After 15 years with few innovations that made their way into our clinics, we have recently seen the arrival of new medications, new versions of tried-and-true workhorses and research that is prompting a new look at the use of steroids in treating dry eye disease (DED). All of this is welcome news; additionally, in these times of ever-higher out-of-pocket medication costs, we may also see a lowered financial burden faced by DED patients, as the arrival of new products competing against existing options could bring prices down.

Cyclosporine A (CsA) has been the cornerstone medical treatment for DED since the approval of Restasis (Allergan). Lifitegrast (Xiidra, Novartis) became the second medication with an on-label approval to treat DED. A close reading of the original produce insert for Flarex under Alcon’s ownership uncovers a rather broad set of approved indications that cover the treatment of ocular surface inflammation. Familiarity with these three medications, as well as the recently approved micelle-encapsulated Cyclosporine A (Cequa, Sun Ophthalmics), informs the present state of DED care.

STANDARD PROTOCOL

DED is a chronic, progressive disease. It is in the chronic treatment of the signs and symptoms of DED that we have begun to see changes in our protocols due to the arrival of newer treatments.

Essentially all of our efforts at treating DED through medications are directed at reducing inflammation on the ocular surface or in the lacrimal functional unit (LFU). The LFU consists of the lacrimal gland, goblet cells and meibomian glands. While it remains unclear whether it is inflammation in the surface or the LFU that initiates DED, it has become abundantly clear that reducing inflammation is a key step towards relieving DED symptoms.

When treating DED, we work under the assumption that inflammation is caused by the activity of T-lymphocytes, which are active in some or all elements of the LFU. Corticosteroids in general are potent suppressors of T-cell activity. Prednisolone, difluprednate, loteprednol and fluorometholone are all effective. When it is necessary to rapidly reduce the signs and/or symptoms of DED, nothing accomplishes this as well as a topical steroid. For this reason, protocols to treat DED in the perioperative period — such as the recent ASCRS-led research by Chris Starr, MD, published this May in Journal of Cataract and Refractive Surgery — usually include the short-term use of topical steroids.

Historically, the ongoing use of topical steroids has not been a common strategy due to possible complications; all steroid drops have the potential to raise IOP, albeit some (eg, difluprednate) more than others (eg, fluorometholone). There is a known risk for cataract formation with prednisolone and dexamethasone.

CYCLOSPORINE

The addition of Restasis (cyclosporine) introduced a new approach to care. Since its arrival about 15 years ago, essentially every DED protocol is now centered around two points: when patients can start Restasis, and making sure they keep taking Restasis.

Cyclosporine A (CsA) is a notoriously difficult ingredient to work with, especially in topical form on the ocular surface. Mark Milner, MD, tells stories of his days as a fellow at Scripps in San Diego, mixing CsA with peanut oil to make an emulsion. The magic of Restasis was the marriage of CsA with the lipid emulsion Endura. With this combination, Allergan was able to make a highly stable, FDA-approved medication proven to increase tear production. While we must admit an uncertainty as to the mechanism of action for CsA on the ocular surface, Allergan has shown that the use of Restasis also appears to reactivate conjunctival goblet cells. According to a 2008 study in Cornea by Pflugfelder et al, a plurality of physicians who treat DED have found that Restasis, when used as properly instructed, effectively treats many patients with inflammation-associated dry eye.

Why have we not had a new CsA drop in the marketplace to offer to our patients? The answer lies in the extreme difficulty in formulating a topical product that is able to overcome the obstacles inherent in a hydrophobic molecule attempting to penetrate ocular tissues. Without access to Endura, which is a proprietary Allergan formulation, the large generic pharmaceutical manufacturers have been stymied.

Sun Ophthalmics has just entered the market with a product, Cequa (cyclosporine ophthalmic solution) 0.09%, that encapsulates the CsA molecule in micelles. It is the first new FDA-approved version of CsA since Restasis. Like Restasis, the breakthough with Cequa is how CsA is delivered. Each hydrophobic CsA molecule is surrounded, or “encapsulated,” by structures called micelles. This micelled-CsA complex is now hydrophilic on its exterior and hydrophobic internally. Once through the ocular surface, the CsA is released. Cequa is a true solution, and it demonstrated excellent corneal and conjunctival penetration in the pivotal Phase 3 “Emerald” trial. Most impressively the Phase 3 trial showed clearing of corneal staining at 28 days after initiation. While all of this is very promising, we will have to wait to see if Cequa performs as expected in the clinic.

ADDITION OF XIIDRA

The first big change since Restasis in how we treat the underlying pathology of DED came with the approval and nearly immediate availability of Xiidra in July 2016. Lifitegrast is an LFA-1 inhibitor that prevents T-cell recruitment and activation in vitro. At the moment, it remains the only medication with an on-label FDA approval to treat both the symptoms and signs (inferior corneal staining) of DED. Of particular note was the finding in one of the Phase 3 trials that symptoms were relieved as early as two weeks after initiating treatment. Unlike CsA, lifitegrast is relatively hydrophilic; Xiidra is lifitegrast in a very simple buffered saline vehicle. Restasis and Xiidra are non-preserved.

A consensus about whether to start anti-inflammatory treatment with CsA or lifitegrast has yet to emerge. Both medications have their champions and detractors. As we have learned more about how Xiidra performs “in the wild,” it is apparent that, like Restasis, it is still important to consider how you will keep a patient on the medication. Discomfort after instillation of various kind and degree continues to be a problem with both, and to some extent this informs the protocol for treatment in most clinics. Given enough time on either medication, the majority of our DED patients will experience some symptom relief, and their doctors will notice a decrease in signs on either medication. Doctors who treat DED tend to favor Restasis or Xiidra based on the success they have had with treatment adherence. Sadly, the initial medication chosen often has more to do with which brand is more fully covered by the patient’s insurance.

There is much to celebrate regarding the successes we have obtained with the use of CsA and lifitegrast. Any new products containing either will have to show equal efficacy; neither patients nor their doctors will tolerate a medication that has more side effects than Restasis and Xiidra.

FLUOROMETHOLONE

One new product now available is not really new at all. In a 2016 issue of Case Reports in Ophthalmology, Machida et al reported on two patients who experienced an improvement in DED symptoms after using fluorometholone. Earlier in 2019, in Acta Ophthalmologica, Taniguchi and Sharma looked at the effect of fluorometholone on the expression of genes responsible for producing mucin in cell cultures from the ocular surface. MUC1, MUC4, MUC16 and MUC19 were all up-regulated leading to greater mucin levels after exposure to fluorometholone.

This is rather exciting news, and it should lead to a greater willingness to prescribe fluorometholone in both early, episodic DED as well as more severe cases in which it is necessary to use more than one anti-inflammatory treatment. When this starts to catch on, I predict a renewal of the acetate vs. alcohol battles that were waged for prednisolone back in the day. (For the record, that is pretty much settled: acetate is more effective.) Back in 1984, in Phase 3 trial results published in Annals of Ophthalmology, fluorometholone acetate went head-to-head with fluorometholone alcohol and prednisolone acetate. In that study, its effect was equal to the prednisolone, and it had the same safety profile as the fluorometholone alcohol formulation. All three remain on the market and available today.

CONCLUSION

Treating the inflammation that underlies DED continues to be the central aspect of all DED protocols. Patients who require chronic treatment are prescribed either Restasis or Xiidra, and physicians typically choose to use the medicine with which they have been most successful.

While there is no lifitegrast alternative on the horizon, Cequa is now available for those patients in whom CsA treatment is a consideration. The vehicle that is used will drive the success or failure of other CsA options, branded or otherwise. The Taniguchi and Sharma study published earlier this year demonstrated an up-regulation of MUC gene activity with fluoromethalone. This finding may prompt DED doctors to prescribe fluorometholone earlier and more frequently. OM

About the Author

Darrell E. White, MD, is the founder of Skyvision Centers, in Westlake, Ohio. Over the past decade his focus on the treatment of dry eye has made SkyVision a “Dry Eye Center of Excellence.” He has held numerous leadership positions including president of the Cleveland Ophthalmological Society, and medical director of the first excimer laser center in Northeast Ohio.

Disclosures: Dr. White disclosed financial relationships with Allergan, EyePoint, Eyevance, Johnson & Johnson, Kala, Novartis, Omeros, Quidel, Renida, Sun and TearLab. He is an equity holder for Eyevance.