Evaluation of Corneal Morphologic and Functional Parameters After Use of Topical Cyclosporine-A 0.05% in Dry Eye

Abstract

Purpose:

To report the effect of topical Cyclosporine-A (CsA) 0.05% on corneal morphologic and functional parameters in patients with dry eye.

Method:

In this prospective and observational study 30 eyes of 30 patients who received topical CsA 0.05% for treatment of dry eye were evaluated. Each clinical examination included a routine Schirmer I test and tear film break-up time (TBUT) was performed at baseline and after 1, 2, 3, and 6 months of treatment. All participants also underwent central corneal thickness (CCT) measurements with ultrasound pachymetry, endothelial cell density (ECD) with specular microscopy, corneal topographical evaluation with Orbscan II, and corneal biomechanical parameters with Ocular Response Analyzer measurements at baseline and after treatment.

Results:

The Schirmer I test and TBUT were significantly improved after treatment (for both; P<0.01). The CCT, topographical findings, ECD, and corneal biomechanical parameters were not significantly different at baseline and follow-up visits (P>0.05). No serious adverse effects were seen at follow up visits.

Conclusion:

The study showed that Topical CsA 0.05% caused no changes on corneal morphology and function.

Introduction

Cyclosporine-A (CsA) is an immunomodulatory agent that primarily suppresses activation and proliferation of T cells. Systemic CsA has been used successfully in solid organ transplantation, treatment of autoimmune diseases, and noninfectious uveitis. Topical CsA with various formulations has been used with an increasing number of ocular surface disorders since 1980s. CsA is commonly used as a steroid-sparing immunosuppressive agent that has been used topically with variable success for various inflammatory ocular conditions, including dry eye, subepithelial infiltrates after adenoviral keratoconjunctivitis, vernal keratoconjunctivitis, corneal graft rejection, atopic keratoconjunctivitis, and graft-versus-host disease.^1–7

The role of inflammation in the pathogenesis of dry eye has been elucidated over the past decade. A decrease in tear production causes chronic inflammation on the ocular surface. This inflammatory response leads to further inflammatory cell infiltration on the ocular surface, increased expression of adhesion molecules and inflammatory cytokines, an increased level of inflammatory cytokines in the tear fluid, and an increased activity of matrix metalloproteinases in the tear fluid and corneal epithelium and increased apoptosis in the ocular surface epithelium. These inflammatory mediators lead to reduced ocular surface sensitivity and secondarily decrease sensory-stimulated reflex tearing. This results in a self-perpetuating cycle of chronic inflammation and continual decrease in tear production.^8–10

A cyclosporine 0.05% ophthalmic emulsion (Restasis; Allergan, Irvine, CA) was approved by the United States Food and Drug Administration for treatment of dry eye syndrome in 2003. Topical cyclosporine blocks T-cell activation and secondarily inhibits the inflammatory process. This leads to an increase in the quality and quantity of tears and decreases the damage to lacrimal gland tissue and the ocular surface.^11–13

To the best of our knowledge, we are unaware of studies that investigate whether cyclosporine therapy in dry eye has any effect on corneal parameters. The aim of this study was to evaluate the safety of topical CsA on corneal morphologic and functional properties.

Methods

Study population and design

This prospective and observational study was performed at the Beyoglu Eye Research and Education Hospital. The study followed the tenets of the Declaration of Helsinki and was approved by the local ethics committee. All participants received oral and written information about the study, and each participant provided written informed consent.

The main inclusion criteria for enrollment were age >18 years; a diagnosis of dry eye disease based on the presence of dry eye disease symptoms, Schirmer I (without anesthesia) scores below 10 mm/5 min, and tear film break-up time (TBUT) below 10 s. One drop of CsA 0.05% (Restasis^®; Allergan, Inc., Irvine, CA) was applied twice daily as monotherapy in each eye for 6 months. New treatments, including any eye drops or punctal plug, were not added after enrollment.

Exclusion criteria for the study were history of systemic or ocular diseases (including ocular surgery and trauma), use of systemic or ophthalmic medications (including artificial tears), and women who were pregnant, planning a pregnancy, or lactating.

Study measurements

The study comprised a baseline visit and 3 follow-up visits after 1, 3, and 6 months of treatment. Each clinical examination included best-corrected visual acuity using a Snellen chart, intraocular pressure (IOP) measurement by a Goldmann applanation tonometer (IOP_GAT), biomicroscopy of the anterior segment, the Schirmer I test, TBUT, and dilated fundus examination.

Study participants underwent central corneal thickness (CCT) measurements with ultrasound pachymetry (DGH-550, DGH Technology, Inc., Exton, PA), endothelial cell density (ECD) with specular microscopy, corneal topographical evaluation with Orbscan II (Bausch & Lomb Laboratories, Inc., Rochester, NY), and corneal biomechanical parameters with Ocular Response Analyzer measurements (Reichert Ophthalmic Instruments, Buffalo, NY).

Main outcome measures

The main outcome measures were the Schirmer I test, TBUT, corneal topographical parameters, corneal biomechanical parameters, ECD, and IOP measurement.

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 16. The right eye of each participant was used for analyses in the study. The normality of the data was confirmed using the Shapiro–Wilk Test (P>0.05). The 2-paired t-test was used to compare the study measurements at baseline and 3 follow-up visits after 1, 3, and 6 months of CsA treatment. Differences with a value of P<0.05 were considered statistically significant.

Results

In this prospective and observational study, 30 eyes of 30 patients were evaluated. The mean±standard deviation age of 22 women and 8 men were 46.4±8.6 years.

Tear film break-up time and Schirmer test

The baseline Schirmer I Test was 5.6±3.6 mm (range, 1 to 10), while the corresponding score after 6 months of treatment was 9.3±5.8 mm (4 to 18) (P=0.001). The TBUT before and after treatment was 3.3±1.5 (range, 1 to 6) and 5.8±3.1 (range, 1 to 15), respectively (P<0.001).

Corneal topographical findings

The Orbscan findings of patients at baseline after treatment are seen in Table 1. The thinnest pachymetries, Keratometry values (K₁ and K₂) and Surface asymmetry index were not significantly different at baseline and follow-up visits (P>0.05).

Table 1.

Corneal Topographical Parameters Measured with Orbscan Before and After Treatment

	Baseline	1 month	3 months	6 months
K₁, D
Mean±SD	43.8±2.2	43.5±2.1	43.3±2.3	43.7±2.2
Range	(39.5–47.6)	(39.4–46.9)	(39.5–47.5)	(39.6–47.4)
P^a		0.834	0.599	0.538
K₂, D
Mean±SD	44.6±2.2	44.3±2.1	44.1±2.1	44.5±2.1
Range	(40.5–47.9)	(40.3–47.8)	(40.4–47.7)	(40.3–47.9)
P^a		0.388	0.670	0.924
SAI
Mean±SD	0.56±0.44	0.69±0.63	0.54±0.46	0.56±0.40
Range	(0.19–2.34)	(0.05–2.54)	(0.10–1.86)	(0.09–1.80)
P^a		0.632	0.828	0.624
Thinnest CT, μm
Mean±SD	540±27	534±34	537±37	535±45
Range	(486–584)	(462–599)	(479–634)	(435–634)
P^a		0.241	0.259	0.592

The 2-paired t-test.

CT, corneal thickness; K, central keratometry; SAI, surface asymmetry index; SD, standard deviation.

Biomechanical parameters

The corneal biomechanical parameters of patients at baseline after treatment are seen in Table 2. The corneal hysteresis (CH) and corneal resistance factor (CRF) were not significantly different at baseline and follow-up visits (P>0.05).

Table 2.

Biomechanical Parameters Measured with Ocular Response Analyzer Before and After Treatment

	Baseline	1 month	3 months	6 months
CH, mmHg
Mean±SD	10.9±1.8	11.2±1.8	11.2±1.5	11.0±1.3
Range	7.0–14.1	7.7–14.0	8.8–14.0	8.0–13.5
P^a		0.194	0.190	0.295
CRF, mmHg
Mean±SD	10.4±1.7	10.5±1.4	10.7±1.4	10.6±1.4
Range	6.0–13.3	7.4–13.3	7.5–13.1	7.4–13.6
P^a		0.288	0.150	0.122

The 2-paired t-test.

CH, corneal hysteresis; CRF, corneal resistance factor.

CCT and ECD

CCT measured with ultrasonic pachymetry and endothelial cell counts determined by specular microscopy are shown in Table 3. The CCT and ECD were not significantly different at baseline and follow-up visits (P>0.05).

Table 3.

Endothelial Cell Density Measured with Specular Microscopy and Central Corneal Thickness Measured with Ultrasonic Pachymeter Before and After Treatment

	Baseline	1 month	3 months	6 months
ECD
Mean±SD	2414±88	2395±75	2413±89	2397±88
Range	2251–2666	2284–2543	2163–2550	2282–2615
P^a		0.178	0.677	0.610
CCT_USG, mm
Mean±SD	549±44	552±38	547±48	551±34
Range	452–603	467–617	402–602	488–602
P^a		0.327	0.889	0.251

The 2-paired t-test.

ECD, endothelial cell density; CCT, central corneal thickness.

Intraocular pressure

Table 4 summarizes the IOP values measured with the ocular response analyzer (ORA) (IOPcc and IOPg) and Goldmann applanation tonometer (IOP_GAT) at baseline and follow-up visits. The IOP_GAT, IOPcc, and IOPg were not significantly different at baseline and follow-up visits (P>0.05).

Table 4.

Intraocular Pressure Measurements Measured with Ocular Response Analyzer and Goldman Applanation Tonometer Before and After Treatment

	Baseline	1 month	3 months	6 months
IOP_GAT, mmHg
Mean±SD	14.1±2.3	13.2±2.4	13.4±3.2	13.3±2.4
Range	(10–18)	(10–18)	(6–18)	(8–20)
P^a		0.148	0.257	0.258
IOPg, mmHg
Mean±SD	13.7±3.4	13.4±4.0	14.3±4.2	14.7±3.9
Range	(7.9–19.1)	(7.25–21.8)	(6.2–22.1)	(6.9–25.1)
P^a		0.511	0.592	0.447
IOPcc, mmHg
Mean±SD	13.9±3.8	13.5±4.7	14.1±4.6	14.3±4.3
Range	(7.9–22.7)	(5.4–22.7)	(5.7–23.4)	(7.5–26.8)
P^a		0.172	0.863	0.426

The 2-paired t-test.

IOP, intraocular pressure; IOP_GAT, IOP measured with Goldmann applanation tonometer; IOPg, Goldmann-related intraocular pressure; IOPcc, corneal compensated intraocular pressure.

Discussion

Consideration of corneal parameters is important in many ophthalmological practices. For example, CCT is important for assessment of intraocular pressure measurement and preoperative LASIK examinations; ECD is considered when planning cataract surgery or refractive lens surgery, and also corneal biomechanical evaluation may be helpful for preoperative screening of refractive surgery candidates, the avoidance of a misinterpretation of the IOP and the differentiation of healthy corneas from abnormal corneas.^14–16 Precise assessment of these parameters is required for appropriate management of patients, so that any factors that affect corneal parameters should be known by clinicians. Previously, many published studies have reported the effect of topical medications on corneal parameters. Price et al. evaluated the effect of gatifloxacin ophthalmic solution 0.3%, and they found that gatifloxacin 0.3% ophthalmic solution did not significantly affect ECD or morphology.¹⁷ Ornek et al. reported that brinzolamide may cause a short-term increase in the human CCT, particularly on the first day.¹⁸ Montero et al. evaluated the effect of topical anesthetics on intraocular pressure and pachymetry. They found that the instillation of topical anesthetics causes a significant reduction in IOP, whereas no statistical significant difference in CCT before and after topical tetracaine chlorohydrate and oxybuprocaine chlorohydrate application.¹⁹ Grüb et al. evaluated the effect of timolol on CCT and ECD. They found that timolol has no effect on ECD.²⁰ Hatanaka et al. indicated that topical therapy with prostaglandin analogs and bimatoprost is associated with CCT reduction over a period of at least 8 weeks.²¹ Rosa et al. found that oxybuprocaine eye drops do not appear to induce a significant corneal swelling and do not affect the measurements when comparing CCT measured with optical or ultrasound devices.²² Grueb et al. found that topical administration of brimonidine 0.1% results in a reversible increase in corneal thickness.²³ Donaldson et al. investigated the effects of moxifloxacin on the cornea of normal human eyes using confocal microscopy and slit-lamp biomicroscopy. They found that moxifloxacin causes no significant epithelial or endothelial toxicity, and has no effect on ocular surface integrity in healthy subjects.²⁴ Ehongo et al. evaluated the effect of topical corneal anesthesia on CH, CRFand IOPg, and IOPcc was measured by ORA. They found no statistical significant difference in these parameters before and after topical oxybuprocaine 0.4% application.²⁵

Cyclosporine ophthalmic solution has previously been reported to be effective for a number of ocular surface conditions. It has been approved by the United States Food and Drug Administration for treatment of moderate to severe dry eye disease. Our study suggested that topical cyclosporine 0.05% treatment provided improvements in Schirmer test results and TBUT scores in patients with dry eye as reported by other studies.^26,27 The CsA likely passes into the corneal epithelium through the tear film and limbus. After topical application of 0.5% CsA, the amount of CsA in the epithelium has been detected to be very high. Among the 3 corneal tissues, epithelium has the highest CsA concentration, followed by endothelium and stroma. It has been also reported that the CsA has poor penetration into the anterior chamber.²⁸ The reported side effects of topical CsA are intense stinging, blurred vision, allergic reaction to oil solvent or CsA itself, tearing, and toxic keratitis.^29–34 Kachi et al. reported a patient who developed bilateral corneal opacities 5 days after beginning topical 2% cyclosporine.³⁵

Although topical CsA has been reported as an excellent safety profile, there have been no studies that evaluate the effect of topical CsA on corneal parameters. In this study, we evaluated the corneal topographical findings using Orbscan, corneal biomechanical parameters using ORA, CCT using ultrasonic pachymetry, and ECD using specular microscopy at baseline and after CsA treatment in patients with dry eye. We found that changes of these corneal parameters were not significant after 1, 3, and 6 months of CsA therapy.

In summary, topical CsA has increasingly gained worldwide popularity in patients with dry eye. This clinical study showed that the administration of Topical CsA 0.05% caused no significant change in corneal topographical findings, corneal biomechanical parameters, CCT, and corneal ECD in patients with dry eye.

Footnotes

Author Disclosure Statement

Financial disclosures: The authors have no financial interest in any of the materials or equipment used in the study.

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