Zusammenfassung
Die Keratokonjunctivitis sicca bei Sjögren-Syndrom ist eine Erkrankung, die zu stark beeinträchtigenden Symptomen sowie zu Hornhautkomplikationen verbunden mit Visusverlust führen kann. Neben entzündlichen Faktoren werden hormonelle Veränderungen sowie neuronale Störungen in der Pathogenese diskutiert. Die Therapie besteht unter anderem aus symptomatischen Maßnahmen (Schutzbrillen, Luftbefeuchter), Beseitigung von Lidanomalien und Refraktionsfehlern, Behandlung einer assoziierten Blepharitis sowie im Absetzen bestimmter Medikamente. Neben einer Vielzahl von Tränenersatzprodukten und autologem Serum stehen heute im Ansatz kausale Medikamente zur Verfügung, wie lokale Kortikosteroide, topisches Ciclosporin A und orale (M1)/M3-Agonisten. Lokale Androgene und Sekretagoga wie Diquafosol-Tetrasodium und 15(S)-HETE zur Therapie des Trockenen Auges sind in klinischer Erprobung.
Abstract
Keratoconjunctivitis sicca in patients with Sjögren’s syndrome is typically associated with severe subjective symptoms and may lead to corneal complications and visual loss. Inflammation, hormonal factors and neuronal dysregulations are discussed as pathogenetic factors. Therapy includes safety goggles, humidifiers, correction of lid anomalies and refraction deficits, treatment of associated blepharitis and discontinuance of specific medications. Besides numerous artificial tears solutions and autologous serum, treatments became available with topical steroids, cyclosporin A and oral muscarinic agonists that target the basic disease mechanisms. Topical androgens and secretagogues such as diquafosol tetrasodium and 15(S)-HETE are in clinical evaluation for the treatment of keratoconjunctivitis sicca.
Schlüsselwörter
Keratokonjunctivitis sicca - Sjögren-Syndrom - kausale Medikamente
Key words
Keratoconjunctivitis sicca - Sjögren’s syndrome - treatments targeting basic disease mechanisms
Literatur
-
1
Balaram M, Schaumberg D A, Dana M R.
Efficacy and tolerability outcomes after punctal occlusion with silicone plugs in dry eye syndrome.
Am J Ophthalmol.
2001;
131
30-36
-
2
Brückner R.
Über einen erfolgreich mit Perandren behandelten Fall von Sjögren’schem Symptomenkomplex.
Ophthalmologica.
1945;
110
37-42
-
3
Christensen M T, Cohen S, Rinehart J. et al .
Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye.
Curr Eye Res.
2004;
28
55-62
-
4
Cohen E J.
Punctal occlusion.
Arch Ophthalmol.
1999;
117
389-390
-
5
Cummins M J, Papas A, Kammer G M. et al .
Treatment of primary Sjögren’s syndrome with low-dose human interferon alpha administered by the oromucosal route: combined phase III results.
Arthritis Rheum.
2003;
49
585-593
-
6
Dinslage S, Stoffel W, Diestelhorst M. et al .
Tolerability and safety of two new preservative-free tear film substitutes.
Cornea.
2002;
21
352-355
-
7
Fox R I, Chan R, Michelson J B. et al .
Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca.
Arthritis Rheum.
1984;
27
459-461
-
8
Fox R I, Konttinen Y, Fisher A.
Use of muscarinic agonists in the treatment of sjögren’s syndrome.
Clin Immunol.
2001;
101
249-263
-
9
Fujihara T, Murakami T, Fujita H. et al .
Improvement of corneal barrier function by the P2Y2 agonist INS365 in a rat dry eye model.
Invest Ophthalmol Vis Sci.
2001;
42
96-100
-
10
Gamache D A, Wei Z Y, Weimer L K. et al .
Preservation of corneal integrity by the mucin secretagogue 15(S)-HETE in a rabbit model of desiccation-induced dry eye.
Adv Exp Med Biol.
2002;
506
335-340
-
11
Gamache D a, McDonough T J, Roberts L. et al .
The mucin secretagogue 15(S)-HETE protects the cornea and improves tear film integrity in a rabbit model of lacrimal gland inflammation induced dry eye.
Ophthalmol Vis Sci.
2003;
44
2498
-
12
Gao J, Schwalb T A, Addeo J V. et al .
The role of apoptosis in the pathogenesis of canine keratoconjunctivitis sicca: the effect of topical cyclosporin A therapy.
Cornea.
1998;
17
654-663
-
13
Geerling G, Hartwig D.
Autologe Serum-Augentropfen zur Therapie der Augenoberfläche.
Ophthalmologe.
2002;
99
949-959
-
14
Geerling G, Honnicke K, Schröder C. et al .
Quality of salivary tears following autologous submandibular gland transplantation for severe dry eye.
Graefe’s Arch Clin Exp Ophthalmol.
1999;
237
546-553
-
15
Goto E, Yagi Y, Kaido M. et al .
Improved functional visual acuity after punctal occlusion in dry eye patients.
Am J Ophthalmol.
2003;
135
704-705
-
16
Goto E, Yukiko Y, Matsumoto Y. et al .
Impaired functional visual acuity of dry eye patients.
Am J Ophthalmol.
2002;
133
181-186
-
17
Gündüz K, Özdemir Ö.
Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjögren’s syndrome.
Acta Ophthalmol.
1994;
72
438-442
-
18
Heiligenhaus A, Koch J M, Kruse F E. et al .
Diagnostik und Differenzierung von Benetzungsstörungen.
Ophthalmologe.
1995;
92
6-11
-
19
Hemady R, Chu W, Foster C S.
Keratoconjunctivitis sicca and corneal ulcers.
Cornea.
1990;
9
170-173
-
20
Iwabuchi Y, Katagiri M, Masuhara T.
Salivary secretion and histopathological effects after single administration of the muscarinic agonist SNI-2011 in MRL7lpr mice.
Arch Int Pharmacodyn Ther.
1994;
328
315-325
-
21
Jones D T, Monroy D, Ji Z. et al .
Sjögren’s syndrome : cytokine and Epstein-Barr viral gene expression within the conjunctival epithelium.
Invest Ophthalmol Vis Sci.
1994;
35
3493-3504
-
22
Kaswan R L, Salisbury M A, Ward D A.
Spontaneous canine keratoconjunctivitis sicca. A useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops.
Arch Ophthalmol.
1989;
107
1210-1216
-
23
Khurshudian A V.
A pilot study to test the efficacy of oral administration of interferon-α lozenges to patients with Sjögren’s syndrome.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
2003;
95
38-44
-
24
Krachmer J H, Laibson P R.
Corneal thinning and perforation in Sjögren’s syndrome.
Am J Ophthamol.
1974;
78
917-920
-
25
Laibovitz R A, Solch S, Andriano K.
Pilot trial of cyclosporine 1 % ophthalmic ointment in the treatment of keratoconjunctivitis sicca.
Cornea.
1993;
12
315-323
-
26
Leloup C, Michaelson D M, Fisher A. et al .
M1 muscarinic receptors block caspase activation by phosphoinositide 3-kinase- and MAPK/ERK-independent pathways.
Cell Death Differ.
2000;
7
825-833
-
27
Lemp M A.
Report of the National Eye Institute/Industry Workshop on clinical trials in dry eye.
CLAO J.
1995;
21
221-232
-
28
Liu Z, Pflugfelder S C.
Corneal surface regularity and the effect of artificial tears in aqueous tear deficiency.
Ophthalmology.
1999;
106
939-943
-
29
Marsh P, Pflugfelder S C.
Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in sjögren syndrome.
Ophthalmology.
1999;
106
811-816
-
30
Misawa M, Ohmori S, Yanaura S.
Effects of bromhexine on the secretions of saliva and tears.
Jpn J Pharmacol.
1985;
39
241-250
-
31
Moore C P, McHugh J B, Thorne J G. et al .
Effect of cyclosporine on conjunctival mucin in a canine keratoconjunctivitis sicca model.
Invest Ophthalmol Vis Sci.
2001;
42
653-659
-
32
Mundasad M V, Novack G D, Allgood V E. et al .
Ocular safety of INS365 ophthalmic solution: a P2Y2 agonist in healthy subjects.
J Ocul Pharmacol Ther.
2001;
17
173-179
-
33
Murakami T, Fujihara T, Nakamura M. et al .
P2Y2 receptor stimulation increases tear fluid secretion in rabbits.
Curr Eye Res.
2000;
21
782-787
-
34
Murakami T, Fujihara T, Nakamura M. et al .
P2Y2 receptor elicits PAS-positive glycoprotein secretion from rabbit conjunctival goblet cells in vivo.
J Ocul Pharmacol Ther.
2003;
19
345-352
-
35 Nepp J, Wedrich A, Akramian A. et al .Dry eye treatment with acupuncture. Sullivan DA Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2 New York (USA); Plenum Press 1998: 1011-1016
-
36
Ono M, Takamura E, Shinozaki K. et al .
Therapeutic effect of cevimeline on dry eye in patients with sjögren’s syndrome: a randomized, double-blind clinical study.
Am J Ophthalmol.
2004;
138
6-17
-
37
Petrone D, Condemi J J, Fife R. et al .
A double-blind, randomized, placebo-controlled study of cevimeline in sjögren’s syndrome patients with xerostomia and keratoconjunctivitis sicca.
Arthritis Rheum.
2002;
46
748-754
-
38
Pflugfelder S C, Solomon A, Stern M E.
The diagnosis and management of dry eye.
Cornea.
2000;
19
644-649
-
39 Pleyer U, Dörner T. Sjögren Syndrom. Messmer EM Diagnose und Therapie der Keratoconjunctivitis sicca Bremen; UNI-Med-Verlag 2001: 80-88
-
40
Sall K, Stevenson O D, Mundorf T K. et al .
Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease.
Ophthalmology.
2000;
107
631-639
-
41
Schaumberg D A, Buring J E, Sullivan D A. et al .
Hormone replacement therapy and dry eye syndrome.
JAMA.
2001;
286
2114-2119
-
42
Schiffman R M, Walt J G, Jacobsen G. et al .
Utility assessment among patients with dry eye disease.
Ophthalmology.
2003;
110
1412-1419
-
43
Schröder C, Sieg P, Framme C. et al .
Autotransplantation der Unterkieferspeicheldrüse bei absoluter Keratoconjunctivitis sicca.
Klin Monatsbl Augenheilkd.
2002;
219
494-501
-
44
Shiozawa K, Tanaka Y, Yoshihara R. et al .
Single-blinded controlled trial of low-dose oral IFN-alpha for the treatment of xerostomia inpatients with Sjögren’s syndrome.
J Interferon Cytokine Res.
1998;
18
255-262
-
45
Smith J K, Siddiqui A A, Modica L A. et al .
Interferon upregulated gene expression of Aquaporin-5 in human parotid glands.
J Interferon Cytokine Res.
1999;
19
929-935
-
46
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
-
47
Stern M E, Beuerman R W, Fox R I. et al .
The pathology of dry eye: the interaction between the ocular surface and lacrimal glands.
Cornea.
1998;
17
584-589
-
48
Stern M E, Gao J, Schwalb T A. et al .
Conjunctival T-cell subpopulations in Sjögren’s and non-Sjögren’s patients with dry eye.
Invest Ophthalmol Vis Sci.
2002;
43
2609-2614
-
49
Stevenson D, Tauber J, Reis B L.
The cyclosporin A phase 2 study group. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease.
Ophthalmology.
2000;
107
967-974
-
50
Sullivan D A, Belanger A, Cermak J M. et al .
Are women with Sjögren’ssyndrome androgen-deficient?.
J Rheumatol.
2003;
30
2413-2419
-
51
Sullivan D A, Edwards J A.
Androgen stimulation of lacrimal gland function in mouse models of sjögren’s syndrome.
J Steroid Biochem Molec Biol.
1997;
60
237-245
-
52
Sullivan D A, Krenzer K L, Sullivan B D. et al .
Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency?.
Invest Ophthalmol Vis Sci.
1999;
40
1261-1265
-
53
Sullivan D A, Sullivan B D, Evans J E. et al .
Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye.
Ann N Y Acad Sci.
2002;
966
211-222
-
54
Sullivan R M, Cermak J M, Papas A S. et al .
Economic and quality of life impact of dry eye symptoms in women with Sjögren’s syndrome.
Adv Exp Med Biol.
2002;
506
1183-1188
-
55
Tai M C, Cosar C B, Cohen E J. et al .
The clinical efficacy of silicone punctal plug therapy.
Cornea.
2002;
21
135-139
-
56
Tauber J, Davitt W F, Bokosky J E. et al .
Double masked, placebo-contolled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye.
Invest Ophthalmol Vis Sci.
2003;
44
3738
-
57
Tsubota K, Goto E, Fujita H. et al .
Treatment of dry eye by autologous serum application in sjögren’s syndrome.
Br J Ophthalmol.
1999;
83
390-395
-
58
Vendramini A C, Soo C, Sullivan D A.
Testosterone-induced suppression of autoimmune disease in lacrimal tissue of a mouse model (NZB/NZWF1) of sjögren’s syndrome.
Invest Ophthalmol Vis Sci.
1991;
32
3002-3006
-
59
Vivino F B, Al-Hashimi I, Khan Z. et al .
Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with sjögren’s syndrome.
Arch Intern Med.
1999;
159
174-181
-
60
Worda C, Nepp J, Huber J C. et al .
Treatment of keratoconjunctivitis sicca with topical androgen.
Maturitas.
2001;
37
209-212
-
61
Yerxa B R, Mundasad M, Sylvester R N. et al .
Ocular safety of INS365 ophthalmic solution, a P2Y2 agonist, in patients with mild to moderate dry eye disease.
Adv Exp Med Biol.
2002;
506
1251-1257
-
62
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
Dr. Elisabeth M. Messmer
Augenklinik der Ludwig-Maximilians-Universität
Mathildenstraße 8
80336 München
Telefon: 0 89/51 50-38 00
Fax: 0 89/51 60-51 60
eMail: emessmer@med.uni-muenchen.de
