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Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study Bernardo Kaplan Moscovici a,b,∗ , Ricardo Holzchuh a,b , Fernando Eiji Sakassegawa-Naves a,b , Diego Ricardo Hoshino-Ruiz a,b , Marcos Bottene Villa Albers a,b , Ruth Miyuki Santo a , Richard Yudi Hida a,b a Department of Ophthalmology, University of São Paulo, School of Medicine (Hospital das Clínicas of da Universidade de São Paulo-São Paulo – HC-USP), Brazil b Department of Ophthalmology, Santa Casa de São Paulo, Brazil

a r t i c l e

i n f o

Article history: Received 14 December 2014 Received in revised form 14 April 2015 Accepted 14 April 2015 Keywords: Keratoconjunctivitis sicca Sjogren’s syndrome Tacrolimus

a b s t r a c t Objective: To describe the clinical efficacy of the treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop. Design: Prospective double-blind randomized study. Setting: Institutional outpatient clinic. Participants: Forty-eight eyes of twenty-four patients with dry eye related to Sjögren syndrome were enrolled in this study. The patients were randomized in 2 groups: tacrolimus (n = 14) and vehicle (n = 10) group. Intervention: The tacrolimus group received a vial containing tacrolimus 0.03% (almond oil as vehicle) and the other group received the almond oil vehicle. All patients were instructed to use the eye drops every 12 h in the lower conjunctival sac. Main outcome measures: Schirmer I test, break-up-time (BUT), corneal fluorescein and Rose Bengal staining scores were evaluated in all patients one day before the treatment (baseline), 7, 14, 28 and 90 days after treatment with the eye drops. Results: The average fluorescein and Rose Bengal scores improved statistically after 7 days of treatment and even more after 90 days. The average Schirmer I and BUT values were unchanged after 7, 14 and 21 days but did show an improvement relative to baseline after 28 days of treatment. Schirmer I, BUT, fluorescein and Rose Bengal did not show any statistical significance in the vehicle group. Conclusion: Topical 0.03% tacrolimus eye drop improved tear stability and ocular surface status in cases of inflammatory or SS-related dry eye. Trial registration: ClinicalTrials.gov Identifier: NCT01850979. © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction Aqueous deficient dry eye is mainly caused by Sjögren’s syndrome (SS), an autoimmune, chronic, inflammatory and systemic disease that most commonly affects the lacrimal and salivary glands. The hyperreactivity of B lymphocytes causes lymphoplasmacytic infiltration, which induces production of antibodies against antigens of the acinar epithelium and ducts of the exocrine lacrimal gland [1–3]. In moderate and severe cases, ocular treatment is focused on increasing lubrication and decreasing

∗ Corresponding author at: Rua Apiacas 600 apto 84, São Paulo, SP 05017020, Brazil. Tel.: +55 11 996140730; fax: +55 11 996140730. E-mail address: [email protected] (B.K. Moscovici).

inflammation with topical autologous serum, topical immunosuppressive agents, and corticosteroid therapy [1–3]. Use of topical non-steroidal immunosuppressant has increased in recent years because topical corticosteroid therapy leads to ocular complications [1–5]. The most commonly used topical immunosuppressants in ophthalmology are tacrolimus (also known as FK506) and cyclosporine A (CsA). Their mechanisms of action are similar, but FK 506 is 10–100 times more potent than CsA. Tacrolimus is a macrolide with immunomodulatory action that was isolated from Streptomyces tsukubaensis fermentation and becomes biologically active only when it binds to immunophilin. Tacrolimus (FK506) inhibits calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis [6–12]. Generally, tacrolimus suppresses the immune

http://dx.doi.org/10.1016/j.clae.2015.04.004 1367-0484/© 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Moscovici BK, et al. Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.04.004

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response by inhibiting the release of other inflammatory cytokines (e.g., IL-3, IL-4, IL-5, IL-8, interferon-alpha, and tumor necrosis factor-alpha) [13–16]. Systemic and topical use of tacrolimus is established in ophthalmologic treatments of immune-mediated diseases [6,14,17–22], uveitis [23,24], graft-versus-host disease [25,26], corneal transplants [8,27–30], and ocular pemphigoid [31]. In veterinary medicine, topical tacrolimus aqueous suspension is a wellestablished treatment for dry eye in dogs [32,33]. In humans, tacrolimus eye drops were reported to be effective in treating severe keratoconjuctival allergy [6,17,19]. Our group previously reported the clinical outcomes of a case series of eight patients with dry eye using 0.03% tacrolimus eye drops [5] based on evidence in treating animals with keratoconjunctivitis sicca (KCS). The effectiveness of tacrolimus is likely to result from a combination of local immunosuppression, proliferation of goblet cells, suppression of lacrimal cell apoptosis, as well as its anti-inflammatory effect. This report describes a prospective controlled double-blinded randomized study of the efficacy of 0.03% tacrolimus eye drops in SS dry eye patients.

2. Methods This prospective controlled double-blind randomized study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board/Ethics Committee of the “Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP)” (Comissão de Ética para Análise de Projetos de Pesquisa – CAPPesq) under protocol number 1307/09 (ClinicalTrials.gov Identifier: NCT01850979). Informed consent was obtained from all participants after the nature and possible consequences of the study had been explained in detail. This study was performed at the outpatient clinic of the Department of Ophthalmology, School of Medicine, University of São Paulo (USP) (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Forty-eight eyes of 24 patients with dry eye (50.5 ± 9.65 years) related to SS, diagnosed by a qualified rheumatologist and an ophthalmologist (following the European criteria) were enrolled in this study [2,34]. All patients enrolled in our study fulfilled the following criteria: (1) SS was diagnosed according to the SS European Criteria [2,34]; (2) chronic symptoms of burning, foreign body sensation, itching in both eyes; (3) daily need of artificial tears; (3) abnormal Schirmer (ST) I test < 5 mm or Rose Bengal staining (RBS) ≥ 4, using van Bijsterveld score [2,35], or break-up-time (BUT) < 5 s in any eye. Patients with (1) any structural abnormalities (lid scarring, entropion, trichiasis, etc.); (2) any inflammation or active structural changes in the iris or anterior chamber; (3) glaucoma; (4) previous eye surgery or punctual occlusion; (5) use of any topical medication other than artificial tears; (6) any systemic or topical antibacterial or anti-inflammatory drug treatment 90 days before study entry; (7) contact lens wearers; (8) the presence of any corneal infection; (9) any corneal diseases (marginal ulcer, opacity, scar, bullous keratopathy, conjunctivochalasis, symblepharon or tumors); (10) pregnancy; (11) changes in immunosuppressive systemic therapy 90 days before study entry were excluded from the study. After analyzing carefully all inclusion and exclusion criteria to avoid and minimize intrinsic/extrinsic bias, 24 patients were found to be eligible for this study (out of 289 patients for our outpatient clinic). Sampling calculation was based on previous pilot study and statistical analysis using WINPEPI program with COMPARE2 module (Version 2.68) to avoid sampling error. To obtain 2.8 mm of difference in Schirmer values between these two groups (vehicle × intervention) and considering 90% power and 0.05

Table 1 baseline severity data for control group and study group. Baseline data

Control group (n = 10)

Fluorescein Rose Bengal Schirmer Break-up-time

1.60 2.50 3.21 2.46

a

± ± ± ±

0.94 0.83 1.93 3.37

Study group (n = 14) 3.25 3.75 5.28 3.75

± ± ± ±

1.84 1.51 3.63 4.02

p 0.0028a 0.0028a 0.0152a 0.3898

The statistically significant data.

significance, 20 eyes were necessary in each group. However, sampling size was increased in 10% in study group because of possible follow-up loss [5]. The patients were randomized in the tacrolimus group (T) (n = 14) or vehicle group (P) (n = 10) (three patients did not make proper follow-up) unequally by double-blinded investigator (R.H.) and a monitoring committee (institutional review board advisor). Randomization was performed using opaque envelopes containing sealed bottles. Both groups received these sealed bottles and the examiner was masked to the group assignment. The T group bottle contained tacrolimus 0.03% (almond oil as vehicle without preservative) and the P group received the almond oil vehicle alone without preservative (Ophthalmos, São Paulo, Brazil). All patients were masked and instructed to administer the eye drops to the lower conjunctival sac every 12 h (twice a day). The administration of any other topical drug was not allowed during the study period. All measurements were performed by the same masked examiner (B.K.M.) under conditions of controlled temperature (19.98 ± 1.27 ◦ C) and humidity (64.23% ± 5.06%). The Schirmer I test (without anesthesia), BUT, corneal fluorescein and Rose Bengal staining scores were evaluated in all patients one day before treatment (D0), 7 (D7), 14 (D14), 28 (D28), and 90 (D90) days after commencement of eye drop treatment. The BUT, Rose Bengal and fluorescein scores were examined by instilling 3 ␮L of a preservative-free combination of 1% Rose Bengal and 1% fluorescein into the conjunctival sac according to the double vital staining method described by Toda and Tsubota [36]. The BUT was measured three times and averaged. The ocular surface staining score was rated from 0–3 (0 = no staining; 1 = mild staining; 2 = moderated staining; and 3 = extensive staining) according to the method of Toda and Tsubota [36]. Schirmer I test was performed using a Whatman 41 paper strip (Ophthalmos, São Paulo, Brazil) placed in the lateral lower conjunctival sac, and the measurement was recorded after 5 min (at least 30 min after BUT and staining scoring) without topical anesthesia. Baseline severity data are shown in Table 1. Most severe cases of dry eye included in the control group were not eligible to continue in the study and was suggested to stop placebo medication by our Institutional Review Board and Medical Ethics Committee. Data were expressed as means ± SD. The Mann–Whitney U test was used to compare the results. In all analysis, P < 0.05 was taken to indicate statistical significance for each time interval of 7, 14, 28 and 90 days. The patients were asked about the outcomes of dry eye symptoms (dryness and burning sensation) by the examiner during the follow-up in both groups for safety reasons. All patients were also questioned regarding any ocular symptoms related to the eye drops at all visits. 3. Results The patients were recruited, received treatment and the data were analyzed in 2010. The trial ended after 3 months of examination of all patients. None of the patients from the study group were excluded from this study. The average fluorescein scores improved significantly in the T group from 3.25 ± 1.84 to 1.93 ± 1.33 after 7 days of

Please cite this article in press as: Moscovici BK, et al. Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.04.004

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treatment (p = 0.008) and even more after 90 days (0.96 ± 1.07; p < 0.0001). All fluorescein scores in the T group were statistically significant as compared to baseline (day 0). The average fluorescein scores did not change significantly in the P group (Fig. 1A). The average scores of Rose Bengal in the T group showed significant improvement after 7 days of treatment from 3.75 ± 1.51 to 2.68 ± 1.28 (p = 0.007) and even more after 90 days (2.04 ± 0.84; p < 0.0001). All Rose Bengal scores in the T group were statistically significant, as compared to baseline (day 0). The average Rose Bengal scores did not change significantly in the P group (Fig. 1B).

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The average Schirmer I values did not improve significantly in the T group after 7, 14 and 21 days. However, there was marked improvement after 28 days of treatment in the T group from 3.21 ± 1.93 mm to 4.61 ± 2.17 mm (p = 0.014) and even more after 90 days (5.43 ± 2.59 mm; p = 0.0006), as compared to baseline (day 0). The average Schirmer I values did not change significantly in the P group (Fig. 1C). The average BUT values did not improve significantly in the T group after 7, 14 or 21 days. However, there was marked improvement after 28 days of treatment from 2.46 ± 3.37 s to 4.46 ± 4.26 s (p = 0.02) and even more after 90 days (5.14 ± 4.02 s; p = 0.004),

Fig. 1. (A) Graph representing the average fluorescein staining score before (0) and after 7, 14, 21, 28, 60 and 90 days of treatment with 0.03% tacrolimus eye drops in dry eyes compared to normal eyes. (B) Graph representing the average Rose Bengal staining score before (B) and after 7, 14, 21, 28, 60 and 90 days of treatment with 0.03% tacrolimus eye drops in dry eyes compared to normal eyes. (C) Graph representing the average Schirmer I test values before (0) and after 7, 14, 21, 28, 60 and 90 days of treatment with 0.03% tacrolimus eye drops in dry eyes compared to normal eyes. (D) Graph representing the average break-up-time (BUT) before (0) and after 7, 14, 21, 28, 60 and 90 days of treatment with 0.03% tacrolimus eye drops in dry eyes compared to normal eyes.

Please cite this article in press as: Moscovici BK, et al. Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.04.004

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Fig. 1. (Continued).

as compared to baseline (day 0). The average BUT values did not change significantly in the P group (Fig. 1D). All patients in the T group showed improvement of dry eye symptoms. One patient in the P group showed mild improvement of symptoms. Eleven patients in the study group complained of burning sensation after the instillation of the eye drops that decreased over time. All patients chose to continue treatment despite the burning sensation. Four patients in the P group complained of burning sensation after the instillation of the eye drops. 4. Discussion Although systemic tacrolimus is routinely used in treatment of autoimmune diseases, its clinical use in ophthalmology has been limited to the treatment of T cell-mediated autoimmune uveitis, allergic blepharoconjunctivitis, prolonging corneal

allograft survival [30,37–41], and in chronic graft-versus-host disease [25,26,42]. The therapeutic effect of topical CsA in dry eyes is achieved by inhibiting T-helper lymphocyte proliferation thus controlling inflammation, infiltrating the lacrimal gland acini and, at least partially, by restoring their secretory functions. The only commercial dose of CsA available is 0.05%, which is effective only in cases of mild to moderate dry eye. A high-dose castor oil-based solution of topical CsA (1–2%) has been reported to improve tear production in animals with KCS [43,44]. In humans, tacrolimus ointment and eye drops are alternatives for use in the treatment of severe cases of lid and ocular allergy when glucocorticoids or antihistamines result in an inadequate response [19,21,22,45,46]. In this study, we observed an improvement of dry eye signs after treatment with 0.03% tacrolimus eye drops. Fluorescein and Rose Bengal scores showed rapid improvement within 7 days,

Please cite this article in press as: Moscovici BK, et al. Treatment of Sjögren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study. Contact Lens Anterior Eye (2015), http://dx.doi.org/10.1016/j.clae.2015.04.004

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but BUT and Schirmer test took 28 days to show significant improvement. Thus, it is likely that inflammatory cytokines were modulated rapidly, while ocular stability requires longer treatment for improvement (BUT). The data presented here confirmed our previous case report [5]. Improvement of Schirmer I test score was not expected as inflammatory modulation may not interfere with tear production. This remains unclear and further studies are currently underway for clarification. Treatment with 0.03% tacrolimus eye drops showed efficacy in patients with Schirmer I test result < 5 mm, Rose Bengal staining score < 4, and BUT < 5 s. Different levels of dry eye severity should also be studied to determine whether this treatment is also effective in comparison with other anti-inflammatory agents. All patients complained of moderate burning sensation for approximately 30 min after topical instillation of eye drops. The irritation and intolerance may limit the use of this medication in some patients, especially in mild cases. Further studies are required to improve these symptoms. Changing the vehicle (castor oil or beta cyclodextrin) or the use of tacrolimus ointment may result in better acceptance [13–15]. Individual tolerance, other preservatives, and vehicles are still under investigation. Data between study group and control group were not compared during the 90-day-period because some of severe cases of dry eye included in the control group were suggested to be excluded from our study by our Institutional Review Board and Medical Ethics Committee. So some baseline data were statistically more severe in study group compared to control group. Thus, more severe cases of the study group turned out to improve fluorescein, Rose Bengal, Schirmer and BUT outcomes using tacrolimus. Symptom-based analysis may be improved with questionnairebased studies. In this study, patients were asked only about dryness and burning sensation (with no grading) for safety reasons, as the Ocular Surface Disease Index (OSDI) questionnaire has not been validated in our country. In this study, we verified the efficacy in improvement of dry eye signs. Larger series with longer duration of follow-up may provide more information, and the use of ointment or better preservatives or vehicles may increase tolerability of the instillation. Impression cytology could secure the safety of this treatment, but topical ointments have been used at higher dosages in dermatology for about 10 years. This study suggests that topical 0.03% tacrolimus eye drops may be effective in the treatment of SS dry eye syndrome.

Financial support None.

Conflict of interest No authors have any financial/conflicting interests to disclose.

Acknowledgments The authors of this article would like to thank Dr. Acacio Alves de Souza Lima Filho for donation of the tacrolimus eye drops for this study. Dr. Moscovici and Dr. Hida contributed equally to the work and request acknowledgment for double first authorship. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/3EEXBt.

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Treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study.

To describe the clinical efficacy of the treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop...
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