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Changing from preserved, to preservative-free cyclosporine 0.1% enhanced triple glaucoma therapy: impact on ocular surface disease—a randomized controlled trial

Eye volume 37, pages 3666–3674 (2023)Cite this article

Subjects

Abstract

Objective

Halting and reversing glaucoma therapy-related ocular surface disease (GTR-OSD) will improve the success of long-term medical therapy, impacting millions of patients worldwide.

Methods

A single-centre, masked, prospective, placebo-controlled, crossover trial of 41 well-controlled open-angle glaucoma subjects with moderate to severe GTR-OSD on preserved latanoprost and dorzolamide/timolol fixed combination (DTFC) therapy was conducted. Subjects were randomized to preservative-free (PF) tafluprost and DTFC with either placebo or cyclosporine 0.1% drops for 6 months and were then crossed over to the opposite therapy. Oxford score of ocular staining was the primary outcome; osmolarity, matrix-metalloproteinase-9 (MMP-9) testing, tear film break-up time (TFBUT), meibomian gland dysfunction (MGD), punctum evaluation, adverse events and diurnal intraocular pressure (IOP) comprised secondary outcomes.

Results

GTR-OSD findings improved with PF therapy. At 6 months the triple PF with placebo group showed improvement compared to baseline in mean Oxford score (mean difference [MD]:−3.76; 95% confidence interval [CI]:−4.74 to −2.77; p < 0.001), osmolarity (MD:−21.93; 95%CI:−27.61 to −16.24 mOsm/l; p < 0.001), punctum stenosis (p = 0.008) and conjunctival hyperaemia (p < 0.001). Similar improvements occurred in the cyclosporine enhanced period, which also provided greater improvement in MMP-9 positivity (24 vs 66%; p < 0.001) and TFBUT (p = 0.022). The cyclosporine group was superior vs placebo in mean Oxford score (MD:−0.78; 95%CI:−1.40 to −0.15); p < 0.001), itchiness and objective adverse events (p = 0.034). Cyclosporine elicited more stinging vs placebo (63 vs 24%; p < 0.001). Both PF regimens reduced mean diurnal IOP more than preserved therapy (14.7 vs 15.9 mmHg; p < 0.001).

Conclusions

Changing from preserved to PF glaucoma medications improves ocular surface health and IOP control. Topical cyclosporine 0.1% further reverses GTR-OSD.

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Fig. 1: Flow chart of the study.
Fig. 2: Bar graphs conveying the primary and secondary outcomes of the study.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Baudouin C, Labbe A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–34.

    Article  CAS  PubMed  Google Scholar 

  2. Banitt M, Jung H. Ocular surface disease in the glaucoma patient. Int Ophthalmol Clin. 2018;58:23–33.

    Article  PubMed  Google Scholar 

  3. Wong ABC, Wang MTM, Liu K, Prime ZJ, Danesh-Meyer HV, Craig JP. Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye. Ocul Surf. 2018;16:289–93.

    Article  PubMed  Google Scholar 

  4. Clayton JA. Dry eye. N. Engl J Med. 2018;378:2212–23.

    Article  CAS  PubMed  Google Scholar 

  5. Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular surface disease in glaucoma patients. Clin Ophthalmol. 2011;5:1575–83.

    PubMed  PubMed Central  Google Scholar 

  6. Holló G, Katsanos A, Boboridis KG, Irkec M, Konstas AGP. Preservative-free prostaglandin analogs and prostaglandin/timolol fixed combinations in the treatment of glaucoma: efficacy, safety and potential advantages. Drugs. 2018;78:39–64.

    Article  PubMed  Google Scholar 

  7. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular surface disease and glaucoma medications: a clinical approach. Eye Contact Lens. 2019;45:11–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Figus M, Agnifili L, Lanzini M, Brescia L, Sartini F, Mastropasqua L, et al. Topical preservative-free ophthalmic treatments: an unmet clinical need. Expert Opin Drug Deliv. 2021;18:655–72.

    Article  PubMed  Google Scholar 

  9. Stalmans I, Lemij H, Clarke J, Baudouin C on behalf of the GOAL study group. Signs and symptoms of ocular surface disease: the reasons for patient dissatisfaction with glaucoma treatments. Clin Ophthalmol. 2020;14:3675–80.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wolfram C, Stahlberg E, Pfeiffer N. Patient-reported nonadherence with glaucoma therapy. J Ocul Pharm Ther. 2019;35:223–8.

    Article  CAS  Google Scholar 

  11. Konstas AGP, Labbe A, Katsanos A, Meier-Gibbons F, Irkec M, Boboridis KG, et al. The treatment of glaucoma using topical preservative-free agents: an evaluation of safety and tolerability. Expert Opin Drug Saf. 2021;20:453–66.

    Article  CAS  PubMed  Google Scholar 

  12. Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride exposure: problems and solutions. Eye. 2022;36:361–8.

    Article  PubMed  Google Scholar 

  13. Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol. 1994;112:1446–54.

    Article  CAS  PubMed  Google Scholar 

  14. Boimer C, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. J Glaucoma. 2013;22:730–5.

    Article  PubMed  Google Scholar 

  15. Chamard C, Larrieu S, Baudouin C, Bron A, Villain M, Daien V. Preservative-free versus preserved glaucoma eye drops and occurrence of glaucoma surgery. A retrospective study based on the French national health insurance information system, 2008-2016. Acta Ophthalmol. 2020;98:e876–881.

    Article  PubMed  Google Scholar 

  16. European Glaucoma Society. Terminology and guidelines for glaucoma. 5th ed. Savona, Italy: PubliComm; 2020.

    Google Scholar 

  17. Musch DC, Gillespie BW, Niziol LM, Lichter PR, Varma R, CIGTS Study Group. Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2011;118:1766–73.

    Article  PubMed  Google Scholar 

  18. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350–5.

    Article  PubMed  Google Scholar 

  19. Portela RC, Fares NT, Machado LF, São Leão AF, de Freitas D, Paranhos A Jr, et al. Evaluation of ocular surface disease in patients with glaucoma: clinical parameters, self-report assessment, and keratograph analysis. J Glaucoma. 2018;27:794–801.

    Article  PubMed  Google Scholar 

  20. Boboridis KG, Konstas AGP. Evaluating the novel application of cyclosporine 0.1% in ocular surface disease. Expert Opin Pharmacother. 2018;19:1027–39.

    Article  CAS  PubMed  Google Scholar 

  21. Labbe A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea. 2012;31:994e9.

    Article  Google Scholar 

  22. Mohammed I, Kulkarni B, Faraj LA, Abbas A, Dua HS, King AJ. Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: A 2-year randomized evaluation study. Clin Exp Ophthalmol. 2020;48:973–82.

    Article  PubMed  Google Scholar 

  23. Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol. 2007;17:341–9.

    Article  CAS  PubMed  Google Scholar 

  24. Steven DW, Alaghband P, Lim KS. Preservatives in glaucoma medication. Br J Ophthalmol. 2018;102:1497–503.

    Article  PubMed  Google Scholar 

  25. Saini M, Dhiman R, Dada T, Tandon R, Vanathi M. Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications. Eye. 2015;29:808–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou XQ, Wei RL. Topical cyclosporine A in the treatment of dry eye: a systematic review and meta-analysis. Cornea. 2014;33:760–7.

    Article  PubMed  Google Scholar 

  27. Kymionis GD, Bouzoukis DI, Diakonis VF, Siganos C. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol. 2008;2:829–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee SY, Wong TT, Chua J, Boo C, Soh YF, Tong L. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity. Eye. 2013;27:1142–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Leonardi A, Messmer EM, Labetoulle M, Amrane M, Garrigue JS, Ismail D, 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. 2019;103:125–31.

    Article  PubMed  Google Scholar 

  30. Konstas AG, Kahook MY, Araie M, Katsanos A, Quaranta L, Rossetti L, et al. Diurnal and 24-h intraocular pressures in glaucoma: monitoring strategies and impact on prognosis and treatment. Adv Ther. 2018;35:1775–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:900–7.

    Article  PubMed  Google Scholar 

  32. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15:276–83.

    Article  PubMed  Google Scholar 

  33. Tomlinson A, Bron AJ, Korb DR, Amano S, Paugh JR, Pearce EI, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Investig Ophthalmol Vis Sci. 2011;52:2006–49.

    Article  Google Scholar 

  34. Kim DW, Seo JH, Lim SH. Evaluation of ocular surface disease in elderly patients with glaucoma: expression of matrix metalloproteinase-9 in tears. Eye. 2021;35:892–900.

    Article  CAS  PubMed  Google Scholar 

  35. Batra R, Tailor R, Mohamed S. Ocular surface disease exacerbated glaucoma: optimizing the ocular surface improves intraocular pressure control. J Glaucoma. 2014;23:56–60.

    Article  PubMed  Google Scholar 

  36. Dubrulle P, Labbé A, Brasnu E, Liang H, Hamard P, Meziani L, et al. Influence of treating ocular surface disease on intraocular pressure in glaucoma patients intolerant to their topical treatments: a report of 10 cases. J Glaucoma. 2018;27:1105–11.

    Article  PubMed  Google Scholar 

  37. Baudouin C, Denoyer A, Desbenoit N, Hamm G, Grise A. In vitro and in vivo experimental studies on trabecular meshwork degeneration induced by benzalkonium chloride (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2012;110:40–63.

    PubMed  PubMed Central  Google Scholar 

  38. Baudouin C, Messmer EM, Aragona P, Geerling G, Akova YA, Benítez-del-Castillo J, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100:300–6.

    Article  PubMed  Google Scholar 

  39. Periman LM, Mah FS, Karpecki PM. A review of the mechanism of action of cyclosporine A: the role of cyclosporine A in dry eye disease and recent formulation developments. Clin Ophthalmol. 2020;14:4187–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schargus M, Ivanova S, Kakkassery V, Dick HB, Joachim S. Correlation of tear film osmolarity and 2 different MMP-9 tests with common dry eye tests in a cohort of non-dry eye patients. Cornea. 2015;34:739–44.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all medical staff of the 1st University Department of Ophthalmology and the patients who participated in this study.

Funding

This study was supported in part by Santen. The sponsor had no involvement in the design of the trial, the analysis or interpretation of results, or the publication of the paper.

Author information

Authors and Affiliations

  1. 1st University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Anastasios-Georgios Konstas, Konstadinos G. Boboridis, Georgios P. Athanasopoulos & Irini C. Voudouragkaki

  2. Department of Epidemiology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Anna-Bettina Haidich & Eirini Pagkalidou

  3. Department of Ophthalmology, University of Ioannina, Ioannina, Greece

    Andreas Katsanos

  4. Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA, USA

    L. Jay Katz

Authors
  1. Anastasios-Georgios Konstas
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Contributions

AGK and KGB contributed to the conception of the study, the examination of patients, and the preparation of the manuscript. GPA, ICV and EP contributed to the examination of patients and drafting parts of the manuscript. ABH contributed to the conception of the study, the statistical analysis and the preparation of the manuscript. AK contributed to the interpretation of results and the preparation of the manuscript. LJK contributed to the conception of the study, the interpretation of results and the preparation of the manuscript. All authors approved the submitted version of the manuscript and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Anastasios-Georgios Konstas.

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Competing interests

AGK: Research funding from Allergan, Bayer, Omni Vision, Pharmaten and Santen; travel support and congress expenses from Vianex and Zwitter; honoraria from Allergan, Esteve Pharmaceuticals, Santen and Vianex. KGB: Honoraria from Laboratoires Théa, Bausch & Lomb, Santen and Novartis. GPA, ABH, ICV and EP: No conflicts of interest. AK: Honoraria and congress expenses from Cooper SA, Santen, Vianex, Zwitter; research funding from Laboratoires Théa. LJK: Grants and research support from Allergan, Diopsys, Heidelberg Engineering, Alcon, Zeiss, Olleyes; consultant/advisory board: Olleyes (stock options); honoraria from Allergan, Glaukos, Bausch & Lomb; Stock shareholder: Glaukos, Mati Therapeutics, Aerie, Olleyes; employment (salary): Glaukos (Chief Medical Officer).

Ethics approval

The research protocol was approved by the Institutional Review Board of the Medical School of Aristotle University and was registered with ClinicalTrials.gov (NCT04673604). The study was conducted in accordance with the tenets of the Declaration of Helsinki.

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Konstas, AG., Boboridis, K.G., Athanasopoulos, G.P. et al. Changing from preserved, to preservative-free cyclosporine 0.1% enhanced triple glaucoma therapy: impact on ocular surface disease—a randomized controlled trial. Eye 37, 3666–3674 (2023). https://doi.org/10.1038/s41433-023-02578-w

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  • DOI: https://doi.org/10.1038/s41433-023-02578-w

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