Dry eye disease (DED) is a complex, chronic and inflammatory condition. The Tear Film and Ocular Surface Dry Eye Workshop (TFOS DEWS) first introduced the concept of the “vicious circle of inflammation” as one of the key factors in the development of DED and included the term “ocular surface inflammation” in its definition.¹

The “vicious circle” — increased tear evaporation and hyperosmolarity, triggering inflammation at the ocular surface — is common across all subtypes of DED, and there are several external factors (examples: environmental stressors, topical drop toxicity, ocular inflammatory conditions) and internal factors (example: systemic inflammatory conditions) that can initiate it. Other ocular surface diseases, such as allergic conjunctivitis or anterior blepharitis, are also pro-inflammatory and may contribute to surface inflammation. Tear hyperosmolarity and expression of inflammatory mediators, such as matrix metalloproteinase-9 (MMP-9), on the ocular surface lead to apoptosis of surface epithelial cells and a decrease in density of goblet cells and mucin production; this further perpetuates the vicious circle of inflammation.

As our understanding of this complex condition increases, so do our available treatment options. Treatment with anti-inflammatory agents is strongly recommended because persistent inflammation can lead to alteration of the sensory pathways (specifically pain perception) on the ocular surface. Therefore, it is of utmost importance to treat the underlying pathology of DED and break the vicious circle of inflammation.

There is a broad classification of pharmacologic anti-inflammatory therapies for DED. Given the focused nature of this review, we present here those therapies that are more readily available for patient use.

GLUCOCORTICOIDS

Topical corticosteroids act via the glucocorticoid receptors and modulate the production of pro-inflammatory pathways. They suppress the synthesis and release of inflammatory cytokines, chemokines and MMP-9. They also induce apoptosis of lymphocytes on the ocular surface.

After just one week of therapy, topical prednisolone acetate was shown to improve both the signs and symptoms of DED. There is well-established efficacy for the use of topical corticosteroids in the short-term; however, long-term use may induce complications including ocular hypertension, cataractogenesis and increased risk of infectious keratitis.

Many treatment regimens involving topical prednisolone acetate have been studied, including variations from one to four times a day for two to four weeks depending on the severity of the DED signs and symptoms. Other studies have evaluated the use of medications such as fluorometholone or loteprednol etabonate, which may have less effect on IOP and an overall improved safety profile.² Pretreatment with topical corticosteroids while concurrently starting other topical therapies (such as cyclosporine-A) has also shown to be effective in rapidly improving corneal staining, conjunctival staining and symptoms of DED.³

The compounding of preservative-free prednisolone eye drops is also gaining popularity as a way to limit ocular surface toxicity.

Lastly, combination corticosteroid/antibiotic drops (loteprednol/tobramycin and dexamethasone/tobramycin) can be employed in cases with significant blepharitis and DED.

NONGLUCOCORTICOID IMMUNOMODULATORS

The anti-inflammatory properties of topical cyclosporine-A are attributed to its inhibition of T-cell activation, thereby preventing the release of inflammatory cytokines. Treatment with cyclosporine-A reduces multiple markers of inflammation and also normalizes tear osmolarity.⁴ It has anti-apoptotic effects on corneal epithelial cells as well, and studies have shown recovery of goblet cell density in the conjunctiva, thereby improving multiple tear film components.⁵ Currently, cyclosporine-A 0.05% is approved for use in DED; however, alternate strengths are available via compounding pharmacies, and newer vehicles for this medication are currently being investigated.

Tacrolimus is an immunomodulator that also inhibits T-cell activation and the subsequent release of inflammatory cytokines. Studies show benefit of this medication in cases refractory to treatment with cyclosporine-A.⁶ It is currently available as an ointment for skin application, with some studies reporting off-label use on the ocular surface. It can also be compounded into an eye drop form for use on the ocular surface.

NSAIDs block cyclooxygenase and the prostaglandin pathway of inflammation but have also been found to reduce ocular discomfort in patients with DED.⁷ Most studies have evaluated NSAIDs in the short term, and caution is suggested in patients with reduced corneal sensitivity due to some reports of corneal melting. Lastly, it should also be avoided in patients who are pregnant or breastfeeding and in patients with history of herpetic uveitis.

LFA-1 ANTAGONISTS

These are among the newest topical immunomodulators introduced for use in DED.

Antagonists inhibit binding between LFA-1 and ICAM-1 (intercellular adhesion molecule 1), which are expressed on epithelial cells, and is a critical step in T-cell activation.

Lifitegrast 5% is indicated for both the signs and symptoms of DED, with studies showing improvement in both corneal and conjunctival staining as well as improvement in ocular surface disease index scores.^8,9

SYSTEMIC AND TOPICAL ANTIBIOTICS

Tetracycline antibiotics, and analogues minocycline and doxycycline, have both antibiotic and anti-inflammatory properties. The anti-inflammatory effect is attributed to decreasing collagenase, phospholipase, MMPs and inflammatory mediators on the ocular surface, especially in those patients with significant meibomian gland dysfunction and ocular rosacea.

Multiple dosing regimens and schedules have been studied, including high dose with quick taper and lower dose for long-term use.

Common side effects include gastrointestinal (GI) upset and photosensitivity, and patients with antibiotic sensitivities may not be good candidates for these medications.

MACROLIDES

Azithromycin controls bacterial over-growth, increases meibomian gland epithelial cell function and has anti-inflammatory properties for the eyelids. It can be prescribed as a topical drop or an oral medication. A common side effect of the oral formulation is GI upset.

DIETARY SUPPLEMENTATION

The essential fatty acid omega-3 and its derivatives can limit the activation of the pro-inflammatory arachidonic acid pathway. This is of benefit in mediating ocular surface inflammation in DED.

Although the literature on the validity of oral supplementation of omega-3s is mixed, patients should be counselled on the benefits of a healthy diet incorporating essential fatty acids.

CONCLUSION

Anti-inflammatory therapies address the underlying source of DED pathology. The selection of an appropriate anti-inflammatory therapy should be based on many factors, including severity of symptoms, determination of primary subtype of DED, patient compliance and financial burden for patients.

Rather than waiting to initiate anti-inflammatory treatment until signs and symptoms of DED are severe, we recommend that it be considered earlier in a patient’s treatment algorithm. OM

REFERENCES

1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15(3):276-83.
2. McGhee CN, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids: benefits and risks. Drug Saf 2002;25(1):33e55.
3. Sheppard JD, Donnenfeld ED, Holland EJ et al. Effect of loteprednol etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 0.05%. Eye Contact Lens 2014;40(5):289e96.
4. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000;118(11):1489e96.
5. Pflugfelder SC, De Paiva CS, Villarreal AL, et al. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea 2008;27(1):64e9.
6. Sanz-Marco E, Udaondo P, García-Delpech S, et al. Treatment of refractory dry eye associated with graft versus host disease with 0.03% tacrolimus eyedrops. J Ocul Pharmacol Ther 2013;29(8):776e83.
7. Singer DD, Kennedy J, Wittpenn JR. Topical NSAIDs effect on corneal sensitivity. Cornea 2015;34(5):541e3.
8. Sheppard JD, Torkildsen GL, Lonsdale JD, et al. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology 2014;121(2):475e83.
9. Tauber J, Karpecki P, Latkany R, et al. Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology 2015;122(12):2423-2431.

About the Authors

Dr. Starr is an associate professor of ophthalmology, director of the refractive surgery service, director of ophthalmic education and co-director of the cornea fellowship program at Weill Cornell Medicine.

Dr. Brissette is an assistant professor of ophthalmology and member of the cornea, cataract and refractive surgery service at Weill Cornell Medicine.

Drs. Starr and Brissette are co-directors of the Ocular Surface & Dry Eye Center at Weill.