Mechanisms of sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review

Abstract

Background Intraocular inflammation is an uncommon but potentially vision-threatening adverse event related to anti-VEGF therapy. This is of increasing importance given both the volume of injections performed, as well as the increased prevalence of inflammation seen with newer anti-VEGF agents. Brolucizumab, the newest anti-VEGF agent, has been associated with an inflammatory retinal vasculitis and the underlying mechanism is unclear. Reviewing potential mechanisms and clinical differences of intraocular inflammation may assist clinicians and scientists in reducing the risk of these events in the future. Observations Two types of inflammation are seen with intravitreal injections, acute onset sterile inflammation and delayed onset inflammatory vasculitis. Acute onset inflammation can be subcategorized into subclinical anterior chamber inflammation and sterile uveitis/endophthalmitis. Subclinical anterior chamber inflammation can occur at rates as high as 19% after intravitreal anti-VEGF injection. Rates of sterile uveitis/endophthalmitis range from 0.05% to 4.4% depending on the anti-VEGF agent. Inflammatory vasculitis is only associated with brolucizumab and occurred in 3.3% of injections according to the post hoc review of the HAWK/HARRIER data. In addition, silicone oil from syringes can induce immunogenic protein aggregates. Agitation of the syringe, freeze thawing, shipping and improper storage prior to injection may increase the amount of silicone oil released from the syringe. Conclusion The main factors which play a role in intraocular inflammation after anti-VEGF injection can be divided into three causes: patient-specific, medication-specific and delivery-specific. The majority of clinically significant inflammation seen after intravitreal injection is an acute onset inflammatory response with most patients recovering baseline VA in 3–5 weeks. The presence of pain, hypopyon, severe anterior chamber reaction, hyperemia and significant vision loss may help distinguish infectious from non-infectious etiologies of post injection inflammation. Avoiding temperature fluctuation, mechanical shock, agitation during transport and handling of syringes/drugs, and the use of SO-free syringes may help minimize intraocular inflammation. While a definitive mechanism has not yet been established, current knowledge of the clinical presentation and vitreous histopathology of brolucizumab-retinal vasculitis favors an auto-immune type IV hypersensitivity reaction.

Brolucizumab: Evaluation of Compassionate Use of a Complex Anti-VEGF Therapy

“…After the first brolucizumab injection, it took as long as 8 weeks (range: 2 to 8 weeks) after for retinal vasculitis, which in this series was typically occlusive and could involve the retinal arteries, veins, and potentially capillaries with a range of severity, to be diagnosed. [9][10][11][12][13][14] These real-world reports reflect the results of the phase III HAWK and HARRIER trial mentioned previously. It was concluded that brolucizumab was generally well received, and as a whole, the AE rates paralleled those with aflibercept within each trial.…”

“…In separate studies, clinical cases of retinal vasculitis after brolucizumab 6mg IVI were gathered from retinal specialists across the US. [9][10][11][12][13][14] One real-world, nonconsecutive series reported 15 eyes with retinal vasculitis and IOI after brolucizumab IVI. After the first brolucizumab injection, it took as long as 8 weeks (range: 2 to 8 weeks) after for retinal vasculitis, which in this series was typically occlusive and could involve the retinal arteries, veins, and potentially capillaries with a range of severity, to be diagnosed.…”

Preventive factors, diagnosis, and management of injection-related endophthalmitis: a literature review

“…While some cases of sterile endophthalmitis may mimic infectious IRE, others are characterized by a milder intraocular inflammation and relatively preserved vision. Symptoms present 1–7 days after the injection with the mean time to presentation in a multi-center study at 2.6 days [ 11 , 14 – 16 ]. Common symptoms include floaters (60%) and blurred vision (93%) with hypopyon (4%), conjunctival injection (10%), and fibrin (3%) occurring significantly less often than in infectious endophthalmitis (Fig.…”

“…Various factors have been suggested to explain sterile IRE post anti-VEGF injection including patient specific (development of antibodies after repeated exposure, retinal disease related compromise of the blood-retinal barrier, and history of intraocular or systemic inflammatory disease), delivery specific (silicone oil in syringes, syringe agitation, inconsistencies in medication handling), and medication specific (contamination with bacterial endotoxin, medication impurities, formulation, and presence of potentially pro-inflammatory Fc portion of antibody) [ 14 , 16 ]. Clusters of sterile IRE related to breakdowns of the manufacturing process, as was the case in an outbreak due to bacterial endotoxin contamination, have been reported [ 39 ].…”

Pitfalls in the Interpretation of Intraocular Inflammation in Response to Intravitreal Brolucizumab Injection

“…Since recognition of this problem, substantial efforts have been undertaken, primarily driven by Novartis, but also by independent experts to understand this phenomenon 4,[7][8][9] and to provide expert guidelines for its treatment. 2,10,11 Real-world evidence gathered from two large us registries (IRIS and Komodo), together covering 21394 injections, indicates that a history of intraocular inflammation or vascular occlusion in the affected eye results in a tenfold increase in the risk of IOI after Brolucizumab from 0.32-0.41% to 3.97-4.68%.…”