Therapiekonzepte zur Behandlung von Patienten mit nicht infektiöser Uveitis: biologische Disease Modifying Antirheumatic Drugs

Zusammenfassung

Biologika stellen eine hochwirksame Therapieoption für verschiedene nicht infektiöse Uveitisformen dar. Einziges zugelassenes Biologikum ist der TNF-α-Inhibitor Adalimumab, alle anderen Präparate müssen im Rahmen einer Off-Label-Therapie gegeben werden. Die Indikation zur Therapieinitiierung mit einem Biologikum besteht, wenn die Erkrankung nicht ausreichend anspricht auf eine Behandlung mit systemischen Steroiden und/oder csDMARDs (konventionell-synthetischen disease modifying antirheumatic drugs) oder diese aufgrund von unerwünschten Wirkungen nicht gegeben werden können. Derzeit in der klinischen Anwendung befindliche biologische DMARD-Präparate wirken über zytokinspezifische Mechanismen (TNF-α-Inhibition, Interferone, Hemmung der Signaltransduktion von Interleukin-1 [IL-1], IL-6 und IL-17) sowie Hemmung der T-Zell-Kostimulation (CTLA-4-Fusionsprotein), oder B-Zell-Depletion (Anti-CD20). Alle Präparate müssen parenteral verabreicht werden. Die Einleitung einer Biologikatherapie sollte nach interdisziplinärer Abstimmung und Ausschluss von Kontraindikationen erfolgen. Ein regelmäßiges klinisches und laborchemisches Monitoring unter der Therapie ist erforderlich.

Abstract

Biologic disease modifying antirheumatic drugs (bDMARDs) can be highly efficient in the treatment of various non-infectious uveitis entities. Currently, the TNF-α-inhibitor Adalimumab is the only in-label therapeutic option, whereas, all other bDMARDs need to be given as an off-label therapy. bDMARDs are indicated in diseases refractory to conventional synthetic DMARD therapy and/or systemic steroids, or in patients in whom treatment with those is not possible due to side effects. Therapeutic mechanisms currently employed are cytokine-specific (interferons, inhibition of TNF-α or of interleukin [IL]-1-, IL-6- or IL-17-signalling), inhibit T cell costimulation (CTLA-4 fusion protein), or act via depletion of B cells (anti-CD20). All bDMARDs need to be administered parenterally, and therapy is initiated by the treating internal specialist only after interdisciplinary coordination of all treating subspecialties and after exclusion of contraindications. Regular clinical and laboratory monitoring is mandatory for all patients while under bDMARD therapy.

Schlüsselwörter

Biologika - Therapie - TNF-α - Uveitis

Key words

biologics - therapy - TNF-α - uveitis

• Literatur

• 1 Heiligenhaus A, Thurau S, Hennig M. et al. Anti-inflammatory treatment of uveitis with biologicals: new treatment options that reflect pathogenetic knowledge of the disease. Graefes Arch Clin Exp Ophthalmol 2010; 248: 1531-1551
• 2 Klaska IP, Forrester JV. Mouse models of autoimmune uveitis. Curr Pharm Des 2015; 21: 2453-2467
• 3 Ramanan AV, Dick AD, Jones AP. et al. Adalimumab plus Methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med 2017; 376: 1637-1646
• 4 Jaffe GJ, Dick AD, Brezin AP. et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med 2016; 375: 932-943
• 5 Nguyen QD, Merrill PT, Jaffe GJ. et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet 2016; 388: 1183-1192
• 6 Sen ES, Sharma S, Hinchcliffe A. et al. Use of adalimumab in refractory non-infectious childhood chronic uveitis: efficacy in ocular disease – a case cohort interventional study. Rheumatology (Oxford) 2012; 51: 2199-2203
• 7 Lerman MA, Burnham JM, Chang PY. et al. Response of pediatric uveitis to tumor necrosis factor-alpha inhibitors. J Rheumatol 2013; 40: 1394-1403
• 8 Dobner BC, Max R, Becker MD. et al. A three-centre experience with adalimumab for the treatment of non-infectious uveitis. Br J Ophthalmol 2013; 97: 134-138
• 9 Calvo-Rio V, Blanco R, Beltran E. et al. Anti-TNF-alpha therapy in patients with refractory uveitis due to Behcetʼs disease: a 1-year follow-up study of 124 patients. Rheumatology (Oxford) 2014; 53: 2223-2231
• 10 Mackensen F, Heinz C, Jakob E. et al. Randomized controlled study to evaluate the efficacy of adalimumab in patients with different forms of refractory uveitis. Ocul Immunol Inflamm 2017;
• 11 Levy-Clarke G, Jabs DA, Read RW. et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014; 121: 785-796.e3
• 12 Cordero-Coma M, Sobrin L. Anti-tumor necrosis factor-alpha therapy in uveitis. Surv Ophthalmol 2015; 60: 575-589
• 13 Miserocchi E, Modorati G, Pontikaki I. et al. Long-term treatment with golimumab for severe uveitis. Ocul Immunol Inflamm 2014; 22: 90-95
• 14 Cordero-Coma M, Calvo-Rio V, Adan A. et al. Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience. Mediators Inflamm 2014; 2014: 717598
• 15 Rudwaleit M, Rosenbaum JT, Landewe R. et al. Observed incidence of uveitis following certolizumab pegol treatment in patients with axial spondyloarthritis. Arthritis Care Res (Hoboken) 2016; 68: 838-844
• 16 Sun M, Yang Y, Yang P. et al. Regulatory effects of IFN-beta on the development of experimental autoimmune uveoretinitis in B10RIII mice. PLoS One 2011; 6: e19870
• 17 Tsambaos D, Eichelberg D, Goos M. Behcetʼs syndrome: treatment with recombinant leukocyte alpha-interferon. Arch Dermatol Res 1986; 278: 335-336
• 18 Lightman S, Taylor SR, Bunce C. et al. Pegylated interferon-alpha-2b reduces corticosteroid requirement in patients with Behcetʼs disease with upregulation of circulating regulatory T cells and reduction of Th17. Ann Rheum Dis 2015; 74: 1138-1144
• 19 Hazirolan D, Stubiger N, Pleyer U. Light on the horizont: biologicals in Behcet uveitis. Acta Ophthalmol 2013; 91: 297-306
• 20 Deuter CM, 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
• 21 Fardeau C, Simon A, Rodde B. et al. Interferon-alpha2a and systemic corticosteroid in monotherapy in chronic uveitis: results of the randomized controlled BIRDFERON study. Am J Ophthalmol 2017; 177: 182-194
• 22 Mackensen F, Jakob E, Springer C. et al. Interferon versus methotrexate in intermediate uveitis with macular edema: results of a randomized controlled clinical trial. Am J Ophthalmol 2013; 156: 478-486.e1
• 23 Tappeiner C, Miserocchi E, Bodaghi B. et al. Abatacept in the treatment of severe, longstanding, and refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol 2015; 42: 706-711
• 24 Hawkins MJ, Dick AD, Lee RJ. et al. Managing juvenile idiopathic arthritis-associated uveitis. Surv Ophthalmol 2016; 61: 197-210
• 25 Birolo C, Zannin ME, Arsenyeva S. et al. Comparable efficacy of abatacept used as first-line or second-line biological agent for severe juvenile idiopathic arthritis-related uveitis. J Rheumatol 2016; 43: 2068-2073
• 26 Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010; 40: 1830-1835
• 27 Zhang R, Tian A, Wang J. et al. miR26a modulates Th17/T reg balance in the EAE model of multiple sclerosis by targeting IL6. Neuromolecular Med 2015; 17: 24-34
• 28 Hohki S, Ohguro N, Haruta H. et al. Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses. Exp Eye Res 2010; 91: 162-170
• 29 Yoshimura T, Sonoda KH, Ohguro N. et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford) 2009; 48: 347-354
• 30 Murray PI, Hoekzema R, van Haren MA. et al. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci 1990; 31: 917-920
• 31 Curnow SJ, Falciani F, Durrani OM. et al. Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Invest Ophthalmol Vis Sci 2005; 46: 4251-4259
• 32 Mesquida M, Molins B, Llorenc V. et al. Targeting interleukin-6 in autoimmune uveitis. Autoimmun Rev 2017; 16: 1079-1089
• 33 Lin P. Targeting interleukin-6 for noninfectious uveitis. Clin Ophthalmol 2015; 9: 1697-1702
• 34 Sepah YJ, Sadiq MA, Chu DS. et al. Primary (month-6) outcomes of the STOP-Uveitis Study: evaluating the safety, tolerability, and efficacy of tocilizumab in patients with noninfectious uveitis. Am J Ophthalmol 2017; 183: 71-80
• 35 Calvo-Rio V, Santos-Gomez M, Calvo I. et al. Anti-interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis-associated uveitis refractory to anti-tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheumatol 2017; 69: 668-675
• 36 Tappeiner C, Mesquida M, Adan A. et al. Evidence for tocilizumab as a treatment option in refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol 2016; 43: 2183-2188
• 37 Quesada-Masachs E, Caballero CM. Subcutaneous tocilizumab may be less effective than intravenous tocilizumab in the treatment of juvenile idiopathic arthritis-associated uveitis. J Rheumatol 2017; 44: 260-261
• 38 Wendling D, Dernis E, Prati C. et al. Onset of inflammatory eye disease under tocilizumab treatment for rheumatologic conditions: a paradoxical effect?. J Rheumatol 2011; 38: 2284
• 39 Nguyen QD, Sundaram PA, Erickson K. et al. Interim results from the SATURN study: sarilumab in non-infectious uveitis (SARIL-NIU). Invest Ophthalmol Vis Sci 2016; 57: 1894
• 40 Maleki A, Meese H, Sahawneh H. et al. Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis. Expert Rev Clin Immunol 2016; 12: 775-786
• 41 Davatchi F, Shams H, Rezaipoor M. et al. Rituximab in intractable ocular lesions of Behcetʼs disease; randomized single-blind control study (pilot study). Int J Rheum Dis 2010; 13: 246-252
• 42 Heiligenhaus A, Miserocchi E, Heinz C. et al. Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab). Rheumatology (Oxford) 2011; 50: 1390-1394
• 43 Miserocchi E, Modorati G, Berchicci L. et al. Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis. Br J Ophthalmol 2016; 100: 782-786
• 44 Brambilla A, Caputo R, Cimaz R. et al. Canakinumab for childhood sight-threatening refractory uveitis: a case series. J Rheumatol 2016; 43: 1445-1447
• 45 Fabiani C, Sota J, Tosi GM. et al. The emerging role of interleukin (IL)-1 in the pathogenesis and treatment of inflammatory and degenerative eye diseases. Clin Rheumatol 2017; 36: 2307-2318
• 46 Fabiani C, Vitale A, Emmi G. et al. Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behcetʼs disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol 2017; 36: 191-197
• 47 Gul A, Tugal-Tutkun I, Dinarello CA. et al. Interleukin-1beta-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcetʼs disease: an open-label pilot study. Ann Rheum Dis 2012; 71: 563-566
• 48 Tugal-Tutkun IM, Kadayifcilar SM, Khairallah MM. et al. Safety and efficacy of gevokizumab in patients with Behcetʼs disease uveitis: results of an exploratory phase 2 study. Ocul Immunol Inflamm 2017; 25: 62-70
• 49 Dick AD, Tugal-Tutkun I, Foster S. et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology 2013; 120: 777-787
• 50 Letko E, Yeh S, Foster CS. et al. Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy. Ophthalmology 2015; 122: 939-948