Anti-inflammatory Safety and Efficacy in OSD

While there is only one prescription medication for the treatment of dry eye, other treatments provide palliative care and help for flareups.

By Marguerite McDonald, MD, FACS

Dry eye is a disorder of the tear film experienced by about 20 million people in United States.¹ A Gallup survey of dry eye sufferers revealed that people feel frustrated with the condition.² Some 83% said they've suffered with dry eye for 2 or more years, and 53% said the treatment they use doesn't last long enough. Patients wish there was a more effective treatment for dry eye.

The poll reflects the discomfort and inconvenience of dry eye. Patients with dry eye may avoid or drop out of contact lens wear or change their lifestyles to cope. Over time, as over-the-counter drops offer less and less relief, patients with dry eye can suffer damage to the interpalpebral ocular surface and experience changes in vision.^3,4 Palliative drops don't treat the underlying inflammatory cause of dry eye or concurrent problems that may exist, such as anterior blepharitis and meibomian gland disease (MGD, also known as posterior blepharitis). Patients need a comprehensive approach, which often includes prescription antiinflammatory drugs.

Long-term Dry Eye Treatment

The approval of cyclosporine ophthalmic emulsion (Restasis) was a watershed moment in the history of dry eye treatment. Until the approval of cyclosporine emulsion, dry eye treatment was limited to palliative measures such as lubrication. Artificial tears offer short-term relief, but they don't stop progression of the disease. Cyclosporine emulsion is the only prescription medication that treats the underlying cause of dry eye.

Dry eye progresses as the underlying lacrimal gland inflammation continues, along with the attendant goblet cell dropout; eventually, the entire ocular surface is involved. Cyclosporine emulsion controls the lacrimal gland inflammation, making it highly effective in treating stage 2 or higher dry eye. Cyclosporine emulsion has a beneficial effect on MGD as well (though it is not considered a first-line treatment for MGD).⁵

Cyclosporine emulsion increases tear production that has been suppressed due to inflammation from keratitis sicca. When we evaluate patients with dry eye and determine their level of severity (from level 1, mild, with no signs on cornea to level 4, severe, with punctate corneal erosions), experts recommend cyclosporine emulsion for patients with a severity level of 2 to 4.⁶ Experts also recommend the insertion of punctal plugs at level 3 (though I prefer to begin using them at a high level 2), but only as an adjunct to cyclosporine emulsion treatment in patients who are still symptomatic. Cyclosporine emulsion targets the inflammation that has disrupted tear production, allowing patients to produce more of their own tears. Cyclosporine emulsion is known to be an effective immuno-modulator, but the exact method of action is unknown; nevertheless, tear production continues to increase over time.

Cyclosporine emulsion is safe for most dry eye patients, many patients with dry eye are middle aged and older, and thus may have preexisting issues, such as glaucoma or recent cataract surgery. They are often on a host of oral medications and frequently have post-menopause-related health problems. Glaucoma patients are often using preserved medications that exacerbate dry eye. They may have a bleb from filtering surgery, which disturbs the normal distribution of tears. Some older dry eye patients also have exposure keratitis caused by laxity of the lower lids. Cyclosporine emulsion works well in all of these patients. It may be wise to switch a glaucoma patient to unit dose unpreserved tears, however, since preserved topical glaucoma medications may exacerbate dry eye.

Studies of Cyclosporine Emulsion

One study of cyclosporine emulsion versus Refresh Endura (Allergan), the vehicle used in Restasis, showed that Schirmer scores improved by greater than or equal to 10 mm in 15% of patients using cyclosporine emulsion, versus 5% using the vehicle. This is an enormous amount of change. Of course, most patients had a statistically and clinically significant improvement in their Schirmer scores, but by less than 10 mm.⁷ Clinicians appreciate that any small increase in Schirmer's scores can be clinically important (I've seen a change of 1 or 2 mm take a patient from contact lens intolerant to tolerant).

Patients using cyclosporine emulsion also had a 191% increase in average goblet cell density after 6 months, compared to 13% with the vehicle.⁸ Cyclosporine emulsion patients showed less reliance on artificial tears.⁹ There was no quantifiable level of cyclosporine emulsion detected in the blood of any of the clinical trial patients, so none of the systemic toxic effects of oral cyclosporine emulsion occurred. Approximately 17% of patients using cyclosporine emulsion had a mild burning sensation on instillation.⁷

In the fight to control dry eye, one important goal is to prevent progression and avoid the risk of vision loss. With this in mind, we asked whether cyclosporine emulsion treatment affects patients' dry eye severity levels over time. Rao¹⁰ showed that after 1 year, 5% of patients using cyclosporine emulsion experienced an increase in severity of at least one level compared to 32.8% of control patients. Clearly, cyclosporine emulsion helps prevent progression.

Treating the Comorbidities

We know some forms of ocular surface disease occur concurrently with dry eye. In some instances, these diseases may actually cause or exacerbate dry eye, which makes their diagnosis and treatment essential to tackling dry eye over the long term. Two common problems are anterior blepharitis and posterior blepharitis.

In a phone study, interviewers asked 5,000 people if they had classic blepharitis symptoms such as itching, burning, crust, flakes, puffiness and redness.¹¹ Except for flaking, which is typically associated with anterior blepharitis, these symptoms are common to both anterior and posterior blepharitis. About 79% had experienced at least one symptom in the past 12 months. The study designers concluded that blepharitis is highly prevalent, but it is underdiagnosed and therefore, undertreated. Once blepharitis is identified, it responds well to a spectrum of treatments, which may include warm compresses, lid hygiene, lubricant drops, azithromycin drops and omega-3 nutritional supplements.

This year, the International Workshop on Meibomian Gland Dysfunction, sponsored by the Tear Film and Ocular Surface Society (TFOS), published its conclusion that meibomian gland dysfunction is a frequent cause of dry eye disease.¹² Inflammation is an important element in the pathophysiology of dry eye and blepharitis, and in the absence of sufficient quantities of clear meibum to prevent evaporation of the tear film, MGD patients can develop evaporative dry eye. Therefore, dry eye and MGD are often pathophysiologically and clinically linked. The International Workshop on Meibomian Gland Dysfunction report recommends azithromycin topical solution (Azasite, Inspire Pharmaceuticals) as primary treatment for patients with stage 2 or higher meibomian gland dysfunction, with good results.¹² At stage 2, oral tetracycline derivatives should be considered as well.

Evaporative dry eye, which is caused by meibomian gland disease, often coexists with dry eye. The two conditions exacerbate each other to cause the telltale, biphasic symptoms: crusty, puffy, red, irritable lids in the morning (caused by MGD) and tired, blurry, red eyes with fluctuating vision in the evening (symptoms of dry eye). Signs of MGD can include lid erythema; lid edema; scurf at the base of the cilia; lid neovascularization; scarring of the meibomian gland orifices; inspissation of the meibomian glands, with turbid secretions that can be expressed with or without pressure; a secondary trichiasis; migration of the meibomian gland orifices; conjunctival and corneal staining; phylectenules, and/or hypotrichosis. Signs of dry eye overlap to a certain degree with the signs of MGD, though tear film alterations (a low tear meniscus, rapid tear break up time, etc) begin at stage 2 dry eye, filamentary keratitis at stage 3, and severe corneal staining and erosions at stage 4.

Additional Treatments

Although cyclosporine emulsion is the only prescription treatment approved for dry eye, other treatments are being investigated. In the meantime, patients may benefit from other short-term and palliative treatments.

• Steroids. Steroids aren't appropriate for long-term control of dry eye because of the accompanying risk of cataract formation, elevated intraocular pressure and exacerbation of potential viral infections. However, dry eye waxes and wanes, and steroids are useful for controlling the occasional flare-up in stage 3 and 4 patients. Steroids also may be used during the induction stage of cyclosporine emulsion therapy to mask the stinging that sometimes occurs during the first 2 to 4 weeks, and to give patients fast symptomatic relief until the cyclosporine emulsion takes effect—usually around 1 month. Loteprednol etabonate (Lotemax, Bausch + Lomb) has become the topical steroid of choice in this regard; it is often given QID for 2 weeks then BID for 2 weeks as cyclosporine emulsion therapy is started. Loteprednol etabonate is also useful for the occasional flare-ups of and blepharitis, as well.

• Combination drugs. Another option for patients with blepharitis flareups is an antibiotic/steroid combination, such as tobramycin 0.3%/dexamethasone 0.05% (Tobradex ST, Alcon). Tobradex has been around for decades and has a good safety profile. This new formulation contains half the dexamethasone of the original Tobradex (.05% vs. 0.1%). For short-term treatment of flareups of blepharitis, this combination is safe and effective.

The manufacturer states that the drug's advanced ionic interaction of tobramycin 0.3%/dexamethasone 0.05% enables the drop's viscosity to increase seven-fold as it hits the ocular surface. It also contains xanthan gum, which makes the drops adhere to the target tissues for increased contact time.

• NSAIDs. Today, there is an interest in exploring the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in long-term dry eye treatment. It seems logical that NSAIDs may have some role in treating dry eye because it is an inflammatory condition. ISTA is currently in phase 3 clinical trials for a bromfenac solution called Remura, which has a lower concentration than Bromday.

• Palliative treatment. Patients with every degree of dry eye—from mild stage 1 to severe stage 4—often use lubricating drops, gels and ointments as needed. This need usually decreases over time with the use of cyclosporine emulsion, as patients produce more of their own tears and higher quality tears. There are many entries in the tear supplement field, including extensive lines of over-the counter-therapies from major pharmaceutical companies such as Allergan (the Refresh line), Alcon (the Systane line), Novartis (the Genteal line), Abbott Medical Optics (the Blink line), and others.

There are new entries in this category every few months. For instance, the recently released Systane Balance (Alcon) drop offers extended relief because it combines propylene glycol 0.6% with oil (a combination that Alcon calls the LipiTech System) to provide the tear film and lipid layer that are lacking in patients with meibomian gland dysfunction. Systane Balance is a stable emulsion in the bottle, activated on the eye at the first blink to create a stable lipid layer for prolonged lubrication and protection.

Smaller companies are also in the mix. Focus Labs offers an artificial tear product, FreshKote, which contains all three layers of the normal tear film: aqueous, mucous and lipid.

The Big Picture

Dry eye is a very common and vexing problem and the incidence increases with age. People are living longer. As such, a larger percentage of the population is taking oral medications (for hypertension, hypercholesterolemia, etc.) and more women are post-menopausal, two risk factors that increase the incidence of dry eye even further. Blepharitis—particularly MGD—is a frequent comorbidity that exacerbates dry eye. In 2011, we can offer our patients effective treatments for both of these conditions.

Cyclosporine emulsion targets an underlying cause of dry eye, increasing tear production and reducing staining and reliance on artificial tears. What's more, dry eye is vulnerable to progression, and artificial tears don't stop that progression. For most patients, long-term use of cyclosporine emulsion controls dry eye and stops progression Artificial tears are palliative, providing temporary symptomatic relief, and topical steroids are useful for flare-ups in more severe cases, but the overall experience with cyclosporine emulsion is one of enhanced comfort and less reliance on palliative measures. ■

References

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9. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000 Apr;107(4):631-639.
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Marguerite McDonald, MD, FACS, is a cornea and refractive surgery specialist at Ophthalmic Consultants of Long Island in Lynbrook, N.Y. She's also a clinical professor of ophthalmology at New York University Langone Medical Center in Manhattan and an adjunct clinical professor of ophthalmology at Tulane University Health Sciences Center in New Orleans. You can reach her at margueritemcdmd@aol.com.