Antientzündliche Therapie beim Trockenen Auge

Zusammenfassung

In der Pathogenese des Trockenen Auges spielt neben der Tränenfilminstabilität und dem Tränenmangel mit Anstieg der Osmolarität vor allem die Entzündung der Augenoberfläche eine entscheidende Rolle. Mittlerweile sind zahlreiche Signalwege, sowie azelluläre und zelluläre Faktoren identifiziert worden, die in einem komplexen System vor allem eine autoreaktive Entzündungsreaktion begünstigen und unterhalten können. Da sich diese autoreaktive Immunreaktion unabhängig vom ursprünglichen Auslöser verselbstständigen kann, ist eine Entzündungsinhibition in der Behandlung des Trockenen Auges essenziell. Derzeit zur Verfügung stehende Wirkstoffe wie Steroide, Ciclosporin A, Antibiotika, Omega-3- und -6-Fettsäuren, etc. weisen alle funktionelle oder rechtliche Limitierungen auf, die eine standardisierte Anwendung erschweren. Antilymphangiogene Substanze haben darüber hinaus das Potenzial, bislang verfügbaren Therapiestrategien zu ergänzen und zu verbessern. Unabhängig von jeder antientzündlichen Therapie ist eine detaillierte Untersuchung jedes Patienten essenziell, da die Komplexität des Krankheitsbild eine individuelle Therapieplanung mit Kombination verschiedener Therapeutika erfordert.

Abstract

Dry-eye is a multifactorial disease consisting of different pathomechanisms including instability of the tearfilm, increase of tearfilm osmolarity and most importantly inflammation of the ocular surface. In this context numerous signalling pathways and related immune mechanisms were identified all pointing towards autoimmune reactions as key parameters within this complex system. As autoimmunity tends to act independently from regulatory mechanisms, inhibition of related inflammatory processes is crucial in dry-eye therapy. Currently therapeutic agents such as steroids, cyclosporin, antibiotics, omega-3 and -6 fatty acids, etc. are available and readily used in daily practice. However, these therapies possess functional or legal restrictions that may limit their application. New strategies such as anti-lymphangiogenic therapies may have the potential to substitute or enhance current treatments. Independent of any anti-inflammatory therapy a detailed examination of the individual patient is necessary due to the complexity of the disease to provide individual and successful treatment.

Schlüsselwörter

Bindehaut - Kornea - Pharmakologie - Trockenes Auge - Entzündung

Key words

conjunctiva - cornea - pharmacology - dry eye - inflammation

• Literatur

• 1 [Anonymous] 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
• 2 Schaumberg DA, Nichols JJ, Papas EB et al. 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
• 3 De Paiva CS, Chotikavanich S, Pangelinan SB et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol 2009; 2: 243-253
• 4 Massingale ML, Li X, Vallabhajosyula M et al. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea 2009; 28: 1023-1027
• 5 Solomon A, Dursun D, Liu Z et al. 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
• 6 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
• 7 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
• 8 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
• 9 Gulati A, Sacchetti M, Bonini S et al. Chemokine receptor CCR5 expression in conjunctival epithelium of patients with dry eye syndrome. Arch Ophthalmol 2006; 124: 710-716
• 10 Cursiefen C, Maruyama K, Bock F et al. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 2011; 208: 1083-1092
• 11 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
• 12 Niederkorn JY, Stern ME, Pflugfelder SC et al. Desiccating stress induces T cell-mediated Sjogren's Syndrome-like lacrimal keratoconjunctivitis. J Immunol 2006; 176: 3950-3957
• 13 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: 2609-2614
• 14 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: 1247-1252
• 15 Cursiefen C, Jacobi C, Dietrich T et al. [Current treatment for dry eye syndrome]. Ophthalmologe 2006; 103: 18-24
• 16 Jacobi C, Cursiefen C. [Ophthalmological complications in Sjogren's syndrome]. Z Rheumatol 2011; 69: 32-40
• 17 Jacobi C, Dietrich T, Cursiefen C et al. [The dry eye. Current concepts on classification, diagnostics, and pathogenesis]. Ophthalmologe 2006; 103: 9-17
• 18 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
• 19 Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology 1999; 106: 811-816
• 20 De Bosscher K, Schmitz ML, Vanden Berghe W et al. Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci U S A 1997; 94: 13504-13509
• 21 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
• 22 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
• 23 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
• 24 Donnenfeld E, Pflugfelder SC. Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol 2009; 54: 321-338
• 25 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
• 26 Sheppard JD, Scoper SV, Samudre S. Topical loteprednol pretreatment reduces cyclosporine stinging in chronic dry eye disease. J Ocul Pharmacol Ther 2011; 27: 23-27
• 27 Kuzin II Snyder JE, Ugine GD et al. Tetracyclines inhibit activated B cell function. Int Immunol 2001; 13: 921-931
• 28 Dougherty JM, McCulley JP, Silvany RE et al. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis Sci 1991; 32: 2970-2975
• 29 Shine WE, McCulley JP, Pandya AG. Minocycline effect on meibomian gland lipids in meibomianitis patients. Exp Eye Res 2003; 76: 417-420
• 30 Ta CN, Shine WE, McCulley JP et al. Effects of minocycline on the ocular flora of patients with acne rosacea or seborrheic blepharitis. Cornea 2003; 22: 545-548
• 31 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
• 32 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
• 33 De Paiva CS, Schwartz CE, Gjörstrup P et al. Resolvin E1 (RX-10001) Reduces Corneal Epithelial Barrier Disruption and Protects Against Goblet Cell Loss in a Murine Model of Dry Eye. Cornea 2012; Jun 17 [Epub ahead of print]
• 34 Dietrich T, Weisbach V, Seitz B et al. [Manufacture of autologous serum eye drops for out-patient therapy: cooperation between ophthalmic clinic and transfusion medicine department]. Ophthalmologe 2008; 105: 1036-1038, 1040-1032
• 35 Fox RI, Chan R, Michelson JB et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum 1984; 27: 459-461
• 36 Tsubota K, Goto E, Fujita H et al. Treatment of dry eye by autologous serum application in Sjogren's syndrome. Br J Ophthalmol 1999; 83: 390-395
• 37 Weisbach V, Dietrich T, Kruse FE et al. HIV and hepatitis B/C infections in patients donating blood for use as autologous serum eye drops. Br J Ophthalmol 2007; 91: 1724-1725
• 38 Cursiefen C, Chen L, Borges LP et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004; 113: 1040-1050
• 39 Bock F, Konig Y, Kruse F et al. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2008; 246: 281-284
• 40 Bock F, Onderka J, Dietrich T et al. Bevacizumab as a potent inhibitor of inflammatory corneal angiogenesis and lymphangiogenesis. Invest Ophthalmol Vis Sci 2007; 48: 2545-2552
• 41 Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007; 7: 585-598
• 42 Jhunjhunwala S, Balmert SC, Raimondi G et al. Controlled release formulations of IL-2, TGF-beta1 and rapamycin for the induction of regulatory T cells. J Control Release 2012; 59(1): 78-84 , Epub 2012 Jan 21