feature
Alternatives for Treatment-Resistant Dry Eye
Several formulations are available or are coming soon.
BY JOSEPH F. MUSSOLINE, M.D.

Despite dry eye's ever-growing prevalence — estimates suggest that 11% to 22% or more of the general population are affected — it remains one of the more difficult ocular conditions for clinicians to treat due to its various and sundry etiologies.1 In attempting to provide solutions to dry eye sufferers, clinicians often turn to tear substitutes, followed in some cases by punctal plugs or prescription medication such as cyclosporine or ocular steroids. For many years, saline was a common dry eye management; it was followed by the advent of polymer eye drops and aqueous artificial tears. Thick ointments were developed for nighttime use, and in the past few years, viscous gel formulations have been created to yield better relief of dry eye signs and symptoms.

Tear Substitutes

The first-line treatment for dry eye is typically a tear substitute. The science behind tear substitutes has advanced greatly in recent years. Many tear substitutes tend to focus on a specific severity of dry eye. Aqueous artificial tears, such as GenTeal (Novartis), Refresh Tears (Allergan) and Tears Again (OCuSOFT), are often suggested for early-stage dry eye patients and those with ocular surfaces that are partially compromised (as indicated by vital dye staining) or tear films that retain some stability in spite of the evident presence of the condition.

Dry eye gels are more viscous than artificial tears, less viscous than ointments, and are generally dispensed from bottles. Gels are often suggested for moderate to severe dry eye. Viscosity is an important property of tear substitutes and is measured in centipoises. Available gels include GenTeal Gel (Novartis), Refresh Liquigel (Allergan), Tears Again Night & Day Gel (OCuSOFT) and Systane Free (Alcon).

Refresh Liquigel and Tears Again Night & Day Gel employ carboxymethylcellulose as their active ingredient. GenTeal Gel contains hydroxypropyl methylcellulose. Newly available, Systane Free is a free-flowing gel that incorporates the gelling agent hydroxypropyl (HP)-guar and the demulcents polyethylene glycol 400 and propylene glycol, which are loosely bonded in the bottle but strengthen to form a structured gel layer that covers the corneal epithelium.2 Because it does not contain traditional preservatives, Systane Free poses no potential threat to advanced dry eye sufferers. The ionic buffer preservation system contained in Systane Free has produced significant results in reducing in vitro bacteria and fungi, meeting both USP and ISO preservative efficacy standards.3

When compared to Refresh Tears in a clinical trial, Systane Free demonstrated a significantly better reduction in corneal staining at 6 weeks, supporting its ability to protect the ocular surface. The HP-guar-based formulation also reduced three common dry eye symptoms — burning, stinging and scratchiness — with statistical significance.4 When tested against a gel, Refresh Liquigel, Systane Free not only exhibited a significantly superior blur profile over
3 minutes post-instillation, but also elicited a statistically significant increase in patient acceptability ratings versus Refresh Liquigel.5 In short, study results suggest Systane Free to be a management well-suited for first-line employment, as well as for concomitant use as part of a treatment system.

Figure. Schirmer strips are used to measure the amount of tears an eye produces. Some therapies aim to increase tear production and use Schirmer tests to determine if such changes are achieved.

The Role of Cyclosporine A

If a patient seems unresponsive to standard methods and has advanced signs and symptoms of dry eye, a clinician might prescribe cyclosporine A (Restasis, Allergan) or an ocular corticosteroid. To date, Restasis is the only FDA-approved active ingredient for increasing tear production in keratoconjunctivitis sicca patients, though there are many promising formulations in the pipeline. The T cell inhibiting action of cyclosporine A is associated with an increase in aqueous tear production in some dry eye patients.6 However, this action is only observed in patients with aqueous deficient dry eye, which is characterized by low tear volume. Relative tear volume estimations can be made using Schirmer strips (Figure), tear meniscus height assessments or fluorophotometry. Even in aqueous-deficient populations, Restasis has only demonstrated significant tear production increase in 15% of patients.⁷

In patients for whom treatment with Restasis does not seem to be working — patients with increased tear volumes or reduced symptoms following therapy — more complete treatment is possible. Studies demonstrate that the concomitant use of an artificial tear can improve the potentially beneficial effects of Restasis. This trial yielded data showing traditional Systane (Alcon) to be an excellent concomitant treatment when dosed in conjunction with Restasis. The Systane and Restasis combination demonstrated significantly superior efficacy in reducing corneal staining and dry eye symptoms when compared to a regimen of Refresh Tears and Restasis.8

This use of Restasis as an adjunct therapy need not be limited to aqueous tears. Gels, with their improved symptomatic relief, should also prove useful concomitantly. However, gels tend to cause blurring of the vision. They also are generally preserved with chemical or oxidative preservatives — and some preservatives exist in both categories that have been shown to have potentially irritating effects in some patients.9 Concomitant dosing with a gel that is not prone to blurring could yield greater efficacy in reducing signs and symptoms during a Restasis treatment regimen.

Restasis Failure

For many dry eye patients, Restasis therapy will prove ineffective or undesirable. This might be due to the subjective inability of cyclosporine to reduce dry eye symptoms or clinical signs, or in some cases could be attributable to the discomfort occasionally brought on by the drop itself. Restasis has been observed to cause ocular burning upon instillation in 17% of patients treated. For those dry eye patients who discontinue dosing with Restasis for efficacy-related, comfort-related, or even cost-related reasons, clinicians must select the best management or combination of managements on a patient-by-patient basis.

In treating a patient who has not responded to Restasis, a solid first step is to educate the patient on the nature of dry eye as a condition and as a component of disease. The better a patient understands dry eye itself, the better he or she will be able to assist in the selection of the most appropriate management system. A trial-and-error process may be used to determine what tear substitute is most agreeable for a patient, and whether punctal plugs or the use of a nighttime ocular ointment may augment a tear's efficacy or comfort. The market for artificial tears and gels is large and varied; unique etiologies of dry eye are equally large and varied. So where does one begin the selection process for the proper management?

Restasis failure does not allow for an easy classification of the nature or severity of an individual's dry eye condition. Therefore, it is best to start patients with an all-purpose tear substitute that does not target a specific severity. Many dry eye products are indicated specifically for mild, moderate, or severe dry eye, or aim to strengthen specific tear film layers (i.e., lipid layer enhancers).

In the Pipeline

Importantly, the partial efficacy of Restasis has inspired the ongoing development of many potential prescription products for dry eye. Among these possible future therapies, the most common variety are known as secretagogues. These include mucin secretagogues such as 15(S)-HETE and ecabet sodium, and compounds such as diquafosol tetrasodium — a P2Y2 agonist that has demonstrated efficacy in reducing corneal staining and improving Schirmer scores. Secretagogues combat deficiencies in one or more layers of the tear film. Anti-evaporatives, such as sodium hyaluronate, aim to prolong break-up time and subsequently reduce dry eye symptoms. Reformulations of cyclosporine A, such as the cationic emulsion Nova 22007 (Novagali) hope to accent the immunomodulating capabilities of the compound, while other immunomodulators such as pimecrolimus are also being tested. Lacritin is an extra-cellular glycoprotein produced naturally by the eye — as a potential treatment it has seen initial efficacy at increasing tear flow in animal models. Other possibilities for dry eye therapy incorporate hormonal treatments and neuronal feedback loop regulators — substances intended to reverse age-related dry eye at the source. In short, the future dry eye treatment market will probably include many varied options.

Whether a patient has failed on Restasis, is using Restasis successfully, or is using some other treatment option such as punctal occlusion, dietary supplements, nighttime ointments or warm compresses, tear substitute use is almost inevitably a component of the treatment system. This could involve concomitant use of a tear substitute with Restasis, when effective, or punctal plugs in more advanced dry eye patients. The addition of any auxiliary treatment option is facilitated by the choice of the most appropriate tear substitute for continued dosing. Meanwhile, dry eye sufferers await the next prescription product to emerge from the pipeline. 

Joseph F. Mussoline, M.D., is a clinical instructor and assistant surgeon at the Wills Eye Hospital in Philadelphia. He is also the surgical director of the Campus Eye Ambulatory Surgery Center in Hamilton, N.J.

References

1. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45:199-201.

2. Rodeheaver D, Griffin J, Hendrix C, et al. Pre-clinical evaluation of a novel artificial tear (AT) for dry eye. Paper presented at: 4th International Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes: Basic Science and Clinical Relevance; November 17-20, 2004; Fajardo, Puerto Rico.

3. Rosenthal RA, Schlech BA, Buck SL. Preservative efficacy of a new lubricant eye drop without traditional preservatives. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); April 30-May 4, 2006; Fort Lauderdale, FL.

4. Rosenthal R, Buck S, Schlech B. Rigorous microbiological testing of a multi-dose tear replacement formulation with no preservatives. Poster presented at: The Association for Research in Vision and Ophthalmology (ARVO) annual meeting; May 1-4, 2005; Fort Lauderdale, FL.

5. Christensen MT, Meadows DL, Tudor MR, Stone RP. A report from clinical evaluations of a new liquid gel concept artificial tear. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); April 30-May 4, 2006; Fort Lauderdale, FL.

6. Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol. 2005;89:1363-1367.

7. Tripathi RC, Parapuram SK, Tripathi BJ, Zhong Y, Chalam KV. Corticosteroids and glaucoma risk. Drugs Aging. 1999;15:439-450.

8. Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens. 2006;32:21-26.

9. Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxic Res. 1992;9:361-375.