Effects of Topical Loteprednol Etabonate on Tear Cytokines and Clinical Outcomes in Moderate and Severe Meibomian Gland Dysfunction: Randomized Clinical Trial

Published:August 13, 2014DOI:


      To assess tear cytokine levels and clinical outcomes in moderate and severe meibomian gland dysfunction (MGD) after 2 months of treatment with topical loteprednol etabonate and eyelid scrubs with warm compresses vs eyelid scrubs with warm compresses alone.


      Randomized controlled trial.


      Patients with moderate and severe MGD were randomized into 2 groups: topical loteprednol etabonate and eyelid scrubs with warm compresses (Group I, 34 eyes) or eyelid scrubs with warm compresses (Group II, 36 eyes). We evaluated cytokine levels, tear film break-up time (TBUT), corneal and conjunctival fluorescein staining, biomicroscopic examination of lid margins and meibomian glands, and the Ocular Surface Disease Index before initiating treatment and 1 month and 2 months after treatment.


      There were significant decreases in the levels of interleukin (IL)-6, IL-8, and IL-1β in Group I, and IL-6 and IL-8 in Group II. Moreover, the observed decreases of these cytokines in Group I were attributed to a remarkable decrease between treatment and 1 month after treatment. In Group I, there were improvements in all of the clinical outcomes, with prominent improvement in TBUT, corneal and conjunctival fluorescein staining, and meibum quality after 1 month of treatment, compared with Group II. An improvement in meibomian gland expressibility and MGD stage reduction were more remarkable in Group I.


      Topical loteprednol etabonate and eyelid scrubs with warm compresses were tolerated and efficacious for the treatment of moderate and severe MGD. We suggest that such beneficial effects could manifest after 1 month.
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        • McCulley J.P.
        • Shine W.E.
        Meibomian gland function and the tear lipid layer.
        Ocul Surf. 2003; 1: 97-106
        • Schaumberg D.A.
        • Nichols J.J.
        • Papas E.B.
        • Tong L.
        • Uchino M.
        • Nichols K.K.
        The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD.
        Invest Ophthalmol Vis Sci. 2011; 52: 1994-2005
        • Mathers W.D.
        Ocular evaporation in meibomian gland dysfunction and dry eye.
        Ophthalmology. 1993; 100: 347-351
        • Nelson J.D.
        • Shimazaki J.
        • Benitez-del-Castillo J.M.
        • et al.
        The international workshop on meibomian gland dysfunction: report of the definition and classification subcommittee.
        Invest Ophthalmol Vis Sci. 2011; 52: 1930-1937
        • Goto E.
        • Endo K.
        • Suzuki A.
        • Fujikura Y.
        • Matsumoto Y.
        • Tsubota K.
        Tear evaporation dynamics in normal subjects and subjects with obstructive meibomian gland dysfunction.
        Invest Ophthalmol Vis Sci. 2003; 44: 533-539
        • Shimazaki J.
        • Sakata M.
        • Tsubota K.
        Ocular surface changes and discomfort in patients with meibomian gland dysfunction.
        Arch Ophthalmol. 1995; 113: 1266-1270
        • Acera A.
        • Rocha G.
        • Vecino E.
        • Lema I.
        • Duran J.A.
        Inflammatory markers in the tears of patients with ocular surface disease.
        Ophthalmic Res. 2008; 40: 315-321
        • Lam H.
        • Bleiden L.
        • de Paiva C.S.
        • Farley W.
        • Stern M.E.
        • Pflugfelder S.C.
        Tear cytokine profiles in dysfunctional tear syndrome.
        Am J Ophthalmol. 2009; 147: 198-205.e191
        • Solomon A.
        • Dursun D.
        • Liu Z.
        • Xie Y.
        • Macri A.
        • Pflugfelder S.C.
        Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease.
        Invest Ophthalmol Vis Sci. 2001; 42: 2283-2292
        • Kang M.H.
        • Kim M.K.
        • Lee H.J.
        • Lee H.I.
        • Wee W.R.
        • Lee J.H.
        Interleukin-17 in various ocular surface inflammatory diseases.
        J Korean Med Sci. 2011; 26: 938-944
        • Geerling G.
        • Tauber J.
        • Baudouin C.
        • et al.
        The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction.
        Invest Ophthalmol Vis Sci. 2011; 52: 2050-2064
        • Knop E.
        • Knop N.
        • Millar T.
        • Obata H.
        • Sullivan D.A.
        The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland.
        Invest Ophthalmol Vis Sci. 2011; 52: 1938-1978
        • Lee H.
        • Min K.
        • Kim E.K.
        • Kim T.I.
        Minocycline controls clinical outcomes and inflammatory cytokines in moderate and severe meibomian gland dysfunction.
        Am J Ophthalmol. 2012; 154: 949-957.e941
        • Foulks G.N.
        • Borchman D.
        • Yappert M.
        • Kim S.H.
        • McKay J.W.
        Topical azithromycin therapy for meibomian gland dysfunction: clinical response and lipid alterations.
        Cornea. 2010; 29: 781-788
        • Perry H.D.
        • Doshi-Carnevale S.
        • Donnenfeld E.D.
        • Solomon R.
        • Biser S.A.
        • Bloom A.H.
        Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction.
        Cornea. 2006; 25: 171-175
        • Arita R.
        • Suehiro J.
        • Haraguchi T.
        • et al.
        Topical diquafosol for patients with obstructive meibomian gland dysfunction.
        Br J Ophthalmol. 2013; 97: 725-729
        • Bodor N.
        • Buchwald P.
        Soft drug design: general principles and recent applications.
        Med Res Rev. 2000; 20: 58-101
        • Friedlaender M.H.
        • Howes J.
        A double-masked, placebo-controlled evaluation of the efficacy and safety of loteprednol etabonate in the treatment of giant papillary conjunctivitis. The Loteprednol Etabonate Giant Papillary Conjunctivitis Study Group I.
        Am J Ophthalmol. 1997; 123: 455-464
        • Dell S.J.
        • Shulman D.G.
        • Lowry G.M.
        • Howes J.
        A controlled evaluation of the efficacy and safety of loteprednol etabonate in the prophylactic treatment of seasonal allergic conjunctivitis. Loteprednol Allergic Conjunctivitis Study Group.
        Am J Ophthalmol. 1997; 123: 791-797
        • Stewart R.
        • Horwitz B.
        • Howes J.
        • Novack G.D.
        • Hart K.
        Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1.
        J Cataract Refract Surg. 1998; 24: 1480-1489
        • Holland E.J.
        • Bartlett J.D.
        • Paterno M.R.
        • Usner D.W.
        • Comstock T.L.
        Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers.
        Cornea. 2008; 27: 50-55
        • Novack G.D.
        • Howes J.
        • Crockett R.S.
        • Sherwood M.B.
        Change in intraocular pressure during long-term use of loteprednol etabonate.
        J Glaucoma. 1998; 7: 266-269
        • Nichols K.K.
        • Foulks G.N.
        • Bron A.J.
        • et al.
        The international workshop on meibomian gland dysfunction: executive summary.
        Invest Ophthalmol Vis Sci. 2011; 52: 1922-1929
        • Cook E.B.
        • Stahl J.L.
        • Lowe L.
        • et al.
        Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: allergics vs. non-allergics.
        J Immunol Methods. 2001; 254: 109-118
        • Arita R.
        • Itoh K.
        • Inoue K.
        • Kuchiba A.
        • Yamaguchi T.
        • Amano S.
        Contact lens wear is associated with decrease of meibomian glands.
        Ophthalmology. 2009; 116: 379-384
        • Pflugfelder S.C.
        • Tseng S.C.
        • Sanabria O.
        • et al.
        Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation.
        Cornea. 1998; 17: 38-56
        • Schiffman R.M.
        • Christianson M.D.
        • Jacobsen G.
        • Hirsch J.D.
        • Reis B.L.
        Reliability and validity of the Ocular Surface Disease Index.
        Arch Ophthalmol. 2000; 118: 615-621
        • Dana M.R.
        • Zhu S.N.
        • Yamada J.
        Topical modulation of interleukin-1 activity in corneal neovascularization.
        Cornea. 1998; 17: 403-409
        • Schafer M.
        • Carter L.
        • Stein C.
        Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue.
        Proc Natl Acad Sci U S A. 1994; 91: 4219-4223
        • Kawasaki S.
        • Kawamoto S.
        • Yokoi N.
        • et al.
        Up-regulated gene expression in the conjunctival epithelium of patients with Sjogren's syndrome.
        Exp Eye Res. 2003; 77: 17-26
        • Contreras-Ruiz L.
        • Ghosh-Mitra A.
        • Shatos M.A.
        • Dartt D.A.
        • Masli S.
        Modulation of conjunctival goblet cell function by inflammatory cytokines.
        Mediators Inflamm. 2013; 2013: 636812
        • Gamache D.A.
        • Dimitrijevich S.D.
        • Weimer L.K.
        • et al.
        Secretion of proinflammatory cytokines by human conjunctival epithelial cells.
        Ocul Immunol Inflamm. 1997; 5: 117-128
        • Higuchi A.
        • Kawakita T.
        • Tsubota K.
        IL-6 induction in desiccated corneal epithelium in vitro and in vivo.
        Mol Vis. 2011; 17: 2400-2406
        • Tishler M.
        • Yaron I.
        • Geyer O.
        • Shirazi I.
        • Naftaliev E.
        • Yaron M.
        Elevated tear interleukin-6 levels in patients with Sjogren syndrome.
        Ophthalmology. 1998; 105: 2327-2329
        • Chen Y.T.
        • 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
        • Tuaillon N.
        • Shen D.F.
        • Berger R.B.
        • Lu B.
        • Rollins B.J.
        • Chan C.C.
        MCP-1 expression in endotoxin-induced uveitis.
        Invest Ophthalmol Vis Sci. 2002; 43: 1493-1498
        • Elner V.M.
        • Strieter R.M.
        • Pavilack M.A.
        • et al.
        Human corneal interleukin-8. IL-1 and TNF-induced gene expression and secretion.
        Am J Pathol. 1991; 139: 977-988
        • Li D.Q.
        • Shang T.Y.
        • Kim H.S.
        • Solomon A.
        • Lokeshwar B.L.
        • Pflugfelder S.C.
        Regulated expression of collagenases MMP-1, -8, and -13 and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells.
        Invest Ophthalmol Vis Sci. 2003; 44: 2928-2936
        • Smith V.A.
        • Rishmawi H.
        • Hussein H.
        • Easty D.L.
        Tear film MMP accumulation and corneal disease.
        Br J Ophthalmol. 2001; 85: 147-153
        • Pavesio C.E.
        • Decory H.H.
        Treatment of ocular inflammatory conditions with loteprednol etabonate.
        Br J Ophthalmol. 2008; 92: 455-459
        • Pflugfelder S.C.
        • Maskin S.L.
        • 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
        • Rhen T.
        • Cidlowski J.A.
        Antiinflammatory action of glucocorticoids–new mechanisms for old drugs.
        N Engl J Med. 2005; 353: 1711-1723
        • Djalilian A.R.
        • Nagineni C.N.
        • Mahesh S.P.
        • Smith J.A.
        • Nussenblatt R.B.
        • Hooks J.J.
        Inhibition of inflammatory cytokine production in human corneal cells by dexamethasone, but not cyclosporin.
        Cornea. 2006; 25: 709-714
        • De Paiva C.S.
        • Corrales R.M.
        • Villarreal A.L.
        • 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
        • Alberth M.
        • Wu W.-M.
        • Winwood D.
        • Bodor N.
        Lipophilicity, solubility and permeability of loteprednol etabonate: a novel, soft anti-inflammatory steroid.
        J Biopharm Sci. 1991; 2: 115-125
        • Druzgala P.
        • Wu W.M.
        • Bodor N.
        Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes.
        Curr Eye Res. 1991; 10: 933-937
        • Goto E.
        • Monden Y.
        • Takano Y.
        • et al.
        Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device.
        Br J Ophthalmol. 2002; 86: 1403-1407
        • Ong B.L.
        • Larke J.R.
        Meibomian gland dysfunction: some clinical, biochemical and physical observations.
        Ophthalmic Physiol Opt. 1990; 10: 144-148
        • Blackie C.A.
        • Solomon J.D.
        • Greiner J.V.
        • Holmes M.
        • Korb D.R.
        Inner eyelid surface temperature as a function of warm compress methodology.
        Optom Vis Sci. 2008; 85: 675-683
        • Korb D.R.
        • Greiner J.V.
        • Glonek T.
        • Esbah R.
        • Finnemore V.M.
        • Whalen A.C.
        Effect of periocular humidity on the tear film lipid layer.
        Cornea. 1996; 15: 129-134


      Hun Lee, MD, is currently pursuing his first year of corneal fellowship in Yonsei University College of Medicine, Severance hospital, Seoul, South Korea. He graduated from Yonsei University College of Medicine in 2006, where he completed his ophthalmology residency in 2011. His research interests are dry eye and refractive surgery.