SEQUENTIAL, ACUTE NONINFECTIOUS UVEITIS ASSOCIATED WITH SEPARATE INTRAVITREAL INJECTIONS OF BEVACIZUMAB AND RANIBIZUMAB Matthew A. Cunningham, MD,* Paul Tlucek, MD,* James C. Folk, MD,*† H. Culver Boldt, MD,* Stephen R. Russell, MD*†
Purpose: To report the unique response of a patient with exudative age-related macular degeneration who developed sequential episodes of acute noninfectious uveitis following separate intravitreal injections of bevacizumab and ranibizumab. Methods: Retrospective interventional case report. Chart review. Results: A 73-year-old white woman, who received monthly intravitreal bevacizumab injections for exudative age-related macular degeneration in the right eye, developed decreased vision 4 days after her last injection. She had trace anterior chamber cells and 1+ vitritis, consistent with a bevacizumab-associated uveitis. The patient improved on topical steroids and cycloplegics. Subsequently, her exudative age-related macular degeneration was treated with monthly ranibizumab injections. Optical coherence tomography demonstrated persistent subretinal fluid despite treatment. Seven days after her 11th ranibizumab injection, she developed sudden decreased vision, 2+ anterior chamber cell, and 4+ vitritis. Presumptive treatment for an exogenous bacterial endophthalmitis was given after a vitreous biopsy was performed, which demonstrated severe sterile infiltrates that were culture negative. All injections were stopped. Three months later, the subretinal fluid had disappeared, the vitritis has nearly resolved, but some intraretinal fluid persisted. Conclusion: Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based vascular endothelial growth factor inhibition implies a suppressive immunomodulatory effect on vascular permeability or choroidal neovascularization. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between choroidal neovascularization, vitritis, and innate and other immunologic processes. RETINAL CASES & BRIEF REPORTS 7:355–358, 2013
supplanted the previous, more specific VEGF inhibitor, pegaptanib sodium. Comparisons of regulation, efficacy, and safety remain controversial but accumulating evidence from the Comparison of Age-related Macular Degeneration Treatments Trial convincingly suggested nonsuperiority of bevacizumab and ranibizumab, two commercially available anti-VEGF agents.1 In this study and in our separate published reports,2 we have reported postinjection uveitis to both bevacizumab and ranibizumab. Herein, we report a unique patient who developed sequential, acute noninfectious uveitis associated with
From the *Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, and †Carver Center for Macular Degeneration, Institute for Vision Research, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
A
ntibody-based vascular endothelial growth factor (VEGF) inhibitors are the current mainstay of treatment of exudative age-related macular degeneration. Both ranibizumab and bevacizumab have largely 355
356
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 4
Fig. 1. Spectral-domain optical coherence tomography of the right macula demonstrating subfoveal subretinal fluid and nasal edema at initial presentation.
separate intravitreal bevacizumab (1.25 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) injections. Case Report A 73-year-old white woman, known to have nonexudative agerelated macular degeneration in both eyes developed onset of metamorphopsia and decreased vision in the right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left eye, with 1+ nuclear sclerotic cataracts in both eyes. The right fundus exhibited scattered exudates; the left had rare macular drusen. By optical coherence tomography, the right macula had subretinal fluid and nasal edema (Figure 1). By fluorescein angiography, a co-localizing region of increasing subretinal and enlarging hyperfluorescence confirmed the presence of occult choroidal neovascularization (CNV). At her initial visit, ranibizumab anti-VEGF therapy (Lucentis; Genetech, South San Francisco, CA) was given in the right eye. As is our custom for a favorably responding eye, the subsequent injections given were of bevacizumab (Avastin; Genentech). She underwent a total of 7 intravitreal injections administered at 4- to 5-week intervals. On the day of her seventh injection, her best-corrected Snellen visual acuity improved to 20/30, despite the persistent presence of varying amounts of subretinal fluid and nasal macular edema. Seven days after her seventh injection, she developed acute decreased vision measured at counting fingers at 3 ft in the right eye. Her visual acuity remained 20/20 in the left eye. In addition, the right eye had keratic precipitates with trace anterior chamber cells and 1+ cells in the anterior vitreous, consistent with a bevacizumab-associated uveitis. She was treated with prednisolone acetate 1% 6 times per day and scopolamine 2 times a day in the right eye. One month later, her vision had improved to 20/40 in the right eye, with resolution of the keratic precipitates. Coherence tomography continued to demonstrate subretinal fluid (Figure 2). Her treatment was then changed to monthly ranibizumab intravitreal injections in the right eye. After several injections, the visual acuity had Supported by the Donald H. Beisner M.D. and Judith Gardner Beisner Chair for Vitreoretinal Diseases and Surgery (J.C.F.), the Marion and Frederich Fuerste Chair in Ophthalmology (H.C.B.), the Dina J. Schrage Professorship for Macular Degeneration (S.R.R.), and an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY, to the Department of Ophthalmology and Visual Sciences, Carver School of Medicine, University of Iowa. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Stephen R. Russell, MD, Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Room 11196 I, Pomerantz Family Pavillion, 200 Hawkins Drive, Iowa City, IA 52242; e-mail: [email protected]
improved to 20/20 in the right eye. A total of 11 injections were administered as subretinal fluid continued to be present. Eight days after the 11th injection of ranibizumab, she developed blurred vision in the right eye, with visual acuity of hand motions, 2+ cell and flare in the anterior chamber, and 4+ vitritis. Standardized echography demonstrated dense vitreous opacities (Figure 3). A vitreous biopsy was performed followed by intravitreal injection of vancomycin (1 mg) and ceftazidime (2.25 mg). Additionally, 1% prednisolone acetate every hour and scopolamine 2 times a day was started. Twenty-four hours later, oral prednisone was begun. The vitreous and anterior chamber cultures were negative. Two weeks later, the visual acuity had improved to 20/100 with 1+ anterior chamber cell and 2+ anterior vitreous cells. Three months after the last intravitreal injection, the visual acuity had improved to 20/30 in the right eye, and the inflammation continues to improve, with resolution of the subretinal fluid but persistence of the intraretinal edema.
Discussion Noninfectious uveitis has been separately associated with intravitreous injections of both bevacizumab and ranibizumab. For the clinician, the immediate dilemma is separating exogenous bacterial endophthalmitis from noninfectious uveitis. Endophthalmitis has a reported rate of 0.1% following intravitreal injection of bevacizumab, which is similar to that of ranibizumab and pegaptanib.3 For postinjection uveitis, one large retrospective series reported rates of 1.57% for bevicizumab and 1.38% for ranibizumab, which were not statistically significantly different.4 Noninfectious uveitis rates typically are found to be 10 times higher than infectious uveitis following intravitreous injection. In this report, we describe a woman who developed noninfectious uveitis to bevacizumab and ranibizumab following temporally separated vitreous injection. Although her negative culture does not guarantee a noninfectious etiology of her ocular inflammation, the patient’s clinical course and normal retinal examination (the absence of retinal hemorrhages) suggest a sterile process. Although a minimal inoculum of a low-grade pathogenic bacteria could conceivably contribute to this or other post-injection uveitis episodes, we cannot determine this by current premortem testing.
357
UVEITIS CAUSED BY BEVACIZUMAB AND RANIBIZUMAB
Fig. 2. One month after bevacizumab-related uveitis, the optical coherence tomography continued to demonstrate subretinal fluid and nasal edema in the right eye.
It is peculiar that our untreated patient, without antiVEGF treatment for 3 months, had resolution of the subretinal fluid. Chronic inflammation has been implicated in the development of exudative age-related macular degeneration,5 and a recent study has shown that inflammatory cytokines stimulate VEGF.6 Our patient had prominent vitritis, which has continued to improve and has nearly resolved. It is plausible that vitritis or associated uveitis may signal escape from anterior chamber associated immune deviation or other intraocular immunological processes that results in a suppressive immunomodulatory effect on vascular permeability or CNV. Presumably, this effect could be mediated by a reduction in inflammatory cytokines, by reduced secretion or by degradation by infiltrating leucocytes. Recently, Antonopoulos et al7 described two patients who developed acute anterior uveitis following intravitreal bevacizumab but not with subsequent ranibizumab. It has been suggested that the Fc protein fragment of bevacizumab provides an immunologic stimulus not present with ranibizumab. However, it is important to note that the Fab fragment sequence in both bevacizumab and ranibizumab is the same, and that in our subject an epitope within this region may cause cross-reactivity to both agents. Alternatively, a postinjection toxic reaction to the excipients within
bevacizumab and ranibizumab may occur as the formulation of both agents are similar.7 The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between CNV, vitritis, and innate and other immunologic processes. Long-term monitoring for inflammatory events, or their absence, that may represent cross-reactivity to antibody-based VEGF inhibitors, especially in patients with previous inflammatory episodes, might be useful in understanding the complex process of CNV inhibition, vitritis, and vascular leakage.
Conclusion Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based VEGF inhibition implies a suppressive immunomodulatory effect on vascular permeability or CNV. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between CNV, vitritis, and innate and other immunologic processes. Key words: neovascular age-related macular degeneration, ranibizumab, bevacizumab, noninfectious uveitis, intravitreal injection, anti–vascular endothelial growth factor. References
Fig. 3. Standardized echography of the right eye demonstrating dense vitreous opacities.
1. Martin DF, Maguire MG, Ying GS, et al; CATT Research Group. Ranibizumab and bevacizumab for neovascular agerelated macular degeneration. N Engl J Med 2011;364:1897– 1908. 2. Kay CN, Tarantola RM, Gehrs KM, et al. Uveitis following inravitreal bevacizumab: a non-infectious cluster. Ophthalmic Surg Lasers Imaging 2011;42:292–296.
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RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 4
3. Jonas JB, Spandau UH, Rensch F, et al. Infectious and noninfectious endophthalmitis after intravitreal bevacizumab. J Ocul Pharmacol Ther 2007;23:240–242. 4. Ladas ID, Karagiannis DA, Rouvas AA, et al. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 injections. Retina 2009;29:313–318. 5. Lommatzsch A, Hermans P, Müller KD, et al. Are low inflammatory reactions involved in exudative age-related macular degeneration? Morphological and immunhistochemical
analysis of AMD associated with basal deposits. Graefes Arch Clin Exp Ophthalmol 2008;246:803–810. 6. Nagineni CN, Kommineni VK, William A, et al. Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration. J Cell Physiol 2012;227:116–126. 7. Antonopoulos C, Stem M, Comer GM. Acute anterior uveitis following intravitreal bevacizumab but not subsequent ranibizumab. Clin Ophthalmol 2011;5:1659–1662.
Purpose: To report the unique response of a patient with exudative age-related macular degeneration who developed sequential episodes of acute noninfectious uveitis following separate intravitreal injections of bevacizumab and ranibizumab. Methods: Retrospective interventional case report. Chart review. Results: A 73-year-old white woman, who received monthly intravitreal bevacizumab injections for exudative age-related macular degeneration in the right eye, developed decreased vision 4 days after her last injection. She had trace anterior chamber cells and 1+ vitritis, consistent with a bevacizumab-associated uveitis. The patient improved on topical steroids and cycloplegics. Subsequently, her exudative age-related macular degeneration was treated with monthly ranibizumab injections. Optical coherence tomography demonstrated persistent subretinal fluid despite treatment. Seven days after her 11th ranibizumab injection, she developed sudden decreased vision, 2+ anterior chamber cell, and 4+ vitritis. Presumptive treatment for an exogenous bacterial endophthalmitis was given after a vitreous biopsy was performed, which demonstrated severe sterile infiltrates that were culture negative. All injections were stopped. Three months later, the subretinal fluid had disappeared, the vitritis has nearly resolved, but some intraretinal fluid persisted. Conclusion: Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based vascular endothelial growth factor inhibition implies a suppressive immunomodulatory effect on vascular permeability or choroidal neovascularization. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between choroidal neovascularization, vitritis, and innate and other immunologic processes. RETINAL CASES & BRIEF REPORTS 7:355–358, 2013
supplanted the previous, more specific VEGF inhibitor, pegaptanib sodium. Comparisons of regulation, efficacy, and safety remain controversial but accumulating evidence from the Comparison of Age-related Macular Degeneration Treatments Trial convincingly suggested nonsuperiority of bevacizumab and ranibizumab, two commercially available anti-VEGF agents.1 In this study and in our separate published reports,2 we have reported postinjection uveitis to both bevacizumab and ranibizumab. Herein, we report a unique patient who developed sequential, acute noninfectious uveitis associated with
From the *Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, and †Carver Center for Macular Degeneration, Institute for Vision Research, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
A
ntibody-based vascular endothelial growth factor (VEGF) inhibitors are the current mainstay of treatment of exudative age-related macular degeneration. Both ranibizumab and bevacizumab have largely 355
356
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 4
Fig. 1. Spectral-domain optical coherence tomography of the right macula demonstrating subfoveal subretinal fluid and nasal edema at initial presentation.
separate intravitreal bevacizumab (1.25 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) injections. Case Report A 73-year-old white woman, known to have nonexudative agerelated macular degeneration in both eyes developed onset of metamorphopsia and decreased vision in the right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left eye, with 1+ nuclear sclerotic cataracts in both eyes. The right fundus exhibited scattered exudates; the left had rare macular drusen. By optical coherence tomography, the right macula had subretinal fluid and nasal edema (Figure 1). By fluorescein angiography, a co-localizing region of increasing subretinal and enlarging hyperfluorescence confirmed the presence of occult choroidal neovascularization (CNV). At her initial visit, ranibizumab anti-VEGF therapy (Lucentis; Genetech, South San Francisco, CA) was given in the right eye. As is our custom for a favorably responding eye, the subsequent injections given were of bevacizumab (Avastin; Genentech). She underwent a total of 7 intravitreal injections administered at 4- to 5-week intervals. On the day of her seventh injection, her best-corrected Snellen visual acuity improved to 20/30, despite the persistent presence of varying amounts of subretinal fluid and nasal macular edema. Seven days after her seventh injection, she developed acute decreased vision measured at counting fingers at 3 ft in the right eye. Her visual acuity remained 20/20 in the left eye. In addition, the right eye had keratic precipitates with trace anterior chamber cells and 1+ cells in the anterior vitreous, consistent with a bevacizumab-associated uveitis. She was treated with prednisolone acetate 1% 6 times per day and scopolamine 2 times a day in the right eye. One month later, her vision had improved to 20/40 in the right eye, with resolution of the keratic precipitates. Coherence tomography continued to demonstrate subretinal fluid (Figure 2). Her treatment was then changed to monthly ranibizumab intravitreal injections in the right eye. After several injections, the visual acuity had Supported by the Donald H. Beisner M.D. and Judith Gardner Beisner Chair for Vitreoretinal Diseases and Surgery (J.C.F.), the Marion and Frederich Fuerste Chair in Ophthalmology (H.C.B.), the Dina J. Schrage Professorship for Macular Degeneration (S.R.R.), and an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY, to the Department of Ophthalmology and Visual Sciences, Carver School of Medicine, University of Iowa. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Stephen R. Russell, MD, Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Room 11196 I, Pomerantz Family Pavillion, 200 Hawkins Drive, Iowa City, IA 52242; e-mail: [email protected]
improved to 20/20 in the right eye. A total of 11 injections were administered as subretinal fluid continued to be present. Eight days after the 11th injection of ranibizumab, she developed blurred vision in the right eye, with visual acuity of hand motions, 2+ cell and flare in the anterior chamber, and 4+ vitritis. Standardized echography demonstrated dense vitreous opacities (Figure 3). A vitreous biopsy was performed followed by intravitreal injection of vancomycin (1 mg) and ceftazidime (2.25 mg). Additionally, 1% prednisolone acetate every hour and scopolamine 2 times a day was started. Twenty-four hours later, oral prednisone was begun. The vitreous and anterior chamber cultures were negative. Two weeks later, the visual acuity had improved to 20/100 with 1+ anterior chamber cell and 2+ anterior vitreous cells. Three months after the last intravitreal injection, the visual acuity had improved to 20/30 in the right eye, and the inflammation continues to improve, with resolution of the subretinal fluid but persistence of the intraretinal edema.
Discussion Noninfectious uveitis has been separately associated with intravitreous injections of both bevacizumab and ranibizumab. For the clinician, the immediate dilemma is separating exogenous bacterial endophthalmitis from noninfectious uveitis. Endophthalmitis has a reported rate of 0.1% following intravitreal injection of bevacizumab, which is similar to that of ranibizumab and pegaptanib.3 For postinjection uveitis, one large retrospective series reported rates of 1.57% for bevicizumab and 1.38% for ranibizumab, which were not statistically significantly different.4 Noninfectious uveitis rates typically are found to be 10 times higher than infectious uveitis following intravitreous injection. In this report, we describe a woman who developed noninfectious uveitis to bevacizumab and ranibizumab following temporally separated vitreous injection. Although her negative culture does not guarantee a noninfectious etiology of her ocular inflammation, the patient’s clinical course and normal retinal examination (the absence of retinal hemorrhages) suggest a sterile process. Although a minimal inoculum of a low-grade pathogenic bacteria could conceivably contribute to this or other post-injection uveitis episodes, we cannot determine this by current premortem testing.
357
UVEITIS CAUSED BY BEVACIZUMAB AND RANIBIZUMAB
Fig. 2. One month after bevacizumab-related uveitis, the optical coherence tomography continued to demonstrate subretinal fluid and nasal edema in the right eye.
It is peculiar that our untreated patient, without antiVEGF treatment for 3 months, had resolution of the subretinal fluid. Chronic inflammation has been implicated in the development of exudative age-related macular degeneration,5 and a recent study has shown that inflammatory cytokines stimulate VEGF.6 Our patient had prominent vitritis, which has continued to improve and has nearly resolved. It is plausible that vitritis or associated uveitis may signal escape from anterior chamber associated immune deviation or other intraocular immunological processes that results in a suppressive immunomodulatory effect on vascular permeability or CNV. Presumably, this effect could be mediated by a reduction in inflammatory cytokines, by reduced secretion or by degradation by infiltrating leucocytes. Recently, Antonopoulos et al7 described two patients who developed acute anterior uveitis following intravitreal bevacizumab but not with subsequent ranibizumab. It has been suggested that the Fc protein fragment of bevacizumab provides an immunologic stimulus not present with ranibizumab. However, it is important to note that the Fab fragment sequence in both bevacizumab and ranibizumab is the same, and that in our subject an epitope within this region may cause cross-reactivity to both agents. Alternatively, a postinjection toxic reaction to the excipients within
bevacizumab and ranibizumab may occur as the formulation of both agents are similar.7 The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between CNV, vitritis, and innate and other immunologic processes. Long-term monitoring for inflammatory events, or their absence, that may represent cross-reactivity to antibody-based VEGF inhibitors, especially in patients with previous inflammatory episodes, might be useful in understanding the complex process of CNV inhibition, vitritis, and vascular leakage.
Conclusion Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based VEGF inhibition implies a suppressive immunomodulatory effect on vascular permeability or CNV. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between CNV, vitritis, and innate and other immunologic processes. Key words: neovascular age-related macular degeneration, ranibizumab, bevacizumab, noninfectious uveitis, intravitreal injection, anti–vascular endothelial growth factor. References
Fig. 3. Standardized echography of the right eye demonstrating dense vitreous opacities.
1. Martin DF, Maguire MG, Ying GS, et al; CATT Research Group. Ranibizumab and bevacizumab for neovascular agerelated macular degeneration. N Engl J Med 2011;364:1897– 1908. 2. Kay CN, Tarantola RM, Gehrs KM, et al. Uveitis following inravitreal bevacizumab: a non-infectious cluster. Ophthalmic Surg Lasers Imaging 2011;42:292–296.
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RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 4
3. Jonas JB, Spandau UH, Rensch F, et al. Infectious and noninfectious endophthalmitis after intravitreal bevacizumab. J Ocul Pharmacol Ther 2007;23:240–242. 4. Ladas ID, Karagiannis DA, Rouvas AA, et al. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 injections. Retina 2009;29:313–318. 5. Lommatzsch A, Hermans P, Müller KD, et al. Are low inflammatory reactions involved in exudative age-related macular degeneration? Morphological and immunhistochemical
analysis of AMD associated with basal deposits. Graefes Arch Clin Exp Ophthalmol 2008;246:803–810. 6. Nagineni CN, Kommineni VK, William A, et al. Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration. J Cell Physiol 2012;227:116–126. 7. Antonopoulos C, Stem M, Comer GM. Acute anterior uveitis following intravitreal bevacizumab but not subsequent ranibizumab. Clin Ophthalmol 2011;5:1659–1662.
