Zusammenfassung
Hintergrund: Zur Behandlung der chronischen endogenen Uveitis werden primär lokale und systemische Kortikosteroide eingesetzt, sobald eine infektiöse Ätiologie ausgeschlossen ist. Sekundär werden oft immunmodulatorische Therapien erforderlich. Methoden: Das Spektrum der therapeutischen Optionen hat sich erheblich verbreitert mit Antiproliferativa und Alkylantien seit etwa 40 und Immunsuppressiva seit 20 Jahren. Ergebnisse: Für die meisten dieser relativ nebenwirkungsreichen Therapien fehlen kontrollierte Studien und klare Therapie-Empfehlungen. Das therapeutische Ansprechen wird erheblich von Krankheitsbild und immungenetischem Hintergrund des Patienten beeinflusst und ist oft schwer vorherzusagen. In den letzten Jahren wurden vermehrt die Vitrektomie und intravitreale Therapien eingesetzt. Seit Kurzem stehen Biologika als neue therapeutische Optionen zur Verfügung. Dazu gehören Interferon α, TNF alpha-Blocker und Antikörper gegen Interleukin, die meist gut verträglich sind und oft besser als immunsuppressive Therapien wirken. Schlussfolgerung: Die Anwendung biologischer Therapeutika bei chronischer endogener Uveitis erscheint auf der Basis persönlicher Erfahrung und publizierter Evidenz eine vielversprechende neue Option und wegen ihrer guten Verträglichkeit auch in der Behandlung von Kindern mit chronischer Uveitis eine attraktive Ergänzung der therapeutischen Optionen. Daten zur Wirksamkeit und den Nebenwirkungen insbesondere bei Langzeittherapie der Uveitis liegen noch nicht vor.
Abstract
Purpose: The treatment of chronic endogenous uveitis has included the use of local and systemic corticosteroids since the early 1950 s, and these still constitute the first-line option in the treatment, once an infectious aetiology has been excluded. Methods: Since the 1960 s, broad experience has been collected with antiproliferative and alcylating agents, and since the 1980 s several immunosuppressants have been employed in the therapy for endogenous uveitis. It has been recognised that the therapeutic response is not only related to a specific uveitic entity, but also to the genetic background of the individual. Results: Therefore, no clear guide lines for therapy exist and, for most of the drugs, controlled studies are not available. Vitrectomy and intravitreal drug delivery have been added as local options on top or in case of failure of systemic therapies. The advent of biological agents, however, i. e. the introduction of interferon α and TNF alpha blocking agents, has opened a new era in the treatment of immunogenetic and autoimmune disorders. Conclusion: Evidence-based knowledge and personal experience have been reviewed to provide an update on the therapeutic strategy for chronic endogenous uveitis. The newly introduced biologicals seem to represent an interesting addition to the existing therapeutic options. Informations pertaining to efficacy and side effects of a long-term treatment of uveitis are, nevertheless, as yet not available.
Schlüsselwörter
chronische Uveitis - Immunsuppressiva - Biologika - Etanercept - Infliximab - Interferon - Steroide - Kortikosteroide
Key words
chronic uveitis - immunosuppressants - biologicals - etanercept - infliximab - interferon - steroids - corticosteroids
Literatur
-
1
Durani O M. et al .
Degree, duration and causes of visual loss in uveitis.
Br J Ophthalmol.
2004;
88
1159-1162
-
2
Pras E, Neumann R, Zandman-Goddard G. et al .
Intraocular inflammation in autoimmune diseases.
Semin Arthrit Rheum.
2004;
34
602-609
-
3
Reeves S W. et al .
Uveitis in the Elderly: Epidemiological Data from the National Long-term Care Survey Medicare Cohort.
Opthalmology.
2006;
113
302-307
-
4
Lustig M J, Cunningham E T.
Use of immunosuppressive agents in uveitis.
Curr Opinion Ophthalmol.
2003;
14
399-412
-
5
Garweg J G, Wanner Jr D, Sarra G M. et al .
The diagnostic yield of vitrectomy specimen analysis in chronic idiopathic endogenous uveitis.
Eur J Ophthalmol.
2006;
16
588-594
-
6
Read R W.
Uveitis: Advances in understanding of pathogenesis and treatment.
Curr Rheumatol Rep.
2006;
8
260-266
-
7
De Smet M.
News on therapies for uveitis.
J Fr Ophtalmol.
2005;
28
556-561
-
8
Gross W L.
New concepts in treatment protocols for severe systemic vasculitis.
Curr Opin Rheumatol.
1999;
11
41-46
-
9
Jabs D A, Rosenbaum J T.
Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.
Am J Ophthalmol.
2001;
131
679
-
10
Bronstein M.
Vogt-Koyanagi-Harada disease; treatment with prednisone.
AMA Arch Ophthalmol.
1957;
57
503-507
-
11
Hogan M J, Kimura S J, O’Connor G R.
Peripheral retinitis and chronic cyclitis in children.
Trans Ophthalmol Soc U K.
1965;
85
39-52
-
12
Hersh E M, Carbone P P, Wong V G. et al .
Inhibition of the primary immune response in man by anti-metabolites.
Cancer Res.
1965;
25
997-1001
-
13
Newell F W, Krill A E.
Treatment of uveitis with azathioprine (Imuran).
Trans Ophthalmol Soc U K.
1967;
87
499-511
-
14
Mathews J D, Crawford B A, Bignell J L. et al .
Azathioprine in active chronic iridocyclitis. A double-blind controlled trial.
Br J Ophthalmol.
1969;
53
327-330
-
15
Gills J P.
Combined medical and surgical therapy for complicated cases of peripheral uveitis.
Arch Ophthalmol.
1968;
79
723-728
-
16
Wong V G.
Immunosuppressive therapy of ocular inflammatory diseases.
Arch Ophthalmol.
1969;
81
628-637
-
17
Nussenblatt R B, Rodrigues M M, Wacker W B. et al .
Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats.
J Clin Invest.
1981;
67
1228-1231
-
18
Androudi Jr S, Brazitikos P, Iaccheri B. et al .
Outcomes of early and late immunomodulatory treatment in patients with HLA-B27-associated chronic uveitis.
Graefes Arch Clin Exp Ophthalmol.
2003;
241
1000-1005
-
19
Lau C H, Comer M, Lightman S.
Long-term efficacy of mycophenolate mofetil in the control of severe intraocular inflammation.
Clin Experiment Ophthalmol.
2003;
31
487-491
-
20
Mochizuki M, Masuda K, Sakane T. et al .
A multicenter clinical open trial of FK 506 in refractory uveitis, including Behcet’s disease. Japanese FK 506 Study Group on Refractory Uveitis.
Transplant Proc.
1991;
23
3343-3346
-
21
Shanmuganathan V A, Casely E M, Raj D. et al .
The efficacy of sirolimus in the treatment of patients with refractory uveitis.
Br J Ophthalmol.
2005;
89
666-669
-
22
Matsumura N, Mizushima Y.
Leucocyte movement and colchicine treatment in Behcet’s disease.
Lancet.
1975;
2 (7939)
813
-
23
Dapsone Jacobs L, Melton M l, Kaufman H E.
Treatment of experimental ocular toxoplasmosis.
Arch Ophthalmol.
1964;
71
111-118
-
24
Temime P, Berard P, Privat Y. et al .
Behcet syndrome treated with chlorambucil.
Bull Soc Fr Dermatol Syphiligr.
1969;
76
433-434
-
25
Nussenblatt R B.
Bench to bedside: new approaches to the immunotherapy of uveitic disease.
Int Rev Immunol.
2002;
21
273-289
-
26
Barg T M, Borovkova N G.
Interferon in the treatment of virus diseases of the conjunctiva and the cornea.
Oftalmol Zh.
1969;
24
286-289
-
27
Pollikoff R, Jankauskas P, DiPuppo A. et al .
Studies on the effect of bacteriaql endotoxin on primary herpetic keratitis.
Invest Ophthalmol.
1968;
7
397-404
-
28
Tsambaos D, Eichelberg D, Goos M.
Behcet’s syndrome: treatment with recombinant leukocyte alpha-interferon.
Arch Dermatol Res.
1986;
278
335-336
-
29
Lightman S, McCluskey P J.
Which way forward for treatment of severe ocular inflammation?.
Clin Experiment Ophthalmol.
2006;
34
293-294
-
30
Hale S, Lightman S.
Anti-TNF therapies in the management of acute and chronic uveitis.
Cytokine.
2006;
33
231-237
-
31
Pipitone N, Olivieri I, Cantini F. et al .
New approaches in the treatment of Adamantiades-Behcet’s disease.
Curr Opin Rheumatol.
2006;
18
3-9
-
32
Nussenblatt R.
Treating intraocular inflammatory disease in the 21st century.
Arch Ophthalmol.
2005;
123
1000-1001
-
33
Horneff G.
Importance of the new biologicals and cytokine antagonists in the treatment of juvenile idiopathic arthritis (JIA).
Z Rheumatol.
2005;
64
317-326
-
34
Evereklioglu C.
Current concepts in the etiology and treatment of Behcet disease.
Surv Ophthalmol.
2005;
50
297-350
-
35
Rosenbaum J T, Smith J R.
Anti-TNF therapy for eye involvement in spondyloarthropathy.
Clin Exp Rheumatol.
2002;
20 (Suppl 28)
S143-S145
-
36
Aeberli D, Oertle S, Mauron H. et al .
Inhibition of the TNF-pathway: use of infliximab and etanercept as remission-inducing agents in cases of therapy-resistant chronic inflammatory disorders.
Swiss Med Wkly.
2002;
132
414-422
-
37
Benezra D, Maftzir G, Barak V.
Blood serum interleukin-1 receptor antagonist in pars planitis and ocular Behcet disease.
Am J Ophthalmol.
1997;
123
593-598
-
38
Lim W K, Fujimoto C, Ursea R. et al .
Suppression of immune-mediated ocular inflammation in mice by interleukin 1 receptor antagonist administration.
Arch Ophthalmol.
2005;
123
957-963
-
39
Nussenblatt R B, Fortin E, Schiffman R. et al .
Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial.
Proc Natl Acad Sci U S A.
1999;
96
7462-7466
-
40
Nussenblatt R B, Peterson J S, Foster C S. et al .
Initial evaluation of subcutaneous daclizumab treatments for noninfectious uveitis: a multicenter noncomparative interventional case series.
Ophthalmology.
2005;
112
764-770
-
41
Li Z, Lim W K, Mahesh S P. et al .
Cutting edge: in vivo blockade of human IL-2 receptor induces expansion of CD56(bright) regulatory NK cells in patients with active uveitis.
J Immunol.
2005;
174
5187-5191. Erratum in: J Immunol 2005; 175: 3447
-
42
Hernandez Garfella M L, Diaz Llopis M, Salom Alonso D. et al .
Recurrent uveitis and therapy with monoclonal antibody (daclizumab).
Arch Soc Esp Oftalmol.
2004;
79
593-598
-
43
Nussenblatt R B, Thompson D J, Li Z. et al .
Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration.
J Autoimmun.
2003;
21
283-293. Erratum in: J Autoimmun 2004; 23: 93
-
44
Papaliodis G N, Chu D, Foster C S.
Treatment of ocular inflammatory disorders with daclizumab.
Ophthalmology.
2003;
110
786-789
-
45
Smith J R, Levinson R D, Holland G N. et al .
Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.
Arthritis Rheum.
2001;
45
252-257
-
46
Reiff A, Takei S, Sadeghi S. et al .
Etanercept therapy in children with treatment-resistant uveitis.
Arthritis Rheum.
2001;
44
1411-1415
-
47
Guignard S, Gossec L, Salliot C. et al .
Efficacy of Tumor Necrosis Factor blockers in reducing uveitis flares in spondylarthropathy patients: a retrospective study.
Ann Rheum Dis.
2006;
Epub ahead of print
-
48
Kahn P, Weiss M, Imundo L F. et al .
Favorable response to high-dose infliximab for refractory childhood uveitis.
Ophthalmology.
2006;
113
864.e1-2. Epub 2006
-
49
Saurenmann R K, Levin A V, Rose J B. et al .
Tumour necrosis factor {alpha} inhibitors in the treatment of childhood uveitis.
Rheumatology.
2006;
45
982-989
-
50
Rajaraman R T, Kimura Y, Li S. et al .
Retrospective case review of pediatric patients with uveitis treated with infliximab.
Ophthalmology.
2006;
113
308-314
-
51
Richards J C, Tay-Kearney M L, Murray K. et al .
Infliximab for juvenile idiopathic arthritis-associated uveitis.
Clin Experiment Ophthalmol.
2005;
33
461-468
-
52
Braun J, Baraliakos X, Listing J. et al .
Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept.
Arthritis Rheum.
2005;
52
2447-2451
-
53
Tugal-Tutkun I, Mudun A, Urgancioglu M. et al .
Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet’s disease: an open-label trial.
Arthritis Rheum.
2005;
52
2478-2484
-
54
Suhler E B, Smith J R, Wertheim M S. et al .
A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes.
Arch Ophthalmol.
2005;
123
903-912
-
55
Lindstedt E W, Baarsma G S, Kuijpers R W. et al .
Anti-TNF-alpha therapy for sight threatening uveitis.
Br J Ophthalmol.
2005;
89
533-536
-
56
Markomichelakis N N, Theodossiadis P G, Pantelia E. et al .
Infliximab for chronic cystoid macular edema associated with uveitis.
Am J Ophthalmol.
2004;
138
648-650
-
57
Benitez-del-Castillo J M, Martinez-de-la-Casa J M, Pato-Cour E. et al .
Long-term treatment of refractory posterior uveitis with anti-TNFalpha (infliximab).
Eye.
2005;
19
841-845
-
58
Ohno S, Nakamura S, Hori S. et al .
Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behcet’s disease with refractory uveoretinitis.
J Rheumatol.
2004;
31
1362-1368
-
59
Murphy C C, Ayliffe W H, Booth A. et al .
Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis.
Ophthalmology.
2004;
111
352-356
-
60
Joseph A, Raj D, Dua H S. et al .
Infliximab in the treatment of refractory posterior uveitis.
Ophthalmology.
2003;
110
1449-1453
-
61
El-Shabrawi Y, Hermann J.
Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis.
Ophthalmology.
2002;
109
2342-2346
-
62
Smith J A, Thompson D J, Whitcup S M. et al .
A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis.
Arthritis Rheum.
2005;
53 (1)
18-23
-
63
Foster C S, Tufail F, Waheed N K. et al .
Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate.
Arch Ophthalmol.
2003;
121
437-440
-
64
Quartier P, Taupin P, Bourdeaut F. et al .
Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type.
Arthritis Rheum.
2003;
48
1093-1101
-
65
Bodaghi B, Bui Q uoc E, Wechsler B. et al .
Therapeutic use of infliximab in sight threatening uveitis: retrospective analysis of efficacy, safety, and limiting factors.
Ann Rheum Dis.
2005;
64
962-964
-
66
Fleischmann R, Iqbal I, Nandeshwar P. et al .
Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept.
Drug Saf.
2002;
25
173-197
-
67
Lim L, Suhler E B, Smith J R.
Biologic therapies for inflammatory eye disease.
Clin Experiment Ophthalmol.
2006;
34
365-374
-
68
Calamia K T.
Current and future use of anti-TNF agents in the treatment of autoimmune, inflammatory disorders.
Adv Exp Med Biol.
2003;
528
545-549
-
69
Estrach C, Mpofu S, Moots R J.
Behcet’s syndrome: response to infliximab after failure of etanercept.
Rheumatology.
2002;
41
1213-1214
-
70
Sfikakis P P, Iliopoulos A, Elezoglou A. et al .
Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction.
Arthritis Rheum.
2005;
52
2513-2518
-
71
Pontikaki I, Gerloni V, Gattinara M. et al .
Side effects of anti-TNFalpha therapy in juvenile idiopathic arthritis.
Reumatismo.
2006;
58
31-38
-
72
Lim W S, Powell R J, Johnston I D.
Tuberculosis and treatment with infliximab.
New Engl J Med.
2002;
346
623-626
-
73
Stewart M W, Alvarez S, Ginsburg W W. et al .
Visual recovery following Mycobacterium chelonae endophthalmitis.
Ocul Immunol Inflamm.
2006;
14
181-183
-
74
Hashkes P J, Shajrawi I.
Sarcoid-related uveitis occurring during etanercept therapy.
Clin Exp Rheumatol.
2003;
21
645-646
-
75
Tauber T, Turetz J, Barash J. et al .
Optic neuritis associated with etanercept therapy for juvenile arthritis.
J AAPOS.
2006;
10
26-29
-
76
Galeria N A, Werth V P, Schumacher H R.
Leukocytoclastic vasculitis due to etanercept.
J Rheumatol.
2000;
27
2041-2044
-
77
Fos F F, Haren van M A, Verhagen de C. et al .
Systemic anti-tumour necrosis factor antibody treatment exacerbates endotoxin-induced uveitis in the rat.
Exp Eye Res.
1995;
61
667-675
-
78
Cope A, Ettinger R. et al .
The role of TNF&alpha and related cytokines in the development and function of the autoreactive T-cell repertoire.
Res Immunol.
1997;
148
307-312
-
79
Von Andrian U H, Mackay C R.
T-cell function and migration: two sides of the same chain.
New Engl J Med.
2000;
343
1020-1034
-
80
Tiliakos A N, Tiliakos N A.
Ocular inflammatory disease in patients with RA taking etanercept: is discontinuation of etanercept necessary?.
J Rheumatol.
2003;
30
2727
-
81
Reddy A R, Backhouse O C.
Does etanercept induce uveitis?.
Br J Ophthalmol.
2003;
87
925
-
82
Kaipiainen-Seppanen O, Leino M.
Recurrent uveitis in a patient with juvenile spondyloarthropathy associated with tumour necrosis factor alpha inhibitors.
Ann Rheum Dis.
2003;
62
88-89
-
83
Sfikakis P P.
Behcet’s disease: a new target for anti-tumour necrosis factor treatment.
Ann Rheum Dis.
2002;
61 Suppl 2
ii51-ii53
-
84
Kotter I, Durk H, Saal J. et al .
Therapy of Behcet’s disease.
Ger J Ophthalmol.
1996;
5
92-97
-
85
Deuter C M, Koetter I, Guenaydin I. et al .
Interferon alfa-2a: a new treatment option for long lasting refractory cystoid macular edema in uveitis? A Pilot Study.
Retina.
2006;
26
786-791
-
86
Tugal-Tutkun I, Guney-Tefekli E, Urgancioglu M.
Results of interferon-alfa therapy in patients with Behcet uveitis.
Graefes Arch Clin Exp Ophthalmol.
2006;
Epub ahead of print
-
87
Becker M D, Heiligenhaus A, Hudde T. et al .
Interferon as a treatment for uveitis associated with multiple sclerosis.
Br J Ophthalmol.
2005;
89
1254-1257
-
88
Kotter I, Vonthein R, Zierhut M. et al .
Differential efficacy of human recombinant interferon-alpha2a on ocular and extraocular manifestations of Behcet disease: results of an open 4-center trial.
Semin Arthritis Rheum.
2004;
33
311-319
-
89
Wechsler B, Bodaghi B, Huong D L. et al .
Efficacy of interferon alfa-2a in severe and refractory uveitis associated with Behcet’s disease.
Ocul Immunol Inflamm.
2000;
8
293-301
-
90
Boyvat A, Sisman-Solak C, Gurler A.
Long-term effects of interferon alpha 2A treatment in Behcet’s disease.
Dermatology.
2000;
201 (1)
40-43
-
91
Demiroglu H, Ozcebe O I, Barista I. et al .
Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behcet’s disease: a randomised trial.
Lancet.
2000;
355 (9204)
605-609. Retraction in: Horton R. Lancet 2000; 356 (9238): 1292
-
92
Georgiou S, Monastirli A, Pasmatzi E. et al .
Efficacy and safety of systemic recombinant interferon-alpha in Behcet’s disease.
J Intern Med.
1998;
243
367-372
-
93
Frassanito M A, Dammacco R, Fusaro T. et al .
Combined cyclosporin-A /prednisone therapy of patients with active uveitis suppresses IFN-gamma production and the function of dendritic cells.
Clin Exp Immunol.
2003;
133
233-239
-
94
Xu H, Silver P B, Tarrant T K. et al .
Tgf-beta inhibits activation and uveitogenicity of primary but not of fully polarized retinal antigen-specific memory-effector T cells.
Invest Ophthalmol Vis Sci.
2003;
44
4805-4812
-
95
Fleisher L N, Ferrell J B, McGahan M C.
Synergistic uveitic effects of tumor necrosis factor-alpha and interleukin-1 beta.
Invest Ophthalmol Vis Sci.
1992;
33
2120-2127
-
96
Murphy C C, Greiner K, Plskova J. et al .
Cyclosporine vs. tacrolimus therapy for posterior and intermediate uveitis.
Arch Ophthalmol.
2005;
123
634-641
-
97
Buggage R R, Matteson D M, Shen de F. et al .
Effect of sex hormones on experimental autoimmune uveoretinitis (EAU).
Immunol Invest.
2003;
32
259-273
-
98
Namazi M R.
Cannabinoids, loratadine and allopurinol as novel additions to the antipsoriatic ammunition.
J Eur Acad Dermatol Venereol.
2005;
19
319-322. Erratum in: J Eur Acad Dermatol Venereol 2005; 19: 529
-
99
Eldem B.
Behcet’s disease and interferon: flaws in research integrity of randomised trial.
Lancet.
2000;
356 (9238)
1351
-
100
Dundar S, Ozcebe O I.
Behcet’s disease and interferon: flaws in research integrity of randomised trial.
Lancet.
2000;
356 (9238)
1351
-
101
Sayek I.
Behcet’s disease and interferon: flaws in research integrity of randomised trial.
Lancet.
2000;
356 (9238)
1351
-
102
Zierhut M.
Riding on a carousel with IFN-alpha and TNF-alpha.
Ocul Immunol Inflamm.
1998;
6
209-210
-
103
Haraoui B.
Differentiating the efficacy of the tumor necrosis factor inhibitors.
Arthritis Rheum.
2005;
52
2447-51
-
104
Reimold A M.
New indications for treatment of chronic inflammation by TNF-alpha blockade.
Am J Med Sci.
2003;
325
75-92
-
105
Biester S, Deuter C, Michels H. et al .
Adalimumab in the Therapy of Uveitis in Childhood.
Br J Ophthalmol.
2006;
Epub ahead of print
-
106
Vazquez-Cobian L B, Flynn T, Lehman T J.
Adalimumab therapy for childhood uveitis.
J Pediatr.
2006;
149
572-575
-
107
Mushtaq B, Saeed T, Situnayake R D. et al .
Adalimumab for sight-threatening uveitis in Behcet’s disease.
Eye.
2006;
Epub ahead of print
Prof. Dr. med. Justus G. Garweg
Swiss Eye Institute, Augenklinik am Lindenhofspital
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