Inflammation and Occlusive Retinal Vasculitis Post Faricimab

Key Points

Question

Is rechallenging patients with history of prior sterile inflammation following administration of an anti–vascular endothelial growth factor (VEGF) agent (faricimab) safe?

Findings

In this case series of 3 patients, 4 eyes were found to have a mild anterior chamber reaction following faricimab injection. Upon rechallenge, 3 of the 4 eyes developed severe, irreversible vision loss from occlusive retinal vasculitis.

Meaning

Rechallenging with the same anti-VEGF agent following prior intraocular inflammatory events should be done with caution.

Abstract

Importance

Randomized clinical trials have shown the safety and efficacy of faricimab as a novel vascular endothelial growth factor and angiopoietin-2 inhibitor in the treatment of neovascular age-related macular degeneration (nAMD) and macular edema of various etiologies. However, more rare adverse events may not be considered in clinical trials.

Objective

To describe 3 eyes that developed irreversible vision loss following initial mild intraocular inflammation (IOI) to faricimab.

Design, Setting, and Participants

This retrospective case series from a single academic tertiary referral center (University of Nebraska Medical Center) from October 2023 to August 2024 included 3 patients who developed occlusive retinal vasculitis (ORV) following an initial sensitization with intravitreal faricimab. Two eyes were being treated with faricimab for nAMD, and the other 2 eyes were treated for diabetic macular edema.

Intervention

Patients exposed to faricimab after the prior development of mild IOI.

Main Outcomes and Measures

Clinical symptoms, signs, and clinical course of patients who were diagnosed with ORV following rechallenge with faricimab.

Results

Mild IOI developed in 4 eyes following faricimab, and ORV developed in 3 eyes with repeated challenge. This resulted in profound, irreversible vision loss, despite treatment with topical and systemic steroids. In the eye that did not develop ORV following rechallenge, there have been no repeated adverse events despite restarting intravitreal faricimab injections.

Conclusions and Relevance

Given these observations with repeated challenge, caution is advisable when using the same biologic after the development of even mild IOI with prior injection. It appears an immunological memory response is elicited with these repeated exposures, resulting in the development of ORV.

This case series among 3 patients at a single tertiary referral clinic describes 3 eyes that developed irreversible vision loss following initial mild intraocular inflammation to faricimab.

Introduction

Faricimab is a vascular endothelial growth factor (VEGF) and angiopoietin-2 inhibitor that has shown efficacy and a reduction in treatment burden in diabetic macular edema and neovascular age-related macular degeneration (nAMD) through extended treatment intervals.^1,2 Faricimab has been shown to be safe in clinical trials and real-world experience, with rare occurrences of intraocular inflammation (IOI) in 0.2% to 0.6% of patients.^2,3 Given the risk of vision loss associated with IOI, a better understanding of clinical phenotypes and risk factors is needed.

Two types of sterile inflammation can be seen with intravitreal anti-VEGF injections: an acute reaction or delayed-onset occlusive retinal vasculitis (ORV). Sterile inflammation typically presents within 5 days of injection with anterior chamber (AC) cell and flare.⁴ The incidence of mild IOI varies among anti-VEGF agents, with rates of 0.09% to 1.1% and 0.02% to 0.16% observed with bevacizumab and ranibizumab, respectively.^5,6 However, the inflammation may mimic endophthalmitis.^4,7

We describe a case series of 3 patients and 4 eyes with mild IOI following faricimab, 3 of which would develop ORV during subsequent rechallenge.

Methods

This faricimab-associated IOI case series describes toxicity to therapy of 4 eyes observed at a tertiary referral clinic (University of Nebraska Medical Center) between October 2023 and August 2024. Review guidelines for a case series outlined by Kempen and colleagues⁸ were used. This deidentified study was deemed exempt by the institutional review board at the University of Nebraska Medical Center.

Results

Case 1

An 89-year-old female with a medical history significant for sarcoidosis with ocular involvement and hypertension was evaluated for recalcitrant nAMD in both eyes despite numerous bevacizumab injections, necessitating a transition to faricimab in both eyes. Visual acuity (VA) prior to faricimab was 20/60 OD and counting fingers (CF) OS. Four weeks after the second faricimab treatment, she reported eye pain and irritation and was found to have multiple mutton-fat keratic precipitates (KP), rare AC cell, and 1+ flare in the left eye, with an unchanged VA and stable posterior examination. Results of a uveitis laboratory evaluation were unremarkable. Faricimab was held due to IOI, which was treated with topical steroids. She later restarted faricimab in her left eye by her local eye care professional and has received 4 more injections since IOI was noted. Last VA examination was 20/200 OS, and inflammation has resolved without further complications.

Case 2

An 86-year-old female with a medical history significant for type 2 diabetes and hypertension was evaluated for nAMD in her right eye. One month after her third faricimab treatment, she was found to have AC inflammation with KP, and injection was held. Results of a focused uveitis laboratory evaluation were unremarkable, and she was treated with topical steroids. One month later, inflammation had resolved, and she received a fourth faricimab treatment. One week later, she developed eye pain and reduction in VA from 20/70 OD to CF OD. Intraocular pressure (IOP) was 2 mm Hg. She had diffuse KPs and 0.5+ AC cell. Posteriorly, there was retinal whitening, inferior vitreous hemorrhage, diffuse retinal hemorrhages, and poor retinal perfusion on fluorescein angiography (FA) consistent with ORV (Figure 1). Due to concern for an underlying infectious etiology, broad spectrum intravitreal antibiotics and antivirals were given and vitreous cultures collected. The patient was treated with topical and oral steroid taper and valacyclovir. Bacterial cultures and viral polymerase chain reactions were negative.

Figure 1. An 86-Year-Old Female Developed Occlusive Retinal Vasculitis (ORV) Following Rechallenge of Faricimab (Case 2).

A, Fundus photograph of the right eye showing vitreous haze, inferior vitreous hemorrhage, retinal whitening, and diffuse retinal hemorrhages 1 week after faricimab injection in the right eye. B, Fluorescein angiography showed substantial retinal nonperfusion consistent with ORV.

Four months after the last faricimab treatment, VA was light perception (LP) OD and IOP was 4 mm Hg. There was nearly 360° of rubeosis, rare cell and flare, and vitreous haze limiting posterior examination. She noted a subjective improvement in pain and vision.

Case 3

A 63-year-old male with a medical history significant for coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, proliferative diabetic retinopathy, and diabetic macular edema previously treated with aflibercept in both eyes developed presumed herpes simplex virus keratitis in his right eye and was prescribed valacyclovir and topical steroids. One month later, VA was 20/200 OD and 20/60 OS when he received the first faricimab treatment in both eyes. He subsequently developed a mild AC reaction and constant redness in both eyes that resolved with topical steroids. An FA examination 2 months later showed good perfusion, with signs of diabetic retinopathy (Figure 2A and B). Twelve days later, he noted worsening vision and pain in both eyes. On examination, VA was LP OD and 20/400 OS, and IOP was elevated into the 30s mm Hg in both eyes. There was 1+ flare and no AC or vitreous cell. There were retinal hemorrhages and arterial occlusions with markedly decreased retinal perfusion consistent with ORV but no signs of viral or bacterial infection (Figure 2C and D). Results of a focused uveitis and embolic workup, including neuroimaging and vasculitis laboratory tests, were unremarkable.

Figure 2. A 63-Year-Old Male Developed Occlusive Retinal Vasculitis (ORV) of Both Eyes Following Faricimab Rechallenge (Case 3).

On the day of faricimab rechallenge, patient underwent fluorescein angiography (FA) of his right (A) and left (B) eyes, which showed signs of diabetic retinopathy. Follow-up fundus imaging of the right eye after severe vision loss noted diffuse retinal hemorrhages and pruned vasculature (C) with limited retinal perfusion on FA (D).

He was prescribed maximum medical therapy for ocular hypertension, a topical and oral steroid taper, and continued valacyclovir. He ultimately required tube shunt placement for recalcitrant IOPs in both eyes. One month later, VA remained unchanged in the right eye and was mildly improved to 20/200 OS, with IOPs normal in both eyes. Corneal edema and conjunctival injection were improving, with a stable posterior examination.

Discussion

While faricimab is typically well tolerated, there have been reports describing more severe IOIs, such as endophthalmitis-like presentations and vasculitis with or without occlusions, with reported rates of ORV of 0.06 case per 10 000 injections.^7,9,10,11,12 Cases of ORV have prompted revisions to prescribing information and the recommendation to discontinue the drug in these patients. However, to our knowledge, this is the first report describing IOI preceding the development of ORV. In most milder cases of IOI, there is unclear guidance, and rechallenging after inflammation has resolved is considered innocuous, allowing continuation of the drug.

There are concerns of higher rates of ORV following injection of several newer agents, including brolucizumab, with rates of ORV of 2.1%.⁴ There have also been reports of retinal vasculitis following pegcetacoplan, with 79% ORV.¹³ The etiology of ORV remains unclear, but proposed mechanisms include the presence of antidrug antibodies (ADA), protein aggregates, or a delayed hypersensitivity reaction.^4,13 There is some similarity between brolucizumab-, pegcetacoplan-, or faricimab–associated retinal vasculitis with vancomycin-associated hemorrhagic ORV,^4,13 which is a delayed, painless vision loss with hemorrhagic vascular occlusions and histopathological findings consistent with a type IV delayed hypersensitivity reaction of primarily the choroid, with secondary involvement of the retina.¹⁴ This study’s cases would expand on these findings to suggest that in some cases, there is a secondary, stronger response with repeat challenge of the same drug, which indicates signs of immunological memory. Unfortunately, it is difficult to appreciate rates of occurrences in small case series such as these and to predict these responses following initially mild IOI, highlighted by the differences in the 3 cases in this series.

ADAs have been found in treatment-naive patients, with rates between 0% to 0.9% and 1% to 3% with ranibizumab and aflibercept, respectively, while brolucizumab expressed the highest rate at 43.7%.⁴ The presence of elevated ADAs in brolucizumab may explain the increased frequency of severe IOI compared to ranibizumab and aflibercept, as the immune system may already be primed to respond with even initial exposure to the drug. It is unclear what is driving this response, but the anti-VEGF molecule may be the root cause of injection-related IOI. The fragment crystallizable (Fc) region present on aflibercept and bevacizumab can interact with retinal Fc receptors and induce proinflammatory responses.⁴ Due to this, faricimab was specifically developed to decrease its inflammatory potential with further modification of the Fc segment, which may explain the good tolerability of the drug.¹⁵

In conclusion, this case series has shown 4 eyes with mild IOI following faricimab, and in 3 of those eyes, the development of ORV with repeated challenge. Given these observations, caution is advisable prior to rechallenging with the same biologic after the development of even mild IOI.¹⁶

Supplement 1.

Data Sharing Statement