REVIEW URRENT C OPINION
Ocular inflammation associated with antivascular endothelial growth factor treatment Howard F. Fine, Greg D. Despotidis, and Jonathan L. Prenner
Purpose of review To describe the diagnosis and management of intraocular inflammation following antivascular endothelial growth factor (VEGF) injections. Recent findings Inflammation following intravitreal anti-VEGF injections can cause a dramatic reduction in acuity. Differentiating factors from truly infectious endophthalmitis include a lack of pain, redness, or hypopyon, although none of these factors is diagnostic. A high suspicion of infectious endophthalmitis should trigger a prompt vitreous tap and injection of intravitreal antibiotics. Conversely, if noninfectious endophthalmitis is suspected, close observation with frequent topical steroids is warranted. Summary Most eyes with noninfectious endophthalmitis following anti-VEGF injection recover within 1 month to baseline acuity with topical corticosteroid treatment. Mechanisms hypothesized to explain postinjection inflammation include patient-specific, delivery-specific, and medication-specific factors. Keywords aflibercept, bevacizumab, intravitreal injection, noninfectious endophthalmitis, ranibizumab
INTRODUCTION The use of antivascular endothelial growth factor (VEGF) medications has increased dramatically over the past decade as they have become the mainstay of treatment for a number of common retinal conditions including neovascular age-related macular degeneration (AMD), retinal vein occlusion (RVO), and diabetic macular edema (DME). Bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eylea) are the most commonly utilized agents. While, overall, these drugs are extremely well tolerated and safe, there are increasing numbers of publications documenting rare inflammatory episodes following their use. Often termed as ‘sterile endophthalmitis’ or ‘noninfectious endophthalmitis’ (NIE), these episodes can cause a marked decline in vision and may be challenging to differentiate from true infectious endophthalmitis.
PRESENTATION OF NONINFECTIOUS ENDOPHTHALMITIS The presentation of sterile inflammation following intravitreal anti-VEGF agents is rapid, typically within 1–4 days of injection. Patients often complain of blurred vision and floaters. In a recent series of 28 cases by Fine et al. [1 ], the acuity dropped from &
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a mean of 20/57 before injection to 20/179 at presentation. Both anterior and posterior segment inflammation were manifest, with the majority of cases graded with mild or moderate inflammation. Retinal hemorrhages were present in about 20% of the cases. Keratic precipitates were rare. Gonioscopy was advisable on examination to exclude a microhypopyon in the early stages of inflammation. Most episodes were managed with frequent topical corticosteroids alone and no antibiotics, confirming their noninfectious nature.
INFECTIOUS VERSUS NONINFECTIOUS ENDOPHTHALMITIS Differentiating infectious endophthalmitis from NIE can be difficult for clinicians. Lack of a hypopyon, lack of pain, and lack of redness can all be Department of Ophthalmology, Rutgers Robert Wood Johnson Medical School, 10 Plum Street Suite 600, New Brunswick NJ 08901, USA Correspondence to Howard F. Fine, MD, MHSc, Department of Ophthalmology, Rutgers, Robert Wood Johnson Medical School, 10 Plum Street Suite 600, New Brunswick, NJ 08901, USA. Tel: +1 732 220 1600; fax: +1 732 220 1603; e-mail: [email protected] Curr Opin Ophthalmol 2015, 26:184–187 DOI:10.1097/ICU.0000000000000154 Volume 26 Number 3 May 2015
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Ocular inflammation associated with anti-VEGF treatment Fine et al. Table 1. Putative mechanisms of inflammation
KEY POINTS Inflammation following anti-VEGF injections can cause a dramatic reduction in acuity. Noninfectious endophthalmitis, in contrast with infectious endophthalmitis, typically lacks pain, redness, and hypopyon. Noninfectious endophthalmitis can be treated with topical corticosteroids and close observation and acuity typically recovers to baseline within 1 month. Mechanisms of noninfectious endophthalmitis include patient-specific, delivery-specific, and medicationspecific factors.
Patient-specific History of uveitis Pro-inflammatory medications (i.e. prostaglandin analogs) Disease-induced impairment of the blood–retinal barrier Anti-idiotypic immune response Delivery-specific Compounding contamination Syringe contamination Temperature fluctuation Air bubbles Drug-specific Formulation (lyophilized versus solubilized)
helpful clues that the postinjection inflammation might be noninfectious, but unfortunately, none of these findings is diagnostic [2 ]. When clinical suspicion is moderate or high for infectious endophthalmitis, prompt vitreous tap and injection of intravitreal antibiotics is warranted. This procedure is relatively benign and timely treatment of infectious endophthalmitis is known to improve outcomes. The clinician is faced with a dilemma when clinical suspicion is low for infectious endophthalmitis. A reasonable management approach may be to treat the patient with hourly topical steroids (such as difluprednate 0.05% emulsion or prednisolone acetate 1%) followed by re-evaluation of the patient within several hours. Development of a hypopyon, an increase in pain, a decrease in acuity, or other clinical deterioration should prompt a tap/injection of intravitreal antibiotics, whereas improvement suggests NIE. &&
MECHANISMS OF INFLAMMATION Several mechanisms have been proposed in the pathogenesis of inflammation following the injection of anti-VEGF medications. The putative mechanisms that elicit inflammation can be broadly classified as medication-specific, delivery-specific, and patient-specific, as given in (Table 1) [1 ]. &
PATIENT FACTORS There are a number of factors particular to individual patients that might theoretically place them at a higher risk of an inflammatory reaction when treated with an anti-VEGF injection. Patients with a prior history of uveitis might logically be more prone to recurrences of inflammation when exposed to an antigen that activates the immune system. Secondly, patients using medications known to be pro-inflammatory to the eye, such as prostaglandin
Endotoxin from manufacturing Nonhuman protein sequence Nonhuman glycosylation Counterfeit drug
analog eye drops used to treat glaucoma, may be predisposed to inflammation. Thirdly, some retinal conditions are known to cause the breakdown of the blood–retinal barrier, such as exudative AMD, possibly degrading the immune-privileged status of the vitreous [3]. Lastly, immune responses have been documented in the serum of a small minority of patients receiving intravitreal medications, an antiidiotypic reaction against the anti-VEGF antibody [4].
DELIVERY FACTORS Bevacizumab for intravitreal use is typically obtained via a compounding pharmacy that aliquots the bottle into individual doses rather than directly from the manufacturer. There have been a few rare but well publicized case series in which breakdown in sterile technique at the compounding pharmacy led to infectious endophthalmitis in a number of patients in a given area [5,6]. Regulation regarding compounding pharmacies continues to evolve. Factors known to unfold or otherwise denature proteins may increase their immunogenicity. Temperature fluctuation is well known to denature proteins [7], and failure to maintain a proper temperature during both shipping and storage has been implicated in increasing the immunogenicity of intravitreal agents. Air bubbles have also been documented to denature proteins in solution [8]. When drawing up anti-VEGF agents from the vial, it is common to inadvertently incorporate bubbles into the syringe. Another link in the delivery chain is the syringe itself. At least one syringe manufacturer has been
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implicated in an outbreak of NIE in 11 patients following intravitreal Avastin [9].
MEDICATION FACTORS Biologic recombinant proteins are produced from biological sources, in contrast to chemically synthesized small-molecule pharmaceuticals, and biologics are often of much greater complexity both in terms of production as well as purification. Therefore, impurities such as endotoxin are a common suspect when biologics incite inflammation [10]. The formulation of a drug may also incite inflammation. The early phase I/II FOCUS (Intravitreal Injections of rhuFab V2 in Combination With Visudyne in Subjects With Age-Related Macular Degeneration) trials of Lucentis utilized a lyophilized formulation which was associated with an 11.4% inflammation rate [11], but when the manufacturer changed to a solubilized formulation that rate plummeted [12]. Nonhuman protein sequences can be immunogenic; therefore, manufacturers exert great effort to humanize as much of a therapeutic protein as possible. Avastin is a humanized antibody, but its production via a Chinese hamster ovary (CHO) cell line could theoretically introduce immunogenic nonhuman glycosylation [3]. Lastly, the presence of counterfeit drug, although rare, has been reported. Wang et al. indicated that 80 out of 116 patients (69%) developed inflammation following intravitreal injection with endotoxin-contaminated counterfeit bevacizumab that infiltrated the drug supply chain in China [13].
BEVACIZUMAB, RANIBIZUMAB, AND AFLIBERCEPT Of the three most commonly used anti-VEGF agents, bevacizumab, ranibizumab, and aflibercept, the majority of publications regarding postinjection inflammation are associated with bevacizumab [3,4,9,13–19] and document an incidence rate as high as 1.1% [4]. Whereas early-phase trials of Lucentis demonstrated elevated rates of inflammation as previously discussed, rates were exceedingly low for the commercially available solubilized formulation. In the phase III AMD trials of Lucentis, the combined rates of uveitis and endophthalmitis were 0.05% in ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) [20] and 0.10% in MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the 186
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Treatment of Neovascular Age-Related Macular Degeneration) [21]. Reports of NIE following US Food and Drug Administration (FDA) approval are scarce [7,22–24]. The rates of inflammation reported in the phase III trials of Eylea were 1–2%. (Aflibercept, FDA package insert, http://www.regeneron.com/Eylea/Eyleafpi.pdf). Hahn et al. [25] published a nonconsecutive series of 15 cases of presumed NIE following Eylea injection gathered by the Therapeutic Surveillance Committee of the American Society of Retina Specialists. Goldberg et al. [2 ] published 20 cases of postinjection inflammation from 5356 Eylea injections, for a rate of 0.37%. Similarly, Fine et al. [1 ] published 28 cases of postinjection inflammation among 5905 Eylea injections, for a rate of 0.47%. Most patients regained baseline acuity within a month following treatment with topical corticosteroids [1 ]. The exact mechanism causing sterile endophthalmitis following most anti-VEGF injections remains unknown. &&
&
&
COMPARING INFLAMMATION RATES BETWEEN AGENTS Comparing the relative rates of intraocular inflammation following Avastin, Lucentis, and Eylea is challenging as the phase III trials were powered to detect differences in efficacy rather than safety. For instance, the year 2 results of the Comparison of Age-related Macular Degeneration Treatment Trials (CATT) found no difference in rate of pseudoendophthalmitis (0.3 versus 0.0%; P ¼ 1.00) or endophthalmitis (0.7 versus 1.2%; P ¼ 0.38) between Lucentis and Avastin, respectively [26]. The VIEW1 and VIEW2 studies comparing monthly Lucentis, monthly Eylea, and bi-monthly Eylea (following an initial 3-monthly doses) reported rates of any intraocular inflammatory response at week 52 (0.8, 0.7, and 0.2%) and at week 96 (1.5, 1.1, and 0.5%) again without statistical difference [27]. A population-based approach is another method to compare relative rates of inflammation or endophthalmitis between drugs. Kiss et al. [28] examined a US administrative claims database for patients with an ICD-9 code of endophthalmitis within 30 days of a ranibizumab or aflibercept injection from November 2011 through May 2013. The endophthalmitis rate was 0.08% (158 cases in 202 225 injections) for ranibizumab versus 0.17% (238 cases in 136 821 injections) for aflibercept. A multivariate analysis controlling for baseline comorbidities and demographics suggests a significantly higher risk of endophthalmitis with aflibercept than ranibizumab (adjusted odds ratio 2.70, 95% confidence interval 2.05–3.56, P < 0.001). Volume 26 Number 3 May 2015
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Ocular inflammation associated with anti-VEGF treatment Fine et al.
CONCLUSION Inflammation following intravitreal anti-VEGF injections can cause a dramatic reduction in acuity. Differentiating factors from truly infectious endophthalmitis include a lack of pain, redness, or hypopyon, although none of these factors is diagnostic. A high suspicion of infectious endophthalmitis should trigger a prompt vitreous tap and injection of intravitreal antibiotics. Conversely, if NIE is suspected, close observation with frequent topical steroids is warranted. Most eyes with NIE following anti-VEGF injection recover within 1 month to baseline acuity with topical corticosteroid treatment. Mechanisms hypothesized to explain postinjection inflammation include patient-specific, delivery-specific, and medication-specific factors. While NIE has been documented following bevacizumab, ranibizumab, and aflibercept, data are meager at present comparing the relative rates of sterile inflammation between these drugs. Acknowledgements None. Financial support and sponsorship CONNECT Network (HF). Conflicts of interest Howard F. Fine: Allergan, Inc.: consultant, research grants; Auris Surgical Robotics, Inc.: consultant, equity interest, patent interest; Bausch & Lomb, Inc.: consultant; Genentech, Inc.: consultant, research grants; Regeneron Pharmaceuticals, Inc.: consultant, research grants. Jonathan L. Prenner: Allergan, Inc.: research grants; Genentech, Inc.: research grants; Neurotech: DSMB member; Ophthotech: consultant, equity interest; Panoptica: consultant; Regeneron Pharmaceuticals, Inc.: research grants. Greg Despotidis: no relevant financial disclosure.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Fine HF, Roth DB, Shah SP, et al. Frequency and characteristics of intraocular & inflammation after aflibercept injection. Retina 2014. [Epub ahead of print] Recent consecutive series characterizing inflammation following aflibercept, clinical characteristics, and hypotheses to explain the inflammation. 2. Goldberg RA, Shah CP, Wiegand TW, Heier JS. Noninfectious inflammation && after intravitreal injection of aflibercept: clinical characteristics and visual outcomes. Am J Ophthalmol 2014; 158:733–737. Recent consecutive series of NIE following anti-VEGF injections and potential mechanisms.
3. Chong DY, Anand R, Williams PD, et al. Characterization of sterile intraocular inflammatory responses after intravitreal bevacizumab injection. Retina 2010; 30:1432–1440. 4. Wickremasinghe SS, Michalova K, Gilhotra J, et al. Acute intraocular inflammation after intravitreous injections of bevacizumab for treatment of neovascular age-related macular degeneration. Ophthalmology 2008; 115:1911–1915. 5. Goldberg RA, Flynn HW Jr, Isom RF, et al. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol 2012; 153:204–208. 6. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. J Am Med Assoc Ophthalmol 2013; 131:864–869. 7. Marticorena J, Romano V, Go´mez-Ulla F. Sterile endophthalmitis after intravitreal injections. Mediators Inflamm 2012; 2012:1–6. 8. Jin T, Zhu J, Wu F, et al. Preparing polymer-based sustained-release systems without exposing proteins to water-oil or water-air interfaces and cross-linking reagents. J Control Release 2008; 128:50–59. 9. Ness T, Feltgen N, Agostini H, et al. Toxic vitreitis outbreak after intravitreal injection. Retina 2010; 30:332–338. 10. Magalha˜es PO1, Lopes AM, Mazzola PG, et al. Methods of endotoxin removal from biological preparations: a review. J Pharm Pharm Sci 2007; 10:388–404. 11. Heier JS, Boyer DS, Ciulla TA, et al. FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol 2006; 124:1532–1542. 12. Wu L, Martı´nez-Castellanos MA, Quiroz-Mercado H, et al. Pan American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008; 246:81–87. 13. Wang F, Yu S, Liu K, et al. Acute intraocular inflammation caused by endotoxin after intravitreal injection of counterfeit bevacizumab in Shanghai, China. Ophthalmology 2013; 120:355–361. 14. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 2006; 90:1344–1349. 15. Shima C, Sakaguchi H, Gomi F. Complications in patients after intravitreal injection of bevacizumab. Acta Ophthalmol 2008; 86:372–376. 16. Georgopoulos M, Polak K, Prager F, et al. Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin). Br J Ophthalmol 2009; 93:457–462. 17. Ladas ID, Karagiannis DA, Rouvas AA, et al. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab: our experience after 2000 injections. Retina 2009; 29:313–318. 18. Johnson D, Hollands H, Hollands S, Sharma S. Incidence and characteristics of acute intraocular inflammation after intravitreal injection of bevacizumab: a retrospective cohort study. Can J Ophthalmol 2010; 45:239–242. 19. Kay CN, Tarantola RM, Gehrs KM, et al. Uveitis following intravitreal bevacizumab: a noninfectious cluster. Ophthalmic Surg Lasers Imaging 2011; 42:292–296. 20. Brown DM, Kaiser PK, Michels M, et al. ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1432–1444. 21. Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1419–1431. 22. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012; 119:1388–1398. 23. Fauser S, Schroeder S, Caramoy A, et al. Intraocular inflammation after intravitreal ranibizumab injections. Acta Ophthalmol 2011; 89:e98–e99. 24. Sharma S, Johnson D, Abouammoh M, et al. Rate of serious adverse effects in a series of bevacizumab and ranibizumab injections. Can J Ophthalmol 2012; 47:275–279. 25. Hahn P, Kim JE, Stinnett S, et al. American Society of Retina Specialists Therapeutic Surveillance Committee. Aflibercept-related sterile inflammation. Ophthalmology 2013; 120:1100–1101. 26. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year, results. Ophthalmology 2012; 119:1388–1398. 27. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014; 121:193–201. 28. Kiss S, Dugel PU, Wilson K, et al. Treatment patterns and associated costs of anti-VEGF therapy for neovascular age-related macular degeneration. 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), 4–8 May, 2014, Orlando, Florida, USA.
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Ocular inflammation associated with antivascular endothelial growth factor treatment Howard F. Fine, Greg D. Despotidis, and Jonathan L. Prenner
Purpose of review To describe the diagnosis and management of intraocular inflammation following antivascular endothelial growth factor (VEGF) injections. Recent findings Inflammation following intravitreal anti-VEGF injections can cause a dramatic reduction in acuity. Differentiating factors from truly infectious endophthalmitis include a lack of pain, redness, or hypopyon, although none of these factors is diagnostic. A high suspicion of infectious endophthalmitis should trigger a prompt vitreous tap and injection of intravitreal antibiotics. Conversely, if noninfectious endophthalmitis is suspected, close observation with frequent topical steroids is warranted. Summary Most eyes with noninfectious endophthalmitis following anti-VEGF injection recover within 1 month to baseline acuity with topical corticosteroid treatment. Mechanisms hypothesized to explain postinjection inflammation include patient-specific, delivery-specific, and medication-specific factors. Keywords aflibercept, bevacizumab, intravitreal injection, noninfectious endophthalmitis, ranibizumab
INTRODUCTION The use of antivascular endothelial growth factor (VEGF) medications has increased dramatically over the past decade as they have become the mainstay of treatment for a number of common retinal conditions including neovascular age-related macular degeneration (AMD), retinal vein occlusion (RVO), and diabetic macular edema (DME). Bevacizumab (Avastin), ranibizumab (Lucentis), and aflibercept (Eylea) are the most commonly utilized agents. While, overall, these drugs are extremely well tolerated and safe, there are increasing numbers of publications documenting rare inflammatory episodes following their use. Often termed as ‘sterile endophthalmitis’ or ‘noninfectious endophthalmitis’ (NIE), these episodes can cause a marked decline in vision and may be challenging to differentiate from true infectious endophthalmitis.
PRESENTATION OF NONINFECTIOUS ENDOPHTHALMITIS The presentation of sterile inflammation following intravitreal anti-VEGF agents is rapid, typically within 1–4 days of injection. Patients often complain of blurred vision and floaters. In a recent series of 28 cases by Fine et al. [1 ], the acuity dropped from &
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a mean of 20/57 before injection to 20/179 at presentation. Both anterior and posterior segment inflammation were manifest, with the majority of cases graded with mild or moderate inflammation. Retinal hemorrhages were present in about 20% of the cases. Keratic precipitates were rare. Gonioscopy was advisable on examination to exclude a microhypopyon in the early stages of inflammation. Most episodes were managed with frequent topical corticosteroids alone and no antibiotics, confirming their noninfectious nature.
INFECTIOUS VERSUS NONINFECTIOUS ENDOPHTHALMITIS Differentiating infectious endophthalmitis from NIE can be difficult for clinicians. Lack of a hypopyon, lack of pain, and lack of redness can all be Department of Ophthalmology, Rutgers Robert Wood Johnson Medical School, 10 Plum Street Suite 600, New Brunswick NJ 08901, USA Correspondence to Howard F. Fine, MD, MHSc, Department of Ophthalmology, Rutgers, Robert Wood Johnson Medical School, 10 Plum Street Suite 600, New Brunswick, NJ 08901, USA. Tel: +1 732 220 1600; fax: +1 732 220 1603; e-mail: [email protected] Curr Opin Ophthalmol 2015, 26:184–187 DOI:10.1097/ICU.0000000000000154 Volume 26 Number 3 May 2015
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Ocular inflammation associated with anti-VEGF treatment Fine et al. Table 1. Putative mechanisms of inflammation
KEY POINTS Inflammation following anti-VEGF injections can cause a dramatic reduction in acuity. Noninfectious endophthalmitis, in contrast with infectious endophthalmitis, typically lacks pain, redness, and hypopyon. Noninfectious endophthalmitis can be treated with topical corticosteroids and close observation and acuity typically recovers to baseline within 1 month. Mechanisms of noninfectious endophthalmitis include patient-specific, delivery-specific, and medicationspecific factors.
Patient-specific History of uveitis Pro-inflammatory medications (i.e. prostaglandin analogs) Disease-induced impairment of the blood–retinal barrier Anti-idiotypic immune response Delivery-specific Compounding contamination Syringe contamination Temperature fluctuation Air bubbles Drug-specific Formulation (lyophilized versus solubilized)
helpful clues that the postinjection inflammation might be noninfectious, but unfortunately, none of these findings is diagnostic [2 ]. When clinical suspicion is moderate or high for infectious endophthalmitis, prompt vitreous tap and injection of intravitreal antibiotics is warranted. This procedure is relatively benign and timely treatment of infectious endophthalmitis is known to improve outcomes. The clinician is faced with a dilemma when clinical suspicion is low for infectious endophthalmitis. A reasonable management approach may be to treat the patient with hourly topical steroids (such as difluprednate 0.05% emulsion or prednisolone acetate 1%) followed by re-evaluation of the patient within several hours. Development of a hypopyon, an increase in pain, a decrease in acuity, or other clinical deterioration should prompt a tap/injection of intravitreal antibiotics, whereas improvement suggests NIE. &&
MECHANISMS OF INFLAMMATION Several mechanisms have been proposed in the pathogenesis of inflammation following the injection of anti-VEGF medications. The putative mechanisms that elicit inflammation can be broadly classified as medication-specific, delivery-specific, and patient-specific, as given in (Table 1) [1 ]. &
PATIENT FACTORS There are a number of factors particular to individual patients that might theoretically place them at a higher risk of an inflammatory reaction when treated with an anti-VEGF injection. Patients with a prior history of uveitis might logically be more prone to recurrences of inflammation when exposed to an antigen that activates the immune system. Secondly, patients using medications known to be pro-inflammatory to the eye, such as prostaglandin
Endotoxin from manufacturing Nonhuman protein sequence Nonhuman glycosylation Counterfeit drug
analog eye drops used to treat glaucoma, may be predisposed to inflammation. Thirdly, some retinal conditions are known to cause the breakdown of the blood–retinal barrier, such as exudative AMD, possibly degrading the immune-privileged status of the vitreous [3]. Lastly, immune responses have been documented in the serum of a small minority of patients receiving intravitreal medications, an antiidiotypic reaction against the anti-VEGF antibody [4].
DELIVERY FACTORS Bevacizumab for intravitreal use is typically obtained via a compounding pharmacy that aliquots the bottle into individual doses rather than directly from the manufacturer. There have been a few rare but well publicized case series in which breakdown in sterile technique at the compounding pharmacy led to infectious endophthalmitis in a number of patients in a given area [5,6]. Regulation regarding compounding pharmacies continues to evolve. Factors known to unfold or otherwise denature proteins may increase their immunogenicity. Temperature fluctuation is well known to denature proteins [7], and failure to maintain a proper temperature during both shipping and storage has been implicated in increasing the immunogenicity of intravitreal agents. Air bubbles have also been documented to denature proteins in solution [8]. When drawing up anti-VEGF agents from the vial, it is common to inadvertently incorporate bubbles into the syringe. Another link in the delivery chain is the syringe itself. At least one syringe manufacturer has been
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185
Retinal, vitreous and macular disorders
implicated in an outbreak of NIE in 11 patients following intravitreal Avastin [9].
MEDICATION FACTORS Biologic recombinant proteins are produced from biological sources, in contrast to chemically synthesized small-molecule pharmaceuticals, and biologics are often of much greater complexity both in terms of production as well as purification. Therefore, impurities such as endotoxin are a common suspect when biologics incite inflammation [10]. The formulation of a drug may also incite inflammation. The early phase I/II FOCUS (Intravitreal Injections of rhuFab V2 in Combination With Visudyne in Subjects With Age-Related Macular Degeneration) trials of Lucentis utilized a lyophilized formulation which was associated with an 11.4% inflammation rate [11], but when the manufacturer changed to a solubilized formulation that rate plummeted [12]. Nonhuman protein sequences can be immunogenic; therefore, manufacturers exert great effort to humanize as much of a therapeutic protein as possible. Avastin is a humanized antibody, but its production via a Chinese hamster ovary (CHO) cell line could theoretically introduce immunogenic nonhuman glycosylation [3]. Lastly, the presence of counterfeit drug, although rare, has been reported. Wang et al. indicated that 80 out of 116 patients (69%) developed inflammation following intravitreal injection with endotoxin-contaminated counterfeit bevacizumab that infiltrated the drug supply chain in China [13].
BEVACIZUMAB, RANIBIZUMAB, AND AFLIBERCEPT Of the three most commonly used anti-VEGF agents, bevacizumab, ranibizumab, and aflibercept, the majority of publications regarding postinjection inflammation are associated with bevacizumab [3,4,9,13–19] and document an incidence rate as high as 1.1% [4]. Whereas early-phase trials of Lucentis demonstrated elevated rates of inflammation as previously discussed, rates were exceedingly low for the commercially available solubilized formulation. In the phase III AMD trials of Lucentis, the combined rates of uveitis and endophthalmitis were 0.05% in ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) [20] and 0.10% in MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the 186
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Treatment of Neovascular Age-Related Macular Degeneration) [21]. Reports of NIE following US Food and Drug Administration (FDA) approval are scarce [7,22–24]. The rates of inflammation reported in the phase III trials of Eylea were 1–2%. (Aflibercept, FDA package insert, http://www.regeneron.com/Eylea/Eyleafpi.pdf). Hahn et al. [25] published a nonconsecutive series of 15 cases of presumed NIE following Eylea injection gathered by the Therapeutic Surveillance Committee of the American Society of Retina Specialists. Goldberg et al. [2 ] published 20 cases of postinjection inflammation from 5356 Eylea injections, for a rate of 0.37%. Similarly, Fine et al. [1 ] published 28 cases of postinjection inflammation among 5905 Eylea injections, for a rate of 0.47%. Most patients regained baseline acuity within a month following treatment with topical corticosteroids [1 ]. The exact mechanism causing sterile endophthalmitis following most anti-VEGF injections remains unknown. &&
&
&
COMPARING INFLAMMATION RATES BETWEEN AGENTS Comparing the relative rates of intraocular inflammation following Avastin, Lucentis, and Eylea is challenging as the phase III trials were powered to detect differences in efficacy rather than safety. For instance, the year 2 results of the Comparison of Age-related Macular Degeneration Treatment Trials (CATT) found no difference in rate of pseudoendophthalmitis (0.3 versus 0.0%; P ¼ 1.00) or endophthalmitis (0.7 versus 1.2%; P ¼ 0.38) between Lucentis and Avastin, respectively [26]. The VIEW1 and VIEW2 studies comparing monthly Lucentis, monthly Eylea, and bi-monthly Eylea (following an initial 3-monthly doses) reported rates of any intraocular inflammatory response at week 52 (0.8, 0.7, and 0.2%) and at week 96 (1.5, 1.1, and 0.5%) again without statistical difference [27]. A population-based approach is another method to compare relative rates of inflammation or endophthalmitis between drugs. Kiss et al. [28] examined a US administrative claims database for patients with an ICD-9 code of endophthalmitis within 30 days of a ranibizumab or aflibercept injection from November 2011 through May 2013. The endophthalmitis rate was 0.08% (158 cases in 202 225 injections) for ranibizumab versus 0.17% (238 cases in 136 821 injections) for aflibercept. A multivariate analysis controlling for baseline comorbidities and demographics suggests a significantly higher risk of endophthalmitis with aflibercept than ranibizumab (adjusted odds ratio 2.70, 95% confidence interval 2.05–3.56, P < 0.001). Volume 26 Number 3 May 2015
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Ocular inflammation associated with anti-VEGF treatment Fine et al.
CONCLUSION Inflammation following intravitreal anti-VEGF injections can cause a dramatic reduction in acuity. Differentiating factors from truly infectious endophthalmitis include a lack of pain, redness, or hypopyon, although none of these factors is diagnostic. A high suspicion of infectious endophthalmitis should trigger a prompt vitreous tap and injection of intravitreal antibiotics. Conversely, if NIE is suspected, close observation with frequent topical steroids is warranted. Most eyes with NIE following anti-VEGF injection recover within 1 month to baseline acuity with topical corticosteroid treatment. Mechanisms hypothesized to explain postinjection inflammation include patient-specific, delivery-specific, and medication-specific factors. While NIE has been documented following bevacizumab, ranibizumab, and aflibercept, data are meager at present comparing the relative rates of sterile inflammation between these drugs. Acknowledgements None. Financial support and sponsorship CONNECT Network (HF). Conflicts of interest Howard F. Fine: Allergan, Inc.: consultant, research grants; Auris Surgical Robotics, Inc.: consultant, equity interest, patent interest; Bausch & Lomb, Inc.: consultant; Genentech, Inc.: consultant, research grants; Regeneron Pharmaceuticals, Inc.: consultant, research grants. Jonathan L. Prenner: Allergan, Inc.: research grants; Genentech, Inc.: research grants; Neurotech: DSMB member; Ophthotech: consultant, equity interest; Panoptica: consultant; Regeneron Pharmaceuticals, Inc.: research grants. Greg Despotidis: no relevant financial disclosure.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Fine HF, Roth DB, Shah SP, et al. Frequency and characteristics of intraocular & inflammation after aflibercept injection. Retina 2014. [Epub ahead of print] Recent consecutive series characterizing inflammation following aflibercept, clinical characteristics, and hypotheses to explain the inflammation. 2. Goldberg RA, Shah CP, Wiegand TW, Heier JS. Noninfectious inflammation && after intravitreal injection of aflibercept: clinical characteristics and visual outcomes. Am J Ophthalmol 2014; 158:733–737. Recent consecutive series of NIE following anti-VEGF injections and potential mechanisms.
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