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Topical cyclosporine for dry eye

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Dr Hugh Bradshaw
BAppSc(Optom) GradCertOcTher
Heron Eyecare, Toowoomba QLD

 

Dry eye disease (DED) or keratoconjunctivitis sicca (KCS) as defined by the 2007 International Dry Eye Workshop is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.1

Significant improvements to evaporative DED treatment have emerged recently with BlephEx, IPL, Lipiflow and other products; however, treatment of other vital components of this multifactorial disease have either not progressed or are unavailable or inaccessible in Australia.

Aqueous deficient dry eye is separated into Sjögren’s-syndrome dry eye and non-Sjögren’s-syndrome dry eye. The mainstay treatment for both aqueous deficient dry eye diseases is artificial tear lubricants. Significant developments in artificial tear lubricants have aided treatment but severe aqueous deficiency particularly in Sjögren’s syndrome is usually a long, uncomfortable battle for the patient.

DED promotes inflammation of the ocular surface. The inflammatory cascade is activated and inflammatory mediators are released into the tears. The result is tear film instability and increased tear osmolarity: a cycle of activity.1 Topical steroids are highly effective at treating inflammation and improving ocular symptoms but long-term usage is not advised due to the well-known side-effects and immunosuppression.

Topical cyclosporine A (CsA) was approved by the US FDA in 2002 and released to market in 2003. It is currently unavailable in commercial form in Australia but as it is on the Optometry Board of Australia drug list for optometrists, it can easily be compounded via appropriate pharmacies.*

Topical CsA is an immunomodulator which improves tear secretion by reducing the suppression of tear production caused by inflammation.2 Indications for usage are aqueous deficient dry eye and ocular surface inflammation treatment.2 A recent systematic review and meta-analysis revealed twice-daily topical CsA resulted in significant improvements to: reflex tear production (Schirmer test without anaesthesia), tear break up time, goblet cell density, corneal fluorescein staining, and ocular surface disease index scores.

Interestingly, the findings of this review found topical CsA to be effective independent of the type of DED (aqueous deficient, evaporative, Sjögren’s syndrome and non-Sjögren’s syndrome). The understanding is that topical CsA reduces T lymphocyte-mediated inflammation which is related to both aqueous deficient and evaporative DED.3 The increase in goblet cell density may improve ocular surface health and tear film stability.

Long-term topical CsA use has been found to be well-tolerated for up to three years.3 Mild to moderate adverse effects have been found to be more common in CsA compared to control groups. The main concern regarding cyclosporine use is systemic absorption due to the side-effects of oral cyclosporine, notably nephrotoxicity and immunosuppression; however, topical CsA emulsion has been found to have no systemic blood levels after nine to 12 months of use with 0.05% twice daily.4

 

214-OL-figure-1

Figure 1. Mechanisms of dry eye9

 

Case report

 

A long-standing now 67-year-old female patient presented on 25 March 2014 with another episode of sore uncomfortable eyes, particularly with near fine work and air conditioning. She had a long history of dry eye disease, Salzmann’s nodular degeneration and nasal pterygia. Her left pterygium and Salzmann’s nodules had been removed three years prior to the appointment. Her systemic medications included hormone replacement therapy and antihypertensive medication. Previous treatment was intensive non-preserved Viscotears and pulsed topical steroid treatments (FML) during symptomatic inflammatory episodes.

Examination showed only trace corneal epithelial staining and meibomian gland dysfunction, but there was conjunctival redness and inflammation of the ocular surface. As these episodes were becoming increasingly regular, the decision to start compounded topical CsA 0.05% twice daily with her existing Viscotears artificial tear lubricants was made rather than another pulsed steroid treatment.

At one month review, symptoms had eased with the patient having ‘bad days’ only once or twice a week and she had reduced use of Viscotears to twice daily herself. At two months review, she reported only occasional sore eyes and examination showed reduced redness and ocular surface inflammation. At three month review, she reported her eyes to be ‘behaving well’ and continued both topical CsA 0.05% and Viscotears twice daily. The patient continued using topical CsA for another year and discontinued only due to compounding supply problems. In 2016, her right pterygium had progressed from the previous year and required removal.

Discussion

This case shows the successful role topical CsA plays in controlling ocular inflammation in dry eye disease and co-pathologies of the ocular surface. In this case, a patient was symptomatic daily prior to treatment and was asymptomatic after three months of treatment.

Inflammation has involvement in DED as previously discussed, but also in Salzmann’s nodular degeneration and pterygium.5,6 Post-pterygium surgery, topical CsA has been shown to reduce recurrence and to inhibit the proliferation of pterygia and normal Tenon’s capsule fibroblasts.7,8 Salzmann’s nodular degeneration most often occurs following chronic ocular surface disease involving the corneal epithelium. This results in high metabolic and proliferating activity of the epithelium so controlling chronic ocular surface disease should help prevent Salzmann’s nodular degeneration occurrence.5

In this case, using topical CsA to treat the primary dry eye condition also benefitted her Salzmann’s nodular degeneration and pterygium, or prevented pterygium recurrence. Inflammation of the ocular surface is a key factor in dry eye pathology. Topical CsA has been shown to effectively reduce T lymphocyte-mediated inflammation to manage DED. Importantly, CsA is effective not just for aqueous deficiency and inflammation, but also for evaporative DED as well.

* In every state except Queensland

 

1.  2007 Report of the International Dry Eye Workshop. The Ocular Surface 2007; 5: 65-204.

2.  RESTASIS (cyclosporine ophthalmic emulsion) 0.05% prescribing information.

3.  Wan KH, Chen LJ, Young AL. Efficacy and safety of topical 0.05% cyclosporine eye drops in the treatment of dry eye syndrome: a systematic review and meta-analysis. The Ocular Surface 2015; 13: 3: 213–225.

4.  Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin A during long-term treatment with cyclosporin A ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002; 18: 411-418.

5.  Eberwein P, Hiss S, Auw-Haedrich C, et al. Epithelial marker expression in Salzmann nodular degeneration shows characteristics of limbal transient amplifying cells and alludes to an involvement of the epithelium in its pathogenesis. Acta Ophthalmol 2010; 88: e184–e189.

6.  Anguria P, Kitinya J, Ntuli S, Carmichael T. The role of heredity in pterygium development. Int J Ophthalmol 2014; 7: 3: 563–573.

7.  Turan-Vural E, Torun-Acar B, Kivanc SA, Acar S. The effect of topical 0.05% cyclosporine on recurrence following pterygium surgery. Clin Ophthalmology 2011; 5: 1: 881–885.

8.  Hercules LA, Viveiros MM, Schellini SA, et al. Exposure of Tenon’s capsule fibroblasts of pterygium to cyclosporin 0.05%. Arg Bras Oftalmol 2006; 69: 831–834.

9.  2007 Report of the International Dry Eye Workshop. The Ocular Surface 2007; 5: 2: 85.



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