicenter, double-blind, parallel group, placebo-controlled clinical study to examine the safety and efficacy of T-Clair SPHP700-3 in the management of mild to moderate dry eye in adults. Cornea. 2011;30(3):265-268.

For your information:

• Eric D. Donnenfeld, MD, can be reached at Ophthalmic Consultants of Long Island, 2000 North Village Ave., Rockville Centre, NY 11570; 516-766-2519; email: eddoph@aol.com.
• Edward J. Holland, MD, can be reached at Cincinnati Eye Institute, 580 South Loop Road, Edgewood, KY 41017; 859-331-9000; email: eholland@holprovision.com.
• Marguerite B. McDonald, MD, can be reached at Ophthalmic Consultants of Long Island, 266 Merrick Road, Lynbrook, NY 11563; 516-593-7709; email: margueritemcdmd@aol.com.
• Stephen C. Pflugfelder, MD, can be reached at Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin St., NC 205, Houston, TX 77030; 713-798-4944; email: stevenp@bcm.tmc.edu.
• Disclosures: Dr. Donnenfeld is a consultant for Alcon, Allergan, Bausch + Lomb and TearLab. Dr. Holland is a consultant for Alcon, Allergan and Bausch + Lomb. Dr. McDonald is a consultant for Allergan, OCuSOFT and TearLab. Dr. Pflugfelder is a consultant for Alcon, Allergan, Bausch + Lomb, GlaxoSmithKline and Mimetogen. He does research for Allergan and Mimetogen.

Considering the risk for increased IOP with use of topical steroids in treatment of inflammatory dry eye disease, are there cases in which the benefit of treatment outweighs the risk?

Steroids complement cyclosporine

William B. Trattler

Inflammation is the major underlying cause of dry eye and ocular surface disease. Inflammation appears to be at the root cause of dry eye, and as well, dry eye results in ocular irritation, which also causes inflammation. Research has shown that there is elevation of inflammatory mediators in the tear film, as well as infiltration of the lacrimal gland with inflammatory cells in patients with dry eye.

Treatments for dry eye that focus on reducing ocular inflammation have been shown to be effective at reducing the signs and symptoms of dry eye. Both topical cyclosporine and topical steroids work to reduce ocular inflammation and play an important role in improving the health of the ocular surface. In my practice, I find that patients who present with dry eye can achieve significant improvement by starting topical cyclosporine twice a day plus 7-day to 10-day pulse dosing of either prednisolone acetate or loteprednol four times a day. By keeping the topical steroids on board for a short period of time, the risks of IOP elevation are kept very low.

Patients with dry eye may also benefit from punctal occlusion, but initiating therapy that reduces ocular inflammation clearly can help patients achieve a rapid improvement in the signs and symptoms of dry eye.

William B. Trattler, MD, is a Healio.com/Ophthalmology Board Member. Disclosure: Dr. Trattler is a consultant for Abbott Medical Optics, Allergan and TearScience.

Steroids should not be used to the exclusion of other treatments

John A. Hovanesian

I use steroids, too. However, besides IOP considerations, there is another disadvantage to their use in the acutely inflamed dry eye. They work almost too well, causing patients to ignore much needed treatments that really target the underlying cause of inflammation: aqueous and lipid deficiency. It is well recognized that inflammation is the end product of an ocular surface that is microscopically injured by a lack of lubrication. In the case of meibomian gland dysfunction, which is present in 70% of cases of dry eye, warm compresses and eyelid hygiene are still the most proven treatments, but they are time-consuming. Whatever the cause, effectively managing dry eye takes discipline on the part of the patient to carry out the prescribed treatments and discipline on the part of the physician to take time to educate patients on what really works rather than just prescribing a steroid for every patient who is uncomfortable.

John A. Hovanesian, MD, FACS, is an OSN Cornea/External Disease Board Member. Disclosure: Dr. Hovanesian is a consultant for Bausch + Lomb, Ista and TearScience.