EDITORIAL
What’s New in Uveitis and Ocular Inflammation? Timothy Y.Y. Lai, MD, FRCS, FRCOphth*Þ
U
veitis and intraocular inflammation are important sight-threatening disorders worldwide, and it has been estimated that uveitis is responsible for around 5% to 10% of blindness in the United States and various Western countries.1 If the uveitis is not treated optimally, visual loss can develop because of various sight-threatening complications including band keratopathy, cataract, glaucoma, cystoid macular edema, retinal scars, and optic neuropathy.2 Among the working age group of 20 to 65 years, uveitis is second only to diabetic retinopathy as a major cause of treatable blindness.3 Therefore, uveitis is an ocular disease that carries a high socioeconomic impact.1 Recent advancements in both basic science and clinical research have greatly enhanced our understanding in the pathogenesis, etiology, and management of uveitis and ocular inflammatory diseases. In this issue of the Asia Pacific Journal of Ophthalmology, Kedhar4 provided an excellent literature review in research and development on ocular immunology and uveitis published in 2011 to 2012. This review gives a very comprehensive snapshot of ‘‘what’s new in uveitis’’ and summarized important findings from various studies including the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study and the Multicenter Uveitis Steroid Treatment (MUST) trial. Both SITE and MUST studies were sponsored by the National Eye Institute, and the results provided important supportive evidence to improve the management of uveitis and our understanding in the risk factors and prognosis of uveitis. In addition to the research topics covered in the review by Kedhar, there are 3 other areas in uveitis with articles published in 2011Y2012 that might be of interest to clinicians. These include genetic studies on uveitis, the use of antiangiogenesis therapy for inflammatory ocular neovascularization, and newer biologic agents for treating uveitis. Over the past few years, a number of studies have been performed to evaluate the association of various genes involved in the immunological system in uveitis. One of these genetic factors is the complement factor H (CFH) gene, which is a key regulator in the alternative complement pathway of the immune system.5,6 The CFH 184G polymorphism has been found to be associated with anterior uveitis, and this association was specific for females.5 Moreover, the CFH I62V polymorphism was also found to be associated with noninfectious intermediate and posterior uveitis.6 These CFH variants might result in structural changes in the CFH protein and can affect the affinity of C3b binding, which subsequently influence the activation of the alternative pathway. Polymorphism in the complement factor B (CFB) gene, an opponent of CFH, has also been found to be associated with anterior uveitis.7 In addition, several studies have also shown that polymorphisms in interleukin and cytokine genes were associated with uveitis and Behc¸et disease.6,8Y10 These studies have enhanced our understanding in the role of genetics in the pathogenesis of uveitis and might provide future potential target for the treatment of intraocular inflammation. Another important recent development in the management of ocular comorbidity associated with uveitis is the availability of antiYvascular endothelial growth factor (VEGF) agents such as intravitreal bevacizumab and ranibizumab for choroidal neovascularization (CNV) secondary to ocular inflammation.11Y14 At present, the use of anti-VEGF agents in CNV secondary to ocular inflammation is considered as off-labeled use. Nonetheless, published studies have demonstrated beneficial visual outcomes following anti-VEGF therapy for inflammatory CNV.11Y14 In particular, the long-term outcome with up to 5 years of follow-up was favorable with no major complication encountered.14 Therefore, it is reasonable to consider anti-VEGF therapy as the standard therapy for CNV due to ocular inflammation. An area of research deficiency highlighted in Kedhar’s4 review is the paucity of large-scale randomized controlled trials for uveitis treatment published in 2011Y2012. Nonetheless, large-scale
From the *Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital; and †2010 Macula & Retina Centre, Kowloon, Hong Kong. Received for publication March 25, 2013; accepted March 29, 2013. The authors have no funding or conflicts of interest to declare. Reprints: Timothy Y.Y. Lai, MD, FRCS, FRCOphth, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle St, Kowloon, Hong Kong. E-mail: [email protected]. Copyright * 2013 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e318294b850
Asia-Pacific Journal of Ophthalmology
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Volume 2, Number 3, May/June 2013
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Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
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Editorial
clinical trials in the use of biologic agents for uveitis are becoming more common. For example, the results of 3 randomized controlled trials in the use of secukinumab, an interleukin 17A inhibitor, for the treatment of noninfectious uveitis have just been published.15 Although the primary efficacy end points were not met in the 3 studies, the secondary efficacy data showed that secukinumab might reduce the use of concomitant systemic immunosuppressive therapy.15 Another biologic agent, gevokizumab, an interleukin 1AYregulating antibody, has been shown to result in rapid and sustained reduction in uveitis and retinal vasculitis in treatment-resistant Behc¸et disease.16 At present, at least 2 large-scale, multicenter, double-masked, randomized controlled trials (EYEGUARD-A and EYEGUARD-C) are being conducted to assess the efficacy and safety of gevokizumab in the treatment of noninfectious uveitis (http://clinicaltrials.gov/ ct2/show/NCT01684345 and http://clinicaltrials.gov/ct2/show/ NCT01747538, accessed March 25, 2013). These 2 phase 3 studies will each recruit more than 300 patients, and the results will be beneficial to demonstrate whether gevokizumab is safe and effective in treating noninfectious uveitis. Hopefully, the research will provide a new effective treatment option that can enhance the management of noninfectious uveitis and prevent blindness caused by uveitis. REFERENCES 1. Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol. 1996;80:844Y848. 2. Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica. 2004;218:223Y236. 3. Lee RW, Dick AD. Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye. 2012;26:17Y28. 4. Kedhar S. Annual review: research in uveitis and ocular inflammation, 2011Y2012. Asia Pac J Ophthalmol. 2013;2:187Y198. 5. Yang MM, Lai TY, Tam PO, et al. CFH 184G as a genetic risk marker for anterior uveitis in Chinese females. Mol Vis. 2011;17:2655Y2664.
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6. Yang MM, Lai TY, Tam PO, et al. Complement factor H and interleukin gene polymorphisms in patients with non-infectious intermediate and posterior uveitis. Mol Vis. 2012;18:1865Y1872. 7. Yang MM, Lai TY, Tam PO, et al. Association of C2 and CFB polymorphisms with anterior uveitis. Invest Ophthalmol Vis Sci. 2012;53:4969Y4974. 8. Lindner E, Weger M, Steinwender G, et al. IL2RA gene polymorphism rs2104286 A9G seen in multiple sclerosis is associated with intermediate uveitis: possible parallel pathways? Invest Ophthalmol Vis Sci. 2011;52:8295Y8299. 9. Ozcimen AA, Dilek K, Bingol U, et al. IL-1 cluster gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet. 2011;38:295Y301. 10. Shahram F, Nikoopour E, Rezaei N, et al. Association of interleukin-2, interleukin-4 and transforming growth factor-beta gene polymorphisms with Behcet’s disease. Clin Exp Rheumatol. 2011;29:S28YS31. 11. Arevalo JF, Adan A, Berrocal MH, et al. Intravitreal bevacizumab for inflammatory choroidal neovascularization: results from the Pan-American Collaborative Retina Study Group at 24 months. Retina. 2011;31:353Y363. 12. Julian K, Terrada C, Fardeau C, et al. Intravitreal bevacizumab as first local treatment for uveitis-related choroidal neovascularization: long-term results. Acta Ophthalmol. 2011;89:179Y184. 13. Mansour AM, Arevalo JF, Faradeau C, et al. Three-year visual and anatomical results of administrating intravitreal bevacizumab in inflammatory ocular neovascularization. Can J Ophthalmol. 2012;47:269Y274. 14. Mansour AM, Mackensen F, Mahendradas P, et al. Five-year visual results of intravitreal bevacizumab in refractory inflammatory ocular neovascularization. Clin Ophthalmol. 2012;6:1233Y1237. 15. Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials [published online ahead of print January 2, 2013]. Ophthalmology. 16. Gui A, Tugal-Tutkun I, Dinarello CA, et al. Interleukin-1AYregulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet’s disease: an open-label pilot study. Ann Rheum Dis. 2012;71:563Y566.
‘‘Vision with action can change the world.’’ V Joel A. Barker
140
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* 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
What’s New in Uveitis and Ocular Inflammation? Timothy Y.Y. Lai, MD, FRCS, FRCOphth*Þ
U
veitis and intraocular inflammation are important sight-threatening disorders worldwide, and it has been estimated that uveitis is responsible for around 5% to 10% of blindness in the United States and various Western countries.1 If the uveitis is not treated optimally, visual loss can develop because of various sight-threatening complications including band keratopathy, cataract, glaucoma, cystoid macular edema, retinal scars, and optic neuropathy.2 Among the working age group of 20 to 65 years, uveitis is second only to diabetic retinopathy as a major cause of treatable blindness.3 Therefore, uveitis is an ocular disease that carries a high socioeconomic impact.1 Recent advancements in both basic science and clinical research have greatly enhanced our understanding in the pathogenesis, etiology, and management of uveitis and ocular inflammatory diseases. In this issue of the Asia Pacific Journal of Ophthalmology, Kedhar4 provided an excellent literature review in research and development on ocular immunology and uveitis published in 2011 to 2012. This review gives a very comprehensive snapshot of ‘‘what’s new in uveitis’’ and summarized important findings from various studies including the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study and the Multicenter Uveitis Steroid Treatment (MUST) trial. Both SITE and MUST studies were sponsored by the National Eye Institute, and the results provided important supportive evidence to improve the management of uveitis and our understanding in the risk factors and prognosis of uveitis. In addition to the research topics covered in the review by Kedhar, there are 3 other areas in uveitis with articles published in 2011Y2012 that might be of interest to clinicians. These include genetic studies on uveitis, the use of antiangiogenesis therapy for inflammatory ocular neovascularization, and newer biologic agents for treating uveitis. Over the past few years, a number of studies have been performed to evaluate the association of various genes involved in the immunological system in uveitis. One of these genetic factors is the complement factor H (CFH) gene, which is a key regulator in the alternative complement pathway of the immune system.5,6 The CFH 184G polymorphism has been found to be associated with anterior uveitis, and this association was specific for females.5 Moreover, the CFH I62V polymorphism was also found to be associated with noninfectious intermediate and posterior uveitis.6 These CFH variants might result in structural changes in the CFH protein and can affect the affinity of C3b binding, which subsequently influence the activation of the alternative pathway. Polymorphism in the complement factor B (CFB) gene, an opponent of CFH, has also been found to be associated with anterior uveitis.7 In addition, several studies have also shown that polymorphisms in interleukin and cytokine genes were associated with uveitis and Behc¸et disease.6,8Y10 These studies have enhanced our understanding in the role of genetics in the pathogenesis of uveitis and might provide future potential target for the treatment of intraocular inflammation. Another important recent development in the management of ocular comorbidity associated with uveitis is the availability of antiYvascular endothelial growth factor (VEGF) agents such as intravitreal bevacizumab and ranibizumab for choroidal neovascularization (CNV) secondary to ocular inflammation.11Y14 At present, the use of anti-VEGF agents in CNV secondary to ocular inflammation is considered as off-labeled use. Nonetheless, published studies have demonstrated beneficial visual outcomes following anti-VEGF therapy for inflammatory CNV.11Y14 In particular, the long-term outcome with up to 5 years of follow-up was favorable with no major complication encountered.14 Therefore, it is reasonable to consider anti-VEGF therapy as the standard therapy for CNV due to ocular inflammation. An area of research deficiency highlighted in Kedhar’s4 review is the paucity of large-scale randomized controlled trials for uveitis treatment published in 2011Y2012. Nonetheless, large-scale
From the *Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital; and †2010 Macula & Retina Centre, Kowloon, Hong Kong. Received for publication March 25, 2013; accepted March 29, 2013. The authors have no funding or conflicts of interest to declare. Reprints: Timothy Y.Y. Lai, MD, FRCS, FRCOphth, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle St, Kowloon, Hong Kong. E-mail: [email protected]. Copyright * 2013 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e318294b850
Asia-Pacific Journal of Ophthalmology
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Volume 2, Number 3, May/June 2013
www.apjo.org
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
139
Asia-Pacific Journal of Ophthalmology
Editorial
clinical trials in the use of biologic agents for uveitis are becoming more common. For example, the results of 3 randomized controlled trials in the use of secukinumab, an interleukin 17A inhibitor, for the treatment of noninfectious uveitis have just been published.15 Although the primary efficacy end points were not met in the 3 studies, the secondary efficacy data showed that secukinumab might reduce the use of concomitant systemic immunosuppressive therapy.15 Another biologic agent, gevokizumab, an interleukin 1AYregulating antibody, has been shown to result in rapid and sustained reduction in uveitis and retinal vasculitis in treatment-resistant Behc¸et disease.16 At present, at least 2 large-scale, multicenter, double-masked, randomized controlled trials (EYEGUARD-A and EYEGUARD-C) are being conducted to assess the efficacy and safety of gevokizumab in the treatment of noninfectious uveitis (http://clinicaltrials.gov/ ct2/show/NCT01684345 and http://clinicaltrials.gov/ct2/show/ NCT01747538, accessed March 25, 2013). These 2 phase 3 studies will each recruit more than 300 patients, and the results will be beneficial to demonstrate whether gevokizumab is safe and effective in treating noninfectious uveitis. Hopefully, the research will provide a new effective treatment option that can enhance the management of noninfectious uveitis and prevent blindness caused by uveitis. REFERENCES 1. Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol. 1996;80:844Y848. 2. Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica. 2004;218:223Y236. 3. Lee RW, Dick AD. Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye. 2012;26:17Y28. 4. Kedhar S. Annual review: research in uveitis and ocular inflammation, 2011Y2012. Asia Pac J Ophthalmol. 2013;2:187Y198. 5. Yang MM, Lai TY, Tam PO, et al. CFH 184G as a genetic risk marker for anterior uveitis in Chinese females. Mol Vis. 2011;17:2655Y2664.
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Volume 2, Number 3, May/June 2013
6. Yang MM, Lai TY, Tam PO, et al. Complement factor H and interleukin gene polymorphisms in patients with non-infectious intermediate and posterior uveitis. Mol Vis. 2012;18:1865Y1872. 7. Yang MM, Lai TY, Tam PO, et al. Association of C2 and CFB polymorphisms with anterior uveitis. Invest Ophthalmol Vis Sci. 2012;53:4969Y4974. 8. Lindner E, Weger M, Steinwender G, et al. IL2RA gene polymorphism rs2104286 A9G seen in multiple sclerosis is associated with intermediate uveitis: possible parallel pathways? Invest Ophthalmol Vis Sci. 2011;52:8295Y8299. 9. Ozcimen AA, Dilek K, Bingol U, et al. IL-1 cluster gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet. 2011;38:295Y301. 10. Shahram F, Nikoopour E, Rezaei N, et al. Association of interleukin-2, interleukin-4 and transforming growth factor-beta gene polymorphisms with Behcet’s disease. Clin Exp Rheumatol. 2011;29:S28YS31. 11. Arevalo JF, Adan A, Berrocal MH, et al. Intravitreal bevacizumab for inflammatory choroidal neovascularization: results from the Pan-American Collaborative Retina Study Group at 24 months. Retina. 2011;31:353Y363. 12. Julian K, Terrada C, Fardeau C, et al. Intravitreal bevacizumab as first local treatment for uveitis-related choroidal neovascularization: long-term results. Acta Ophthalmol. 2011;89:179Y184. 13. Mansour AM, Arevalo JF, Faradeau C, et al. Three-year visual and anatomical results of administrating intravitreal bevacizumab in inflammatory ocular neovascularization. Can J Ophthalmol. 2012;47:269Y274. 14. Mansour AM, Mackensen F, Mahendradas P, et al. Five-year visual results of intravitreal bevacizumab in refractory inflammatory ocular neovascularization. Clin Ophthalmol. 2012;6:1233Y1237. 15. Dick AD, Tugal-Tutkun I, Foster S, et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials [published online ahead of print January 2, 2013]. Ophthalmology. 16. Gui A, Tugal-Tutkun I, Dinarello CA, et al. Interleukin-1AYregulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet’s disease: an open-label pilot study. Ann Rheum Dis. 2012;71:563Y566.
‘‘Vision with action can change the world.’’ V Joel A. Barker
140
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* 2013 Asia Pacific Academy of Ophthalmology
Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
