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Exploration of efficacy and mechanism of 0.05% cyclosporine eye drops (II) monotherapy in allergic conjunctivitis-associated dry eye

Eye volume 38, pages 937–944 (2024)Cite this article

Subjects

Abstract

Purpose

To explore the efficacy and relevant mechanism of 0.05% cyclosporine A (CsA) eye drops (II) monotherapy in patients with allergic conjunctivitis-associated dry eye (ACDE).

Methods

Prospective, randomized, controlled study. Fifty-three patients with mild-to-moderate ACDE were randomly assigned to two groups. The CsA group received 0.05% CsA eye drops (II) monotherapy four times daily. The control group received 0.1% olopatadine twice daily combined with 0.1% preservative-free artificial tears four times daily. Clinical symptoms and signs, tear total IgE, and lymphotoxin-α (LT-α) concentrations were assessed at pre- and post-treatment days 7, 30, and 60. And we further measured six tear cytokines levels using a microsphere-based immunoassay.

Results

The CsA group showed significant improvement in symptoms (Ocular Surface Disease Index and itching scores) and signs (conjunctival hyperaemia, conjunctival oedema, conjunctival papillae, tear break-up time (TBUT), corneal fluorescein staining, and goblet cell density) at each follow-up period compared to pre-treatment (all P < 0.050). And its improvement in itching scores (P7th < 0.001, P30th = 0.039, and P60th = 0.031) and TBUT (P7th = 0.009, P30th = 0.003, and P60th = 0.005) was more significant than the control group at all follow-up periods. The tear total IgE, interleukin (IL)-5, IL-6, periostin, eotaxin-3, and MMP-9 levels significantly decreased in the CsA group at day 60 after treatment (all P < 0.050). And the changed values in tear total IgE were positively correlated with the change in itching scores.

Conclusions

0.05% CsA eye drops (II) monotherapy can rapidly improve the symptoms and signs, especially in ocular itching and TBUT, in patients with ACDE. And its efficacy is superior to 0.1% olopatadine combined with artificial tears. Moreover, CsA downregulates the expression levels of tear inflammatory cytokines, including tear total IgE, IL-5, IL-6, periostin, eotaxin-3, and MMP-9. Among that, the reduction in tear total IgE levels may reflect the improvement of ocular itching.

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Fig. 1: Comparison of changes in clinical parameters after treatment in two groups of ACDE patients.
Fig. 2: Tear cytokines profiles in two groups at pre-treatment and post-treatment.
Fig. 3: Comparison of the changed values in tear cytokine concentration between the two groups and their correlation with changes in clinical parameters.

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Data availability

The data is available from the corresponding author upon reasonable request.

References

  1. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo C-K, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276–83.

    PubMed  Google Scholar 

  2. Villani E, Rabbiolo G, Nucci P. Ocular allergy as a risk factor for dry eye in adults and children. Curr Opin Allergy Clin Immunol. 2018;18:398–403.

    PubMed  Google Scholar 

  3. Leonardi A, Modugno RL, Salami E. Allergy and dry eye disease. Ocul Immunol Inflamm. 2021;29:1168–76.

    PubMed  Google Scholar 

  4. Dominick LO, Justin TK, Jennifer H, Eric B, Milton MH. Prevalence of allergic conjunctivitis, ocular surface disease subtypes, and mixed disease. Invest Ophthalmol Vis Sci. 2014;55:2751.

    Google Scholar 

  5. Akasaki Y, Inomata T, Sung J, Nakamura M, Kitazawa K, Shih KC, et al. Prevalence of comorbidity between dry eye and allergic conjunctivitis: a systematic review and meta-analysis. J Clin Med. 2022;11:3643.

    PubMed  PubMed Central  Google Scholar 

  6. Chen L, Pi L, Fang J, Chen X, Ke N, Liu Q. High incidence of dry eye in young children with allergic conjunctivitis in Southwest China. Acta Ophthalmol. 2016;94:e727–30.

    PubMed  Google Scholar 

  7. Dupuis P, Prokopich CL, Hynes A, Kim H. A contemporary look at allergic conjunctivitis. Allergy Asthma Clin Immunol. 2020;16:5.

    PubMed  PubMed Central  Google Scholar 

  8. Nye M, Rudner S, Bielory L. Emerging therapies in allergic conjunctivitis and dry eye syndrome. Expert Opin Pharmacother. 2013;14:1449–65.

    CAS  PubMed  Google Scholar 

  9. Nguyen E, Yanes D, Imadojemu S, Kroshinsky D. Evaluation of cyclosporine for the treatment of DRESS syndrome. JAMA Dermatol. 2020;156:704–6.

    PubMed  PubMed Central  Google Scholar 

  10. Fauquert J-L. Diagnosing and managing allergic conjunctivitis in childhood: the allergist’s perspective. Pediatr Allergy Immunol. 2019;30:405–14.

    PubMed  Google Scholar 

  11. Raizman MB, Hamrah P, Holland EJ, Kim T, Mah FS, Rapuano CJ, et al. Drug-induced corneal epithelial changes. Surv Ophthalmol. 2017;62:286–301.

    PubMed  Google Scholar 

  12. Gao M, Zhao L, Liang R, Zhu Q, Zhao Q, Kong X. Evaluation of the efficacy and safety of topical 0.05% cyclosporine eye drops (II) in the treatment of dry eye associated with Primary Sjögren’s Syndrome. Ocul Immunol Inflamm. 2023;31:1662–1668.

  13. Labib BA, Chigbu DI. Therapeutic targets in allergic conjunctivitis. Pharm (Basel). 2022;15:547.

    CAS  Google Scholar 

  14. Bao J, Tian L, Meng Y, Wu B, Wang J, He J, et al. Total IgE in tears accurately reflects the severity and predicts the prognosis of seasonal allergic conjunctivitis. Clin Transl Allergy. 2022;12:e12139.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin X, Huang J-F, Liu Z. Large scale, prospective, multicenter, clinical evaluation of point-of-care lymphotoxin alpha (LTA) test in dry eye disease. Investig Ophthalmol Vis Sci. 2020;61:116.

    Google Scholar 

  16. Suárez-Cortés T, Merino-Inda N, Benitez-Del-Castillo JM. Tear and ocular surface disease biomarkers: a diagnostic and clinical perspective for ocular allergies and dry eye disease. Exp Eye Res. 2022;221:109121.

    PubMed  Google Scholar 

  17. Rhim JW, Eom Y, Yoon EG, Park SY, Choi Y, Song JS, et al. Efficacy of a 0.05% cyclosporine a topical nanoemulsion in dry eyes with obstructive meibomian gland dysfunction. Jpn J Ophthalmol. 2022;66:254–63.

    CAS  PubMed  Google Scholar 

  18. Asian Dry Eye Association China Chapter. Chinese expert consensus on dry eye: definition and classification (2020). Chin J Ophthalmol. 2020;56:418–22.

    Google Scholar 

  19. Nelson JD, Havener VR, Cameron JD. Cellulose acetate impressions of the ocular surface. Dry eye states. Arch Ophthalmol. 1983;101:1869–72.

    CAS  PubMed  Google Scholar 

  20. Patel D, Wairkar S. Recent advances in cyclosporine drug delivery: challenges and opportunities. Drug Deliv Transl Res. 2019;9:1067–81.

    CAS  PubMed  Google Scholar 

  21. Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea. 2012;31:1386–93.

    PubMed  Google Scholar 

  22. Leong E, Pang Z, Stadnyk AW, Lin TJ. Calcineurin Aα contributes to IgE-dependent mast-cell mediator secretion in allergic inflammation. J Innate Immun. 2022;14:320–34.

    CAS  PubMed  Google Scholar 

  23. Kam KW, Chen LJ, Wat N, Young AL. Topical olopatadine in the treatment of allergic conjunctivitis: a systematic review and meta-analysis. Ocul Immunol Inflamm. 2017;25:663–77.

    PubMed  Google Scholar 

  24. Vichyanond P, Kosrirukvongs P. Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis. Curr Allergy Asthma Rep. 2013;13:308–14.

    CAS  PubMed  Google Scholar 

  25. Villareal AL, Farley W, Pflugfelder SC. Effect of topical ophthalmic epinastine and olopatadine on tear volume in mice. Eye Contact Lens. 2006;32:272–6.

    PubMed  Google Scholar 

  26. Wan KH-N, Chen LJ, Rong SS, Pang CP, Young AL. Topical cyclosporine in the treatment of allergic conjunctivitis: a meta-analysis. Ophthalmology. 2013;120:2197–203.

    PubMed  Google Scholar 

  27. Leonardi A, Messmer EM, Labetoulle M, Amrane M, Garrigue J-S, 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.

    PubMed  Google Scholar 

  28. Cui H, Liu F, Fang Y, Wang T, Yuan B, Ma C. Neuronal FcεRIα directly mediates ocular itch via IgE-immune complex in a mouse model of allergic conjunctivitis. J Neuroinflamm. 2022;19:55.

    CAS  Google Scholar 

  29. Ambroziak AM, Szaflik J, Szaflik JP, Ambroziak M, Witkiewicz J, Skopiński P. Immunomodulation on the ocular surface: a review. Cent Eur J Immunol. 2016;41:195–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hashimoto T, Mishra SK, Olivry T, Yosipovitch G. Periostin, an emerging player in itch sensation. J Invest Dermatol. 2021;141:2338–43.

    CAS  PubMed  Google Scholar 

  31. Izuhara K, Nunomura S, Nanri Y, Ono J, Takai M, Kawaguchi A. Periostin: an emerging biomarker for allergic diseases. Allergy. 2019;74:2116–28.

    PubMed  Google Scholar 

  32. García-Posadas L, Hodges RR, Diebold Y, Dartt DA. Context-dependent regulation of conjunctival goblet cell function by allergic mediators. Sci Rep. 2018;8:12162.

    PubMed  PubMed Central  Google Scholar 

  33. Yoon K-C, Jeong I-Y, Park Y-G, Yang S-Y. Interleukin-6 and tumor necrosis factor-alpha levels in tears of patients with dry eye syndrome. Cornea. 2007;26:431–7.

    PubMed  Google Scholar 

  34. Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regulation of IL-6 and TNF-alpha via calcineurin in human skeletal muscle cells. Cytokine. 2006;36:141–7.

    CAS  PubMed  Google Scholar 

  35. Cook EB, Stahl JL, Barney NP, Graziano FM. Olopatadine inhibits TNF-alpha release from human conjunctival mast cells. Ann Allergy Asthma Immunol. 2000;84:504–8.

    CAS  PubMed  Google Scholar 

  36. Nakae S, Suto H, Kakurai M, Sedgwick JD, Tsai M, Galli SJ. Mast cells enhance T cell activation: Importance of mast cell-derived TNF. Proc Natl Acad Sci USA. 2005;102:6467–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kang MJ, Kim HS, Kim MS, Kim EC. The Correlation between matrix metalloproteinase-9 point-of-care immunoassay, tear film osmolarity, and ocular surface parameters. J Ophthalmol. 2022;2022:6132016.

    PubMed  PubMed Central  Google Scholar 

  38. Chen H, Chen H, Liang L, Zhong Y, Liang Y, Yu Y, et al. Evaluation of tear protein markers in dry eye disease with different lymphotoxin-alpha expression levels. Am J Ophthalmol. 2020;217:198–211.

    CAS  PubMed  Google Scholar 

  39. Davies K, Mirza K, Tarn J, Howard-Tripp N, Bowman SJ, Lendrem D, et al. Fatigue in primary Sjögren’s syndrome (pSS) is associated with lower levels of proinflammatory cytokines: a validation study. Rheumatol Int. 2019;39:1867–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ma J, Li C, Zhao Y, Shen Z, Hu B, Peng R, et al. Ophthalmic manifestations are associated with reduced tear lymphotoxin-α levels in chronic ocular graft-versus-host disease. BMC Ophthalmol. 2022;22:18.

    PubMed  PubMed Central  Google Scholar 

  41. Messmer EM, von Lindenfels V, Garbe A, Kampik A. Matrix metalloproteinase 9 testing in dry eye disease using a commercially available point-of-care immunoassay. Ophthalmology. 2016;123:2300–8.

    PubMed  Google Scholar 

  42. Park JY, Kim BG, Kim JS, Hwang JH. Matrix metalloproteinase 9 point-of-care immunoassay result predicts response to topical cyclosporine treatment in dry eye disease. Transl Vis Sci Technol. 2018;7:31.

    PubMed  PubMed Central  Google Scholar 

  43. Kuprash DV, Boitchenko VE, Yarovinsky FO, Rice NR, Nordheim A, Rühlmann A, et al. Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta, in human peripheral blood mononuclear cells. Blood. 2002;100:1721–7.

    CAS  PubMed  Google Scholar 

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Funding

This study was funded by the Beijing Bethune Charitable Foundation Project (BJ-GY2021008J), and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-037A).

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Author notes

  1. These authors contributed equally: Xiting Jiao, Yuanyuan Qi.

Authors and Affiliations

  1. Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China

    Xiting Jiao, Yuanyuan Qi, Ning Gao, Chen Zhang, Shaozhen Zhao & Ruibo Yang

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  1. Xiting Jiao
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Contributions

XTJ and YYQ participated in the patient’s follow-up and evaluation, data analysis, and drafted the manuscript. NG was responsible for patient enrolment and follow-up. CZ was responsible for the revision of the article. SZZ and RBY participated in project supervision, data interpretation, and manuscript revision.

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Correspondence to Shaozhen Zhao or Ruibo Yang.

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Jiao, X., Qi, Y., Gao, N. et al. Exploration of efficacy and mechanism of 0.05% cyclosporine eye drops (II) monotherapy in allergic conjunctivitis-associated dry eye. Eye 38, 937–944 (2024). https://doi.org/10.1038/s41433-023-02807-2

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