Efficacy, safety, and tolerability of pharmacological treatments for moderate-to-severe dry eye disease: systematic review of randomized controlled trials
Keywords:
Cyclosporine, Dry eye syndromes, Hyaluronic acid, Lifitegrast, Ophthalmic solutionsAbstract
Dry eye disease (DED) is characterized by impaired tear film homeostasis and ocular surface inflammation. Topical ocular medications for moderate-to-severe DED include hyaluronic acid (HA), cyclosporine A (CsA), serum eyedrops (SE), and lifitegrast. Effective HA-based formulations and regimens include topical aqueous HA 0.15% and 0.18%, HA gel 0.30%, sequential administration of HA 0.30% and 0.15%, a combination of HA 0.15% and polyethylene glycol, and multi-agent eyedrops containing 0.15% HA. Preservative-free hydrocortisone and loteprednol, known as soft steroids, are effective and have a reduced risk of steroid-related adverse effects. Effective CsA formulations include 0.05% CsA gel, CsA nanoemulsions, water-free CsA, and CsA combinations with lubricants (eg, HA). Autologous, allogeneic, and umbilical cord serum eyedrops, as well as the novel lymphocyte function-associated antigen-1 antagonist lifitegrast, are also effective. Various treatment options may improve treatment adherence. Long-term and large-scale studies are required to confirm the therapeutic efficacies of these treatments.
References
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017;15:276-83.
Shih KC, Lai JSM, Ng ALK. Management of dry eye disease: a systematic approach for the primary care physician. Hong Kong Pract 2016;38:113-9.
O’Neil EC, Henderson M, Massaro-Giordano M, Bunya VY. Advances in dry eye disease treatment. Curr Opin Ophthalmol 2019;30:166-78.
Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol 2017;182:90-8.
Patel VD, Watanabe JH, Strauss JA, Dubey AT. Work productivity loss in patients with dry eye disease: an online survey. Curr Med Res Opin 2011;27:1041-8.
Aragona P, Giannaccare G, Mencucci R, Rubino P, Cantera E, Rolando M. Modern approach to the treatment of dry eye, a complex multifactorial disease: a P.I.C.A.S.S.O. board review. Br J Ophthalmol 2021;105:446-53.
Baudouin C, Aragona P, Van Setten G, et al. Diagnosing the severity of dry eye: a clear and practical algorithm. Br J Ophthalmol 2014;98:1168-76.
The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75-92.
Ang BCH, Sng JJ, Wang PXH, Htoon HM, Tong LHT. Sodium hyaluronate in the treatment of dry eye syndrome: a systematic review and meta-analysis. Sci Rep 2017;7:9013.
Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefes Arch Clin Exp Ophthalmol 2006;244:109-12.
You IC, Li Y, Jin R, Ahn M, Choi W, Yoon KC. Comparison of 0.1%, 0.18%, and 0.3% hyaluronic acid eye drops in the treatment of experimental dry eye. J Ocul Pharmacol Ther 2018;34:557-64.
Lemp MA. Management of dry eye disease. Am J Manag Care 2008;14(3 Suppl):S88-101.
Gomes JAP, Santo RM. The impact of dry eye disease treatment on patient satisfaction and quality of life: a review. Ocul Surf 2019;17:9-19.
Lee JE, Kim S, Lee HK, et al. A randomized multicenter evaluation of the efficacy of 0.15% hyaluronic acid versus 0.05% cyclosporine A in dry eye syndrome. Sci Rep 2022;12:18737.
Calonge M, Sahyoun M, Baillif S, et al. Sodium hyaluronate 0.30% ocular gel versus sodium hyaluronate 0.18% eye drop in the treatment of moderate to severe dry eye disease. Eur J Ophthalmol 2023;33:188-95.
Jun JH, Bang SP, Park HS, et al. A randomized multicenter clinical evaluation of sequential application of 0.3% and 0.15% hyaluronic acid for treatment of dry eye. Jpn J Ophthalmol 2022;66:58-67.
Labetoulle M, Mortemousque B; CBL-101 Study Group. Performance and safety of a sodium hyaluronate tear substitute with polyethylene glycol in dry eye disease: a multicenter, investigator-masked, randomized, noninferiority trial. J Ocul Pharmacol Ther 2022;38:607-16.
Roszkowska AM, Inferrera L, Spinella R, et al. Clinical efficacy, tolerability and safety of a new multiple-action eyedrop in subjects with moderate to severe dry eye. J Clin Med 2022;11:6975.
Hynnekleiv L, Magno M, Vernhardsdottir RR, et al. Hyaluronic acid in the treatment of dry eye disease. Acta Ophthalmol 2022;100:844-60.
Zheng X, Goto T, Ohashi Y. Comparison of in vivo efficacy of different ocular lubricants in dry eye animal models. Invest Ophthalmol Vis Sci 2014;55:3454-60.
Oechsner M, Keipert S. Polyacrylic acid/polyvinylpyrrolidone bipolymeric systems. I. Rheological and mucoadhesive properties of formulations potentially useful for the treatment of dry-eye-syndrome. Eur J Pharm Biopharm 1999;47:113-8.
Pires NR, Cunha PLR, Maciel JS, et al. Sulfated chitosan as tear substitute with no antimicrobial activity. Carbohydr Polym 2013;91:92-9.
De Paiva CS, Corrales RM, Villarreal AL, et al. Apical corneal barrier disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline. Invest Ophthalmol Vis Sci 2006;47:2847-56.
Lekhanont K, Leyngold IM, Suwan-Apichon O, Rangsin R, Chuck RS. Comparison of topical dry eye medications for the treatment of keratoconjunctivitis sicca in a botulinum toxin B-induced mouse model. Cornea 2007;26:84-9.
De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye. Exp Eye Res 2006;83:526-35.
Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000;11:478-83.
McGhee CNJ, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids: benefits and risks. Drug Saf 2002;25:33-55.
Sheppard JD, Comstock TL, Cavet ME. Impact of the topical ophthalmic corticosteroid loteprednol etabonate on intraocular pressure. Adv Ther 2016;33:532-52.
Adatia FA, Michaeli-Cohen A, Naor J, Caffery B, Bookman A, Slomovic A. Correlation between corneal sensitivity, subjective dry eye symptoms and corneal staining in Sjögren’s syndrome. Can J Ophthalmol 2004;39:767-71.
Menchini M, Sartini F, Figus M, Gabbriellini G. Short-term results of a pulsed therapy with hydrocortisone eye drops to treat moderate to severe dry eye in primary Sjögren syndrome patients. Graefes Arch Clin Exp Ophthalmol 2023;261:1029-36.
Yin J, Kheirkhah A, Dohlman T, Saboo U, Dana R. Reduced efficacy of low-dose topical steroids in dry eye disease associated with graft-versus-host disease. Am J Ophthalmol 2018;190:17-23.
Comstock TL, Paterno MR, Bateman KM, Decory HH, Gearinger M. Safety and tolerability of loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension in pediatric subjects. Paediatr Drugs 2012;14:119-30.
Amon M, Busin M. Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use. Int Ophthalmol 2012;32:507-17.
Deveney T, Asbell PA. Patient and physician perspectives on the use of cyclosporine ophthalmic emulsion 0.05% for the management of chronic dry eye. Clin Ophthalmol 2018;12:569-76.
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.
Mah F, Milner M, Yiu S, Donnenfeld E, Conway TM, Hollander DA. PERSIST: Physician’s Evaluation of Restasis(®) Satisfaction in Second Trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clin Ophthalmol 2012;6:1971-6.
Periman LM, Perez VL, Saban DR, Lin MC, Neri P. The immunological basis of dry eye disease and current topical treatment options. J Ocul Pharmacol Ther 2020;36:137-46.
Sall K, Stevenson OD, Mundorf TK, Reis BL. 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. Ophthalmology 2000;107:631-9.
Kim CY, Park KH, Ahn J, et al. Treatment patterns and medication adherence of patients with glaucoma in South Korea. Br J Ophthalmol 2017;101:801-7.
White DE, Zhao Y, Ogundele A, et al. Real-world treatment patterns of cyclosporine ophthalmic emulsion and lifitegrast ophthalmic solution among patients with dry eye. Clin Ophthalmol 2019;13:2285-92.
Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res 2012;47:66-80.
Kallab M, Szegedi S, Hommer N, et al. Topical low dose preservative-free hydrocortisone reduces signs and symptoms in patients with chronic dry eye: a randomized clinical trial. Adv Ther 2020;37:329-41.
Peng WY, Chen RX, Dai H, et al. Efficacy, safety, and tolerability of a novel cyclosporine, a formulation for dry eye disease: a multicenter phase II clinical study. Clin Ther 2021;43:613-28.
Peng W, Jiang X, Zhu L, et al. Cyclosporine A (0.05%) ophthalmic gel in the treatment of dry eye disease: a multicenter, randomized, double-masked, phase III, COSMO trial. Drug Des Devel Ther 2022;16:3183-94.
Eom Y, Yoon KC, Kim HK, Song JS, Hyon JY, Kim HM. A multicenter, randomized, double-blind evaluation of the efficacy of TJO-087 versus 0.05% cyclosporine A in moderate to severe dry eye. J Ocul Pharmacol Ther 2023;39:27-35.
Rao AT, Gupta A, Chauhan T, et al. Efficacy and safety of 0.05% micellar nano-particulate (MNP) cyclosporine ophthalmic emulsion in the treatment of moderate-to-severe keratoconjunctivitis sicca: a 12-week, multicenter, randomized, active-controlled trial. BMC Ophthalmol 2023;23:121.
Akpek EK, Wirta DL, Downing JE, et al. Efficacy and safety of a water-free topical cyclosporine, 0.1%, solution for the treatment of moderate to severe dry eye disease: the ESSENCE-2 randomized clinical trial. JAMA Ophthalmol 2023;141:459-66.
Shin J, Rho CR, Hyon JY, Chung TY, Yoon KC, Joo CK. A randomized, placebo-controlled phase II clinical trial of 0.01% or 0.02% cyclosporin A with 3% trehalose in patients with dry eye disease. J Ocul Pharmacol Ther 2021;37:4-11.
Priani D, Muhiddin HS, Sirajuddin J, Eka HB, Bahar B, Bukhari A. Effectiveness of topical cyclosporin-A 0.1% compared to combined topical cyclosporin-A 0.1% with topical sodium hyaluronate on interleukin-6 levels in the tears of patients with dry eye disease. Vision (Basel) 2023;7:31.
Higuchi A. Autologous serum and serum components. Invest Ophthalmol Vis Sci 2018;59:DES121-DES129.
Giannaccare G, Carnevali A, Senni C, Logozzo L, Scorcia V. Umbilical cord blood and serum for the treatment of ocular diseases: a comprehensive review. Ophthalmol Ther 2020;9:235-48.
Wong J, Govindasamy G, Prasath A, et al. Allogeneic umbilical cord plasma eyedrops for the treatment of recalcitrant dry eye disease patients. J Clin Med 2023;12:6750.
Kumari N, Kusumesh R, Kumari R, Sinha BP, Singh V. Comparative evaluation of effectiveness of twenty versus fifty percent autologous serum eye drops in treatment of dry eye. Indian J Ophthalmol 2023;71:1603-7.
van der Meer PF, Verbakel SK, Honohan Á, et al. Allogeneic and autologous serum eye drops: a pilot double-blind randomized crossover trial. Acta Ophthalmol 2021;99:837-42.
Mukhopadhyay S, Sen S, Datta H. Comparative role of 20% cord blood serum and 20% autologous serum in dry eye associated with Hansen’s disease: a tear proteomic study. Br J Ophthalmol 2015;99:108-12.
Rodríguez Calvo-de-Mora M, Domínguez-Ruiz C, Barrero-Sojo F, et al. Autologous versus allogeneic versus umbilical cord sera for the treatment of severe dry eye disease: a double-blind randomized clinical trial. Acta Ophthalmol 2022;100:e396-e408.
Haber SL, Benson V, Buckway CJ, Gonzales JM, Romanet D, Scholes B. Lifitegrast: a novel drug for patients with dry eye disease. Ther Adv Ophthalmol 2019;11:2515841419870366.
Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci 2011;52:3174-80.
Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R. Lifitegrast, a novel integrin antagonist for treatment of dry eye disease. Ocul Surf 2016;14:207-15.
Abidi A, Shukla P, Ahmad A. Lifitegrast: a novel drug for treatment of dry eye disease. J Pharmacol Pharmacother 2016;7:194-8.
Tauber J, Karpecki P, Latkany R, et al. Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology 2015;122:2423-31.
Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology 2017;124:53-60.
Holland EJ, Jackson MA, Donnenfeld E, et al. Efficacy of lifitegrast ophthalmic solution, 5.0%, in patients with moderate to severe dry eye disease: a post hoc analysis of 2 randomized clinical trials. JAMA Ophthalmol 2021;139:1200-8.
Boboridis KG, Konstas AGP. Evaluating the novel application of cyclosporine 0.1% in ocular surface disease. Expert Opin Pharmacother 2018;19:1027-39.
Leonardi A, Van Setten G, Amrane M, 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 2016;26:287-96.
Stevenson D, Tauber J, Reis BL. 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 2000;107:967-74.
Rodriguez-Garcia A, Babayan-Sosa A, Ramirez-Miranda A, et al. A practical approach to severity classification and treatment of dry eye disease: a proposal from the Mexican Dry Eye Disease Expert Panel. Clin Ophthalmol 2022;16:1331-55.
Foulks GN, Forstot SL, Donshik PC, et al. Clinical guidelines for management of dry eye associated with Sjögren disease. Ocul Surf 2015;13:118-32.
Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017;15:575-628.
de Oliveira RC, Wilson SE. Practical guidance for the use of cyclosporine ophthalmic solutions in the management of dry eye disease. Clin Ophthalmol 2019;13:1115-22.
Barber LD, Pflugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005;112:1790-4.
Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003;22:640-50.
Pellegrini M, Bernabei F, Moscardelli F, et al. Assessment of corneal fluorescein staining in different dry eye subtypes using digital image analysis. Transl Vis Sci Technol 2019;8:34.
Paugh JR, Tse J, Nguyen T, Sasai A, et al. Efficacy of the fluorescein tear breakup time test in dry eye. Cornea 2020;39:92-8.
Begley CG, Himebaugh N, Renner D, et al. Tear breakup dynamics: a technique for quantifying tear film instability. Optom Vis Sci 2006;83:15-21.
Guyatt GH, Oxman AD, Kunz R, et al. What is “quality of evidence” and why is it important to clinicians? BMJ 2008;336:995-8.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Hong Kong Journal of Ophthalmology
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The Journal has a fully Open Access policy and publishes all articles under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence. For any use other than that permitted by this license, written permission must be obtained from the Journal.
