Modern Perspectives on Dry Eye Disease

European Ophthalmic Review, 2017;11(Suppl 2):2–6

Abstract:

Dry eye disease (DED), a disease of the lacrimal functional unit, is a complex autoimmune-based chronic inflammatory condition that can have a significant negative impact on quality of life and the patient’s ability to effectively carry out everyday activities. Further, DED may lead to contact lens intolerance, and may adversely affect refractive surgical outcomes and be associated with post-ocular surgery complications. The ocular surface system is in constant dynamic equilibrium; however, if damage is severe or too prolonged, repair mechanisms can fail, initiating a feedback loop of increasing inflammation known as the ‘vicious cycle’. Stress to the ocular surface triggers the initial inflammatory events that lead to autoimmunity; autoantibodies may contribute to complementdependent ocular surface pathology. With an aging population and with lifestyles becoming increasingly dependent on screen technology, the burden of DED is likely to escalate in the future. There are multiple challenges in the management of DED, not least the lack of medications for chronic use.
Keywords: Dry eye disease (DED), ocular surface system, immunopathogenesis, anti-inflammatory therapy
Disclosure: Maurizio Rolando has the following potential conflicts of interest to report as consultant, speaker or research grant recipient: Alcon, Allergan, Bausch & Lomb, Eupharma, Farmigea, Horus, Medivis, Novartis, Pfizer, Santen, Sifi, Shire, SOOFT, Thea, TRB Chemedica. Michael E Stern has worked as a consultant for Allergan, Shire, Novaliq and an employee of ImmunEyez, LLC. Over the past 12 months, Margarita Calonge has had research contracts, consultantships, given lectures and been involved in advisory boards for the following: Allergan, Chiesi, Esteve, Ferrer International, Horus Pharma, Santen, Shire and Zealand Pharma. However, Margarita Calonge has no financial interest in any product or technology presented in this symposium. This article covers to proceedings of a symposium
Acknowledgments: Medical writing support, including preparation of the drafts under the guidance of the authors, was provided by Catherine Amey, Touch Medical Media. This report is based on a non-CME educational program sponsored by Shire and held at SOE 2017 on 10 June in Barcelona, Spain.
Received: July 14, 2017 Published Online: September 21, 2017
Correspondence: Maurizio Rolando, ISPRE Ophthalmics Genoa Via Antiochia 29 R, 16129 Genoa, Italy. E. maurizio.rolando@gmail.com
Support: The publication of this article was supported an Independent Educational Grant from Shire. The views and opinions expressed in the article are those of the authors and not necessarily those of Shire.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

The Changing Landscape of Dry Eye Disease in Europe Maurizio Rolando ISPRE Ophthalmics, Genoa, Italy

The latest model of dry eye disease (DED) states that: ‘Dry eye is a multifactorial disease of the ocular surface characterised by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.’1 The ocular surface system is in a constant dynamic equilibrium, always adapting to changing environmental and external insults. However, if the initial damage is severe or too prolonged, repair mechanisms can fail, ultimately resulting in a feedback loop of escalating inflammation termed the ‘vicious cycle’.2 Once the cycle is initiated, the continuous environmental challenge acting on a compromised ocular surface allows the vicious cycle to perpetuate, even if the initial cause has been removed or reduced.3–5 The most frequent results of the vicious cycle are: tear instability, epithelial malfunction/ damage and inflammation.6 Tear film abnormalities are associated with hyper-evaporation and reduced tear clearance.7 The resulting increased osmolarity leads to eye irritation, which, if persistent, causes production of pro-inflammatory cytokines on the ocular surface to be upregulated. The result is a chronic immuno-inflammatory condition, with the recruitment, activation and involvement of regulators, helper and killer lymphocytes. Pathophysiological factors that contribute to this immune-mediated disorder include: aqueous deficiency, mucin abnormalities, and evaporation (as occurs in Meibomian gland disease [MGD] or when the blink rate exceeds the tear film break-up time [TBUT]).7 There are multiple causes and contributors to an abnormal tear film, which include ageing, dry environment, hormonal changes, medications, blepharitis, surgery (laser-assisted in situ keratomileusis [LASIK]) and autoimmune disease.7

The prevalence estimates of DED in Europe8–11 are consistent with global data, which indicate a prevalence of between 7% and 30%.12 The exact prevalence is difficult to accurately determine due to a lack of consensus on diagnostic methods, a mismatch between signs and symptoms, and the use of restricted cohorts that have traditionally excluded younger individuals with multiscreen lifestyles. While the typical patient seen in the past might have been female and aged over 50 years,4 modern patients may be younger contact lens wearers.13 With the average UK adult now spending more time using digital media than sleeping,14 lifestyle-driven DED is set to increase. This increase is in combination with the rise due to the ageing population.

DED can have a substantial effect on general quality of life (QoL) and health-related QoL.4 In fact, a utility assessment of 44 patients in the UK with DED found that severe DED may impact a patient’s life to a similar extent as dialysis and severe angina.15 This impact can be on everyday activities such as reading, working, computer use, watching television and daytime or night-time driving, and as such is an important public health problem.16 It can also result in contact lens intolerance and discontinuation.4 In general, the impact of DED persists over long periods of time and increases with disease progression and/or severity.17 DED is often chronic and progressive. In a study of 398 men and 386 women who reported they had DED and responded to a questionnaire, those who reported severe symptoms of DED in the past were more likely to report worsening odds ratio (OR) 1.79 (1.07–3.00).18


An analysis of data from 648 patients with DED (82.7% female; mean age 55.8 year, standard deviation: 15.6 years) from the Groningen LOngitudinal Sicca StudY (GLOSSY), found that greater symptoms versus signs were highly associated with lower self-perceived health (p19 This discrepancy highlights the importance of accounting for both signs and symptoms in DED. Significant predictors of greater symptoms than signs were: chronic pain syndrome; atopic diseases; a known allergy, use of antihistamines; depression; use of antidepressants; and osteoarthritis.

DED can adversely affect refractive surgery outcomes and may be associated with increased risk of infection/post-ocular surgery complications.4 Further, cataract surgery in patients with DED can be associated with ocular morbidity.4 The risk for refractive regression after LASIK has been shown to increase in patients with chronic dry eye (27% of patients [12/45] with chronic DED versus 7% of patients [35/520] without DED [p20 In a Korean study, 48 eyes of 34 patients who underwent uncomplicated phacoemulsification were divided into two groups: those with pre-existing DED before cataract surgery and those without. Compared with the non-DED group, the DED group had significantly higher ocular symptom scores, lower TBUT, higher lid margin abnormalities, meibum quality and expressibility scores after cataract surgery.21 There were also significant correlations between interleukin (IL)-6 and parameters of DED. Furthermore, the presence of dry eyerelated changes in osmolarity is a significant cause of error in the measurement of the intraocular lens to be implanted.22


Summary

The prevalence of DED in Europe is consistent with global estimates: 7–22%. The burden of DED is likely to escalate in the future, with an ageing population and as lifestyles become increasingly dependent on multiscreen technologies. DED is often a chronic disease that can impact everyday activities and could lead to contact lens intolerance. In addition, DED may adversely affect refractive surgical outcomes and may be associated with post-ocular surgery complications.


Immunopathogenesis of Dry Eye Disease and its Clinical Relevance Michael E Stern ImmunEyez, LLC, CA and Baylor College of Medicine, TX, US

DED is a disease of the lacrimal functional unit;23 which, in the normal individual provides a homeostatic environment to the ocular surface through its regulation of tear film composition.24 The three main tear film components are, firstly, the mucins (secreted in soluble form by the conjunctival goblet cells and expressed as transmembrane entities across the ocular surface epithelium). This provides viscosity and stability during blink cycle. Secondly, the aqueous consists of a complex mixture of proteins, mucins, electrolytes etc., and, thirdly, the lipid layer (secreted by the Meibomian glands along the lid margin) that helps to maintain a smooth optical surface and prevent evaporation.24 New research suggests that mixing of the mucin and aqueous layer occurs, which forms a hydrated gel that is then covered by the lipid layer.24 In a typical patient with chronic DED, the tear film features both aqueous deficiency and an altered lipid layers and mucin profile.25

One of the most common mucins in humans, soluble mucin 5AC is greatly decreased in DED due to a loss of goblet cells and this impacts on viscosity of the tear film.25 Antimicrobial proteins such as lactoferrin and lysozyme are lower in concentration while pro-inflammatory cytokines such as IL-1 and tumour necrosis factor (TNF)-α are increased and proteases are activated, which in addition to eliciting a pro-inflammatory environment on the ocular surface, degrade extracellular matrix and epithelial tight junctions.24 Finally, increased electrolyte concentrations such as sodium ions elevate tear osmolarity. Patients with DED display an array of inflammatory markers such as pro-inflammatory cytokine/chemokine expression, upregulation of human leukocyte antigen (HLA) expression, elevated expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and infiltration of inflammatory cells.26

In a comparison of cytokine/chemokine levels in 23 patients with DED versus nine control subjects, levels of the following were significantly (p27 This acute inflammation leads to self-antigen-driven autoimmunity (Figure 2).23,28 Induction of pro-inflammatory factors may be initiated by stress-induced signal transduction pathways or aberrant Toll-like receptor (TLR) signalling.28 Antigen-presenting cells (APCs) internalise autoantigens, process and present immunogenic epitopes and upregulate expression of costimulatory molecules. C-C chemokine receptor type 7 (CCR7), which is expressed on APCs, directs trafficking to the draining cervical lymph node, activating pathogenic lymphocytes.29 The local cytokine milieu, produced by mature APCs, influence activation and differentiation of autoreactive T-helper 1


(Th1cells), which mediate immunity against intracellular pathogens and secrete, among other cytokines, IFN-gamma. Th17 cells, which are involved in several inflammatory diseases, are also activated; these secrete IL-17 and promote elevation in proinflammatory cytokine and chemokine production in a variety of cell types as well as contributing to the regulatory T cell (Treg) defect in DED.30

Autoreactive lymphocytes potentiate the chronic autoimmune response and mediate different pathological consequences on the ocular surface.28 IFN-gamma, derived from Th1 cells, alters mucins on corneal epithelial cells and has devastating effects on the integrity of the ocular surface.31,32 These include epithelial cell apoptosis in both the conjunctiva and lacrimal glands, reduced goblet cell density and squamous metaplasia.33 IL-17 increases matrix metalloproteinase (MMP) 3/9 expression and induces corneal epithelial barrier dysfunction.30,32 Th17-related cytokines have been shown to correlate with disease severity.


Summary

DED is a complex autoimmune-based chronic inflammatory disease.28 Stress to the ocular surface triggers the initial inflammatory events that lead to autoimmunity.28 Cytokines present within ocular surface tissues affects T cell differentiation into Th1 and Th17 cells.28 Autoantibodies derived from autoreactive B cells appear to contribute to complementdependent ocular surface pathology.28


Challenges in the Management of Dry Eye Disease

General therapeutic schemes are laid out by the Dry Eye Syndrome Preferred Practice Patterns of the American Academy of Ophthalmology;34 the 2006 International Task Force (ITF) Delphi Panel Guidelines for Dry Eye35 and the 2007 Report of the International Dry Eye Workshop (DEWS).4 An update of the Report of the International DEWS (DEWS II) is expected in July 2017 but was not available at the time of writing. Disease severity is considered to be the most important factor for treatment decision-making and has been categorised into four levels (Table 1).36

Inflammation is always present in DED, regardless of the type of DED.4 Anti-inflammatory agents used to tackle this are all offlabel and include topical steroids, topical azithromycin and oral tetracyclines (doxycycline). Topical steroids most frequently utilised in the short-term therapy for DED are loteprednol etabonate,37–39 fluorometholone40,41 and glucocorticoid.42,43 In a randomised, vehiclecontrolled trial, three-week topical 0.1% fluorometholone therapy was shown to be effective not only in reducing ocular surface signs in patients with DED but also in preventing exacerbation by exposure to desiccating stress.41

Immunomodulatory agents used in DED include topical cyclosporin A, tacrolimus and lifitegrast. Cyclosporin A has restricted availability worldwide whereas lifitegrast is not approved yet outside the US.44 Topical cyclosporin A inhibits T-cell-mediated inflammation and activation and has anti-inflammatory, anti-apoptotic and immunomodulatory effects.45 Its use also brings about an increase in lacrimal gland production of tears.45 Topical 0.05% unpreserved cyclosporin A is not approved in the European Union while 0.1% topical unpreserved cyclosporin A has recently become available in some EU countries.46 Clinical trials have shown that topical cyclosporin A decreased lymphocyte infiltration and activation, and markers of apoptosis and proinflammatory cytokines.45 In general, improved symptom scores, decreased ocular staining, and increased Schirmer scores were observed with cyclosporin A treatment.47 Goblet cell density, tear meniscus height and volume and corneal sensitivity have also been shown to improve,47 as well as decreased use of artificial tears.48 Topical tacrolimus, an immunomodulatory macrolide, has a similar mechanism of action to cyclosporin A with 10- to 100-times more potency.49 It inhibits calcium-dependent events such as IL-2 gene transcription, nitric oxide synthase activation, cell degranulation and apoptosis.49 Topical tacrolimus suppresses the immune response by inhibiting the release of other inflammatory cytokines (IL-3, 4, 5 and 8, IFNα, TNFα).49 Topical lifitegrast targets ICAM-1/ lymphocyte functionassociated antigen (LFA)-1,50,51 interrupting the inflammatory cycle.52 5% topical lifitegrast solution is currently approved only in the US.53 Clinical trials of the potential benefits of lifitegrast showed reduced signs of DED as measured by corneal and conjunctival staining, and reduced symptoms of eye dryness and discomfort.54–58 In addition, it was generally well tolerated, as evidenced by short-term (84 day) clinical trials and a longer term (360 day) safety study.54–58



Summary of challenges in the management of dry eye disease
  • Lifestyle modifications (e.g. environmental, nutritional, omega 3 supplements).
  • Withdraw any non-required topical/systemic medications.
  • Treat MGD aggressively.
  • Artificial tear substitutes are always indicated.
  • Autologous serum and derivatives are very useful when indicated.
  • Tear drainage blockade is controversial
  • Doxycycline oral/azithromycin topical or oral, for eyelids and cornea.
  • Topical steroids short-term are essential, though an improved safety profile is needed.
  • Topical cyclosporin: prepare ocular surface for tolerance.
  • Topical lifitegrast: limited real-world experience in the US, no experience elsewhere.
  • Systemic immunosuppressants: Sjögren’s syndrome, graft-versushost disease.
  • The most significant challenge is the scarcity of medications available for chronic use.

Discussion
Q: Are there any notable trends with respect to prevalence of DED?
We are observing a rise in prevalence owing to MGD. We are now seeing more young people with DED due in part to over-use of screens and the effect of pollution on the ocular surface.
Q. What are the three top bio markers for DED?
IL-6, which is a precursor of Th 17-mediated inflammation; epidermal growth factor receptor; and MMP9 are the most studied although the biomarker may vary depending on the drug.
Q. What in general drives patients to your office: signs, symptoms or both?
Most patients present because of their symptoms and the impact they have on their lives, for example, their ability to work and drive.
Q. If inflammation is under control, do we break the vicious cycle and restore ocular surface heath?
Resolution of the disease or at least disease control is possible with long-term suppression of inflammation. For optimal results, we need an anti-inflammatory agent for chronic use (many years).
Q. What antigen plays a key role in the vicious cycle?
There are two hypotheses: destroyed pathogenic bacteria may release antigens; or TLRs may be activated by DNA segments shredded from apoptosis.
Q. When are punctal plugs useful?
These can be harmful in that they can maintain the inflammatory soup present on the ocular surface. They should not be used in the case of MGD or blepharitis in general and whenever improvement is not observed, the plugs should be removed.
References:
1. Persico J, International Dry Eye Workshop II. Presented at ARVO 2017, 2017. Available at: www.reviewofoptometry.com/article/ zen-and-the-art-of-dry-eye (acessed 22 June 2017).
2. Baudouin C, [A new approach for better comprehension of diseases of the ocular surface], J Fr Ophtalmol, 2007;30:239–46.
3. 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.
4. Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007), Ocul Surf, 2007;5:179–93.
5. Baudouin C, Messmer EM, Aragona P, 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.
6. Aragona P, Rolando M, Towards a dynamic customised therapy for ocular surface dysfunctions, Br J Ophthalmol, 2013;97:955–60.
7. Rolando M, Geerling G, Dua HS, Emerging treatment paradigms of ocular surface disease: proceedings of theOcular Surface Workshop, Br J Ophthalmol, 2010;94(Suppl 1):i1–9.
8. Viso E, Rodriguez-Ares MT, Gude F, Prevalence of and associated factors for dry eye in a Spanish adult population (the Salnes Eye Study), Ophthalmic Epidemiol, 2009;16:15–21.
9. Bjerrum KB, Keratoconjunctivitis sicca and primary Sjogren’s syndrome in a Danish population aged 30-60 years, Acta Ophthalmol Scand, 1997;75:281–6.
10. Malet F, Le Goff M, Colin J, et al., Dry eye disease in French elderly subjects: the Alienor Study, Acta Ophthal, 2014;92:e429–36.
11. Vehof J, Kozareva D, Hysi PG, Hammond CJ, Prevalence and risk factors of dry eye disease in a British female cohort, Br J Ophthalmol, 2014;98:1712–7.
12. Fridman M et al., A Systematic Literature Review and Meta- Analysis of Dry Eye Disease Prevalence Based on 30 Studies From Around the Globe. Presented at: ASCRS 2017, Los Angeles, CA, May 5–9.
13. Uchino M, Schaumberg DA, Dogru M, et al., Prevalence of dry eye disease among Japanese visual display terminal users, Ophthalmology, 2008;115:1982–8.
14. Ofcom Communications Market Report 2016. Available at: www.ofcom.org.uk/research-and-data/multi-sector-research/ cmr/cmr16 (accessed 22 June 2017).
15. Buchholz P, Steeds CS, Stern LS, et al., Utility assessment to measure the impact of dry eye disease, Ocul Surf, 2006;4:155–61.
16. Miljanovic B, Dana R, Sullivan DA, Schaumberg DA, Impact of dry eye syndrome on vision-related quality of life, Am J Ophthalmol, 2007;143:409–15.
17. McDonald M, Patel DA, Keith MS, Snedecor SJ, Economic and humanistic burden of dry eye disease in Europe, North America, and Asia: a systematic literature review, Ocul Surf, 2016;14:144–67.
18. Lienert J, Tarko L, Uchino M, et al., Long-term natural history of dry eye disease from the patient’s perspective, Ophthalmology, 2016;123:425–33.
19. Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ, Predictors of discordance between symptoms and signs in dry eye disease, Ophthalmology, 2017;124:280–6.
20. Albietz JM, Lenton LM, McLennan SG, Chronic dry eye and regression after laser in situ keratomileusis for myopia, J Cataract Refract Surg, 2004;30:675–84.
21. Park Y, Hwang HB, Kim HS, Observation of influence of cataract surgery on the ocular surface, PloS One, 2016;11:e0152460.
22. Epitropoulos AT, Matossian C, Berdy GJ, et al., Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning, J Cataract Refract Surg, 2015;41:1672–7.
23. Stern ME, Schaumburg CS, Pflugfelder SC, Dry eye as a mucosal autoimmune disease, Int Rev Immunol, 2013;32:19–41.
24. Peters E, Colby, K, Chapter 3, The Tear Film. In: Tasman W, Jaeger EA (ed), Duane’s Ophthalmology, Philadelphia: Lippincott Williams & Wilkins, 2009.
25. Pflugfelder S, Beuerman R, Stern ME, Dry Eye and Ocular Surface Disorders, (first edn), CRC Press, 2004.
26. 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.
27. Enriquez-de-Salamanca A, Castellanos E, Stern ME, et al., Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease, Mol Vis, 2010;16:862–73.
28. Stern ME, Schaumburg CS, Dana R, et al., Autoimmunity at the ocular surface: pathogenesis and regulation, Mucosal Immunol, 2010;3:425–42.
29. Saban DR, The chemokine receptor CCR7 expressed by dendritic cells: a key player in corneal and ocular surface inflammation, Ocul Surf, 2014;12:87–99.
30. Chauhan SK, El Annan J, Ecoiffier T, et al., Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression, J Immunol, 2009;182:1247–52.
31. de Paiva CS, Villarreal AL, Corrales RM, et al., IFN– Promotes goblet cell loss in response to desiccating ocular stress, Invest Ophthalmol Vis Sci, 2006;47:5579. E-Abstract.
32. De Paiva CS, Chotikavanich S, Pangelinan SB, et al., IL-17 disrupts corneal barrier following desiccating stress, Mucosal Immunol, 2009;2:243–53.
33. De Paiva CS, Villarreal AL, Corrales RM, et al., Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma, Invest Ophthalmol Vis Sci, 2007;48:2553–60.
34. Dry Eye Syndrome Preferred Practice Patterns of the American Academy of Ophthalmology 2013. Available at: www.aao. org/preferred-practice-pattern/dry-eye-syndrome-ppp--2013 (accessed 26 June 2017).
35. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007), Ocul Surf, 2007;5:163–78.
36. Behrens A, Doyle JJ, Stern L, et al., Dysfunctional tear syndrome: a Delphi approach to treatment recommendations, Cornea, 2006;25:900–7.
37. Pflugfelder SC, Maskin SL, Anderson B, et al., A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance, Am J Ophthalmol, 2004;138:444–57.
38. Jung HH, Ji YS, Sung MS, et al., Long-term outcome of treatment with topical corticosteroids for severe dry eye associated with sjogren’s syndrome, Chonnam Med J, 2015;51:26–32.
39. Lee H, Chung B, Kim KS, et al., Effects of topical loteprednol etabonate on tear cytokines and clinical outcomes in moderate and severe meibomian gland dysfunction: randomized clinical trial, Am J Ophthalmol, 2014;158:1172–83.e1.
40. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE, The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study, Am J Ophthalmol, 2003;136:593–602.
41. Pinto-Fraga J, Lopez-Miguel A, Gonzalez-Garcia MJ, et al., Topical fluorometholone protects the ocular surface of dry eye patients from desiccating stress: a randomized controlled clinical trial, Ophthalmology, 2016;123:141–53.
42. Marsh P, Pflugfelder SC, Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome, Ophthalmology, 1999;106:811–6.
43. Sainz De La Maza Serra M, Simon Castellvi C, Kabbani O, [Nonpreserved topical steroids and lacrimal punctal occlusion for severe keratoconjunctivitis sicca], Archivos de la Sociedad Espanola de Oftalmologia, 2000;75:751–6.
44. FDA News Release, FDA approves new medication for dry eye disease [press release] 12 July 2016. Available at www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm510720. htm (accessed 17 August 2017)..
45. Donnenfeld E, Pflugfelder SC, Topical ophthalmic cyclosporine: pharmacology and clinical uses, Surv Ophthalmol, 2009;54:321–38.
46. Ikervis, European Medicines Agency 2015. Available at: www. ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/ medicines/002066/smops/Positive/human_smop_000783. jsp&mid=WC0b01ac058001d127 (accessed 26 June 2017).
47. Ames P, Galor A, Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence, Clin Investig (Lond), 2015;5:267–85.
48. 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.
49. Moscovici BK, Holzchuh R, Sakassegawa-Naves FE, et al., Treatment of Sjogren’s syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study, Cont Lens Anterior Eye, 2015;38:373–8.
50. Gao J, Morgan G, Tieu D, et al., ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjogrens syndrome-like MRL/lpr mice, Exp Eye Res, 2004;78:823–35.
51. Stern ME, Gao J, Schwalb TA, et al., Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye, Invest Ophthalmol Vis Sci, 2002;43:2609–14.
52. Perez VL, Pflugfelder SC, Zhang S, et al., Lifitegrast, a novel integrin antagonist for treatment of dry eye disease, Ocul Surf, 2016;14:207–15.
53. FDA approves new medication for dry eye disease 2016. Available at: www.fda.gov/newsevents/newsroom/ pressannouncements/ucm510720.htm (accessed 26 June 2107).
54. Semba CP, Swearingen D, Smith VL, et al., Safety and pharmacokinetics of a novel lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) in healthy adults, J Ocul Pharmacol Ther, 2011;27:99–104.
55. Sheppard JD, Torkildsen GL, Lonsdale JD, et al., Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study, Ophthalmology, 2014;121:475–83.
56. 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.
57. 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.
58. Donnenfeld ED, Karpecki PM, Majmudar PA, et al., Safety of lifitegrast ophthalmic solution 5.0% in patients with dry eye disease: a 1-year, multicenter, randomized, placebo-controlled study, Cornea, 2016;35:741–8.
Keywords: Dry eye disease (DED), ocular surface system, immunopathogenesis, anti-inflammatory therapy