Molecular evidence for the role of inflammation in dry eye disease

REFERENCES

• Schein OD, Munoz B, Tielsch JM et al. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997; 124: 723–728.
   PubMed Web of Science ®Google Scholar
• The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5: 93–107.
   PubMed Web of Science ®Google Scholar
• Mathers WD, Shields WJ, Sachdev MS et al. Meibomian gland dysfunction in chronic blepharitis. Cornea 1991; 10: 277–285.
   PubMed Web of Science ®Google Scholar
• Epstein RJ, Stulting RD, Hendricks RL et al. Corneal neovascularization. Pathogenesis and inhibition. Cornea 1987; 6: 250–257.
   PubMed Web of Science ®Google Scholar
• Mathers WD. Ocular evaporation in meibomian gland dysfunction and dry eye. Ophthalmology 1993; 100: 347–351.
   PubMed Web of Science ®Google Scholar
• Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol 1995; 113: 1266–1270.
   PubMed Web of Science ®Google Scholar
• Brown MM, Brown GC, Brown HC et al. Value‐based medicine, comparative effectiveness, and cost‐effectiveness analysis of topical cyclosporine for the treatment of dry eye syndrome. Arch Ophthalmol 2009; 127: 146–152.
   PubMedGoogle Scholar
• Buchholz P, Steeds CS, Stern LS et al. Utility assessment to measure the impact of dry eye disease. Ocul Surf 2006; 4: 155–161.
   PubMed Web of Science ®Google Scholar
• Craig JP, Nichols KK, Akpek EK et al. TFOS DEWS II definition and classification report. Ocul Surf 2017; 15: 276–283.
   PubMed Web of Science ®Google Scholar
• Bron AJ, de Paiva CS, Chauhan SK et al. TFOS DEWS II pathophysiology report. Ocul Surf 2017; 15: 438–510.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Acera A, Rocha G, Vecino E et al. Inflammatory markers in the tears of patients with ocular surface disease. Ophthalmic Res 2008; 40: 315–321.
   PubMed Web of Science ®Google Scholar
• Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye Contact Lens 2014; 40: 248–256.
   PubMed Web of Science ®Google Scholar
• Stern ME, Beuerman RW, Fox RI et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea 1998; 17: 584–589.
   PubMed Web of Science ®Google Scholar
• Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune‐mediated ocular surface disorder. Arch Ophthalmol 2012; 130: 90–100.
   PubMed Web of Science ®Google Scholar
• Chen YT, Nikulina K, Lazarev S et al. Interleukin‐1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjogren's syndrome. Am J Pathol 2010; 177: 1333–1343.
   PubMed Web of Science ®Google Scholar
• Baudouin C, Messmer EM, Aragona P. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol 2016; 100: 300–306.
   PubMed Web of Science ®Google Scholar
• Pflugfelder SC, de Paiva CS, Li DQ et al. Epithelial‐immune cell interaction in dry eye. Cornea 2008; 27: S9–S11.
   PubMed Web of Science ®Google Scholar
• Schrader S, Mircheff AK, Geerling G. Animal models of dry eye. Dev Ophthalmol 2008; 41: 298–312.
   PubMedGoogle Scholar
• Willcox MDP, Argüeso P, Georgiev GA et al. TFOS DEWS II tear film report. Ocul Surf 2017; 15: 366–403.
   PubMed Web of Science ®Google Scholar
• Corrales RM, Stern ME, De paiva CS et al. Desiccating stress stimulates expression of matrix metalloproteinases by the corneal epithelium. Invest Ophthalmol Vis Sci 2006; 47: 3293–3302.
   PubMed Web of Science ®Google Scholar
• Rosette C, Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 1996; 274: 1194–1197.
   PubMed Web of Science ®Google Scholar
• Massingale ML, Li X, Vallabhajosyula M et al. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea 2009; 28: 1023–1027.
   PubMed Web of Science ®Google Scholar
• 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: 862–873.
   PubMed Web of Science ®Google Scholar
• Jackson DC, Zeng W, Wong CY et al. Tear interferon‐gamma as a biomarker for evaporative dry eye disease. Invest Ophthalmol Vis Sci 2016; 57: 4824–4830.
   PubMed Web of Science ®Google Scholar
• Mosmann TR. T lymphocyte subsets, cytokines, and effector functions. Ann N Y Acad Sci 1992; 664: 89–92.
   PubMed Web of Science ®Google Scholar
• Mosmann TR, Sad S. The expanding universe of T‐cell subsets: Th1, Th2 and more. Immunol Today 1996; 17: 138–146.
   PubMedGoogle Scholar
• 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: 2553–2560.
   PubMed Web of Science ®Google Scholar
• Lam H, Bleiden L, de Paiva CS et al. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol 2009; 147: 198–205.e1.
   PubMed Web of Science ®Google Scholar
• Pflugfelder SC, De paiva CS, Villarreal AL et al. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor‐beta2 production. Cornea 2008; 27: 64–69.
   PubMed Web of Science ®Google Scholar
• Strong B, Farley W, Stern ME et al. Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. Cornea 2005; 24: 80–85.
   PubMed Web of Science ®Google Scholar
• Hershey GK. IL‐13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 2003; 111: 677–690.
   PubMed Web of Science ®Google Scholar
• Lee MH, Choi JW, Jang WR et al. Activation of eosinophils is more closely linked with interleukin‐5 and nitric oxide production than tumor necrosis factor‐alpha and immunoglobulin E levels. Acta Haematol 2013; 130: 238–241.
   Web of Science ®Google Scholar
• De paiva CS, Raince JK, Mcclellan AJ et al. Homeostatic control of conjunctival mucosal goblet cells by NKT‐derived IL‐13. Mucosal Immunol 2011; 4: 397–408.
   PubMed Web of Science ®Google Scholar
• Bettelli E, Carrier Y, Gao W et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.
   PubMed Web of Science ®Google Scholar
• Bettelli E, Oukka M, Kuchroo VK. T(H)‐17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 8: 345–350.
   PubMed Web of Science ®Google Scholar
• Chen Z, O'shea JJ. Th17 cells: a new fate for differentiating helper T cells. Immunol Res 2008; 41: 87–102.
   PubMed Web of Science ®Google Scholar
• De paiva CS, Chotikavanich S, Pangelinan SB et al. IL‐17 disrupts corneal barrier following desiccating stress. Mucosal Immunol 2009; 2: 243–253.
   PubMed Web of Science ®Google Scholar
• Katsifis GE, Rekka S, Moutsopoulos NM et al. Systemic and local interleukin‐17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis. Am J Pathol 2009; 175: 1167–1177.
   PubMed Web of Science ®Google Scholar
• Zhang N, Pan HF, Ye DQ. Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 2011; 353: 41–46.
   Web of Science ®Google Scholar
• Chotikavanich S, de Paiva CS, de Li Q et al. Production and activity of matrix metalloproteinase‐9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci 2009; 50: 3203–3209.
   PubMed Web of Science ®Google Scholar
• Li DQ, Chen Z, Song XJ et al. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2004; 45: 4302–4311.
   PubMed Web of Science ®Google Scholar
• Pflugfelder SC, Farley W, Luo L et al. Matrix metalloproteinase‐9 knockout confers resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol 2005; 166: 61–71.
   PubMed Web of Science ®Google Scholar
• Kaufman HE. The practical detection of mmp‐9 diagnoses ocular surface disease and may help prevent its complications. Cornea 2013; 32: 211–216.
   PubMed Web of Science ®Google Scholar
• Brignole F, Pisella PJ, Goldschild M et al. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci 2000; 41: 1356–1363.
   PubMed Web of Science ®Google Scholar
• Tsubota K, Fujita H, Tsuzaka K et al. Quantitative analysis of lacrimal gland function, apoptotic figures, Fas and Fas ligand expression of lacrimal glands in dry eye patients. Exp Eye Res 2003; 76: 233–240.
   PubMed Web of Science ®Google Scholar
• 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: 823–835.
   PubMed Web of Science ®Google Scholar
• Semba CP, Gadek TR. Development of lifitegrast: a novel T‐cell inhibitor for the treatment of dry eye disease. Clin Ophthalmol 2016; 10: 1083–1094.
   PubMed Web of Science ®Google Scholar
• El annan J, Chauhan SK, Ecoiffier T et al. Characterization of effector T cells in dry eye disease. Invest Ophthalmol Vis Sci 2009; 50: 3802–3807.
   PubMed Web of Science ®Google Scholar
• Chauhan SK, Jin Y, Goyal S et al. A novel pro‐lymphangiogenic function for Th17/IL‐17. Blood 2011; 118: 4630–4634.
   Web of Science ®Google Scholar
• Chen Y, Chauhan SK, Lee HS et al. Chronic dry eye disease is principally mediated by effector memory Th17 cells. Mucosal Immunol 2014; 7: 38–45.
   Web of Science ®Google Scholar
• Li X, Li X, Qian L et al. T regulatory cells are markedly diminished in diseased salivary glands of patients with primary Sjogren's syndrome. J Rheumatol 2007; 34: 2438–2445.
   PubMed Web of Science ®Google Scholar
• Crispin JC, Martinez A, Alcocer‐varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2003; 21: 273–276.
   PubMed Web of Science ®Google Scholar
• Ehrenstein MR, Evans JG, Singh A et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti‐TNFalpha therapy. J Exp Med 2004; 200: 277–285.
   PubMed Web of Science ®Google Scholar
• Stapleton F, Alves M, Bunya VY et al. TFOS DEWS II epidemiology report. Ocul Surf 2017; 15: 334–365.
   PubMed Web of Science ®Google Scholar
• Izumi Y, Ida H, Huang M et al. Characterization of peripheral natural killer cells in primary Sjogren's syndrome: impaired NK cell activity and low NK cell number. J Lab Clin Med 2006; 147: 242–249.
   PubMed Web of Science ®Google Scholar
• Barabino S, Montaldo E, Solignani F et al. Immune response in the conjunctival epithelium of patients with dry eye. Exp Eye Res 2010; 91: 524–529.
   PubMed Web of Science ®Google Scholar
• Chen Y, Chauhan SK, Saban DR et al. Interferon‐gamma‐secreting NK cells promote induction of dry eye disease. J Leukoc Biol 2011; 89: 965–972.
   PubMed Web of Science ®Google Scholar
• Luo L, Li DQ, Corrales RM et al. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye Contact Lens 2005; 31: 186–193.
   PubMedGoogle Scholar
• De paiva CS, Pangelinan SB, Chang E et al. Essential role for c‐Jun N‐terminal kinase 2 in corneal epithelial response to desiccating stress. Arch Ophthalmol 2009; 127: 1625–1631.
   Google Scholar
• Li DQ, Luo L, Chen Z et al. JNK and ERK MAP kinases mediate induction of IL‐1beta, TNF‐alpha and IL‐8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res 2006; 82: 588–596.
   PubMed Web of Science ®Google Scholar
• Fabiani C, Barabino S, Rashid S et al. Corneal epithelial proliferation and thickness in a mouse model of dry eye. Exp Eye Res 2009; 89: 166–171.
   PubMed Web of Science ®Google Scholar
• Beardsley RM, De paiva CS, Power DF et al. Desiccating stress decreases apical corneal epithelial cell size‐‐modulation by the metalloproteinase inhibitor doxycycline. Cornea 2008; 27: 935–940.
   Web of Science ®Google Scholar
• Luo L, Li DQ, Pflugfelder SC. Hyperosmolarity‐induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways. Cornea 2007; 26: 452–460.
   PubMed Web of Science ®Google Scholar
• Yeh S, Song XJ, Farley W et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci 2003; 44: 124–129.
   PubMed Web of Science ®Google Scholar
• Muller LJ, Marfurt CF, Kruse F et al. Corneal nerves: structure, contents and function. Exp Eye Res 2003; 76: 521–542.
   PubMed Web of Science ®Google Scholar
• Lee HK, Ryu IH, Seo KY et al. Topical 0.1% prednisolone lowers nerve growth factor expression in keratoconjunctivitis sicca patients. Ophthalmology 2006; 113: 198–205.
   PubMed Web of Science ®Google Scholar
• Benitez del castillo JM, Wasfy MA et al. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci 2004; 45: 3030–3035.
   PubMed Web of Science ®Google Scholar
• Goyal S, Chauhan SK, El annan J et al. Evidence of corneal lymphangiogenesis in dry eye disease: a potential link to adaptive immunity? Arch Ophthalmol 2010; 128: 819–824.
   PubMed Web of Science ®Google Scholar
• Skobe M, Dana R. Blocking the path of lymphatic vessels. Nat Med 2009; 15: 993–994.
   PubMed Web of Science ®Google Scholar
• Dursun D, Kim MC, Solomon A et al. Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase‐9, doxycycline and corticosteroids. Am J Ophthalmol 2001; 132: 8–13.
   PubMed Web of Science ®Google Scholar
• 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: 2847–2856.
   PubMed Web of Science ®Google Scholar
• Jones L, Downie LE, Korb D et al. TFOS DEWS II management and therapy report. Ocul Surf 2017; 15: 575–628.
   PubMed Web of Science ®Google Scholar
• 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: 526–535.
   PubMed Web of Science ®Google Scholar
• Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology 1999; 106: 811–816.
   PubMed Web of Science ®Google Scholar
• Avunduk AM, Avunduk MC, Varnell ED et al. 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.
   PubMed Web of Science ®Google Scholar
• 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: 444–457.
   PubMed Web of Science ®Google Scholar
• Mcghee CN, Dean S, Danesh‐meyer H. Locally administered ocular corticosteroids: benefits and risks. Drug Saf 2002; 25: 33–55.
   PubMed Web of Science ®Google Scholar
• Hong S, Kim T, Chung SH et al. Recurrence after topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren's syndrome. J Ocul Pharmacol Ther 2007; 23: 78–82.
   PubMed Web of Science ®Google Scholar
• Yoshida A, Fujihara T, Nakata K. Cyclosporin A increases tear fluid secretion via release of sensory neurotransmitters and muscarinic pathway in mice. Exp Eye Res 1999; 68: 541–546.
   PubMed Web of Science ®Google Scholar
• Schultz C. Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis 2014; 6: 37–42.
   PubMedGoogle Scholar
• 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: 967–974.
   PubMed Web of Science ®Google Scholar
• Sall K, Stevenson OD, Mundorf TK et al. 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: 631–639.
   PubMed Web of Science ®Google Scholar
• Hoy SM. Ciclosporin ophthalmic emulsion 0.1%: a review in severe dry eye disease. Drugs 2017; 77: 1909–1916.
   PubMed Web of Science ®Google Scholar
• Shih KC, Lun CN, Jhanji V et al. Systematic review of randomized controlled trials in the treatment of dry eye disease in Sjogren syndrome. J Inflamm 2017; 14: 26.
   Google Scholar
• Culbertson WW, Huang AJ, Mandelbaum SH et al. Effective treatment of phlyctenular keratoconjunctivitis with oral tetracycline. Ophthalmology 1993; 100: 1358–1366.
   PubMed Web of Science ®Google Scholar
• Voils SA, Evans ME, Lane MT et al. Use of macrolides and tetracyclines for chronic inflammatory diseases. Ann Pharmacother 2005; 39: 86–94.
   PubMed Web of Science ®Google Scholar
• Stone DU, Chodosh J. Oral tetracyclines for ocular rosacea: an evidence‐based review of the literature. Cornea 2004; 23: 106–109.
   PubMed Web of Science ®Google Scholar
• Gilbard JP. Dry eye, blepharitis and chronic eye irritation: divide and conquer. J Ophthalmic Nurs Technol 1999; 18: 109–115.
   PubMedGoogle Scholar
• Seal DV, Wright P, Ficker L et al. Placebo controlled trial of fusidic acid gel and oxytetracycline for recurrent blepharitis and rosacea. Br J Ophthalmol 1995; 79: 42–45.
   Web of Science ®Google Scholar
• Bartholomew RS, Reid BJ, Cheesbrough MJ et al. Oxytetracycline in the treatment of ocular rosacea: a double‐blind trial. Br J Ophthalmol 1982; 66: 386–388.
   PubMed Web of Science ®Google Scholar
• Nikodemova M, Watters JJ, Jackson SJ et al. Minocycline down‐regulates MHC II expression in microglia and macrophages through inhibition of IRF‐1 and protein kinase C (PKC)alpha/betaII. J Biol Chem 2007; 282: 15208–15216.
   PubMed Web of Science ®Google Scholar
• Solomon A, Rosenblatt M, Li DQ et al. Doxycycline inhibition of interleukin‐1 in the corneal epithelium. Invest Ophthalmol Vis Sci 2000; 41: 2544–2557.
   PubMed Web of Science ®Google Scholar
• Akamatsu H, Asada M, Komura J et al. Effect of doxycycline on the generation of reactive oxygen species: a possible mechanism of action of acne therapy with doxycycline. Acta Derm Venereol 1992; 72: 178–179.
   PubMed Web of Science ®Google Scholar
• Pruzanski W, Greenwald RA, Street IP et al. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992; 44: 1165–1170.
   PubMed Web of Science ®Google Scholar
• Yoo SE, Lee DC, Chang MH. The effect of low‐dose doxycycline therapy in chronic meibomian gland dysfunction. Korean J Ophthalmol 2005; 19: 258–263.
   PubMedGoogle Scholar
• Del rosso JQ, Webster GF, Jackson M et al. Two randomized phase III clinical trials evaluating anti‐inflammatory dose doxycycline (40‐mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol 2007; 56: 791–802.
   PubMed Web of Science ®Google Scholar
• Aronowicz JD, Shine WE, Oral D et al. Short term oral minocycline treatment of meibomianitis. Br J Ophthalmol 2006; 90: 856–860.
   PubMed Web of Science ®Google Scholar
• Foulks GN, Borchman D, Yappert M et al. Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study. Cornea 2013; 32: 44–53.
   PubMed Web of Science ®Google Scholar
• Kashkouli MB, Fazel AJ, Kiavash V et al. Oral azithromycin versus doxycycline in meibomian gland dysfunction: a randomised double‐masked open‐label clinical trial. Br J Ophthalmol 2015; 99: 199–204.
   PubMed Web of Science ®Google Scholar
• Liu Y, Kam WR, Ding J et al. Effect of azithromycin on lipid accumulation in immortalized human meibomian gland epithelial cells. JAMA Ophthalmol 2014; 132: 226–228.
   PubMed Web of Science ®Google Scholar
• Liu Y, Kam WR, Ding J et al. Can tetracycline antibiotics duplicate the ability of azithromycin to stimulate human meibomian gland epithelial cell differentiation? Cornea 2015; 34: 342–346.
   PubMed Web of Science ®Google Scholar
• Hooks MA. Tacrolimus, a new immunosuppressant‐a review of the literature. Ann Pharmacother 1994; 28: 501–511.
   PubMed Web of Science ®Google Scholar
• Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T‐lymphocyte activation. Nature 1992; 357: 695–697.
   PubMed Web of Science ®Google Scholar
• Mori A, Suko M, Kaminuma O et al. IL‐2‐induced IL‐5 synthesis, but not proliferation, of human CD4+ T cells is suppressed by FK506. J Immunol 1997; 158: 3659–3665.
   PubMed Web of Science ®Google Scholar
• Reinhard T, Reis A, Mayweg S et al. Topical Fk506 in inflammatory corneal and conjunctival diseases. A pilot study. Klin Monbl Augenheilkd 2002; 219: 125–131.
   Web of Science ®Google Scholar
• Holland EJ, Whitley WO, Sall K et al. Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. Curr Med Res Opin 2016; 32: 1759–1765.
   PubMed Web of Science ®Google Scholar
• James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000; 71: 343s–348s.
   PubMed Web of Science ®Google Scholar
• Simopoulos AP. The importance of the ratio of omega‐6/omega‐3 essential fatty acids. Biomed Pharmacother 2002; 56: 365–379.
   PubMed Web of Science ®Google Scholar
• Endres S, Ghorbani R, Kelley VE et al. The effect of dietary supplementation with n‐3 polyunsaturated fatty acids on the synthesis of interleukin‐1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320: 265–271.
   PubMed Web of Science ®Google Scholar
• Nettleton JA. Omega‐3 fatty acids: comparison of plant and seafood sources in human nutrition. J Am Diet Assoc 1991; 91: 331–337.
   PubMed Web of Science ®Google Scholar
• Wojtowicz JC, Butovich I, Uchiyama E et al. Pilot, prospective, randomized, double‐masked, placebo‐controlled clinical trial of an omega‐3 supplement for dry eye. Cornea 2011; 30: 308–314.
   PubMed Web of Science ®Google Scholar
• Miljanovic B, Trivedi KA, Dana MR et al. Relation between dietary n‐3 and n‐6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr 2005; 82: 887–893.
   PubMed Web of Science ®Google Scholar
• Barabino S, Rolando M, Camicione P et al. Systemic linoleic and gamma‐linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea 2003; 22: 97–101.
   PubMed Web of Science ®Google Scholar
• Deinema LA, Vingrys AJ, Wong CY et al. A randomized, double‐masked, placebo‐controlled clinical trial of two forms of Omega‐3 supplements for treating dry eye disease. Ophthalmology 2017; 124: 43–52.
   PubMed Web of Science ®Google Scholar
• Kangari H, Eftekhari MH, Sardari S et al. Short‐term consumption of oral omega‐3 and dry eye syndrome. Ophthalmology 2013; 120: 2191–2196.
   PubMed Web of Science ®Google Scholar
• Downie LE, Gad A, Wong CY et al. Modulating contact lens discomfort with anti‐inflammatory approaches: a randomized controlled trial. Invest Ophthalmol Vis Sci 2018; 59: 3755–3766.
   Web of Science ®Google Scholar
• Asbell PA, Maguire MG, Pistilli M et al. n‐3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med 2018; 378: 1681–1690.
   PubMed Web of Science ®Google Scholar
• Belch JJ, Hill A. Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr 2000; 71: 352s–356s.
   PubMed Web of Science ®Google Scholar
• Aragona P, Bucolo C, Spinella R et al. Systemic omega‐6 essential fatty acid treatment and pge1 tear content in Sjogren's syndrome patients. Invest Ophthalmol Vis Sci 2005; 46: 4474–4479.
   PubMed Web of Science ®Google Scholar
• Sheppard JD Jr, Singh R, Mcclellan AJ et al. Long‐term supplementation with n‐6 and n‐3 PUFAs improves moderate‐to‐severe keratoconjunctivitis sicca: a randomized double‐blind clinical trial. Cornea 2013; 32: 1297–1304.
   PubMed Web of Science ®Google Scholar
• Kokke KH, Morris JA, Lawrenson JG. Oral omega‐6 essential fatty acid treatment in contact lens associated dry eye. Cont Lens Anterior Eye 2008; 31: 141–146.
   PubMedGoogle Scholar
• He J, Bazan HE. Omega‐3 fatty acids in dry eye and corneal nerve regeneration after refractive surgery. Prostaglandins Leukot Essent Fatty Acids 2010; 82: 319–325.
   Web of Science ®Google Scholar
• Lemp MA. Advances in understanding and managing dry eye disease. Am J Ophthalmol 2008; 146: 350–356.
   PubMed Web of Science ®Google Scholar