Efficacy of Switching from Cyclosporine A 0.05% Anionic Emulsion to Cyclosporine A 0.1% Cationic Emulsion in Patients with Dry Eye Associated with Sjögren's Syndrome

Abstract

Purpose:

To evaluate the clinical efficacy of switching from cyclosporine A (CsA) 0.05% anionic emulsion (CsA AE) to CsA 0.1% cationic emulsion (CsA CE) in patients with dry eye (DE) associated with Sjögren's syndrome (SS).

Methods:

Forty patients with SS-associated DE who were unresponsive to CsA AE for 6 months were enrolled. After baseline measurements, the CsA AE was switched to CsA CE. The ocular surface disease index (OSDI), Sjögren's International Collaborative Clinical Alliance (SICCA), and Schirmer's test scores and tear film breakup time (TBUT) were evaluated at baseline and 1 and 3 months after switching.

Results:

Two patients dropped out, and 38 were analyzed. OSDI and SICCA ocular staining scores were significantly reduced at 1 and 3 months after switching, compared with the baseline scores (all P < 0.01). Although no significant changes were noted in the corneal staining scores (CSSs), patients with higher baseline CSS (≥4) showed an improvement in the scores at 1 month (P = 0.03) and 3 months (P = 0.01) after switching. There were no significant changes in TBUT and Schirmer's test scores during the follow-up periods.

Conclusions:

In patients with SS-associated DE, switching from CsA AE to CsA CE was effective in improving ocular symptoms and conjunctival staining. In addition, corneal staining was decreased in patients with severe keratitis.

Introduction

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by the infiltration of lymphocytes into exocrine glands such as the sebaceous, sweat, salivary, and lacrimal glands.¹ This disease manifests with moderate-to-severe dry eye (DE) and dry mouth, and may accompany other systemic manifestations.² To relieve moderate-to-severe DE in SS by medical treatments, understanding the underlying mechanism of inflammation is important. Inflammation plays a key role in the pathogenesis of SS-associated DE (SS-DE).^1,3

Anti-inflammatory therapy, such as topical corticosteroids and cyclosporine A (CsA), provides several benefits, especially in the treatment of moderate-to-severe DE, when artificial tears are not sufficient.^4,5 CsA inhibits T cell activation and downregulates inflammatory cytokine levels in the conjunctiva and lacrimal glands.⁶ Topical CsA has been proven effective in improving symptoms of moderate-to-severe DE in many clinical trials.^7–10

A CsA 0.1% (1 mg/mL) cationic emulsion (CsA CE) is used to treat moderate-to-severe DE.^11,12 In contrast with CsA 0.05% anionic emulsion (CsA AE), CsA CE has a longer residence time and higher ocular bioavailability in the tear film over the entire anionic ocular surface.^11,13 Thus, it can improve the ocular delivery of CsA and enhance its immunomodulatory benefits. CsA CE could reduce corneal fluorescein staining and inflammatory marker levels as well as symptom scores in moderate-to-severe and severe DE.^4,14–16 Although the superiority of CsA CE over CsA AE in decreasing inflammation and apoptosis has been demonstrated in human epithelial cells, clinical studies comparing the efficacy of the two agents have not been performed.¹⁷ In this study, we aimed to evaluate the efficacy of switching to CsA CE from CsA AE in patients with SS-DE.

Methods

Patients diagnosed with SS-DE from March to September 2018 at the Department of Ophthalmology of Chonnam National University Hospital were enrolled in this prospective study at the point of switching from CsA AE to CsA CE. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards of Chonnam National University Hospital (CNUH 2020-093). Written informed consent was obtained from all subjects after an explanation of the purpose and study requirements.

Study population and designs

A total of 40 eyes of 40 SS-DE patients who were unresponsive to topical CsA AE (RESTASIS^®; Allergan, Inc., Irvine, CA) applied twice daily for at least 6 months before study enrollment and were switched to CsA CE (Ikervis^®; Santen SAS, Evry, France) applied once daily were included. Unresponsiveness was considered if (1) Sjögren's International Collaborative Clinical Alliance (SICCA) score was >5, and (2) persistent DE symptom was present after 6 months of CsA AE instillation. All subjects were instructed to continue the instillation of preservative-free artificial tears, 0.1% sodium hyaluronate (Hyalu mini 0.1%^®; Hanmi Pharm. Co., Seoul, Korea), 4–6 times daily according to the patient's needs. The diagnosis of SS was made according to the guidelines of the American College of Rheumatology and the European League Against Rheumatism SS diagnostic criteria revised in 2016.¹⁸ Recruited subjects met the following inclusion criteria: (1) ≥18 years and <60 years of age, (2) SICCA ocular staining score >5, and (3) positive DE symptoms, including eye fatigue, discomfort, and heaviness. The exclusion criteria for this study were as follows: (1) use of systemic or topical immunomodulators such as steroid and CsA and systemic medication that can affect tear production (pilocarpine, hormonal therapy, systemic NSAIDs, etc.) within 6 months, (2) a history of contact lens use, glaucoma, ocular infection, or inflammation, and (3) a history of ocular surgery or laser therapy within 6 months before study enrollment. The study consisted of 3 scheduled visits over 12 weeks (baseline, 1, and 3 months).

Outcome measurements

At each visit, the ocular surface disease index (OSDI) questionnaire, SICCA ocular staining score in the cornea (0–6) and the conjunctiva (0–6), tear film breakup time (TBUT), and Schirmer's test score were evaluated. For the analysis of SICCA ocular staining score, TBUT, and Schirmer's test score, the eye with worse SICCA ocular staining score was chosen. When both eyes had the same value, the right eye was chosen for analysis.

The OSDI questionnaire was used to quantify the symptoms of ocular irritation, vision-related quality of life, and environmental triggers. The total OSDI score, which ranged from 0 to 100, was analyzed.¹⁹

All clinical assessments were carried out by one blinded clinician (H.J.Y) in order of conjunctival and corneal staining, assessing TBUT, and performing Schirmer's test in a constant temperature (22°C–25°C) and humidity (40%–50%). Staining scores were evaluated according to the SICCA grading.²⁰ The double vital staining method using 1% preservative-free fluorescein (Alcon, Fort Worth, TX) and 1% preservative-free lissamine green (Leiter's Pharmacy, San Jose, CA) dye solutions was used.²¹ Conjunctival staining scores were determined for nasal and temporal bulbar conjunctiva separately. Each region was recorded quantitatively as 0–3 (0 = 0–9 dots, 1 = 10–32 dots, 2 = 33–100 dots, and 3 = more than 100 dots). The corneal staining score (CSS) was determined by punctate epithelial erosions (PEE) and scored as 0–6 (1 = 1–5 PEE, 2 = 6–30 PEE, 3 = more than 30 PEE), and an additional point was added if (1) PEE occurred in the central 4-mm diameter area of the cornea; (2) one or more filaments were seen anywhere on the cornea; or (3) one or more patches of confluent staining, including linear stains, were found anywhere on the cornea. The patients were subdivided into the higher baseline CSS group (≥4) and the lower baseline CSS group (<4) according to the severity of baseline staining in the cornea. The total ocular staining scores were calculated as the sum of the scores for each region.

TBUT was assessed using a moistened fluorescein strip (Haag-Streit, Koeniz, Switzerland), and the time interval between the last complete blinking and the first appearance of a dry spot or disruption of the tear film was recorded. The examination was repeated thrice, and the mean time was used for the analysis. Schirmer's test scores were measured using a calibrated sterile strip (Color Bar Schirmer's Tear Test; Eagle Vision, Inc., Memphis, TN) with topical anesthesia (0.5% proparacaine chloride). Sterile strips were placed in the lateral canthus away from the cornea, left for 5 min with the eyes closed. Schirmer's test scores were recorded in millimeters of wetting for 5 min.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences v23.0 for Windows (SPSS, Inc., Chicago, IL). All variables were tested for normality of distribution by the Shapiro–Wilk test. Data are presented as mean ± standard deviation. The paired t-test was used to compare changes in variables that satisfy normal distribution before and after treatment. P value <0.05 was considered statistically significant. The percentage of responders in OSDI (≥25% improvement) and CSS (≥2 grades) at 3 months were calculated to see the efficacy in individuals. Patients who dropped out of the study were considered nonresponders. Sample size calculation was based on the result of a previous study on the effect of CsA AE in moderate-to-severe DE.²²

Results

The baseline clinical characteristics of the subjects are summarized in Table 1. The data on the pretreatment state of CsA AE (initial state) was obtained reviewing the electronic medical records of the participants. The initial state values for OSDI score, TBUT, Schirmer's test score, total ocular staining score, CSS, and temporal and nasal conjunctival staining were 53.85 ± 22.63, 3.58 ± 0.96 s, 0.53 ± 1.09 mm/5 min, 8.03 ± 2.03, 3.43 ± 1.26, 2.23 ± 0.70, and 2.38 ± 0.77, respectively (Supplementary Table S1). After at least 6 months of treatment with CsA AE, there was a significant decrease in TBUT (P < 0.01), but not in OSDI score, Schirmer's test score, and corneal and conjunctival staining. All patients were diagnosed with SS in the department of rheumatology of our center and had positive antinuclear Ab and anti-SSA Ab. During the study, severe irritation was noted in one patient (2.5%), and a headache was noted in another patient (2.5%) within 1 week. They were instructed to stop eye drops instillation and were excluded from the study. A total of 38 patients were included in the follow-up study.

Table 1.

Baseline Characteristics of Patients with Dry Eye Associated with Sjögren's Syndrome

Characteristics	(N = 38)
Age, years	55.1 ± 8.4
Gender, M:F	1:37
BCVA, logMAR	0.02 ± 0.04
OSDI score	51.4 ± 17.8
TBUT, seconds	4.55 ± 1.13
Schirmer's test score, mm/5 min	4.82 ± 1.28
Total ocular staining score	7.55 ± 1.71
CSS	3.13 ± 1.40
Conjunctival staining score
Temporal	2.00 ± 0.68
Nasal	2.43 ± 0.71

All continuous variables are presented as mean ± standard deviation.

BCVA, best corrected visual acuity; CSS, corneal staining score; logMAR, logarithm of minimal angle of resolution; OSDI, ocular surface disease index; TBUT, tear film breakup time.

The mean OSDI score was 51.4 ± 17.8 at baseline, 47.1 ± 16.9 at 1 month, and 40.7 ± 14.5 at 3 months. Compared with the baseline, it significantly improved at 1 and 3 months after switching (both P < 0.01). ODSI score also showed a significant decrease at 1 and 3 months after switching compared with the initial state before CsA AE treatment (both P < 0.01). The SICCA ocular staining scores compared with baseline measurements are shown in Fig. 1. The total ocular staining score was 7.55 ± 1.71 at baseline and was significantly decreased at 1 month (6.95 ± 1.72, P < 0.01) and 3 months (6.35 ± 1.81, P < 0.01). The nasal conjunctival staining score was 2.43 ± 0.71 at baseline and was significantly decreased at 1 month (2.08 ± 0.76, P < 0.01) and 3 months (1.88 ± 0.72, P < 0.01). The temporal conjunctival staining scores were 2.00 ± 0.68 at baseline and 1.88 ± 0.69 (P = 0.09) at 1 month, and it significantly decreased to 1.58 ± 0.78 (P < 0.01) at 3 months (Fig. 2). All values regarding conjunctival staining were significantly decreased at 1 and 3 months after switching compared with the initial state (all P < 0.05). CSS at baseline, 1, and 3 months were 3.13 ± 1.40, 3.00 ± 1.26 (P = 0.20), and 2.90 ± 1.24 (P = 0.08), respectively. In the higher CSS group, CSS was significantly decreased at 1 month (4.33 ± 0.82, P = 0.03) and 3 months (4.07 ± 1.03, P = 0.01) after switching compared with baseline (4.73 ± 0.88). In contrast, no significant changes were noted in the lower CSS group at 1 month (2.20 ± 0.65, P = 0.71) and 3 months (2.20 ± 0.71, P = 0.75), compared with baseline (2.16 ± 0.37). When compared with the initial state, the CSS was significantly decreased at 3 months (P = 0.02), but not at 1 month (P = 0.07) after switching.

FIG. 1.

The ocular staining scores of the patients with DE associated with SS. Total ocular staining score improved from baseline at 1 and 3 months after switching from cyclosporine A 0.05% anionic emulsion to cyclosporine A 0.1% cationic emulsion (A). Conjunctival staining at the nasal conjunctiva improved at both 1 and 3 months, but the temporal conjunctival staining improved only at 3 months (B, C). CSS showed no significant change during the follow-up period (D). (*P < 0.05). CSS, corneal staining score; DE, dry eye; SS, Sjögren's syndrome.

FIG. 2.

The CSS in the patients with higher baseline CSS group showed a significant decrease in the score at 1 and 3 months after switching from cyclosporine A 0.05% anionic emulsion to cyclosporine A 0.1% cationic emulsion (A). However, patients with lower baseline CSS showed no significant change (B) (*P < 0.05).

TBUT values at baseline, 1, and 3 months were 4.55 ± 1.13, 4.80 ± 1.38 (P = 0.13), and 4.73 ± 1.66 (P = 0.42), respectively. The Schirmer's test scores were 4.82 ± 1.28, 4.75 ± 1.24 (P = 0.25), and 4.92 ± 1.33 (P = 0.31), respectively (Fig. 3). TBUT was significantly decreased at 1 and 3 months compared with pretreatment state of CsA AE (both P < 0.01), but not Schirmer's test scores (P = 0.57 and 0.21 at 1 and 3 months).

FIG. 3.

TBUT (A) and Schirmer's test scores (B) of the participants. There were no significant changes in the parameters at 1 and 3 months after switching from cyclosporine 0.05% anionic emulsion to cyclosporine 0.1% cationic emulsion.

The percentages of responders defined as ≥25% decrease in OSDI score and ≥2 decreases in CSS at 3 months were 35% (14/40) and 5% (2/40), respectively. CSS-responder percentage in the higher CSS group was 13% (2/15). The changes of OSDI and ocular surface staining in individuals at 1 and 3 months after switching are described in Supplementary Fig. S1.

Discussion

Inflammation in the lacrimal gland and ocular surface is a key factor in DE.^11,23 Topical CsA emulsions inhibit the production and release of proinflammatory cytokines, including interleukin (IL) 2 or T cell growth factor, and upregulate the release of anti-inflammatory cytokines.²⁴ The mechanism of action is primarily by inhibiting T lymphocytes and secondarily by inhibiting apoptosis in other cell types.²⁵ In a randomized double-masked phase 3 trial, DE patients treated with CsA AE instillation showed significantly greater improvement in blurred vision and punctate corneal fluorescein staining than vehicle-treated patients.⁷ CsA AE was also effective in reducing histocompatibility human leukocyte antigen-DR isotype gene (HLA-DR) levels on epithelial cells, which represents the level of inflammation.²⁶

However, patients with severe inflammatory DE such as SS-DE might have inadequate responses to twice-daily instillation of conventional CsA AEs. In SS-DE, lacrimal gland function is deteriorated by inflammatory activity within the gland. Those with severely deteriorated lacrimal gland function with irreversible damage may not respond to the conventional concentration of CsA AE. Accordingly, patients with a longer duration of SS might not properly respond to the treatment. SS-DE patients also have higher expression of HLA-DR and higher levels of IL-17, IL-4, and IL-10 in the tear film.^27–29 Inadequate response might be due to an increased inflammatory cytokine in the tear film. Systemic inflammation is suggested as the origin of ocular surface inflammation in SS-DE.³⁰ Patients who were using systemic anti-inflammatory agents were excluded from this study. Although the effect of systemic medication on secretory glands is controversial, the participants who were not using systemic medication would have been more difficult to control the inflammation on the ocular surface.

Dastjerdi et al.³¹ suggested increasing the frequency of CsA AE instillation in DE patients who experienced no improvement from the twice-a-day regimen and showed the effectiveness of more frequent use in their study. Daull et al.¹² showed that CsA CE was more effective than CsA AE in delivering CsA to target tissues of rabbit eyes. Unlike CsA AE, the electrostatic interactions between the positively charged droplets and negatively charged mucus proteins of the corneal epithelium give CsA CE longer residence time and higher ocular bioavailability than previous CsA formulations.^11–13 In systemic immunosuppression, CsA has a clear dose–response effect.³² However, topical CsA has failed to demonstrate clear dose–response relationships in phase II and III clinical trials.^7,8 The lack of additional therapeutic benefit with increasing concentration >0.05% has been overcome by changing the formulation into the cationic emulsion, making a higher concentration of topical CsA available for DE with higher inflammatory features, such as SS-DE.^23,31 Therefore, comparing the effect of different forms and concentrations of CsA eye drops is a clinically important issue.

In this study, after switching from CsA AE to CsA CE in patients with SS-DE, subjective OSDI scores significantly improved at 1 and 3 months. In addition, a significant improvement in ocular staining score was observed after CsA AE switching. The nasal conjunctival staining was improved at 1 and 3 months, and temporal conjunctival staining was improved at 3 months after switching. Although no changes were found in the CSS, the higher baseline CSS group showed a significant improvement in CSS at 1 and 3 months. TBUT and Schirmer's test scores showed no significant changes. The percentages of patients with ≥25% decrease in OSDI score and ≥2 grades decrease in CSS at 3 months compared with baseline were 35% and 5%, respectively. The ≥2 grades decrease in CSS was noted only in those with baseline CSS ≥4.

The more prominent improvement in conjunctival staining in the nasal conjunctiva at 1 month after switching can be explained by several assumptions. At baseline, the staining of the nasal conjunctiva was significantly higher than that of the temporal conjunctiva. This finding appears to be consistent with that of prior studies showing that the nasal conjunctiva showed greater staining than the temporal conjunctiva and cornea in patients with SS-DE.^33,34 This conjunctival staining distribution might be due to the longer exposure of the nasal conjunctiva, which is the route for tear drainage, to by-products of inflammation.^34,35 Similarly, the more prominent improvement in the nasal conjunctival staining may be attributed to the difference in the residence time of the drug on the ocular surface between the nasal and temporal conjunctiva.

Interestingly, the CSS was not significantly improved in our study. Previous studies demonstrated that CsA CE has the greatest benefit for keratitis in DE patients.^4,16,22,36 The SICCANOVE and SANSIKA were multicenter randomized double-masked parallel-group controlled studies conducted to assess the treatment effect of CsA CE in DE, moderate-to-severe DE, and severe keratitis patients, including SS patients.^22,36 The SICCANOVE study showed that CsA CE had the greatest treatment benefit in severe DE patients who had high corneal fluorescein staining (4 by modified Oxford scale).³⁶ In addition, the SANSIKA study showed that the use of CsA CE was associated with a significantly higher CSS response rate versus that of the vehicle.²² Additional analysis focused on the subsets of patients with higher CSS (≥4) was performed in this study. Significant improvement of CSS in the higher baseline CSS (≥4) group, but not in the lower baseline CSS (<4) group, at 1 and 3 months was noted. This result is consistent with that of previous studies that reported that CsA CE was effective in severe keratitis.

This study has several limitations. The sample size and the follow-up period may not be sufficient to prove the clinical significance of the results. The study was limited only to patients with SS-DE, not those with non-SS DE. A more detailed information on serology, inflammatory cytokines, and matrix metallopeptidase 9 in the tear film, and tear osmolarity would yield a higher quality outcome. Further studies with larger sample sizes and longer follow-up periods, including the comparison between SS-DE and non-SS DE, are needed. The unresponsiveness in the inclusion criteria was defined when patients complained of persistent DE symptoms and this may be a subjective measure. To see what kind of patients would not respond to either CsA AE or CsA CE, a controlled study with an objective measure of unresponsiveness such as a symptom questionnaire would be necessary. We only evaluated CsA AE among many other forms of 0.05% topical CsA, such as aqueous solutions and other types of emulsions. Other forms of 0.05% CsA might yield different results. There was no washout period. There may have been an additive effect from CsA AE, which was instilled before the instillation of the switched CsA CE. This 3-month study period exceeded the washout periods of other clinical studies; however, a longer follow-up period may provide more precise results. The instillation frequency was different before and after switching. When designing the protocol, we adopted the optimal frequency of instillation for each agent referring to previous clinical studies.^4,31 Although the direct comparison might be difficult between two agents due to instillation frequency, this study aims to see the effect of switching the agents as treated in actual clinical practice. The subgroup analysis was only carried out according to the CSS. Additional studies subdividing SS-DE patients according to nasal conjunctival epitheliopathy, OSDI, TBUT, and Schirmer's test results would be necessary. Despite these limitations, the strength of this study is that it is the first to identify the clinical effects of switching the therapy from CsA AE to CsA CE.

Conclusions

In patients with SS-DE who were not responsive to previous CsA AE treatment, switching to CsA CE could improve symptoms and conjunctival staining scores, which may also contribute to CSS improvement in cases of severe keratitis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Technology Innovation Program (20009481) funded by the Ministry of Trade, Industry and Energy, Republic of Korea, the Korea Health Technology R&D Project (HR20C0021050020) through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea, and the Chonnam National University Hospital Biomedical Research Institute (BCRI 20072).

Supplementary Material

References

Jonsson

, Vogelsang

, Volchenkov

, et al. The complexity of Sjögren's syndrome: novel aspects on pathogenesis. Immunol. Lett. 141:1–9, 2011.

Nguyen

C.Q.

, and Peck

A.B.

Unraveling the pathophysiology of Sjogren syndrome-associated dry eye disease. Ocul. Surf. 7:11–27, 2009.

Stern

M.E.

, Beuerman

R.W.

, Fox

R.I.

, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 17:584, 1998.

Leonardi

, Messmer

E.M.

, Labetoulle

, et al. Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies. Br. J. Ophthalmol. 103:125–131, 2019.

Foulks

G.N.

, Forstot

S.L.

, Donshik

P.C.

, et al. Clinical guidelines for management of dry eye associated with Sjögren disease. Ocul. Surf. 13:118–132, 2015.

Adler

, and Villiger

P.M.

Inhibitors of T cell activation in the treatment of Sjögren's syndrome. Curr. Treat. Options Rheum. 1:269–276, 2015.

Sall

, Stevenson

O.D.

, Mundorf

T.K.

, and Reis

B.L.

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. Ophthalmol. 107:631–639, 2000.

Stevenson

, Tauber

, and Reis

B.L.

Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology. 107:967–974, 2000.

Sall

K.N.

, Cohen

S.M.

, Christensen

M.T.

, and Stein

J.M.

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. 32:21–26, 2006.

10.

Roberts

C.W.

, Carniglia

P.E.

, and Brazzo

B.G.

Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea. 26:805–809, 2007.

11.

Lallemand

, Daull

, Benita

, Buggage

, and Garrigue

J.-S.

Successfully improving ocular drug delivery using the cationic nanoemulsion, novasorb. J. Drug Deliv. 2012:604204, 2012.

12.

Daull

, Lallemand

, Philips

, et al. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits. Cornea. 32:345–354, 2013.

13.

Daull

, Lallemand

, and Garrigue

J.-S.

Benefits of cetalkonium chloride cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery. J. Pharm. Pharmacol. 66:531–541, 2014.

14.

Pisella

P.-J.

, Labetoulle

, Doan

, et al. Topical ocular 0.1% cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program. Clin. Ophthalmol. 12:289–299, 2018.

15.

Boboridis

K.G.

, and Konstas

A.G.P.

Evaluating the novel application of cyclosporine 0.1% in ocular surface disease. Expert Opin. Pharmacother. 19:1027–1039, 2018.

16.

Baudouin

, de la Maza

M.S.

, Amrane

, et al. One-year efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease. Eur. J. Ophthalmol. 27:678–685, 2017.

17.

Hwang

S.-B.

, Park

J.H.

, Kang

S.-S.

, et al. Protective effects of cyclosporine A emulsion versus cyclosporine A cationic emulsion against desiccation stress in human corneal epithelial cells. Cornea. 39:508–513, 2020.

18.

Shiboski

C.H.

, Shiboski

S.C.

, Seror

, et al. ACR-EULAR Classification Criteria for primary Sjögren's Syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 69:35–45, 2017.

19.

Schiffman

R.M.

, Christianson

M.D.

, Jacobsen

, Hirsch

J.D.

, and Reis

B.L.

Reliability and validity of the Ocular Surface Disease Index. Arch. Ophthalmol. 118:615–621, 2000.

20.

Whitcher

J.P.

, Shiboski

C.H.

, Shiboski

S.C.

, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome International Registry. Am. J. Ophthalmol. 149:405–415, 2010.

21.

Yoon

K.-C.

, Mun

G.-H.

, Kim

S.-D.

, et al. Prevalence of eye diseases in South Korea: data from the Korea National Health and Nutrition Examination Survey 2008-2009. Korean J. Ophthalmol. 25:421–433, 2011.

22.

Leonardi

, Van Setten

, Amrane

, et al. Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial. Eur. J. Ophthalmol. 26:287–296, 2016.

23.

Stern

M.E.

, and Pflugfelder

S.C.

Inflammation in dry eye. Ocul. Surf. 2:124–130, 2004.

24.

Byun

Y.-S.

, Rho

C.R.

, Cho

, et al. Cyclosporine 0.05% ophthalmic emulsion for dry eye in Korea: a prospective, multicenter, open-label, surveillance study. Korean J. Ophthalmol. 25:369–374, 2011.

25.

Waldmeier

P.C.

, Zimmermann

, Qian

, Tintelnot-Blomley

, and Lemasters

J.J.

Cyclophilin D as a drug target. Curr. Med. Chem. 10:1485–1506, 2003.

26.

Kunert

K.S.

, Tisdale

A.S.

, Stern

M.E.

, Smith

J.A.

, and Gipson

I.K.

Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch. Ophthalmol. 118:1489–1496, 2000.

27.

Brignole

, Pisella

P.J.

, Goldschild

, De Saint Jean

, Goguel

, and Baudouin

Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest. Ophthalmol. Vis. Sci. 41:1356–1363, 2000.

28.

Tsubota

, Fukagawa

, Fujihara

, et al. Regulation of human leukocyte antigen expression in human conjunctival epithelium. Invest. Ophthalmol. Vis. Sci. 40:28–34, 1999.

29.

Lee

S.Y.

, Han

S.J.

, Nam

S.M.

, et al. Analysis of tear cytokines and clinical correlations in Sjögren syndrome dry eye patients and non-Sjögren syndrome dry eye patients. Am. J. Ophthalmol. 156:247–253.e1, 2013.

30.

Fujita

, Igarashi

, Kurai

, Sakane

, Yoshino

, and Takahashi

Correlation between dry eye and rheumatoid arthritis activity. Am. J. Ophthalmol. 140:808–813, 2005.

31.

Dastjerdi

M.H.

, Hamrah

, and Dana

High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea. 28:1091–1096, 2009.

32.

Babany

, Morris

R.E.

, Babany

, and Kates

R.E.

Evaluation of the in vivo dose-response relationship of immunosuppressive drugs using a mouse heart transplant model: application to cyclosporine. J. Pharmacol. Exp. Ther. 244:259–262, 1988.

33.

Yoon

K.-C.

, Im

S.-K.

, Kim

H.-G.

, and You

I.-C.

Usefulness of double vital staining with 1% fluorescein and 1% lissamine green in patients with dry eye syndrome. Cornea. 30:972–976, 2011.

34.

Begley

C.G.

, Chalmers

R.L.

, Abetz

, et al. The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest. Ophthalmol. Vis. Sci. 44:4753–4761, 2003.

35.

Pflugfelder

S.C.

, Tseng

S.C.G.

, Sanabria

, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 17:38, 1998.

36.

Baudouin

, Figueiredo

F.C.

, Messmer

E.M.

, et al. A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye. Eur. J. Ophthalmol. 27:520–530, 2017.

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