The Challenge of Treating the Severest Forms of Chronic Noninfectious Posterior and Panuveitis

Abstract

Background Noninfectious posterior and panuveitis may exhibit a chronic relapsing clinical course and are challenging to treat. Most affected patients are continuously treated with systemic immunosuppressive therapy, which is potentially associated with significant adverse side effects.

Methods A cohort of 18 patients presenting with severe noninfectious posterior or panuveitis were evaluated with respect to the clinical course of the disease, with particular focus on best-corrected visual acuity (BCVA), treatment duration, remission rates, reported negative side effects, and the necessity for switching medication.

Results The mean follow-up was 27.8 months. Although BCVA improved significantly, complete or partial remission was observed in only 66.7% of patients. Of the patients, 72.2% underwent a change in medical treatment due to either adverse events or inefficacy of medication.

Conclusion Despite new immunosuppressive therapies, effective treatment of severe noninfectious posterior and panuveitis remains a major challenge. We discuss the urgent need for novel treatment strategies in order to prevent systemic adverse effects, and to improve visual outcome and quality of life.

Zusammenfassung

Hintergrund Nicht infektiöse posteriore Uveitis und Panuveitis verursachen häufig chronisch rezidivierende Verläufe bis hin zu irreversibler Erblindung. Eine effektive Behandlung ist nach wie vor schwierig. Die meisten Patienten erhalten eine systemische immunsuppressive Medikation, die häufig mit schwerwiegenden Nebenwirkungen einhergeht.

Methodik Eine Kohorte mit 18 Patienten mit gesicherter Diagnose einer nicht infektiösen posterioren oder Panuveitis wurde bez. des Krankheitsverlaufs ausgewertet. Unser Fokus lag dabei vor allem auf der Entwicklung der visuellen Funktion, der Krankheitsdauer, Remissionsraten, Nebenwirkungen der Therapie und erforderlichen Umstellungen der Medikation.

Ergebnisse Die mittlere Beobachtungszeit lag bei 27,8 Monaten. Obwohl der Visus sich insgesamt signifikant verbesserte, kam es nur in 66,7% der Fälle zu einer kompletten oder teilweisen Remission. Bei 72,2% der Patienten musste die Therapie aufgrund von Nebenwirkungen oder mangelnder Effektivität umgestellt werden.

Schlussfolgerung Trotz neuer immunsuppressiver oder -modulatorischer Therapieoptionen und gutem Zugang zu diesen ist eine effektive Behandlung schwerer nicht infektiöser posteriorer oder Panuveitis eingeschränkt. Wir diskutieren den dringenden Bedarf an neuen Therapieoptionen für diese Erkrankung, um systemische Nebenwirkungen zu vermeiden und die Visusfunktion und Lebensqualität zu verbessern.

Conclusion

• Noninfectious posterior and panuveitis may cause a chronic relapsing clinical course resulting in blindness and are challenging to treat. Most affected patients are continuously treated with systemic immunosuppressive therapy potentially associated with significant adverse side effects.

• Due to rare occurrence, heterogeneous disease courses, and individual treatment, current data regarding treatment success in noninfectious posterior and panuveitis are poor. We therefore evaluated an available patient cohort in a longitudinal manner.

• Rates of remission are unsatisfactory despite novel treatment strategies and excellent access to treatment in our cohort.

• Changes in medication due to inefficacy or severe adverse effects are frequent.

• We see an urgent need for novel treatment strategies to prevent systemic adverse effects and improve visual outcome in noninfectious posterior and panuveitis.

Key words

noninfectious uveitis - birdshot chorioretinopathy - serpiginous choroiditis - Behçets syndrome - Vogt-Koyanagi-Harada syndrome

Schlüsselwörter

nicht infektiöse Uveitis - Birdshot-Chorioretinopathie - serpiginöse Choroiditis - Behçet-Syndrom - Vogt-Koyanagi-Harada-Syndrom

Publikationsverlauf

Eingereicht: 26. Januar 2023

Angenommen: 06. April 2023

Artikel online veröffentlicht:
12. Juli 2023

• References

• 1 Grajewski RS, Caramoy A, Frank KF. et al. Spectrum of Uveitis in A German Tertiary Center: Review of 474 Consecutive Patients. Ocul Immunol Inflamm 2015; 23: 346-352
• 2 Jabs DA, Nussenblatt RB, Rosenbaum JT. et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140: 509-516
• 3 Durrani OM, Tehrani NN, Marr JE. et al. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol 2004; 88: 1159-1162
• 4 Miserocchi E, Fogliato G, Modorati G. et al. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol 2013; 23: 705-717
• 5 Thorne JE, Suhler E, Skup M. et al. Prevalence of Noninfectious Uveitis in the United States: A Claims-Based Analysis. JAMA Ophthalmol 2016; 134: 1237-1245
• 6 Pleyer U, Stubiger N. New pharmacotherapy options for noninfectious posterior uveitis. Expert Opin Biol Ther 2014; 14: 1783-1799
• 7 van Laar JAM, Rothova A, Missotten T. et al. Diagnosis and treatment of uveitis; not restricted to the ophthalmologist. J Clin Transl Res 2015; 2015: 94-99
• 8 Charkoudian LD, Ying GS, Pujari SS. et al. High-dose intravenous corticosteroids for ocular inflammatory diseases. Ocul Immunol Inflamm 2012; 20: 91-99
• 9 Cordero-Coma M, Salazar-Mendez R, Yilmaz T. Treatment of severe non-infectious uveitis in high-risk conditions (Part I): pregnancy and malignancies, management and safety issues. Expert Opin Drug Saf 2015; 14: 1071-1086
• 10 Hassan M, Karkhur S, Bae JH. et al. New therapies in development for the management of non-infectious uveitis: A review. Clin Exp Ophthalmol 2019; 47: 396-417
• 11 Jabs DA, Rosenbaum JT, Foster CS. et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 2000; 130: 492-513
• 12 Leclercq M, Langlois V, Girszyn N. et al. Comparison of conventional immunosuppressive drugs versus anti-TNF-alpha agents in non-infectious non-anterior uveitis. J Autoimmun 2020; 113: 102481
• 13 Sadiq MA, Agarwal A, Hassan M. et al. Therapies in Development for Non-Infectious Uveitis. Curr Mol Med 2015; 15: 565-577
• 14 Shahab MA, Mir TA, Zafar S. Optimising drug therapy for non-infectious uveitis. Int Ophthalmol 2019; 39: 1633-1650
• 15 Grotting LA, Papaliodis GN. A Review of the Course and Treatment of Non-Infectious Uveitis during Pregnancy. Semin Ophthalmol 2017; 32: 75-81
• 16 Valenzuela RA, Flores I, Urrutia B. et al. New Pharmacological Strategies for the Treatment of Non-Infectious Uveitis. A Minireview. Front Pharmacol 2020; 11: 655
• 17 Deuter CME, Zierhut M, Igney-Oertel A. et al. Tocilizumab in Uveitic Macular Edema Refractory to Previous Immunomodulatory Treatment. Ocul Immunol Inflamm 2017; 25: 215-220
• 18 Kok H, Lau C, Maycock N. et al. Outcome of intravitreal triamcinolone in uveitis. Ophthalmology 2005; 112: 1916.e1-1916.e7
• 19 Lightman S, Belfort jr. R, Naik RK. et al. Vision-related functioning outcomes of dexamethasone intravitreal implant in noninfectious intermediate or posterior uveitis. Invest Ophthalmol Vis Sci 2013; 54: 4864-4870
• 20 Steeples LR, Anand N, Moraji J. et al. Clinical Outcomes of Intravitreal Preservative-Free Triamcinolone Preparation (Triesence^®) for Cystoid Macular Oedema and Inflammation in Patients with Uveitis. Ocul Immunol Inflamm 2018; 26: 997-1004
• 21 Jaffe GJ, Martin D, Callanan D. et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006; 113: 1020-1027
• 22 Lowder C, Belfort jr. R, Lightman S. et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011; 129: 545-553
• 23 Massa H, Georgoudis P, Panos GD. Dexamethasone intravitreal implant (OZURDEX^®) for macular edema secondary to noninfectious uveitis: a review of the literature. Ther Deliv 2019; 10: 343-351
• 24 Valdes LM, Sobrin L. Uveitis Therapy: The Corticosteroid Options. Drugs 2020; 80: 765-773
• 25 Campochiaro PA, Brown DM, Pearson A. et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012; 119: 2125-2132
• 26 Levinson RD, Brezin A, Rothova A. et al. Research criteria for the diagnosis of birdshot chorioretinopathy: results of an international consensus conference. Am J Ophthalmol 2006; 141: 185-187
• 27 Standardization of Uveitis Nomenclature (SUN) Working Group. Classification Criteria for Birdshot Chorioretinitis. Am J Ophthalmol 2021; 228: 65-71
• 28 [Anonymous] Criteria for diagnosis of Behcetʼs disease. International Study Group for Behcetʼs Disease. Lancet 1990; 335: 1078-1080
• 29 International Team for the Revision of the International Criteria for Behcetʼs Disease (ITR-ICBD). The International Criteria for Behcetʼs Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: 338-347
• 30 Read RW, Holland GN, Rao NA. et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131: 647-652
• 31 Urzua CA, Herbort jr. C, Valenzuela RA. et al. Initial-onset acute and chronic recurrent stages are two distinctive courses of Vogt-Koyanagi-Harada disease. J Ophthalmic Inflamm Infect 2020; 10: 23
• 32 Nussenblatt RB, Palestine AG, Chan CC. et al. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985; 92: 467-471
• 33 German Ophthalmological Society and the Professional Association of Ophthalmologists. Guideline no. 24b, 2017.
• 34 Hatemi G, Christensen R, Bang D. et al. 2018 update of the EULAR recommendations for the management of Behcetʼs syndrome. Ann Rheum Dis 2018; 77: 808-818
• 35 Kotter I, Aepinus C, Graepler F. et al. HHV8 associated Kaposiʼs sarcoma during triple immunosuppressive treatment with cyclosporin A, azathioprine, and prednisolone for ocular Behcetʼs disease and complete remission of both disorders with interferon alpha. Ann Rheum Dis 2001; 60: 83-86
• 36 Mishima S, Masuda K, Izawa Y. et al. The eighth Frederick H. Verhoeff Lecture. presented by saiichi mishima, MD Behcetʼs disease in Japan: ophthalmologic aspects. Trans Am Ophthalmol Soc 1979; 77: 225-279
• 37 Benezra D, Cohen E. Treatment and visual prognosis in Behcetʼs disease. Br J Ophthalmol 1986; 70: 589-592
• 38 Rothova A, Berendschot TT, Probst K. et al. Birdshot chorioretinopathy: long-term manifestations and visual prognosis. Ophthalmology 2004; 111: 954-959
• 39 Read RW, Rao NA, Cunningham ET. Vogt-Koyanagi-Harada disease. Curr Opin Ophthalmol 2000; 11: 437-442
• 40 Annamalai R, Sudharshan S, Biswas J. Clinical Features, Investigations, Management, and Prognosis of Serpiginous Choroiditis. Asia Pac J Ophthalmol (Phila) 2012; 1: 287-295
• 41 Quillen DA, Davis JB, Gottlieb JL. et al. The white dot syndromes. Am J Ophthalmol 2004; 137: 538-550
• 42 Duica I, Voinea LM, Mitulescu C. et al. The use of biologic therapies in uveitis. Rom J Ophthalmol 2018; 62: 105-113
• 43 Neri P, Arapi I, Nicolai M. et al. Biologic Therapy in Inflammatory Eye Conditions (Ophthalmology): Safety Profile. Curr Drug Saf 2016; 11: 47-54
• 44 Rosenbaum JT, Bodaghi B, Couto C. et al. New observations and emerging ideas in diagnosis and management of non-infectious uveitis: A review. Semin Arthritis Rheum 2019; 49: 438-445
• 45 Borras-Blasco J, Castera DE, Cortes X. et al. Effectiveness of infliximab, adalimumab and golimumab for non-infectious refractory uveitis in adults. Int J Clin Pharmacol Ther 2015; 53: 377-390
• 46 Burek-Michalska A, Turno-Krecicka A. Adalimumab in the treatment of non-infectious uveitis. Adv Clin Exp Med 2020; 29: 1231-1236
• 47 Hasegawa E, Takeda A, Yawata N. et al. The effectiveness of adalimumab treatment for non-infectious uveitis. Immunol Med 2019; 42: 79-83
• 48 LaMattina KC, Goldstein DA. Adalimumab for the treatment of uveitis. Expert Rev Clin Immunol 2017; 13: 181-188
• 49 Miserocchi E, Giuffre C, Cornalba M. et al. JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39: 847-851
• 50 Atzeni F, Talotta R, Nucera V. et al. Adverse events, clinical considerations and management recommendations in rheumatoid arthritis patients treated with JAK inhibitors. Expert Rev Clin Immunol 2018; 14: 945-956
• 51 Lee DJ. Intraocular Implants for the Treatment of Autoimmune Uveitis. J Funct Biomater 2015; 6: 650-666
• 52 Touhami S, Diwo E, Seve P. et al. Expert opinion on the use of biological therapy in non-infectious uveitis. Expert Opin Biol Ther 2019; 19: 477-490
• 53 Bae JH, Lee SC. Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet disease. Retina 2012; 32: 1395-1402
• 54 Gorovoy I, Prechanond T, Abia M. et al. Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid. Cornea 2013; 32: 1171-1173
• 55 Taylor SR, Habot-Wilner Z, Pacheco P. et al. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology 2009; 116: 797-801
• 56 Taylor SRJ, Banker A, Schlaen A. et al. Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. Retina 2013; 33: 2149-2154
• 57 Cabahug VLO, Uy HS, Yu-Keh E. et al. Outcomes of treatment with sirolimus for non-infectious uveitis: a meta-analysis and systematic review. Clin Ophthalmol 2019; 13: 649-669
• 58 Jeong Y, Ryu JS, Park UC. et al. Corneal Epithelial Toxicity after Intravitreal Methotrexate Injection for Vitreoretinal Lymphoma: Clinical and In Vitro Studies. J Clin Med 2020; 9: 2672
• 59 Kuroiwa N, Abematsu N, Matsuo Y. et al. [A case of intraocular lymphoma having retinal adverse events associated with intravitreal methotrexate]. Nihon Ganka Gakkai Zasshi 2011; 115: 611-616
• 60 Zhou X, Zhou X, Shi H. et al. Reduced frequency of Intravitreal methotrexate injection lowers the risk of Keratopathy in Vitreoretinal lymphoma patients. BMC Ophthalmol 2020; 20: 189
• 61 Gensler G, Clemons TE, Domalpally A. et al. Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study. Ophthalmol Retina 2018; 2: 441-450
• 62 Merrill PT, Clark WL, Banker AS. et al. Efficacy and Safety of Intravitreal Sirolimus for Noninfectious Uveitis of the Posterior Segment: Results from the Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program. Ophthalmology 2020; 127: 1405-1415
• 63 Giganti M, Beer PM, Lemanski N. et al. Adverse events after intravitreal infliximab (Remicade). Retina 2010; 30: 71-80
• 64 Hamza MME, Macky TA, Sidky MK. et al. Intravitreal infliximab in refractory uveitis in Behcetʼs disease: A safety and efficacy clinical study. Retina 2016; 36: 2399-2408
• 65 Hamam RN, Barikian AW, Antonios RS. et al. Intravitreal Adalimumab in Active Noninfectious Uveitis: A Pilot Study. Ocul Immunol Inflamm 2016; 24: 319-326
• 66 Leal I, Rodrigues FB, Sousa DC. et al. Efficacy and safety of intravitreal anti-tumour necrosis factor drugs in adults with non-infectious uveitis – a systematic review. Acta Ophthalmol 2018; 96: e665-e675
• 67 Dong X, Shi W, Yuan G. et al. Intravitreal implantation of the biodegradable cyclosporin A drug delivery system for experimental chronic uveitis. Graefes Arch Clin Exp Ophthalmol 2006; 244: 492-497
• 68 Kasper M, Gabriel D, Moller M. et al. Cyclosporine A-Loaded Nanocarriers for Topical Treatment of Murine Experimental Autoimmune Uveoretinitis. Mol Pharm 2018; 15: 2539-2547
• 69 Pehlivan SB, Yavuz B, Calamak S. et al. Preparation and in vitro/in vivo evaluation of cyclosporin A-loaded nanodecorated ocular implants for subconjunctival application. J Pharm Sci 2015; 104: 1709-1720
• 70 Alshamsan A, Abul Kalam M, Vakili MR. et al. Treatment of endotoxin-induced uveitis by topical application of cyclosporine a-loaded PolyGel in rabbit eyes. Int J Pharm 2019; 569: 118573
• 71 Garg V, Jain GK, Nirmal J. et al. Topical tacrolimus nanoemulsion, a promising therapeutic approach for uveitis. Med Hypotheses 2013; 81: 901-904
• 72 Garg V, Nirmal J, Riadi Y. et al. Amelioration of Endotoxin-Induced Uveitis in Rabbit by Topical Administration of Tacrolimus Proglycosome Nano-Vesicles. J Pharm Sci 2021; 110: 871-875
• 73 Kasper M, Gabriel D, Moller M. et al. Novel everolimus-loaded nanocarriers for topical treatment of murine experimental autoimmune uveoretinitis (EAU). Exp Eye Res 2018; 168: 49-56
• 74 Afarid M, Lashkarizadeh H, Ashraf MJ. et al. The efficacy of intravitreal interferon alpha-2b for the treatment of experimental endotoxin-induced uveitis. Indian J Ophthalmol 2016; 64: 376-381
• 75 Farvardin M, Afarid M, Mehryar M. et al. Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina 2010; 30: 1530-1535
• 76 Farvardin M, Afarid M, Shahrzad S. Long-term effects of intravitreal infliximab for treatment of sight-threatening chronic noninfectious uveitis. J Ocul Pharmacol Ther 2012; 28: 628-631
• 77 Donmez O, Yaman A, Ozturk T. et al. The efficacy of systemic and intravitreal infliximab treatments in an endotoxin-induced uveitis model. Cutan Ocul Toxicol 2019; 38: 360-369
• 78 Hosseini H, Safaei A, Khalili MR. et al. Intravitreal infliximab in experimental endotoxin-induced uveitis. Eur J Ophthalmol 2009; 19: 818-823
• 79 Yuksel E, Hasanreisoglu B, Yuksel N. et al. Comparison of acute effect of systemic versus intravitreal infliximab treatment in an experimental model of endotoxin-induced uveitis. J Ocul Pharmacol Ther 2014; 30: 74-80
• 80 Zhang R, Qian J, Li X. et al. Treatment of experimental autoimmune uveoretinitis with intravitreal injection of infliximab encapsulated in liposomes. Br J Ophthalmol 2017; 101: 1731-1738
• 81 Chen Z, Yang M, Wang Q. et al. Hydrogel eye drops as a non-invasive drug carrier for topical enhanced Adalimumab permeation and highly efficient uveitis treatment. Carbohydr Polym 2021; 253: 117216