Inflammation in Dry Eye Disease

How targeted therapy can treat the disease and not just dry eye symptoms


Inflammation in Dry Eye Disease

How targeted therapy can treat the disease and not just dry eye symptoms.

By Paul Karpecki, OD, FAAO

Dr. Karpecki is clinical director of Corneal Services and Ocular Surface Research at the Koffler Vision Group-Kentucky Center for Sight. He is a paid consultant to Allergan, B&L, TearLab, AMO, OcuSoft, Odyssey Medical, Focus Labs, and Inspire Pharmaceuticals but has no financial interest in any of the products mentioned in this article.

With the current prevalence of dry eye, there's an incredible opportunity for eyecare practitioners to focus on this area of disease management.

Dry eye research shows that there are significant underlying osmolarity fluctuations that quickly result in an inflammatory response. There is also evidence establishing the relationship between inflammation and dry eye, which supports use of anti-inflammatory therapy.

Decreased tear secretion, osmolarity changes, and desiccation promote ocular surface inflammation. An increase in T-cell infiltration has been measured on dry eye patients' conjunctiva. In fact, it is becoming clear that dry eye is a chronic progressive disease and warrants prompt treatment of the disease and inflammation to allow for more natural tears.

According to the Schepens Eye Research Institute at Harvard University, about 6 million women and 3 million men in the United States have moderate-to-severe symptoms of dry eye disease, with an additional 20 million to 30 million experiencing mild cases. Also, the Beaver Dam studies indicate that greater than 13 percent of the population older than 40 suffers from dry eye. In yet another study by Nichols and colleagues in 2005, it was noted that more than 50 percent of contact lens patients suffer from dry eye symptoms.

With the prevalence of dry eye and with new therapies and expert consensus protocols available, treating this condition can be rewarding to practices and patients. But research shows that this may not be occurring.

Patient Response

What puts the current state of dry eye disease management into perspective is what patients think of how we are — or are not — effectively managing this disease. Perhaps the best source of information to illustrate this is the 2008 Gallup Poll survey. The two main items gleaned from that survey were that a significant percentage of patients suffer from dry eye and also that most patients do not feel that their practitioners are adequately managing their dry eye disease.

The poll surveyed 751 patients in the United States who had known dry eye disease. The results showed that a surprising number of patients visit practitioners in search of adequate treatment for dry eye and that the average patient had already tried more than three brands of artificial tears. The survey also indicated that 72 percent had practitioners recommend artificial tears for their dry eye problem (n=541); 82 percent somewhat agree or strongly agree that they wish there was something more effective to treat their dry eye (n=751); and 97 percent reported that their dry eye condition is frustrating (n=751).

These numbers are higher than in previous Gallup research, suggesting that practitioners still don't fully understand the unmet need and accompanying frustration and debilitation secondary to dry eye disease. It also demonstrates that practitioners are recommending palliative treatments rather than treating the disease. This would be analogous to an internist diagnosing diabetes and then waiting for signs of kidney disease or retinopathy before beginning treatment.

Certainly in mild cases of episodic dry eye, palliative options are a starting point, just as diet and exercise might be sufficient for borderline or pre-diabetes. But recall that the surveyed patients had already tried three different artificial tears and still had symptoms of dry eye disease. This goes beyond a mild case of episodic dry eye. And still, 72 percent visited practitioners who offered artificial tears as their only treatment plan.

Predisposing Factors

Many causes play a role in dry eye development. Predisposing conditions include environmental factors such as computer usage, reading time, smoking, windy or dusty work environments, airline travel, low humidity climates, winter months, and exogenous irritants. These environmental causes can exacerbate the dry eye associated with contact lens wear. Often causes are associated with systemic diseases including rheumatoid arthritis, diabetes, and thyroid dysfunction. Dry eye can also be a side effect of taking certain medications such as those used to treat allergies, Accutane (isotretenoin), antidepressants, and birth control pills, to name a few.

Menopausal women prescribed estrogen alone as hormone replacement therapy are seven times more likely to develop dry eye, although there is an increase in dry eye among patients taking hormone replacement therapy of any type. Age and gender also seem to play a role in the incidence of dry eye occurrence. According to a Women's Health Study, 5 million men and women older than 50 in the United States have dry eye syndrome. The incidence of dry eye in women is almost two times that of men.

It's evident that any of the multitude of predisposing factors can then lead to disease progression. Osmolarity changes ensue from environmental causes; medication, hormonal changes, and many potential predisposing factors can then cause an inflammatory response and symptoms. This was also evident in research that involved using hyperosmolar saline on the ocular surface of mice in which the researchers noted a pro-inflammatory stress release.

Addressing Eyelid Pathology

Blepharitis is a common culprit in dry eye disease. The two forms include anterior and posterior blepharitis. Posterior blepharitis is also referred to as meibomitis or meibomian gland disease (MGD). Like dry eye disease, blepharitis (anterior and posterior) is one of the most common chronic ocular disease conditions that practitioners face.

Studies show that patients who have posterior blepharitis, for example, have altered tear lipid layers and likely an increase in dry eye disease. Studies also show that besides an infectious process, inflammation plays a key role in the pathogenesis of this disease. For this reason, patients who have blepharitis will benefit from therapeutic agents that have antibacterial and anti-inflammatory properties. Combination agents containing corticosteroids and antibiotics such as Zylet (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension, Bausch & Lomb), Tobradex (tobramycin and dexamethasone, Alcon), and Blephamide (sodium sulfacetamide 10% and prednisolone acetate 0.2%, Allergan) have been effective in treating the inflammation and bacterial colonization.

AzaSite (azithromycin ophthalmic solution 1%, Inspire Pharmaceuticals), a commonly used agent in clinical practice for managing lid disease, has demonstrated effective clinical results in managing blepharitis. In one study, 21 patients diagnosed with posterior blepharitis were randomized between warm compresses alone versus warm compresses and azithromycin. Based on the severity of eyelid debris, eyelid redness, eyelid swelling, and quality of the meibomian gland secretions, there was significant improvement in the group using AzaSite. Another study involved 75 patients who had anterior blepharitis randomized into groups to compare azithromycin 1% to erythromycin ointment applied to the eyelid margins. At four weeks, total clinical resolution was 98 percent for the azithromycin-treated group and 37.5 percent for the erythromycin-treated group. Note that there are no medications specifically approved by the U.S. Food and Drug Administration (FDA) to manage blepharitis.

It is also beneficial in managing blepharitis to recommend lid hygiene such as lid scrub products and hot compresses. Because lid disease, like dry eye disease, is a chronic condition, it may warrant periodic treatment with some of the therapeutic agents previously discussed. Other effective long-term therapies that have demonstrated anecdotal benefit include omega-3 supplements, cyclosporine drops, and regular lid hygiene and hot compresses. Oral tetracyclines, including low dose doxycycline (<50mg dosage), is also effective in managing blepharitis.

The Role of Artificial Tears

Although it is critically important to treat dry eye disease at the onset of diagnosis with a therapeutic medication, there is still a need for artificial tears in the palliative management of patients. The foundation drop in managing the disease is cyclosporine or Restasis (Allergan), which is indicated for dry eye disease management. Other medications such as loteprednol are effective in managing inflammation associated with ocular surface disease; for short-term therapy it has been successful in clinic and has even helped compliance.

Targeted therapies, such as loteprednol 0.5% with cyclosporine, are typically dosed b.i.d. after an initial q.i.d. corticosteroid dosing, thus leaving time during the day when patients may still have occasional dry eye symptoms. Artificial tears would be the ideal recommendation for periodic symptoms while the targeted medications treat the disease itself.

Just as it would seem odd for an internist to hand a patient a handful of various pills for hypertension, giving a patient a handful of artificial tears is similarly unusual to most patients. Instead, make a recommendation based on clinical findings. "Suggested Artificial Tear Use" found below offers anecdotal evidence suggesting what type of artificial tear would most likely work best in certain circumstances. Again, these would be used in addition to targeted therapies that treat the underlying disease of dry eye inflammation.

Suggested Artificial Tear Use
Standard Aqueous Deficient Dry Eye Disease Several high-quality artificial tears are appropriate for this category of patients, including Optive (Allergan), Systane Ultra (Alcon), Blink Tears (Abbott Medical Optics), Soothe Lubricant Eye Drops (Bausch & Lomb), GenTeal (Novartis Ophthalmics), Oasis Tears (Oasis Inc.), and TheraTears (Advanced Vision Research).
Lid Disease Patients who have meibomian gland dysfunction seem to do better with a mineral oil-based artificial tear such as Soothe XP (B&L), which contains various weight mineral oils and statistically improves the lipid layer thickness.
Contact Lens Dry Eye Although many experience symptomatic relief with artificial tears, it appeared in our experience that Blink Contacts lens rewetting drops (Abbott Medical Optics) was one of the more successful options. Another effective drop is Refresh Contacts (Allergan). Other artificial tears such as Soothe XP work well for lens wearers who have significant lid disease. FreshKote (Focus Laboratories) is effective in patients who have chronic superficial punctate keratitis.
Severe Dry Eye For anyone who needs to use tears more than four times a day because of severe symptoms or extremely low aqueous production, non-preserved artificial tears are recommended. Patients who have significant corneal pathology seem to do extremely well with FreshKote, which is sold behind the counter and requires a prescription or that the patient asks the pharmacist for it by name. Lacrisert (hydroxypropyl cellulose ophthalmic insert, Aton Pharma), a tiny preservative-free, once-daily, sustained-release ocular insert that provides continual lubrication, may also benefit patients who require artificial tears six-to-10 times per day or in place of ointments at night for some patients.
Lid Closure Problems Patients who have lagophthalmos, stroke-related or cranial nerve-related closure problems, and very severe dry eye are virtually the only cases in which I consider artificial tear ointments. A high concentration artificial tear such as FreshKote or an artificial tear with hyaluronic acid such as Blink Tears or Oasis Tears or a gel type drop during the day may also be beneficial.
Allergy Sufferers Because many of these patients are also sensitive to preservatives, I like preservative-free tear products such as Allergan's Refresh Plush and AMO's Blink Tears Preservative Free or Allergan's Refresh Plus preservative-free tears in conjunction with topical allergy therapies.

Dry Eye Disease Inflammation, Progression

Studies show that dry eye is not simply a nuisance condition but a true progressive disease. Research has revealed that dry eye disease causes measurable damage to the interpalpebral ocular surface. Another study showed that osmolarity changes, caused by numerous predisposing factors, will result in an inflammatory response that may lead to ocular surface damage. Another study showed that activated T-cells in the lacrimal glands may cause ocular surface disease damage. So by not targeting the inflammation, patients are likely to progress and may experience continued ocular surface damage.

Perhaps the best example of how inflammation progresses when dry eye disease is treated only with artificial tears compared to a therapeutic agent that targets the disease would be the Cyclosporine Phase III Pivotal FDA Clinical trial. In this study, 453 patients were randomized between cyclosporine 0.05% b.i.d. versus a vehicle b.i.d. The vehicle was Endura (now Refresh Dry Eye Therapy, Allergan), a castor oil emulsion and effective artificial tear. Thus there was essentially an opportunity to compare treatment results with artificial tears to a targeted medication. Patients were allowed to use artificial tears, such as Refresh Plus (Allergan), as they felt necessary.

Six month data showed that Schirmer scores increased for the cyclosporine arm but decreased in the artificial tear arm. In addition, corneal staining was lower in the cyclosporine arm, and biopsies showed that goblet cell density increased by 191 percent in patients receiving cyclosporine compared to only 13 percent in those receiving artificial tears alone. Perhaps even more telling is that the group receiving only artificial tears had an increase in inflammatory markers of more than 39 percent compared to baseline measurements. This suggests that the disease progresses when palliative options are the only treatment recommended by practitioners.

Another study by Rao (2008) showed progression in dry eye severity in patients using only artificial tears. In this study, 74 patients were enrolled and, based on the International Task Force (ITF) guidelines, were rated from grade 1 to grade 4 based on severity scores. Equal numbers of patients were graded as grade 2 and grade 3 for the Restasis arm and the Endura arm of the study. Schirmer scores, tear film breakup time (TBUT), and corneal staining all improved in the Restasis arm but demonstrated little or no improvement in the Endura or artificial tear arm. The most telling statistic of this masked clinical trial was that at the end of the one-year study, 31.8 percent of the Restasis group improved one full level on the severity scale versus 5.5 percent of patients in the Endura group.

Treating at the Earliest Stage of Diagnosis

There have been numerous studies showing therapeutic agents' effect on moderate-to-severe dry eye patients, but few on managing mild dry eye patients. A study by Sall et al (2000) included patients who had mild dry eye, and the data again supported that treating dry eye disease with medications targeting the disease processes has a statistical benefit. Mild, moderate, and severe dry eye patients improved statistically more when receiving cyclosporine compared to those using only artificial tears in the two tests measured (TBUT and corneal staining). This study is unique in that statistical improvement was also noted in patients diagnosed with mild dry eye. We can interpret this study to reflect that the moment a diagnosis is made, practitioners should prescribe a targeted treatment as opposed to simply making palliative recommendations.

Punctal Plugs
Punctal plugs are also a very effective treatment option in managing dry eye. One study on contact lens dry eye showed a 34 percent improvement in wearing time after inferior insertion of silicone punctal plugs. Studies also suggest that the new approach to managing dry eye includes punctal occlusion but with concurrent or prior anti-inflammatory therapy.

Medications Targeting Inflammation

Cyclosporine is approved to treat dry eye disease and can increase patients' tears. In the pivotal FDA clinical trial, the six-month measurements comparing Restasis to placebo showed a statistically significant increase in Schirmer tear scores (P<0.007). Other measurements that showed statistical improvement included blurred vision, itching, and corneal staining. Reliance on artificial tear use was dramatically and statistically reduced, inferring that treating the underlying disease may result in less need for palliative therapies.

Perhaps the reason for this finding is the targeting of the underlying inflammatory components. Flow cytometric analysis of inflammatory markers in kera-toconjunctivitis sicca (KCS) treated with cyclosporine A provided an objective measurement of its effect on inflammatory cells. Topical cyclosporine A reduced various immune or apoptosis (cell death) related markers in the conjunctival epithelial cells whereas the vehicle, a control tear substitute, had almost no effect. This effect is then evident on the goblet cell density, which has been shown to produce mucin in the tear film.

Studies have revealed that cyclosporine emulsion, but not artificial tears, increases goblet cell density and production of the immunoregulatory factor TGF-beta2 in the bulbar conjunctiva in dry eye patients. This was also evident in the pivotal FDA clinical trials in which patients treated with cyclosporine A had a 191 percent increase in goblet cell density after six months of treatment.

Corticosteroids have long been known to treat the inflammation associated with dry eye disease. A 1998 study by Prabhasawat and Tseng using non-preserved methylprednisolone in known dry eye patients demonstrated an improvement of more than 80 percent in clinical signs and symptoms. Another study by Marsh and Pflugfelder (1999) using corticosteroids in patients who have Sjögren's Syndrome and KCS noted dramatic improvement in the ocular surface, including significant improvement in filamentary keratitis. However, corticosteroids that are ketone-based, such as methylprednisolone, used in these studies required very short-term pulsed therapy (e.g. two weeks) for safety. This wasn't ideal for chronic conditions such as dry eye disease.

The first ester-based steroid, loteprednol, changed that as it showed good safety and efficacy in treating ocular surface inflammation with longer-term therapy. In a 2004 study by Pflugfelder and colleagues, patients were prescribed loteprednol 0.5% q.i.d. for four weeks and showed significant improvement in corneal staining, chemosis, and injection scores compared to artificial tears alone. In fact, when looking at just the dry eye patients who scored 10 and higher on staining scores, every category measured had the same or improved results compared to placebo/artificial tears alone. There was even statistical improvement in surface irregularity scores compared to the use of artificial tears alone.

Oral doxycycline is also used in managing ocular surface diseases and is likely effective due to its antiinflammatory properties. Studies by Darsun have shown that oral doxycycline and corticosteroids can inhibit enzymes produced by inflammatory cells such as matrix metalloproteinase-9 in preventing ocular surface damage. Studies have also revealed that low doses of doxycycline, a tetracycline derivative, have significant anti-inflammatory properties.

Essential Fatty Acids

Research shows that omega-3 supplements such as fish oils (EPA/DHA) and omega-6s such as gamma-linolenic acid (GLA) decrease prostaglandins and inflammation. A 2005 study by Aragona and colleagues showed that GLA given for one month to patients with primary Sjögren's syndrome increased tear levels of the anti-inflammatory eicosanoid PGE1, and ocular surface status and dry eye symptoms improved statistically. Two weeks after ending supplementation, tear PGE1 declined to near baseline levels.

Another randomized, placebo-controlled study on supplemental GLA and linoleic acid (LA) by Barabino and colleagues in 2003 showed improvement in symptom scores and lissamine green staining as well as ocular surface inflammation reduction compared to the placebo group.


According to the most recent Gallup Poll, patients do not feel that their dry eye disease is being adequately managed, and most practitioners are simply providing palliative care rather than targeting the underlying disease process. Inflammation is at the root of dry eye disease and appears to develop quickly in the disease process. Targeted therapies such as cyclosporine A, corticosteroids, oral doxycycline, and essential fatty acid supplements have known effects on ocular surface inflammation.

Dry eye disease has a considerable impact on the quality of life that patients experience. Understanding the underlying causes of this disease, the need for prompt treatment, and the fact that it is a progressive disease will help prevent potential long-term damage to the ocular surface, grow your practice, and create satisfied patients. CLS

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