DRY EYE REPORT

Exploring Rx Dry Eye Treatments

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By Michael Mayers, OD, FAAO

Dry eye disease is a challenging chronic inflammatory condition that often requires multiple therapies throughout the course of a year. Topical steroids, nonsteroidal antiinflammatory medications (NSAIDs) and cyclosporine emulsion are typically employed to squelch the chronic inflammation caused by dry eye syndrome — but all medications come with risks. As practitioners, we may focus on the benefits of a particular medication, but it's important to remember that long-term therapies can have potentially severe ocular and systemic effects. This article explores current peer-reviewed studies and typical clinical usage of the different drug classes used to treat dry eye.

Dry Eye Pathophysiology Snapshot

Inflammation in dry eye can be caused by multiple mechanisms. Mucin, aqueous and lipid deficiencies may coexist. Also, high tear osmolarity and tear film instability have been identified as mutually occurring global processes.¹ One of the more common inflammatory markers for identifying dry eye patients is HLA-DR.² Regardless of the mechanism, the end result is an unhappy patient that may require immediate medical attention and ocular triaging for inflammation and discomfort.

Blocking the Inflammation Pathway

Arachidonic acid is the primary chemical that initiates the inflammatory cascade. Corticosteroids work by inhibiting phosophlipase A, which prevents arachodonic acid accumulation. Nonsteroidal anti-inflammatory medications work further downstream in the cascade by blocking the COX enzyme, preventing the release of chemicals such as prostaglandin into the bloodstream (Figure 1). Cyclosporine A is a potent immunomodulator and acts by inhibiting T-cell maturation, thus suppressing inflammatory mediators.

Figure 1. NSAIDs work by blocking the COX enzyme.

Corticosteroids

Corticosteroids are potent and effective antiinflammatory drugs used to control dry eye. Many practitioners use steroids for short-pulse dosing to control underlying inflammation. One study of 1% nonpreserved methylprednisolone topically administered 3-4 times daily in Sjogren's patients showed a marked decrease in symptoms, improved corneal staining scores and completely eliminated symptoms in some dry eye subjects.³ Thus, dry eye patients suffering from corneal epithelial disease have also benefited from steroid therapy. Studies comparing corticosteroids head-to-head with nonsteroidal antiinflammatory drops have shown that corticosteroids dominated the NSAID group from both a subjective and objective observation.⁴ However, these potent ocular steroids come with side effects and contraindications that must be considered. Potential side effects and contraindications are:

• Increased IOP
• Cataracts
• Potential for infection
• Viral disease
• Glaucoma/ocular hypertension

Current literature is dividing steroids into “hard” and “soft” steroids. Hard steroids may include: difluprednate ophthalmic emulsion (Durezol, Alcon); prednisolone acetate; and dexamethasone. Soft steroids may include: 0.2% loteprednol etabonate (Alrex, Bausch + Lomb) 0.5% loteprednol etabonate (Lotemax, Bausch + Lomb); and fluorometholone (FML, Allergan).

Remember that approximately 4-7% of your patients will have a significant IOP spike after 1 month of steroid intervention on so-called “hard” steroids, such as prednisolone compared to a 2% increase in IOP when using 0.5% loteprednol etabonate.^5,6 With that in mind, current mainstream therapies have switched to using softer steroids due to their lower risk of IOP spike.⁷ One study dosed FML in children for 8 weeks following strabismus surgery — 6 times per day in one group and 3 times per day in the other. The study found that IOP increased significantly in both groups compared with preoperative values, but the group dosed 6 times per day reached their peak IOP earlier in the treatment course. There were no significant differences in healing rates between the two groups.⁸ Another study examining 0.5% loteprednol found evidence suggesting that loteprednol quickly becomes metabolized to inactive metabolites, thus yielding a better safety profile than other corticosteroids.⁵ Overall, the steroid class is generally safe especially if using “softer” steroids for dry eye treatment.

NSAID Meltdowns

NSAIDs have been around for many years, though primary eyecare providers have not embraced this drug class due to its potential for causing corneal melts. In the late 1990s, a specific NSAID, generic diclofenac, was recalled due to a high percentage of patients developing corneal ulceration and melts.⁹ It was hypothesized that the active molecule was not causing the melts. Instead, it was believed that another ingredient used in the manufacturing of diclofenac was the causative agent.⁹ Case reports have reported no direct link between the use of NSAIDs and corneal melts. In a case report of 11 patients who developed corneal complications with NSAIDs, every patient had a history of ocular surgery and eight were using concomitant corticosteroid.⁸

Systemic conditions must be accounted for when prescribing NSAIDs. Remember to exercise caution in patients with:

• Bleeding disorders
• Known aspirin-induced asthma or sensitivity
• Delayed healing response
• Using blood thinners

The most common ocular side effects with topical NSAIDs are conjunctival injection and stinging.¹⁰ The stinging is transient and usually subsides within a few seconds to minutes.

NSAIDs should not be ruled out when considering dry eye treatment, especially with a severe steroid responder. Also, watch for new NSAID formulations to become available — one specifically (Bromfenac, ISTA Pharmaceuticals) is currently in phase III clinical trials.¹⁰

Use of Immunomodulators

Immunomodulators are drugs that alter the immune system by suppressing or exciting it. Restasis is an immunosuppressant that potentially decreases T-cell activation and subsequent inflammatory chemical mediators. It has been shown to effectively treat moderate to severe dry eye disease. Initially, it was approved for the treatment of reduced tear production (low Schirmer's score) due to ocular inflammation but other benefits aside from the FDA indication have been discovered, such as increased conjunctival goblet cell density and decreased immune activation markers.^12,13 Restasis is usually dosed b.i.d. OU and should not be used in patients with active ocular infection or a history of herpetic eye disease. The most common side effect of Restasis is burning upon instillation. One study examined patients that had an inadequate response to Restasis b.i.d OU for at least 4 months by increasing their frequency (off label) of the drug to 3-4 times daily.¹⁴ These patients were diagnosed with severe dry eye disease, such as Sjogren's syndrome (primary and secondary) or ocular graft versus host disease. The study concluded that mean corneal fluorescein staining scores improved (staining decreased) from baseline and the global physician assessment of dry eye status was favorable in 16 of 22 patients. There were no adverse effects other than burning. Irritation was noted in 3 of 22 patients. Another study compared differing concentrations of cyclosporine A (0.05% and 0.1%) for twice a day therapy in moderate to severe dry eye patients. The results for both concentrations had similar positive outcomes for dry eye disease, excellent safety profiles and no significant ocular or systemic adverse effects.¹⁵ In summary, Restasis has demonstrated excellent results with long-term use for the treatment of dry eye with very few adverse events.

Current Mainstream Treatments

In 2006, the Asclepius Panel met to decide treatment regimens and therapy initiations based on the Delphi Panel 2004 scales for dry eye. Their recommendations were to institute corticosteroids in conjunction with Restasis earlier (less severe dry eye) for long-term treatment and management (see chart at right). As you can see, starting a steroid (Lotemax) q.i.d OU for 2 weeks then tapering it and adding Restasis seems to be common treatment for moderate to severe dry eye. One of the reasons to start Lotemax initially is because it not only sequesters inflammation quickly, but one study discovered that pretreatment with Lotemax decreased stinging of Restasis by 75%.16

In clinic, when I have a dry eye patient that is insistent on leaving with a prescription for Restasis before instituting a steroid, I make an analogy to a sprained ankle or joint. If we can ice the joint and prevent future swelling and inflammation from setting in, then the recovery will be quicker and less painful. Patients usually relate to this analogy and are more willing to trust and accept advice for future treatments.

Take Home

Attacking dry eye with artificial tears is commonly accepted for patients with mild symptoms, mild conjunctival staining and no corneal staining. For patients with more severe signs or symptoms, initiating an aggressive treatment plan will increase your level of positive outcomes in patients with moderate to severe dry eye while minimizing adverse events.

References

1. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221-232.
2. Tsubota K, Fujihara T, Saito K, Takeuchi T. Conjunctival epithelium expression of HLA-DR in dry eye patients. Ophthalmologica. 1999;213(1):16-9.
3. Marsh P, Pfludgelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology. 1999;106(4):811-816.
4. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am J Ophthalmol. 2003;136(4):593-602.
5. Armaly MF, Becker B. Intraocular pressure response to topical corticosteroids. Fed Proc. 1965;24(6):1274-1278.
6. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol. 2004;138(3):444-457.
7. Abelson M, Sleeper A. Insights on anti-inflammatories. Review of Ophthalmology. June 2005.
8. Fan DS, Ng JS, Lam DS. A prospective study on hypertensive and anti-inflammatory response to different dosages of fluorometholone in children. Ophthalmology. 2001;108(11):1973-1977.
9. Flach AJ. Corneal melts associated with topically applied nonsteroidal antiinflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-10; discussion 210-212.
10. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. 2001;108(5):936-944.
11. A dose ranging study to evaluate safety and efficacy of bromfenac ophthalmic solution in dry eye disease. Available at: http://clinicaltrials.gov/ct2/show/NCT01212471?term=non-steroidal+antiinflammatory&cond=Dry+eye&rank=1; last accessed August 18, 2011.
12. Kunert KS, Tisdale AS, Gipson IK. Goblet Cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. 2002;120(3):330-337.
13. Brignole F, et al. Flow cytometric analysis of inflammmatory markers in KCS : 6-month treatment with topical cyclosporine A. Invest Ophthalmol Vis Sci. 2001;42(1):90-95.
14. Dastjerdi MH, Hamrah P, Dana R. High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea. 2009 Dec;28(10):1091-1096.
15. 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;107(4):631-639.
16. Sheppard J. Topical loteprednol pretreatment to reduce cyclosporine stinging. Paper presented at: Annual Meeting of the American Society of Cataract and Refractive Surgery; April 30-May 5, 2005; Philadelphia, Pa. Abstract 3984.

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Dr. Mayers is the founder of Mayers Eye Solutions, a private practice in Powell, Ohio. E-mail him at mayersod@gmail.com.