1040-5488/15/9205-e97/0 VOL. 92, NO. 5, PP. e97Ye105 OPTOMETRY AND VISION SCIENCE Copyright * 2015 American Academy of Optometry
CLINICAL CASE
Intravitreal Aflibercept after Bilateral Bevacizumab-Induced Iritis Leonid Skorin, Jr.* and Lucas Genereux†
ABSTRACT Purpose. To present a case of neovascular age-related macular degeneration treated with aflibercept intravitreal injections after bilateral bevacizumab injections, administered on separate dates, resulted in bilateral iritis. Case Report. A 73-year-old woman with a previous history of two episodes of nongranulomatous iritis in her right eye that was believed to be associated with her systemic diagnosis of rheumatoid arthritis was treated with intravitreal bevacizumab injections for bilaterally occurring neovascular age-related macular degeneration. Initial bevacizumab injections in each eye administered sequentially over a week’s time resulted in immediate-onset nongranulomatous iritis in each eye. Subsequent intravitreal injections of aflibercept were administered, and therapeutic benefit was achieved without occurrence of iritis. Conclusions. In cases where intravitreal bevacizumab results in anterior uveitis, aflibercept may be a safe alternative therapeutic choice for the treatment of neovascular age-related macular degeneration. (Optom Vis Sci 2015;92:e97Ye105) Key Words: wet age-related macular degeneration (ARMD), antiYvascular endothelial growth factor (anti-VEGF), intravitreal injection, bevacizumab, ranibizumab, aflibercept, iritis
S
ince the inception of antiYvascular endothelial growth factor (anti-VEGF) medications in 2005, millions of patients with neovascular age-related macular degeneration (wet-ARMD) have experienced their vision-saving capabilities. These medications have drastically improved the visual prognosis for patients with the number one cause of blindness in the developed world.1 Where clinicians were once forced with adopting a wait-and-hope treatment strategy, they now have a viable option to not only halt but also reverse the progression of the disease. Neovascularization and increased vascular permeability in proliferative retinopathies such as wet-ARMD have been shown to be largely mediated by the release of vascular endothelial growth factor (VEGF).2 Since this discovery, inhibiting VEGF’s effects has become the main target in the treatment of such pathologies. Many formulations of these medications have been proposed and tested. Today, there are three anti-VEGF medications that are being used in the treatment of wet-ARMD. The three treatment options in our armamentarium against wet-ARMD are intravitreal injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA), bevacizumab (Avastin; *OD, DO, MS, FAAO † BA Department of Ophthalmology, Mayo Clinic Health System, Albert Lea, Minnesota (LS, Jr.); and Pacific University College of Optometry, Forest Grove, Oregon (LG).
Genentech), and aflibercept (Eylea; Regeneron, Tarrytown, NY). Although each of these drugs is formulated to combat the effects of VEGF, they are all unique in their own way. Bevacizumab was the first medication in this category used for the treatment of wet-ARMD, and its groundbreaking use was initiated as an off-label treatment. Originally formulated to combat metastatic colorectal cancer, bevacizumab is a recombinant humanized full-length antibody that binds all isoforms of VEGF.2 Bevacizumab’s ability to combat wet-ARMD was revealed through the SANA (Systemic Avastin Therapy for Neovascular Age-Related Macular Degeneration) study.3 The SANA study showed that systemic bevacizumab reduced leakage from neovascularization, and its positive effects were evident through both objective and subjective measures.3 Objectively, decreased central retinal thickness was measured using optical coherence tomography (OCT), and subjective benefits of bevacizumab were evident through increased visual acuity.3 Ranibizumab was formulated specifically for ocular use with the goal of maximizing penetration to the inner retina in mind. It is a recombinant humanized antibody fragment that binds VEGF and inhibits the interaction between VEGF and its receptors.4 Ranibizumab is FDA (Food and Drug Administration) approved to treat wet-ARMD, as well as diabetic macular edema and macular edema secondary to retinal vein occlusions. For comparison’s sake, Krohne et al. have determined 1.5 mg intravitreal bevacizumab to have a half-life of 9.82 days,5 whereas 0.5 mg intravitreal ranibizumab had a half-life of 7.19 days.6
Optometry and Vision Science, Vol. 92, No. 5, May 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
e98 Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
reactive to light and did not show an afferent pupillary defect. Intraocular pressures were 16 mm Hg in her right eye and 14 mm Hg in her left eye. Anterior segment evaluation of both eyes showed normal structure of the lids, conjunctiva, and cornea. The patient’s irides were flat and without neovascularization. The anterior chamber was quiet with no cells or flare. Posterior chamber intraocular lenses were present in each eye.
Testing and Treatment
FIGURE 1. Fundus image of the right eye.
Aflibercept is the newest addition to our therapeutic arsenal against wet-ARMD. Its mechanism of action is similar to bevacizumab and ranibizumab in that it antagonizes VEGF, but it also binds to platelet-derived growth factor.7 Further, aflibercept has been shown to have a greater binding affinity than either bevacizumab or ranibizumab and has been shown to maintain significant binding affinity to VEGF for between 10 and 12 weeks after injection.8 It is also FDA approved to treat wet-ARMD. Aflibercept is formulated through the fusion of specific domains from human VEGF receptors 1 and 2 with the Fc portion of human immunoglobulin G.9
CASE REPORT Presentation
Dilated fundus examination showed clear vitreous and healthy optic nerves without neovascularization of the disc. Posterior pole findings included cystoid macular edema, prominent pigment mottling, and multiple, discrete subretinal hemorrhages in the macula of the right eye (Fig. 1). Left eye posterior pole showed a central hemorrhage with slight edema (Fig. 2). Neither eye showed microaneurysms, venous beading, intraretinal microvascular abnormalities, vitreal hemorrhages, hard exudates, or neovascularization that would suggest that the observed retinal thickening was secondary to diabetic retinopathy. Optical coherence tomography showed central cystoid edema in the right eye with a pigment epithelial defect, and the central macular thickness was measured at 349 Km (Fig. 3). Optical coherence tomography of the left eye showed trace amount of cystic edema and a central macular thickness of 336 Km (Fig. 4). A retinal consultation was obtained. The retinal specialist performed a fluorescein angiography that showed the source of the fluid to be choroidal neovascularization, with identified leaking vessels in the nasal macular in the right eye and temporal macula in the left (Figs. 5 and 6). There was no petal-shaped hyperfluorescence within the maculas during the late phases. This indicated that the observed cystoid macular edema was not a consequence of cataract surgery. The retinal specialist confirmed the diagnosis of wet-ARMD and scheduled the patient to receive a series of bevacizumab intravitreal injections at our office. The patient presented back to our clinic 4 days after being seen by the retina specialist for her first intravitreal injection. Her examination findings were unchanged from her initial visit. After
A 73-year-old woman presented to our clinic with a complaint of reduced vision in each eye. The patient’s ocular history was positive for two episodes of nongranulomatous anterior uveitis in her right eye that was believed to be associated with her systemic diagnosis of rheumatoid arthritis. The first episode of iritis was 3 years before her current office visit. The second iritis episode occurred 1 year before her current presentation. Because the patient had a known diagnosis of rheumatoid arthritis, no additional work-up of her two occurrences of iritis was performed. She was also pseudophakic in both eyes. Both eyes had cataract surgery 2 months before her current presentation. Her medical history consisted of the diagnoses of type 2 diabetes mellitus, rheumatoid arthritis, hypertension, and hypothyroidism. Her arthritis was being treated with acetaminophen and subcutaneous methotrexate. Her hypertension was being treated with hydrochlorothiazide. Her hypothyroidism was being treated with levothyroxine.
Physical Examination The patient’s visual acuities were 20/25 j 2 in her right eye and 20/30 + 1 in her left eye. Her pupils were equal, round, and
FIGURE 2. Fundus image of the left eye.
Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
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FIGURE 3. Horizontal and vertical OCT line scans of the right eye at the initial visit before the injection of bevacizumab. Central intraretinal edema was seen in the horizontal scan. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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e100 Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
FIGURE 4. Horizontal and vertical OCT line scans of the left eye at the initial visit before the injection of bevacizumab. Central intraretinal edema was seen in the horizontal scan. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
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Two-Day Follow-up, Right Eye On the return examination 2 days later, the patient presented with visual acuity of 20/60 j 2 in her right eye. The decreased visual acuity was thought to be attributed to cycloplegic-induced glare. Her right eye’s intraocular pressure was 18 mm Hg. She reported to be compliant with the prescribed topical medications. Slit lamp examination revealed resolving iritis. Dilated fundus examination remained unchanged. She was instructed to decrease her prednisolone dose to one drop every 4 hours and to continue cyclopentolate dosage as previously prescribed.
Five-Day Follow-up, Right Eye and Procedure, Left Eye
FIGURE 5. Late-phase fluorescein angiogram, right eye.
sterilization with topical moxifloxacin 0.5% and betadine 5.0%, local anesthesia was administered with topical tetracaine hydrochloride 0.5% and lidocaine hydrochloride 3.5% ophthalmic gel. An intravitreal injection of 1.25 mg bevacizumab was administered 3.25 mm posterior to the infratemporal limbus. After checking for proper perfusion of the retinal tissue and assessing gross visual acuity, a quarter-inch strip of erythromycin 0.5% was placed in the lower cul-de-sac of the patient’s right eye. She was scheduled to return for her first injection in her left eye the following week. The patient was instructed to return to the clinic if she experienced an increase in discomfort or noted any redness or decreased vision.
Five days later, the patient reported for her planned left eye’s bevacizumab injection. At this time, visual acuity was 20/30 + 1 in her right eye and 20/20 j 2 in her left eye. Intraocular pressure was 14 mm Hg in each eye. Slit lamp examination revealed normal findings for all structures with noted resolution of iritis in her right eye. The exact same bevacizumab intravitreal injection procedure was performed in the left eye that was done previously in the right eye. The injection was performed without complication, and the patient was told to return to the clinic if she experienced any pain or reduction in vision.
One-Day Follow-up, Left Eye The following day, the patient reported to the clinic complaining of the same pain and photophobia in the left eye that she had experienced 1 week prior in the right eye. Visual acuity in the left eye was 20/50 + 1. Intraocular pressure was 20 mm Hg in the left eye. Slit lamp examination of the left eye revealed normal
One-Day Follow-up, Right Eye The following day, the patient reported to the clinic complaining of pain that had persisted throughout the night. The patient noted that her eye was particularly sensitive to touch and light. The visual acuity in her right eye had diminished to 20/40 + 2. Her pupils remained normal. Intraocular pressure was determined to be 12 mm Hg in her right eye and 15 mm Hg in her left eye. Slit lamp examination of the right eye revealed circumlimbal injection and grade 2+ cells in the anterior chamber without hypopyon. The patient’s lids, cornea, and lens were all unremarkable, and there were no peripheral anterior or posterior synechiae. Dilated fundus examination showed edema and hemorrhaging as noted previously. Her vitreous was clear, with no signs of vitritis. The peripheral retina was flat without holes for the entire 360 degrees, and there were no signs of vascular sheathing or pars planitis. Based on these findings, the diagnosis of new-onset nongranulomatous anterior uveitis was made after finding no signs of endophthalmitis. Topical therapy of prednisolone acetate 1.0% every 2 hours and cyclopentolate 1.0% four times a day was initiated, and the patient was instructed to return in 2 days or immediately if she perceived her condition to be worsening.
FIGURE 6. Late-phase fluorescein angiogram, left eye.
Optometry and Vision Science, Vol. 92, No. 5, May 2015
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e102 Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
eyelids, conjunctiva, cornea, and posterior chamber intraocular lens. Her anterior chamber showed grade 3+ cells without hypopyon. No peripheral anterior or posterior synechiae were present.
Prednisolone acetate 1.0% every 2 hours and cyclopentolate 1.0% four times a day were prescribed. The patient was to return to the clinic in 4 days or if she felt her condition worsened.
FIGURE 7. Horizontal and vertical OCT line scans of the right eye 1 month after injection. Central intraretinal edema is resolved. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
Four-Day Follow-up, Left Eye Four days later, the patient returned to the clinic and the anterior chamber of her left eye showed the presence of a trace amount of cells. At this time, the patient was instructed to taper off her anti-inflammatory medications in both eyes and to return for her previously scheduled intravitreal anti-VEGF injection for her right eye.
One-Month Follow-up, Right Eye One month after the initial injection of bevacizumab, the patient reported for the second injection for her right eye. Visual acuity was 20/20 j 1 in the right eye and 20/20 j 2 in the left eye. Intraocular pressure was 18 mm Hg in the right eye. Slit lamp examination was unremarkable and without signs of iritis. Dilated fundus examination of the right eye showed one remaining hemorrhage and possible central edema. Optical coherence tomography showed resolving edema and a central macular thickness of 277 Km (Fig. 7). At this appointment, an injection of 2.0 mg aflibercept was administered using the same protocol that was used during the prior bevacizumab injection to her right eye. With her history of presumed iatrogenic iritis in mind, the patient was instructed to return to the clinic should the signs and symptoms of iritis return. This injection was well received and tolerated without manifestation of iritis. One week later, the patient reported for an aflibercept injection in her left eye. At that time, visual acuity was 20/20 in each eye. Anterior segment evaluation was unremarkable and without signs of iritis in either eye. Dilated fundus examination revealed normal posterior pole and peripheral retinal tissue, OCT showed no remaining edema, and the central macula was measured at 277 Km (Fig. 8). Our retina consultant follows a loading regimen of monthly injections for the first 3 months, after which the patient is reassessed. Continued treatment is determined based on loss of vision, the presence of subretinal fluid or cystoid macular edema on OCT, or leakage on fluorescein angiography. This injection was also well tolerated without precipitation of iritis. The patient has not developed iritis in either eye with subsequent aflibercept injections.
DISCUSSION The initial manifestation of iritis in the patient’s right eye raised the question of its etiology. The systemic diagnoses of rheumatoid arthritis and the previous history of iritis in the same eye meant that the observed uveitis could have been a recurrence not related to the intravitreal injection. The decision to continue with the planned bevacizumab injection in the left eye proved to be valuable in the diagnosis. The fact that iritis developed in the fellow left eye, which did not have a history of uveitis, in a similar time frame, was highly suggestive of the injection being the cause and argues against a simple recurrence. Different lot numbers of bevacizumab were used in the two eyes, which essentially eliminated a tainted batch of the drug as the cause. The observation that the iritis developed after two intravitreal bevacizumab injections, in separate eyes, but not after an injection of aflibercept also made
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the trauma from the procedure itself a less likely cause. Given all of the clinical evidence, the most likely etiology of the observed iritis was a reaction specifically to bevacizumab. Noninfectious inflammation after intravitreal injection of all three previously discussed medications has been reported with slightly varying rates.10 Bevacizumab has been found to have a rate of inflammation of 0.14% in one study reporting on 7113 injections from patients in 12 countries.11 These incidents were reported to have occurred between 2 and 7 days after injection, whereas in both the cases reported here, the iritis developed immediately.8 Another study showed that 0.09% of patients receiving bevacizumab intravitreal injections developed uveitis.12 A rate of inflammation of 2.1% was reported in patients receiving 0.5 mg ranibizumab in one study.13 The incidence of noninfectious inflammation secondary to intravitreal aflibercept injection was reported in a different study as 0.37%.10 In an 8-month period after this study ended, the rate of inflammation in 3222 injections was a mere 0.03%.10 This appeared to be more in line with the manufacturer’s postmarketing data from November 2011 to December 2013.10 In the period between November 2011 and December 2013, more than a million injections were performed, and the reported rate of inflammation was found to be 0.04%.10 There are a variety of studies on the side effects of these medications. Most of these studies have found the incidence of inflammation to be similar. However, no studies report on the incidence of inflammation in patients with a previous history of uveitis. In fact, several studies actually consider a history of uveitis diagnosis to be an exclusion criterion. Thus, the incident rate of uveitis in these patients could be different from those reported. Once the injection of bevacizumab yielded anterior uveitis in the patient’s left eye as well, the decision was made to use one of the other two medications available to treat wet-ARMD. In doing so, a better understanding of whether inflammation secondary to the trauma from the procedure itself of the bevacizumab would be gained. The only decision was which medication to use. The structural similarities between bevacizumab and ranibizumab are well noted. The main difference is that ranibizumab is a much shorter fragment of the antibody. Bevacizumab is a full-length antibody that includes both the Fab and Fc fragments. Conversely, ranibizumab is only made up of the Fab portion.14 With this structural difference in mind, it appears plausible that patients who cannot tolerate bevacizumab may, in fact, have no problems with subsequent ranibizumab injections. A case report by Antonopoulos et al. describe a case of a patient who developed iritis with bevacizumab, received a ranibizumab injection without complication, and then underwent another bevacizumab injection that elicited another anterior chamber reaction. The patient has since been treated with ranibizumab without complication.15 In another case report, a patient developed iritis after being switched from ranibizumab injections to bevacizumab.15 This patient was then placed back on ranibizumab injections without complication.15 These reports fall in line with the claim by Chong et al.16 that if indeed inflammation in bevacizumab patients is attributed to a specific immune response to the bevacizumab drug, there is no cross-reactivity with ranibizumab. Conversely, Damasceno et al. reported on a case in which both bevacizumab and ranibizumab caused subsequent iritis reactions. However, this patient developed her inflammation after ranibizumab
Optometry and Vision Science, Vol. 92, No. 5, May 2015
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e104 Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
in one eye and then developed uveitis in the other eye after bevacizumab injection 3 months later.14 A literature search did not result in any reported cases of aflibercept injections administered after inflammatory reactions stemming from bevacizumab treatment. Although the mechanism
responsible for inflammatory reaction after anti-VEGF intravitreal injection is not well understood, there are cases where patients develop reactions to both bevacizumab and ranibizumab. One hypothesis is that there is something immunogenic in bevacizumab for certain patients. Because ranibizumab is a shorter
FIGURE 8. Horizontal and vertical OCT line scans of the left eye 1 month after injection. Central intraretinal edema is resolved. Optometry and Vision Science, Vol. 92, No. 5, May 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
fragment of the bevacizumab antibody, it appears plausible that there may be some cross-reactivity for certain patients. Without a large-scale study comparing the cross-reactivity of all three medications, one cannot be sure of the presence or absence of any cross-reactivity between the medications. The decision to use aflibercept for continued therapy of the reported patient was based on the fact that it was the most structurally dissimilar medication to the initial agent. The only question was if the patient would be as responsive to aflibercept as she was to bevacizumab. Singh et al.17 reported that patients previously responsive to bevacizumab and ranibizumab can be successfully treated with aflibercept with as good or better results.
CONCLUSION The mechanism by which the anti-VEGF medications cause uveitic reactions is not understood. In the reported case, a systematic process of elimination led to the belief that the observed iritis was caused by the specific drug that was initially injected. Whether it is anecdotal or not, the use of aflibercept as a substitution medication when bevacizumab injections cannot be tolerated may be the best choice of action. Aflibercept is the most dissimilar to the other drugs structurally, and the literature suggests that patients previously controlled with either ranibizumab or bevacizumab can also be controlled with aflibercept. Received September 8, 2014; accepted December 11, 2014.
REFERENCES 1. Zarbin MA, Casaroli-Marano RP, Rosenfeld PJ. Age-related macular degeneration: clinical findings, histopathology and imaging techniques. Dev Ophthalmol 2014;53:1Y32. 2. Ladas ID, Karagiannis DA, Rouvas AA, Kotsolis AI, Liotsou A, Vergados I. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 injections. Retina 2009;29:313Y8. 3. Rosenfeld PJ, Martidis A, Tennant MTS. Age-related macular degeneration. In: Yanoff M, Duker JS, eds. Ophthalmology, 3rd ed. St. Louis, MO: Mosby Elsevier; 2009;658Y73. 4. Abu-Yaghi NE, Buettner H, Bakri SJ. Retina and vitreal disease. In: Onofrey BE, Skorin L, Holdeman NR, eds. Ocular Therapeutics Handbook: A Clinical Manual, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:483Y7. 5. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 2008;146:508Y12.
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6. Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol 2012;154:682Y6.e2. 7. Rosenfeld PJ. My use of aflibercept in clinical practice. Retina Today 2012;50. 8. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667Y8. 9. VEGF TRAP-EYE (aflibercept ophthalmic solution) Ophthalmologic Drugs Advisory Committee. Regeneron Pharmaceuticals, Inc., 2011. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugs AdvisoryCommittee/UCM259143.pdf. Accessed February 7, 2015. 10. Goldberg RA, Shah CP, Wiegand TW, Heier JS. Noninfectious inflammation after intravitreal injection of aflibercept: clinical characteristics and visual outcomes. Am J Ophthalmol 2014;158:733Y7.e1. 11. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344Y9. 12. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, Arevalo JF, Berrocal MH, Farah ME, Maia M, Roca JA, Rodriguez FJ. Twelvemonth safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008;246:81Y7. 13. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432Y44. 14. Damasceno N, Horowitz S, Damasceno E. Anterior uveitis after treatment of age-related macular degeneration with ranibizumab and bevacizumab: uncommon complication. Clin Ophthalmol 2012;6:1201Y5. 15. Antonopoulos C, Stem M, Comer GM. Acute anterior uveitis following intravitreal bevacizumab but not subsequent ranibizumab. Clin Ophthalmol 2011;5:1659Y62. 16. Chong DY, Anand R, Williams PD, Qureshi JA, Callanan DG. Characterization of sterile intraocular inflammatory responses after intravitreal bevacizumab injection. Retina 2010;30:1432Y40. 17. Singh RP, Srivastava S, Ehlers JP, Bedi R, Schachat AP, Kaiser PK. A single-arm, investigator-initiated study of the efficacy, safety and tolerability of intravitreal aflibercept injection in subjects with exudative age-related macular degeneration, previously treated with ranibizumab or bevacizumab: 6-month interim analysis. Br J Ophthalmol 2014;98:i22Y7.
Leonid Skorin, Jr. Mayo Clinic Health System 404 W. Fountain Street Albert Lea, MN 56007 e-mail: [email protected]
Optometry and Vision Science, Vol. 92, No. 5, May 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
CLINICAL CASE
Intravitreal Aflibercept after Bilateral Bevacizumab-Induced Iritis Leonid Skorin, Jr.* and Lucas Genereux†
ABSTRACT Purpose. To present a case of neovascular age-related macular degeneration treated with aflibercept intravitreal injections after bilateral bevacizumab injections, administered on separate dates, resulted in bilateral iritis. Case Report. A 73-year-old woman with a previous history of two episodes of nongranulomatous iritis in her right eye that was believed to be associated with her systemic diagnosis of rheumatoid arthritis was treated with intravitreal bevacizumab injections for bilaterally occurring neovascular age-related macular degeneration. Initial bevacizumab injections in each eye administered sequentially over a week’s time resulted in immediate-onset nongranulomatous iritis in each eye. Subsequent intravitreal injections of aflibercept were administered, and therapeutic benefit was achieved without occurrence of iritis. Conclusions. In cases where intravitreal bevacizumab results in anterior uveitis, aflibercept may be a safe alternative therapeutic choice for the treatment of neovascular age-related macular degeneration. (Optom Vis Sci 2015;92:e97Ye105) Key Words: wet age-related macular degeneration (ARMD), antiYvascular endothelial growth factor (anti-VEGF), intravitreal injection, bevacizumab, ranibizumab, aflibercept, iritis
S
ince the inception of antiYvascular endothelial growth factor (anti-VEGF) medications in 2005, millions of patients with neovascular age-related macular degeneration (wet-ARMD) have experienced their vision-saving capabilities. These medications have drastically improved the visual prognosis for patients with the number one cause of blindness in the developed world.1 Where clinicians were once forced with adopting a wait-and-hope treatment strategy, they now have a viable option to not only halt but also reverse the progression of the disease. Neovascularization and increased vascular permeability in proliferative retinopathies such as wet-ARMD have been shown to be largely mediated by the release of vascular endothelial growth factor (VEGF).2 Since this discovery, inhibiting VEGF’s effects has become the main target in the treatment of such pathologies. Many formulations of these medications have been proposed and tested. Today, there are three anti-VEGF medications that are being used in the treatment of wet-ARMD. The three treatment options in our armamentarium against wet-ARMD are intravitreal injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA), bevacizumab (Avastin; *OD, DO, MS, FAAO † BA Department of Ophthalmology, Mayo Clinic Health System, Albert Lea, Minnesota (LS, Jr.); and Pacific University College of Optometry, Forest Grove, Oregon (LG).
Genentech), and aflibercept (Eylea; Regeneron, Tarrytown, NY). Although each of these drugs is formulated to combat the effects of VEGF, they are all unique in their own way. Bevacizumab was the first medication in this category used for the treatment of wet-ARMD, and its groundbreaking use was initiated as an off-label treatment. Originally formulated to combat metastatic colorectal cancer, bevacizumab is a recombinant humanized full-length antibody that binds all isoforms of VEGF.2 Bevacizumab’s ability to combat wet-ARMD was revealed through the SANA (Systemic Avastin Therapy for Neovascular Age-Related Macular Degeneration) study.3 The SANA study showed that systemic bevacizumab reduced leakage from neovascularization, and its positive effects were evident through both objective and subjective measures.3 Objectively, decreased central retinal thickness was measured using optical coherence tomography (OCT), and subjective benefits of bevacizumab were evident through increased visual acuity.3 Ranibizumab was formulated specifically for ocular use with the goal of maximizing penetration to the inner retina in mind. It is a recombinant humanized antibody fragment that binds VEGF and inhibits the interaction between VEGF and its receptors.4 Ranibizumab is FDA (Food and Drug Administration) approved to treat wet-ARMD, as well as diabetic macular edema and macular edema secondary to retinal vein occlusions. For comparison’s sake, Krohne et al. have determined 1.5 mg intravitreal bevacizumab to have a half-life of 9.82 days,5 whereas 0.5 mg intravitreal ranibizumab had a half-life of 7.19 days.6
Optometry and Vision Science, Vol. 92, No. 5, May 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
e98 Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
reactive to light and did not show an afferent pupillary defect. Intraocular pressures were 16 mm Hg in her right eye and 14 mm Hg in her left eye. Anterior segment evaluation of both eyes showed normal structure of the lids, conjunctiva, and cornea. The patient’s irides were flat and without neovascularization. The anterior chamber was quiet with no cells or flare. Posterior chamber intraocular lenses were present in each eye.
Testing and Treatment
FIGURE 1. Fundus image of the right eye.
Aflibercept is the newest addition to our therapeutic arsenal against wet-ARMD. Its mechanism of action is similar to bevacizumab and ranibizumab in that it antagonizes VEGF, but it also binds to platelet-derived growth factor.7 Further, aflibercept has been shown to have a greater binding affinity than either bevacizumab or ranibizumab and has been shown to maintain significant binding affinity to VEGF for between 10 and 12 weeks after injection.8 It is also FDA approved to treat wet-ARMD. Aflibercept is formulated through the fusion of specific domains from human VEGF receptors 1 and 2 with the Fc portion of human immunoglobulin G.9
CASE REPORT Presentation
Dilated fundus examination showed clear vitreous and healthy optic nerves without neovascularization of the disc. Posterior pole findings included cystoid macular edema, prominent pigment mottling, and multiple, discrete subretinal hemorrhages in the macula of the right eye (Fig. 1). Left eye posterior pole showed a central hemorrhage with slight edema (Fig. 2). Neither eye showed microaneurysms, venous beading, intraretinal microvascular abnormalities, vitreal hemorrhages, hard exudates, or neovascularization that would suggest that the observed retinal thickening was secondary to diabetic retinopathy. Optical coherence tomography showed central cystoid edema in the right eye with a pigment epithelial defect, and the central macular thickness was measured at 349 Km (Fig. 3). Optical coherence tomography of the left eye showed trace amount of cystic edema and a central macular thickness of 336 Km (Fig. 4). A retinal consultation was obtained. The retinal specialist performed a fluorescein angiography that showed the source of the fluid to be choroidal neovascularization, with identified leaking vessels in the nasal macular in the right eye and temporal macula in the left (Figs. 5 and 6). There was no petal-shaped hyperfluorescence within the maculas during the late phases. This indicated that the observed cystoid macular edema was not a consequence of cataract surgery. The retinal specialist confirmed the diagnosis of wet-ARMD and scheduled the patient to receive a series of bevacizumab intravitreal injections at our office. The patient presented back to our clinic 4 days after being seen by the retina specialist for her first intravitreal injection. Her examination findings were unchanged from her initial visit. After
A 73-year-old woman presented to our clinic with a complaint of reduced vision in each eye. The patient’s ocular history was positive for two episodes of nongranulomatous anterior uveitis in her right eye that was believed to be associated with her systemic diagnosis of rheumatoid arthritis. The first episode of iritis was 3 years before her current office visit. The second iritis episode occurred 1 year before her current presentation. Because the patient had a known diagnosis of rheumatoid arthritis, no additional work-up of her two occurrences of iritis was performed. She was also pseudophakic in both eyes. Both eyes had cataract surgery 2 months before her current presentation. Her medical history consisted of the diagnoses of type 2 diabetes mellitus, rheumatoid arthritis, hypertension, and hypothyroidism. Her arthritis was being treated with acetaminophen and subcutaneous methotrexate. Her hypertension was being treated with hydrochlorothiazide. Her hypothyroidism was being treated with levothyroxine.
Physical Examination The patient’s visual acuities were 20/25 j 2 in her right eye and 20/30 + 1 in her left eye. Her pupils were equal, round, and
FIGURE 2. Fundus image of the left eye.
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FIGURE 3. Horizontal and vertical OCT line scans of the right eye at the initial visit before the injection of bevacizumab. Central intraretinal edema was seen in the horizontal scan. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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FIGURE 4. Horizontal and vertical OCT line scans of the left eye at the initial visit before the injection of bevacizumab. Central intraretinal edema was seen in the horizontal scan. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Two-Day Follow-up, Right Eye On the return examination 2 days later, the patient presented with visual acuity of 20/60 j 2 in her right eye. The decreased visual acuity was thought to be attributed to cycloplegic-induced glare. Her right eye’s intraocular pressure was 18 mm Hg. She reported to be compliant with the prescribed topical medications. Slit lamp examination revealed resolving iritis. Dilated fundus examination remained unchanged. She was instructed to decrease her prednisolone dose to one drop every 4 hours and to continue cyclopentolate dosage as previously prescribed.
Five-Day Follow-up, Right Eye and Procedure, Left Eye
FIGURE 5. Late-phase fluorescein angiogram, right eye.
sterilization with topical moxifloxacin 0.5% and betadine 5.0%, local anesthesia was administered with topical tetracaine hydrochloride 0.5% and lidocaine hydrochloride 3.5% ophthalmic gel. An intravitreal injection of 1.25 mg bevacizumab was administered 3.25 mm posterior to the infratemporal limbus. After checking for proper perfusion of the retinal tissue and assessing gross visual acuity, a quarter-inch strip of erythromycin 0.5% was placed in the lower cul-de-sac of the patient’s right eye. She was scheduled to return for her first injection in her left eye the following week. The patient was instructed to return to the clinic if she experienced an increase in discomfort or noted any redness or decreased vision.
Five days later, the patient reported for her planned left eye’s bevacizumab injection. At this time, visual acuity was 20/30 + 1 in her right eye and 20/20 j 2 in her left eye. Intraocular pressure was 14 mm Hg in each eye. Slit lamp examination revealed normal findings for all structures with noted resolution of iritis in her right eye. The exact same bevacizumab intravitreal injection procedure was performed in the left eye that was done previously in the right eye. The injection was performed without complication, and the patient was told to return to the clinic if she experienced any pain or reduction in vision.
One-Day Follow-up, Left Eye The following day, the patient reported to the clinic complaining of the same pain and photophobia in the left eye that she had experienced 1 week prior in the right eye. Visual acuity in the left eye was 20/50 + 1. Intraocular pressure was 20 mm Hg in the left eye. Slit lamp examination of the left eye revealed normal
One-Day Follow-up, Right Eye The following day, the patient reported to the clinic complaining of pain that had persisted throughout the night. The patient noted that her eye was particularly sensitive to touch and light. The visual acuity in her right eye had diminished to 20/40 + 2. Her pupils remained normal. Intraocular pressure was determined to be 12 mm Hg in her right eye and 15 mm Hg in her left eye. Slit lamp examination of the right eye revealed circumlimbal injection and grade 2+ cells in the anterior chamber without hypopyon. The patient’s lids, cornea, and lens were all unremarkable, and there were no peripheral anterior or posterior synechiae. Dilated fundus examination showed edema and hemorrhaging as noted previously. Her vitreous was clear, with no signs of vitritis. The peripheral retina was flat without holes for the entire 360 degrees, and there were no signs of vascular sheathing or pars planitis. Based on these findings, the diagnosis of new-onset nongranulomatous anterior uveitis was made after finding no signs of endophthalmitis. Topical therapy of prednisolone acetate 1.0% every 2 hours and cyclopentolate 1.0% four times a day was initiated, and the patient was instructed to return in 2 days or immediately if she perceived her condition to be worsening.
FIGURE 6. Late-phase fluorescein angiogram, left eye.
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eyelids, conjunctiva, cornea, and posterior chamber intraocular lens. Her anterior chamber showed grade 3+ cells without hypopyon. No peripheral anterior or posterior synechiae were present.
Prednisolone acetate 1.0% every 2 hours and cyclopentolate 1.0% four times a day were prescribed. The patient was to return to the clinic in 4 days or if she felt her condition worsened.
FIGURE 7. Horizontal and vertical OCT line scans of the right eye 1 month after injection. Central intraretinal edema is resolved. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
Four-Day Follow-up, Left Eye Four days later, the patient returned to the clinic and the anterior chamber of her left eye showed the presence of a trace amount of cells. At this time, the patient was instructed to taper off her anti-inflammatory medications in both eyes and to return for her previously scheduled intravitreal anti-VEGF injection for her right eye.
One-Month Follow-up, Right Eye One month after the initial injection of bevacizumab, the patient reported for the second injection for her right eye. Visual acuity was 20/20 j 1 in the right eye and 20/20 j 2 in the left eye. Intraocular pressure was 18 mm Hg in the right eye. Slit lamp examination was unremarkable and without signs of iritis. Dilated fundus examination of the right eye showed one remaining hemorrhage and possible central edema. Optical coherence tomography showed resolving edema and a central macular thickness of 277 Km (Fig. 7). At this appointment, an injection of 2.0 mg aflibercept was administered using the same protocol that was used during the prior bevacizumab injection to her right eye. With her history of presumed iatrogenic iritis in mind, the patient was instructed to return to the clinic should the signs and symptoms of iritis return. This injection was well received and tolerated without manifestation of iritis. One week later, the patient reported for an aflibercept injection in her left eye. At that time, visual acuity was 20/20 in each eye. Anterior segment evaluation was unremarkable and without signs of iritis in either eye. Dilated fundus examination revealed normal posterior pole and peripheral retinal tissue, OCT showed no remaining edema, and the central macula was measured at 277 Km (Fig. 8). Our retina consultant follows a loading regimen of monthly injections for the first 3 months, after which the patient is reassessed. Continued treatment is determined based on loss of vision, the presence of subretinal fluid or cystoid macular edema on OCT, or leakage on fluorescein angiography. This injection was also well tolerated without precipitation of iritis. The patient has not developed iritis in either eye with subsequent aflibercept injections.
DISCUSSION The initial manifestation of iritis in the patient’s right eye raised the question of its etiology. The systemic diagnoses of rheumatoid arthritis and the previous history of iritis in the same eye meant that the observed uveitis could have been a recurrence not related to the intravitreal injection. The decision to continue with the planned bevacizumab injection in the left eye proved to be valuable in the diagnosis. The fact that iritis developed in the fellow left eye, which did not have a history of uveitis, in a similar time frame, was highly suggestive of the injection being the cause and argues against a simple recurrence. Different lot numbers of bevacizumab were used in the two eyes, which essentially eliminated a tainted batch of the drug as the cause. The observation that the iritis developed after two intravitreal bevacizumab injections, in separate eyes, but not after an injection of aflibercept also made
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the trauma from the procedure itself a less likely cause. Given all of the clinical evidence, the most likely etiology of the observed iritis was a reaction specifically to bevacizumab. Noninfectious inflammation after intravitreal injection of all three previously discussed medications has been reported with slightly varying rates.10 Bevacizumab has been found to have a rate of inflammation of 0.14% in one study reporting on 7113 injections from patients in 12 countries.11 These incidents were reported to have occurred between 2 and 7 days after injection, whereas in both the cases reported here, the iritis developed immediately.8 Another study showed that 0.09% of patients receiving bevacizumab intravitreal injections developed uveitis.12 A rate of inflammation of 2.1% was reported in patients receiving 0.5 mg ranibizumab in one study.13 The incidence of noninfectious inflammation secondary to intravitreal aflibercept injection was reported in a different study as 0.37%.10 In an 8-month period after this study ended, the rate of inflammation in 3222 injections was a mere 0.03%.10 This appeared to be more in line with the manufacturer’s postmarketing data from November 2011 to December 2013.10 In the period between November 2011 and December 2013, more than a million injections were performed, and the reported rate of inflammation was found to be 0.04%.10 There are a variety of studies on the side effects of these medications. Most of these studies have found the incidence of inflammation to be similar. However, no studies report on the incidence of inflammation in patients with a previous history of uveitis. In fact, several studies actually consider a history of uveitis diagnosis to be an exclusion criterion. Thus, the incident rate of uveitis in these patients could be different from those reported. Once the injection of bevacizumab yielded anterior uveitis in the patient’s left eye as well, the decision was made to use one of the other two medications available to treat wet-ARMD. In doing so, a better understanding of whether inflammation secondary to the trauma from the procedure itself of the bevacizumab would be gained. The only decision was which medication to use. The structural similarities between bevacizumab and ranibizumab are well noted. The main difference is that ranibizumab is a much shorter fragment of the antibody. Bevacizumab is a full-length antibody that includes both the Fab and Fc fragments. Conversely, ranibizumab is only made up of the Fab portion.14 With this structural difference in mind, it appears plausible that patients who cannot tolerate bevacizumab may, in fact, have no problems with subsequent ranibizumab injections. A case report by Antonopoulos et al. describe a case of a patient who developed iritis with bevacizumab, received a ranibizumab injection without complication, and then underwent another bevacizumab injection that elicited another anterior chamber reaction. The patient has since been treated with ranibizumab without complication.15 In another case report, a patient developed iritis after being switched from ranibizumab injections to bevacizumab.15 This patient was then placed back on ranibizumab injections without complication.15 These reports fall in line with the claim by Chong et al.16 that if indeed inflammation in bevacizumab patients is attributed to a specific immune response to the bevacizumab drug, there is no cross-reactivity with ranibizumab. Conversely, Damasceno et al. reported on a case in which both bevacizumab and ranibizumab caused subsequent iritis reactions. However, this patient developed her inflammation after ranibizumab
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in one eye and then developed uveitis in the other eye after bevacizumab injection 3 months later.14 A literature search did not result in any reported cases of aflibercept injections administered after inflammatory reactions stemming from bevacizumab treatment. Although the mechanism
responsible for inflammatory reaction after anti-VEGF intravitreal injection is not well understood, there are cases where patients develop reactions to both bevacizumab and ranibizumab. One hypothesis is that there is something immunogenic in bevacizumab for certain patients. Because ranibizumab is a shorter
FIGURE 8. Horizontal and vertical OCT line scans of the left eye 1 month after injection. Central intraretinal edema is resolved. Optometry and Vision Science, Vol. 92, No. 5, May 2015
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Intravitreal Aflibercept after Bilateral Bevacizumab-Induced IritisVSkorin and Genereux
fragment of the bevacizumab antibody, it appears plausible that there may be some cross-reactivity for certain patients. Without a large-scale study comparing the cross-reactivity of all three medications, one cannot be sure of the presence or absence of any cross-reactivity between the medications. The decision to use aflibercept for continued therapy of the reported patient was based on the fact that it was the most structurally dissimilar medication to the initial agent. The only question was if the patient would be as responsive to aflibercept as she was to bevacizumab. Singh et al.17 reported that patients previously responsive to bevacizumab and ranibizumab can be successfully treated with aflibercept with as good or better results.
CONCLUSION The mechanism by which the anti-VEGF medications cause uveitic reactions is not understood. In the reported case, a systematic process of elimination led to the belief that the observed iritis was caused by the specific drug that was initially injected. Whether it is anecdotal or not, the use of aflibercept as a substitution medication when bevacizumab injections cannot be tolerated may be the best choice of action. Aflibercept is the most dissimilar to the other drugs structurally, and the literature suggests that patients previously controlled with either ranibizumab or bevacizumab can also be controlled with aflibercept. Received September 8, 2014; accepted December 11, 2014.
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Leonid Skorin, Jr. Mayo Clinic Health System 404 W. Fountain Street Albert Lea, MN 56007 e-mail: [email protected]
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