Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Inflammatory Reaction After Aflibercept Intravitreal Injections Associated With Silicone Oil Droplets Released From Syringes: A Case-Control Study

Gustavo Barreto Melo, MD, PhD; Ana Carolina Migliorini Figueira, PhD; Fernanda Aparecida Heleno Batista, PhD; Acácio Alves Souza Lima Filho, PhD; Eduardo Büchele Rodrigues, MD, PhD; Rubens Belfort Jr., MD, PhD; Maurício Maia, MD, PhD

Abstract

BACKGROUND AND OBJECTIVE:

To determine factors causing inflammation after intravitreal aflibercept injections.

PATIENTS AND METHODS:

This case-control study included aflibercept-treated eyes with inflammation post-injection and aflibercept-treated control eyes. Medical records were analyzed to identify contributing factors. Biophysical tests were performed to characterize properties of particle aggregation. Institutional review board approval was obtained.

RESULTS:

Inflammation developed in six eyes; three patients had anterior uveitis, and five had vitreous cells. Oil droplets were seen in all cases. Saldanha Rodrigues (SR) syringes were used in all cases. Among controls, SR and Becton-Dickinson syringes were used in 10 and 17 eyes, respectively. Regression analysis showed an association between SR syringes and inflammation (odds ratio = 21.66; 95% confidence interval, 1.10–425.06; P = .043). Biophysical analyses primarily showed aggregation possibly from free oil droplets or protein-oil droplet aggregation.

CONCLUSIONS:

Post-injection inflammation was associated with SR syringes. Silicone oil droplets, especially after syringe agitation, might play a role in the inflammatory reaction.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:288–294.]

Abstract

BACKGROUND AND OBJECTIVE:

To determine factors causing inflammation after intravitreal aflibercept injections.

PATIENTS AND METHODS:

This case-control study included aflibercept-treated eyes with inflammation post-injection and aflibercept-treated control eyes. Medical records were analyzed to identify contributing factors. Biophysical tests were performed to characterize properties of particle aggregation. Institutional review board approval was obtained.

RESULTS:

Inflammation developed in six eyes; three patients had anterior uveitis, and five had vitreous cells. Oil droplets were seen in all cases. Saldanha Rodrigues (SR) syringes were used in all cases. Among controls, SR and Becton-Dickinson syringes were used in 10 and 17 eyes, respectively. Regression analysis showed an association between SR syringes and inflammation (odds ratio = 21.66; 95% confidence interval, 1.10–425.06; P = .043). Biophysical analyses primarily showed aggregation possibly from free oil droplets or protein-oil droplet aggregation.

CONCLUSIONS:

Post-injection inflammation was associated with SR syringes. Silicone oil droplets, especially after syringe agitation, might play a role in the inflammatory reaction.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:288–294.]

Introduction

Vascular endothelial growth factor (VEGF) is an important mediator of abnormal vascular permeability and angiogenesis in the eye.1 Intravitreous injections of anti-VEGF agents are the standard treatment for many retinal diseases, such as neovascular age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion.2 Three commonly used intravitreous VEGF inhibitors, aflibercept (Eylea; Regeneron, Tarrytown, NY), bevacizumab (Avastin; Genentech, South San Francisco, CA), and ranibizumab (Lucentis; Genentech, South San Francisco, CA), are beneficial and relatively safe for treating these diseases,2 but the U.S. Food and Drug Administration and the Brazilian Agência Nacional de Vigilância Sanitária have approved only aflibercept and ranibizumab. Bevacizumab, which is not approved for any ocular indication, is used widely as an off-label treatment for most retinal diseases associated with VEGF activity.2–4 Despite the risk of infectious endophthalmitis, mild and moderate noninfectious inflammation has been reported.5–8 Williams et al.6 reported rates of noninfectious vitritis of 0.10% after 66,356 bevacizumab injections, 0.02% after 26,161 ranibizumab injections, and 0.16% after 8,071 aflibercept injections. The American Society of Retina Specialists (ASRS) Therapeutic Surveillance Committee received notifications of 56 cases of aflibercept-related sterile inflammation from December 1, 2011, through February 12, 2014.8 However, the authors did not identify any risk factors or the pathogenesis.

We report a cluster of cases with inflammatory reactions after intravitreal injections of aflibercept possibly associated with release of silicone oil droplets from the syringes. Additionally, and due to this suspicion, we performed a biophysical study to determine the origin of this inflammation.

Patients and Methods

This was a case-control study that was designed after six patients developed symptoms and signs of inflammation after intravitreal injections of aflibercept from May to August 2016 in one ophthalmic setting. The institutional review board approved the study.

The medical records were analyzed to identify possible contributing factors associated with this cluster of inflammatory cases, such as age, gender, visual acuity (VA), diagnosis, times to presentation and resolution, signs and symptoms, brands of the syringes, presence of silicone oil droplets in the vitreous cavity, and others. Cases were defined as those presenting with signs of inflammation after intravitreal injection of aflibercept from May to August 2016; the control subjects had all been injected with the same substance during the same time frame.

All injections were performed in a standardized fashion. Briefly, a pre-injection topical anesthetic and povidone iodine were instilled, a lid speculum was put in place, and aflibercept was drawn from the vial. The surgeon agitated the syringes before the injection to separate any air from the medication. The injections were administered 3.0 mm to 3.5 mm from the limbus. Antibiotic drops were prescribed for 7 days after the injections. The technique was the same during the previous year except for a switch in the syringe brand from 1-mL Becton-Dickinson (BD) tuberculin syringes to 1 mL Saldanha Rodrigues (SR) luer slip syringes.

Biophysical Analysis

We performed dynamic light-scattering (DLS) assays to analyze possible aggregates that might have formed in aflibercept and bevacizumab samples. The main objective was to determine if a substance such as silicone oil was present in the syringe that might have affected the aggregation states of the proteins that constitute the medicine samples or if intense agitation might have interfered with sample aggregation. To perform this experiment, samples of bevacizumab and aflibercept were diluted to 1 mg/mL (for standardization purposes) in a buffer containing the same formulation described by the manufacturers, as described in the package insert. After dilution, the measurements were obtained using ZetaSizer Nano ZS90 equipment (Malvern Instruments, Malvern, UK), according to the automatic set-up of the DLS device. Each sample was measured in triplicate and measurements were taken under different conditions (ie, samples with no intervention, samples passed through BD or SR syringes, samples passed through BD or SR syringes and intensely agitated, and samples passed through BD or SR syringes intensely agitated and centrifuged for 10 minutes at 4°C at 10,000 rotations per minute [rpm]).

We also performed sedimentation velocity experiments in an analytical ultracentrifuge (AUC) (Beckman Coulter, Barueri, SP, Brazil). Samples diluted to 1 mg/mL were set up in an AUC An50Ti rotor (Optima XL-A, Beckman Coulter, Barueri, SP, Brazil) and centrifuged at 42,000 rpm for 12 hours at 20°C. The data were measured by ultraviolet (UV) 280-nm absorbance and analyzed with Sedfit software.9 ( http://www.analyticalultracentrifugation.com/sedfit.htm). Size distribution analysis of the macromolecules was performed by sedimentation velocity ultracentrifugation and Lamm-equation modeling.9

Samples also were subjected to gel permeation chromatography/size exclusion chromatography (GPC-SEC) coupled with right-angle light scattering, low-angle light scattering, and refractive index detectors using OMINISEC software (Malvern Instruments, Malvern, UK). Samples were run at 5 mg/mL (100 μL) and pre-equilibrated with a buffer containing 10 mM sodium phosphate at pH 6.2, 40 mM sodium chloride, and 5% sucrose. Chromatography was performed on a TSK-gel G3000 SW 7.2 mm × 30 cm (Tosoh Bioscience, Griesheim, Germany) column through a 35-mL isocratic elution at 0.8 mL/min. To calibrate chromatography and detectors, a bovine serum albumin solution (5 mg/mL, 100 μL) was used as a control.

Statistical Analysis

Firth's univariate logistic regression was used to assess the association of individual characteristics of the cases and controls. Odds ratios (ORs) were determined with a confidence interval (CI) of 95%. A P value of less than .05 was considered significant.

Results

Inflammation developed in six eyes of six patients (four women, two men; mean age: 63.5 years) from May to August 2016 (Tables 1 and 2). Twenty-seven eyes of 17 subjects treated with aflibercept during the same period served as controls. These 33 eyes encompass the total number of eyes treated with aflibercept throughout the whole period of the study by a single retina specialist (GBM). None of the individuals underwent injection in both eyes with SR syringe and aflibercept. Those subjects who had the contralateral eye treated during the study period were injected with a BD syringe. Three study patients reported with the chief complaint of pain, and anterior chamber cells were observed during slit-lamp evaluation. Vitreous cells were present in five of the six study patients. Most individuals (83%) developed an inflammatory reaction within 3 days after intravitreal injection of aflibercept. Slit-lamp examinations showed oil droplets in the vitreous in all cases (Figure 1). All patients recovered from the inflammatory reaction up to 3 weeks after onset, with complete VA recovery in 83%. All cases were injected with the same batch (448J) of SR syringes. Among the controls, inflammation did not develop in 10 eyes in which SR syringes (same batch as in cases) were used, or in 17 eyes in which BD syringes were used. Firth's univariate logistic regression (OR: 21.66; 95% CI, 1.10–425.06; P = .043) identified an association between the SR syringes and inflammation. The same lot of aflibercept (#52246C) was used for all cases. A total of 33 eyes were injected with aflibercept from this lot, resulting in six cases of inflammation (in all of which the SR syringe was used) and 27 eyes that did not get inflammation (including 10 eyes in which an SR syringe was used and 17 eyes in which a BD syringe was used). BD tuberculin syringes had always been the standard and the only model used by the author; however, SR syringes were used for a short time until their suspected association with the development of inflammation.

Case-Control Analysis Including Sex, Ocular Diagnosis, History of Diabetes and Hypertension, Brand of Syringe, and Age

Table 1:

Case-Control Analysis Including Sex, Ocular Diagnosis, History of Diabetes and Hypertension, Brand of Syringe, and Age

Summary of Cases With an Inflammatory Response After Aflibercept Intravitreal Injection With the Saldanha Rodrigues Syringe at Presentation

Table 2:

Summary of Cases With an Inflammatory Response After Aflibercept Intravitreal Injection With the Saldanha Rodrigues Syringe at Presentation

(A, B) Two cases with round intravitreal material suggestive of silicone oil droplets after complete resolution of the inflammatory reaction. Saldanha Rodrigues syringes had been used in all cases.

Figure 1.

(A, B) Two cases with round intravitreal material suggestive of silicone oil droplets after complete resolution of the inflammatory reaction. Saldanha Rodrigues syringes had been used in all cases.

One patient in this series who had had a previous inflammatory reaction was treated 1 month later with aflibercept from the same lot administered via a BD syringe. No signs or symptoms of inflammation were observed, which suggested that this particular case had not developed as a result of a patient-specific immunologic response. Of note, none of the case and control eyes in this study had a prior history of any intraocular inflammatory events.

Because infectious endophthalmitis did not develop in any patients, they did not undergo aqueous tap and vitreous biopsy or intravitreal antibiotic injection. Treatment included administration of a corticosteroid and mydriatic drops for 2 to 3 weeks. It is noteworthy that other patients were treated during the same time frame with different combinations of bevacizumab, ranibizumab, or aflibercept and BD or SR syringes. Silicone oil droplets were observed in many patients in whom SR syringes were used, even after treatment with bevacizumab and ranibizumab, and none presented with inflammation (data not shown). Likewise, no patients treated with the combination of aflibercept and BD syringes developed any signs of an inflammatory response. After August 2016, SR syringes were no longer used in our setting. No additional cases of inflammatory reactions occurred.

Biophysical Assays

Aflibercept dimer has a hydrodynamic radius (Rh) of 3.04 nm, and the bevacizumab dimer has an Rh of 3.48 nm. DLS characterization of bevacizumab and aflibercept showed that samples not subjected to severe agitation had only one molecular size in solution with an Rh of about 5.8 nm to 6 nm (Figure 2). The experimental Rh values identified by DLS for these proteins are larger than those estimates based on their primary structures.

Profiles of the light-scattering intensities of aflibercept and bevacizumab during passage through Becton-Dickinson (BD) and Saldanha Rodrigues (SR) syringes and subjected to agitation only or followed by centrifugation. (A, B) Light-scattering intensities of aflibercept. (C, D) Light-scattering intensities of bevacizumab. The agitated samples form different kinds of aggregates.

Figure 2.

Profiles of the light-scattering intensities of aflibercept and bevacizumab during passage through Becton-Dickinson (BD) and Saldanha Rodrigues (SR) syringes and subjected to agitation only or followed by centrifugation. (A, B) Light-scattering intensities of aflibercept. (C, D) Light-scattering intensities of bevacizumab. The agitated samples form different kinds of aggregates.

Rh values of 5.9 nm and 5.8 nm for bevacizumab and aflibercept, respectively, seem to be related to dimers of each glycosylated protein. In addition, passing samples through BD and SR syringes did not affect the particle sizes in solution, except for aflibercept, which showed little protein aggregation after passage through the SR syringes (7.2% of species had a Rh of 241.70 nm). However, agitation seems to be an important factor in generating large species for both medications, since in both syringes, we observed two or three species of aggregates, with high Rh values. Interestingly, after aflibercept was agitated in the BD syringes, no protein dimer was seen in solution but only aggregates. Finally, after centrifugation, all samples recovered most of the protein dimer (Rh: 5.8 nm). These data were analyzed based on the scattering intensities. Data analysis based on mass showed that these aggregates corresponded to a minor population of molecules in the samples.

AUC the calculated MWs for bevacizumab varied between 119.4 kDa ± 7.8 kDa and 129.1 kDa ± 5.3 kDa and for aflibercept between 91.8 kDa ± 4.7 kDa and 101.7 kDa ± 5.5 kDa, which pointed to the dimeric state of both proteins. The AUC data indicated that the molecular masses of both drugs agreed with the calculated MWs, with all samples comprised mostly of unaggregated proteins. However, larger species were observed in solution that corresponded to sedimentation (S) coefficient values between 7.5 S and 10 S, but with very little intensity.

Finally, the measured masses and Rh values from the GPC-SEC experiments also did not show any detectable aggregates. The MWs also agreed with the predicted MWs. Bevacizumab had an average MW of 113 kDa ±0.8 kDa and Rh of 4.2 nm and aflibercept 94 kDa ±2 kDa and Rh of 4.5 nm.

Discussion

Our case-control study identified a significant association between the development of inflammation in the cases in which SR syringes were used, which seemed to release silicone oil droplets frequently during injection. The ASRS Therapeutic Surveillance Committee issued an alert regarding the presence of droplets in the vitreous cavity of patients who underwent intravitreal injections of different drugs and requested that all members report this adverse event. Khurana et al.10 reported that the incidence of silicone oil droplets after bevacizumab injections was 0.03% (one out of 3,230) from October 2015 to April 2016 and 1.7% (59 out of 3,402) from May to November 2016. The investigators concluded that increased intravitreal silicone oil was associated with bevacizumab prepared with insulin syringes. Priming the syringe before injection was associated with a lower frequency of this complication.

The inner surface of the SR syringe is coated with dimethylsiloxane and polydimethylsiloxane. Some studies have reported more intense protein aggregation and insoluble molecules resulting from agitation and the presence of the silicone oil.11–13 This agreed with the observation that the surgeon performing the injections in this study (GBM) usually strongly agitated the syringe to separate the liquid from the air to prevent the release of air bubbles into the vitreous cavity.

Many studies have reported an important association of silicone oil-water interfaces (siliconized syringe walls), air-water interfaces (air bubbles), and agitation stress (occurring during end-over-end rotation, as well as flicking of the syringe at the time of injection) as triggers leading to protein aggregation and particle formation.11–13 The highest particle concentrations were found in agitated, siliconized syringes containing an air bubble.12 The particles formed in this condition consisted of silicone oil droplets and aggregated protein, as well as agglomerates of protein aggregates and silicone oil. This observation was enhanced when abatacept (Orencia; Bristol-Myers Squibb, New York, NY), a fusion protein, was compared with lower levels of particle formation with monoclonal immunoglobulin G antibodies (adalimumab [Humira; AbbVie, North Chicago, IL] and bevacizumab showed similar findings).11 Since aflibercept is a fusion protein, we hypothesized that it should be more prone to yield insoluble and protein aggregates than other anti-VEGF. In addition, these studies have led to the belief that flicking the syringe to deliver a minimal amount of air into the vitreous cavity could potentiate particle formation. Finally, silicone oil droplets also were reported to act as immunologic adjuvants.14 Therefore, we also thought that the inflammatory reaction observed in the current patients might have been caused by those interactions.

Schargus et al.15 conducted steady-state biophysical analyses that showed that original prefilled ranibizumab glass syringes, original vials with aflibercept, and repacked ready-to-use plastic syringes filled with bevacizumab from a compounding pharmacy are similar regarding particulate purity and silicone oil microdroplet count. The current results suggested that aggregation observed in DLS assays might result from free oil droplets, protein-oil droplet interaction and aggregation, or, less probably, temporary protein aggregation that is reversible after centrifugation. DLS is a technique that measures fluctuations of scattered light without discriminating between molecules or other solution components, such as oil droplets.16

However, AUC experiments showed almost no detectable protein aggregation. AUC is a versatile, powerful method to quantitatively analyze macromolecules in solution, mainly because it is a nondestructive technique that can characterize samples in solution in their native state.17–20 However, the characterization of oil droplets was impossible using this technique, since these particles did not absorb light at UV 280 nm. In addition, the GPC-SEC technique also did not detect any aggregates of bevacizumab or aflibercept, indicating that there were insufficient amounts of detectable aggregates and most samples were represented by protein dimers in solution.

In summary, biophysical characterization showed that intense agitation of samples passed through syringes might be important for aggregate formation. However, these aggregates do not seem to be formed exclusively by protein, in that AUC almost did not detect any of them, or, moreover, the amount of these aggregates represents the minority of species in solution under the experimental conditions. GPC-SEC also did not detect any other representative peak of aggregation. In other words, the results suggested that agitation of the samples subjected to syringe passage might be important in forming other species in solution, which might be comprised of oil droplets, and should be investigated further.

In conclusion, this case-control study suggested a possible link between development of inflammation after aflibercept injections and the silicone oil droplets released by SR syringes. All patients had an inflammatory reaction (ie, primarily anterior uveitis and vitritis) after intravitreal injection of aflibercept. All patients recovered fairly well after a short time, and most attained the same final VA as the pre-injection level. We hypothesized that silicone oil droplets, especially after agitation (flicking), might play a role in the inflammatory reaction observed in these patients.

References

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Case-Control Analysis Including Sex, Ocular Diagnosis, History of Diabetes and Hypertension, Brand of Syringe, and Age

CasesControlsAllStatisticsStatistics

No. (%)No. (%)No. (%)OR (95% CI)P Value*

Sex
  Male2 (33.3)12 (44.4)14 (42.4)Reference
  Female4 (66.7)15 (55.6)19 (57.6)1.45 (0.26–8.07).670

Diagnosis
  AMD2 (50)16 (59.3)19 (57.6)Reference
  DME2 (33.3)6 (22.2)8 (24.2)1.81 (0.28–11.64).531
  RVO edema0 (0.0)3 (11.1)3 (9.1)0.67 (0.03–16.19).807
  Myopic CNV1 (16.7)2 (7.4)3 (9.1)2.83 (0.27–29.06).382

Diabetes
  Yes4 (66.7)17 (63)21 (63.6)0.92 (0.16–5.20).930
  No2 (33.3)10 (37)12 (36.4)Reference

Hypertension
  Yes5 (83.3)16 (59.3)21 (63.6)0.39 (0.05–2.77).347
  No1 (16.7)11 (40.7)12 (36.4)Reference

Syringe
  BD0 (0.0)17 (63)17 (51.5)Reference
  SR6 (100)10 (37)16 (48.5)21.66 (1.10–425.06)).043

Age (Years)63.5 ± 2.7470.74 ± 2.3269.42 ± 2.010.95 (0.87–1.03).205

Previous Injections6.00 ± 1.636.14 ± 0.826.12±0.720.99 (0.81–1.22).959

Summary of Cases With an Inflammatory Response After Aflibercept Intravitreal Injection With the Saldanha Rodrigues Syringe at Presentation

CaseAgeGenderDiagnosisPrior IVIPrior IVAIPrior IVRIPrior IVBIDays to PresBlurry visionPain and CIAC cellsVitreous cellsVisible Oil Droplets in the Vitreous
168MaleNAMD60151YesNoNoYesYes
262FemaleDME31202YesYesYesYesYes
359FemaleDME1210202YesYesYesYesYes
474MaleNAMD94325NoNoNoYesYes
555FemalemCNV11002NoYesYesNoYes
663FemaleNAMD52033NoNoNoYesYes
Authors

From Hospital de Olhos de Sergipe, Aracaju- SE, Brazil (GBM); Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, São Paulo, Brazil (ACMF, FAHB); and Federal University of São Paulo, São Paulo-SP, Brazil (GBM, AASLF, EBR, RBJ, MM).

Presented orally at the ASRS Annual Meeting, July 21, 2018, in Vancouver, Canada.

The authors report no relevant financial disclosures.

The authors would like to thank the Spectroscopy and Calorimetry Laboratory facility from the Brazilian Biosciences National Laboratory and the Brazilian Center for Research in Energy and Materials for providing the infrastructure to perform the biophysical experiments.

Address correspondence to Gustavo Barreto Melo, MD, PhD, Rua Campo do Brito, 995 São José, Aracaju, SE, 49020-380, Brazil; email: gustavobmelo@yahoo.com.br.

Received: July 31, 2018
Accepted: December 19, 2018

10.3928/23258160-20190503-05

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