Wenn Tränenersatzmittel nicht mehr ausreichen: die Bedeutung von Entzündungsprozessen beim Trockenen Auge. Praktische Aspekte einer antientzündlichen Therapie des Trockenen Auges

Uwe Pleyer; Gerd Geerling; Stefan Schrader; Christina Jacobi; Friedemann Kimmich; Elisabeth Messmer

doi:10.1055/a-1115-4756

Klinische Monatsblätter für Augenheilkunde, Inhaltsverzeichnis

Klin Monbl Augenheilkd 2020; 237(05): 655-668
DOI: 10.1055/a-1115-4756

Übersicht

Georg Thieme Verlag KG Stuttgart · New York

Wenn Tränenersatzmittel nicht mehr ausreichen: die Bedeutung von Entzündungsprozessen beim Trockenen Auge. Praktische Aspekte einer antientzündlichen Therapie des Trockenen Auges

If Artificial Tears Arenʼt Enough. The Importance of Inflammatory Processes in Dry Eye Disease. Practical Aspects of an Anti-Inflammatory Therapy of Dry Eye Disease

Uwe Pleyer

¹Universitäts-Augenklinik, Charité – Campus Virchow-Klinik, Berlin

,

Gerd Geerling

²Augenklinik, Universitätsklinikum Düsseldorf

,

Stefan Schrader

³Augenheilkunde, Universitätsklinik für Augenheilkunde PIUS-HOSPITAL, Oldenburg

,

Christina Jacobi

⁴Augenklinik, Universität Erlangen-Nürnberg, Erlangen

,

Friedemann Kimmich

⁵eyecons, Pfinztal

,

Elisabeth Messmer

⁶Augenklinik, Ludwig-Maximilians-Universität München, Medizinische Fakultät

› Institutsangaben

Abstract

Zusammenfassung

Das Trockene Auge stellt eine heterogene Erkrankung der Augenoberfläche dar. Das Krankheitsbild hat multifaktorielle Ursachen und geht normalerweise mit einer Erhöhung der Osmolarität des Tränenfilms und mit Entzündungsprozessen der Gewebe der Augenoberfläche einher. Die Bedeutung der Entzündung beim Trockenen Auge geht nicht zuletzt auch aus der aktuellen Definition des Dry Eye Workshops (DEWS) hervor. Das Verständnis der Pathomechanismen und therapeutischen Möglichkeiten für diese Entzündungsprozesse ist daher für das Management des Trockenen Auges von zentraler Bedeutung. Der Beitrag fasst den aktuellen Kenntnisstand zum Thema „Entzündung und Trockenes Auge“ zusammen und versucht, praktische Empfehlungen für die Diagnostik, Verlaufskontrolle und die Anwendung der aktuell verfügbaren Therapieoptionen für die dem Trockenen Auge zugrunde liegenden Entzündungsprozesse zu geben.

Abstract

Dry eye disease (DED) is a heterogenous disease of the ocular surface. Multiple pathogenetic factors are responsible for the disease process, but DED is generally linked to an increase in the osmolarity of the tear film and to inflammation of the ocular surface. The significance of inflammatory processes in DED is highlighted in the most recent definition of dry eye in the Dry Eye Workshop (DEWS). It is therefore critically important for the management of dry eye disease to understand the pathomechanisms and therapeutic options for the treatment of inflammatory processes. This review summarizes our current knowledge on Inflammation associated with DED and provides practical recommendations for the diagnosis and monitoring of the disease, as well as the use of currently available therapeutic options to counteract inflammation in DED.

Schlüsselwörter

Trockenes Auge - Entzündung - Ciclosporin A - Kortikosteroide

Key words

dry eye - inflammation - ciclosporine A - corticosteroids

Volltext

Referenzen

Literatur
1 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
2 Viso E, Rodríguez-Ares MT, Abelenda D. et al. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. Invest Ophthalmol Vis Sci 2012; 53: 2601-2606
3 Vehof J, Kozareva D, Hysi PG. et al. Prevalence and risk factors of dry eye disease in a British female cohort. Br J Ophthalmol 2014; 98: 1712-1717
4 Malet F, Le Goff M, Colin J. et al. Dry eye disease in French elderly subjects: the Alienor Study. Acta Ophthalmol 2014; 92: e429-e436 doi:10.1111/aos.12174
5 Nelson JD, Craig JP, Akpek EK. et al. TFOS DEWS II Introduction. Ocul Surf 2017; 15: 269-275
6 Craig JP, Nichols KK, Akpek EK. et al. TFOS DEWS II Definition and Classification Report. Ocul Surf 2017; 15: 276-283
7 [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
8 Wilson SE. Inflammation: a unifying theory for the origin of dry eye syndrome. Manag Care 2003; 12 (Suppl.) S14-S19
9 Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology 2017; 124 (Suppl.) S4-S13
10 Brignole F, Pisella PJ, Goldschild M. et al. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eye. Invest Ophthalmol Vis Sci 2000; 41: 1356-1363
11 Baudouin C. The pathology of dry eye. Surv Ophthalmol 2001; 45 (Suppl.) S211-S220
12 Stern ME, Schaumburg CS, Dana R. et al. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunol 2010; 3: 425-442
13 Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol 2013; 32: 19-41
14 Jones L, Downie LE, Korb D. et al. TFOS DEWS II management and therapy report. Ocul Surf 2017; 15: 575-628
15 Bron AJ, de Paiva CS, Chauhan SK. et al. TFOS DEWS II pathophysiology report. Ocul Surf 2017; 15: 438-510
16 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
17 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
18 Gilbard JP, Rossi SR, Gray KL. et al. Tear film osmolarity and ocular surface disease in two rabbit models for keratoconjunctivitis sicca. Invest Ophthalmol Vis Sci 1988; 29: 374-378
19 Gilbard JP. Tear film osmolarity and keratoconjunctivitis sicca. CLAO J 1985; 11: 243-250
20 Rhee MK, Mah FS. Inflammation in dry eye disease: how do we break the cycle?. Ophthalmology 2017; 124 (11 Suppl.): S14-S19
21 Papas EB. Key factors in the subjective and objective assessment of conjunctival erythema. Invest Ophthalmol Vis Sci 2000; 41: 687-691
22 Yang S, Lee HJ, Kim DY. et al. The use of conjunctival staining to measure ocular surface inflammation in patients with dry eye. Cornea 2019; 38: 698-705
23 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
24 Sullivan BD, Whitmer D, Nichols KK. et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010; 51: 6125-6130
25 Jacobi C, Jacobi A, Kruse FE. et al. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea 2011; 30: 1289-1292
26 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
27 Geerling G, Joussen AM, Daniels JT. et al. Matrix metalloproteinases in sterile corneal melts. Ann N Y Acad Sci 1999; 878: 571-574
28 Messmer EM, von Lindenfels V, Garbe A. et al. Matrix metalloproteinase 9 testing in dry eye disease using a commercially available point-of-care immunoassay. Ophthalmology 2016; 123: 2300-2308
29 Sambursky R, Davitt WF, Friedberg M. et al. Prospective, multicenter, clinical evaluation of point-of-care matrix metalloproteinase-9 test for confirming dry eye disease. Cornea 2014; 33: 812-818
30 Pisella PJ, Brignole F, Debbasch C. et al. Flow cytometric analysis of conjunctival epithelium in ocular rosacea and keratoconjunctivitis sicca. Ophthalmology 2000; 107: 1841-1849
31 Brignole-Baudouin F, Riancho L, Ismail D. et al. Correlation between the inflammatory marker HLA-DR and signs and symptoms in moderate to severe dry eye disease. Invest Ophthalmol Vis Sci 2017; 58: 2438-2448
32 Messmer EM. Konfokale In-vivo-Mikroskopie – Korrelation zu histologischen Befunden. Klin Monatsbl Augenheilkd 2012; 229: 696-704
33 Kheirkhah A, Rahimi Darabad R, Cruzat A. et al. Corneal epithelial immune dendritic cell alterations in sub- types of dry eye disease: a pilot in vivo confocal microscopic study. Invest Ophthalmol Vis Sci 2015; 56: 7179-7185
34 Villani E, Garoli E, Termine V. et al. Corneal confocal microscopy in dry eye treated with corticosteroids. Optom Vis Sci 2015; 92: e290-e295 doi:10.1097/OPX.0000000000000600
35 Berufsverband der Augenärzte Deutschlands (BVA), Deutsche Ophthalmologische Gesellschaft (DOG). Leitlinie Nr. 11: „Trockenes Auge“ (Sicca-Syndrom) und Blepharitis. Im Internet: https://augeninfo.de/leit/leit11.pdf Stand: 30.03.2020
36 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
37 Bae CH, Chen SM, Lee HM. et al. The effect of doxycycline on PMA-induced MUC5B expression via MMP-9 and p38 in NCI-H292 cells. Clin Exp Otorhinolaryngol 2011; 4: 177-183
38 Yildiz E, Yenerel NM, Turan-Yardimci A. et al. Comparison of the clinical efficacy of topical and systemic azithromycin treatment for posterior blepharitis. J Ocul Pharmacol Ther 2018; 34: 365-372
39 Singer DD, Kennedy J, Wittpenn JR. Topical NSAIDs effect on corneal sensitivity. Cornea 2015; 34: 541-543
40 Rolando M, Barabino S, Alongi S. et al. Topical non-preserved diclofenac therapy for keratoconjunctivitis sicca. Adv Exp Med Biol 2002; 506: 1237-1240
41 Scheinman RI, Cogswell PC, Lofquist AK. et al. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270: 283-286
42 Pedersen S, OʼByrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997; 52 (39 Suppl.): S1-S34
43 Barton M, Filardo EJ, Lolait SJ. et al. Twenty years of the G protein-coupled estrogen receptor GPER: historical and personal perspectives. J Steroid Biochem Mol Biol 2018; 176: 4-15
44 Leibowitz HM. Management of inflammation in the cornea and conjunctiva. Ophthalmology 1980; 87: 753-758
45 Polansky JR, Weinreb RN. Steroids as anti-inflammatory Agents. In: Sears ML. ed. Pharmacology of the Eye. New York: Springer; 1984: 459-538
46 Pleyer U, Ursell PG, Rama P. Intraocular pressure effects of common topical steroids for post-cataract inflammation: are they all the same?. Ophthalmol Ther 2013; 2: 55-72
47 Cantrill HL, Palmberg PF, Zink HA. et al. Comparison of in vitro potency of corticosteroids with ability to raise intraocular pressure. Am J Ophthalmol 1975; 79: 1012-1017
48 Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res 2012; 47: 66-80
49 Dolder R, Skinner FS. Hrsg. Ophthalmika – Pharmakologie, Biopharmazie und Galenik der Augenarzneimittel. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 1990
50 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
51 Olmiere C, Raveu A, Baudouin C. T1565, a new efficient and safe preservative free hydrocortisone. ARVO 2017, Poster 1079 – B0367. Im Internet: https://studyres.com/doc/17129574/arvo-2017-annual-meeting-abstracts-160-anti Stand: 30.03.2020
52 Araki-Sasaki K, Katsuta O, Mano H. et al. The effects of oral and topical corticosteroid in rabbit corneas. BMC Ophthalmol 2016; 16: 160 doi:10.1186/s12886-016-0339-5
53 Kashani S, Mearza AA. Uses and safety profile of ciclosporin in ophthalmology. Expert Opin Drug Saf 2008; 7: 79-89
54 Kunert KS, Tisdale AS, Stern ME. et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect of conjunctival lymphocytes. Arch Ophthalmol 2000; 118: 1489-1496
55 Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol 2002; 120: 330-337
56 Lallemand F, Daull P, Benita S. et al. Successfully improving ocular drug delivery using the cationic nanoemulsion, Novasorb. J Drug Deliv 2012; 2012: 604204 doi:10.1155/2012/604204
57 Daull P, Lallemand F, Philips B. et al. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits. Cornea 2013; 32: 345-354
58 Li Y, Johnson N, Capano M. et al. Cyclophyllin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem J 2004; 383: 101-109
59 Agarwal P, Rupenthal ID. Modern approaches to the ocular delivery of cyclosporine A. Drug Discov Today 2016; 21: 977-988
60 Hoy SM. Ciclosporin ophthalmic solution emulsion 0.1 %: a review in severe dry eye disease. Drugs 2017; 77: 1909-1916
61 Liaw JH, Rojanasakul YY, Robinson JR. The effect of drug charge type and charge-density on corneal transport. Int J Pharm 1992; 88: 111-124
62 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
63 Baiza-Durán L, Medrano-Palafox J, Hernández-Quintela E. et al. A comparative clinical trial of the efficacy of two different aqueous solutions of cyclosporine for the treatment of moderate-to-severe dry eye syndrome. Br J Ophthalmol 2010; 94: 1312-1315
64 Wiederholt M, Kössendrup D, Schulz W. et al. Pharmacokinetic of topical cyclosporin A in the rabbit eye. Invest Ophthalmol Vis Sci 1986; 27: 519-524
65 Hoffmann F, Wiederholt M. Topical cyclosporin A in the treatment of corneal graft reaction. Cornea 1986; 5: 129
66 Daull P, Feraille L, Barabino S. et al. Efficacy of a new topical cationic emulsion of cyclosporine A on dry eye clinical signs in an experimental mouse model of dry eye. Exp Eye Res 2016; 153: 159-164
67 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: 287-296
68 Park JY, Kim BG, Kim JS. et al. Matrix metalloproteinase 9 point-of-care immunoassay result predicts response to topical cyclosporine treatment in dry eye disease. Transl Vis Sci Technol 2018; 7: 31 doi:10.1167/tvst.7.5.31
69 Sheppard JD, Donnenfeld ED, Holland EJ. et al. Effect of loteprednol etabonate 0.5 % on initiation of dry eye treatment with topical cyclosporine 0.05 %. Eye Contact Lens 2014; 40: 289-296
70 Hristov N, Kortuem K, Priglinger S. et al. Topisches Ciclosporin A 0,1 % in der Therapie des Trockenen Auges mit schwerer Keratopathie. Poster PSa03-10, vorgestellt auf der DOG in Bonn 2018. Abstractband DOG 2018. Ophthalmologe 2018; 115 (Suppl. 01) 1-194 doi:10.1007/s00347-018-0760-7
71 Donnenfeld ED, Perry HD, Nattis AS. et al. Lifitegrast for the treatment of dry eye disease in adults. Expert Opin Pharmacother 2017; 18: 1517-1524
72 Chung JK, Spencer E, Hunt M. et al. Ocular distribution and pharmacokinetics of lifitegrast in pigmented rabbits and mass balance in beagle dogs. J Ocul Pharmacol Ther 2018; 34: 224-232
73 Sheppard JD, Torkildsen GL, Lonsdale JD. et al. OPUS-1 Study Group. Lifitegrast ophthalmic solution 5.0 % for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology 2014; 121: 475-483
74 Baudouin C, de la Maza MS, Amrane M. et al. One-year efficacy and safety of 0.1 % cyclosporine a cationic emulsion in the treatment of severe dry eye disease. Eur J Ophthalmol 2017; 27: 678-685
75 Rao SN. Topical cyclosporine 0.05 % for the prevention of dry eye disease progression. J Ocul Pharmacol Ther 2010; 26: 157-164
76 Rao SN. Reversibility of dry eye deceleration after topical cyclosporine 0.05 % withdrawal. J Ocul Pharmacol Ther 2011; 27: 603-609
77 Leonardi A, Messmer EM, Labetoulle M. et al. Efficacy and safety of 0.1 % ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies. Br J Ophthalmol 2019; 103: 125-131
78 Barber LD, Pflugfelder SC, Tauber J. et al. 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: 1790-1794
79 Su MY, Perry HD, Barsam A. et al. The effect of decreasing the dosage of cyclosporine A 0.05 % on dry eye disease after 1 year of twice-daily therapy. Cornea 2011; 30: 1098-1104
80 Wilson SE, Perry HD. Long-term resolution of chronic dry eye symptoms and signs after topical cyclosporine treatment. Ophthalmology 2007; 114: 76-79
81 Straub M, Bron AM, Muselier-Mathieu A. et al. Long-term outcome after topical ciclosporin in severe dry eye disease with a 10-year follow-up. Br J Ophthalmol 2016; 100: 1547-1550
82 Labetoulle M, Leonardi A, Amrane M. et al. Persistence of efficacy of 0.1 % cyclosporin a cationic emulsion in subjects with severe keratitis due to dry eye disease: a nonrandomized, open-label extension of the SANSIKA study. Clin Ther 2018; 40: 1894-1906
83 Pisella PJ, Labetoulle M, Doan S. et al. Topical ocular 0.1 % cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program. Clin Ophthalmol 2018; 12: 289-299
84 Clegg JP, Guest JF, Lehman A. et al. The annual cost of dry eye syndrome in France, Germany, Italy, Spain, Sweden and the United Kingdom among patients managed by ophthalmologists. Ophthalmic Epidemiol 2006; 13: 263-274
85 SANSIKA Studie SANSIKA study, data on file Safety population. Persönliche Information Santen Inc. 22.02.2019
86 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
87 Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 0.05 % cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea 2012; 31: 1386-1393
88 Zhou XQ, Wei RL. Topical cyclosporine A in the treatment of dry eye: a systematic review and meta-analysis. Cornea 2014; 33: 760-767
89 Guzey M, Karaman SK, Satici A. et al. Efficacy of topical cyclosporine A in the treatment of severe trachomatous dry eye. Clin Exp Ophthalmol 2009; 37: 541-549