Faricimab-Associated Retinal Vasculitis

Abstract

Purpose: To report a case of retinal vasculitis after intravitreal faricimab-svoa injection. Methods: A case and its management were reviewed. Results: A 77-year-old woman presented with a painless decrease in visual acuity (VA) to counting fingers after receiving an intravitreal faricimab-svoa injection for neovascular age-related macular degeneration. An examination showed an anterior chamber reaction without hypopyon. Vitritis was present with numerous scattered retinal hemorrhages. Fluorescein angiography showed delayed filling with extensive vascular leakage consistent with nonocclusive vasculitis. The patient was immediately treated with intravenous steroids, resulting in rapid improvement and recovery of her 20/40 baseline VA. The vasculitis resolved without occlusion. Conclusions: Faricimab-svoa can be associated with significant vasculitis. Prompt treatment with intravenous steroids can be beneficial in the recovery of sight.

Introduction

Intravitreal injections (IVIs) of pharmacologic agents are the most common eye procedures performed worldwide for various ophthalmic indications. ¹ The prevalence of infectious endophthalmitis after intravitreal therapy ranges from 0.015% to 0.083%, and the rates of sterile inflammation have ranged from 0.05% to 4.4%.^1,2 Although rare, intraocular inflammation can result in profound vision loss. More recently, retinal vasculitis has been reported with newer biologics.^3,4

Faricimab-svoa (Vabysmo, Roche/Genentech) is a new, monoclonal, bispecific antibody-targeting vascular endothelial growth factor (VEGF) and angiopoietin 2. ⁵ It is highly effective in preventing vision loss from neovascular age-related macular degeneration (nAMD), diabetic macular edema, and edema from retinal vein occlusion.^5,6 Phase 3 clinical trials, postmarketing surveillance, and retrospective reviews have found a low incidence of serious ocular adverse events.^7,8

To our knowledge, this is the first published account of retinal vasculitis associated with a faricimab injection.

Case Report

A 77-year-old White woman with active nAMD in the right eye and nonexudative AMD in the left eye presented with painless decreased vision and floaters in the right eye 2 days after receiving an IVI of faricimab-svoa (6 mg/0.05 mL). Her medical history included controlled hypothyroidism and hyperlipidemia. Current medications included estradiol, levothyroxine, and pravastatin. The surgical history, family history, social history, and a detailed review of systems focused on rheumatologic conditions were noncontributory. Before receiving this faricimab injection, the patient had 4 bevacizumab injections before transitioning to an every 8-week faricimab injection regimen for the 13 months before presentation. In total, she had previously received 7 faricimab injections.

On examination, the Snellen visual acuity (VA) in the right eye had decreased from a baseline of 20/40 to counting fingers; the VA in the left eye was 20/20. The intraocular pressure was normal in both eyes. A slitlamp examination of the right eye showed a clear conjunctiva, a clear cornea, 2+ anterior chamber cells, and a nuclear sclerotic cataract. There was no fibrin or hypopyon. A posterior segment examination of the right eye showed vitritis obscuring the optic nerve, perivascular sheathing, macular drusen, and numerous intraretinal hemorrhages in all 4 quadrants (Figure 1). The only finding in the left eye was macular drusen. Intravenous fluorescein angiography (FA) showed slow filling with increasing vascular leakage in later frames (Figure 1). A vitreous tap was performed, and the specimen was sent for Gram stain, bacterial cultures, and viral polymerase chain reaction (PCR) for herpes virus and varicella-zoster virus.

Figure 1.

Fundus photographs and intravenous fluorescein angiography (FA) of the right eye with vasculitis and painless loss of vision after the eighth injection with faricimab-svoa for neovascular age-related macular degeneration. (A) Vitritis, perivascular sheathing, and diffuse intraretinal hemorrhages in the periphery on the day of presentation. (B) Early-phase FA shows delayed vascular filling and blockage from vitreous opacities and retinal hemorrhages. (C) Midphase shows progressive filling with extensive vascular leakage consistent with vasculitis. (D) Worsening leakage is noted in late-phase FA. Intravenous methylprednisolone was given, followed by oral prednisone. (E) Fundus photograph and IVFA 10 days after presentation show improvement in vitritis, vascular sheathing, and intraretinal hemorrhages. (F) FA shows no leading edge of dye and suggests a more rapid transit due to better blood flow. There is also significant improvement in vascular leakage at midphase (G) and late phase (H). (I) Only a few vitreous opacities and intraretinal hemorrhages remain 30 days after presentation, and there is complete resolution of the perivascular sheathing. Eighty days after presentation, the patient began to notice increasing central blur, and FA concentrating on the macula showed early hyperfluorescence (J) with progressive leakage in the midphase (K) and late phase (L) from her active choroidal neovascular membrane, prompting treatment with intravitreal ranibizumab.

Intravitreal vancomycin (1 mg) and ceftazidime (2.25 mg) were injected, and the patient was started on valacyclovir 2 g 3 times daily. However, the lack of pain, absence of hypopyon, and presence of prominent vasculitis after an IVI of faricimab raised concern for a noninfectious inflammatory process. The patient was instructed to use topical prednisolone every hour while awake. Given the high suspicion of an inflammatory process and poor filling on FA, 250 mg of intravenous methylprednisolone was delivered every 6 hours for 3 days. The frequency was reduced to every 12 hours on day 4 and day 5, followed by a 6-week oral prednisone taper starting at 1 mg/kg.

The patient was seen daily for follow-up, and there was significant improvement in both anterior and posterior chamber inflammation on day 3. Over the following 10 days, the anterior chamber inflammation resolved and there was rapid improvement in the vitritis, intraretinal hemorrhages, vascular sheathing, and vascular filling and leakage on FA (Figure 1).

Gram stain showed white blood cells and no organisms. The final vitreous culture showed scant Staphylococcus aureus and skin flora, which was noted on the final report as a suspected contaminant by the performing laboratory. The PCR results were not available because of mishandling by the laboratory. With the rapid improvement in the examination findings, the index of suspicion for viral retinitis was low and the valacyclovir was stopped after 1 week.

One month after the initial presentation, the VA had improved to 20/50 with resolution of the anterior segment inflammation, vitritis, perivascular sheathing, and intraretinal hemorrhages (Figure 1). However, the patient had recurrent subretinal fluid (SRF) from nAMD. Repeat intravitreal anti-VEGF options were discussed with the patient. Given her recent clinical course, she deferred treatment. At a 2-week follow-up, she had increased central blurring and the SRF had increased with corresponding macular leakage on FA (Figure 1). Intravitreal ranibizumab (0.5 mg/0.05 mL) was given. At a 4-week return visit, the patient received repeat intravitreal ranibizumab (0.5 mg/0.05 mL). Her VA returned to the baseline level at 20/40, and the SRF continued to improve on OCT. There were no further instances of an inflammatory reaction.

Conclusions

The rate of adverse events associated with faricimab injections has been low after US Food and Drug Administration approval.^7,9 To our knowledge, this is the first published detailed report of a presumed faricimab-associated retinal vasculitis, although there has been acknowledgment of other possible cases in the literature. ⁴

An infectious etiology should be considered when inflammation follows any intraocular procedure. This is especially true when there is associated pain, conjunctival injection, anterior chamber hypopyon or fibrinous reactions, and vitritis. Infection can cause vasculitis, although there is usually pain with prominent anterior segment findings.^10,11 Our patient presented with acute painless vision loss and lacked significant anterior chamber findings, making infection less likely. Nevertheless, she was given intravitreal antibiotics and oral valacyclovir pending laboratory testing. The laboratory report suggested scant growth of S aureus along with skin flora, which was listed as likely contamination of the specimen.

Previous reports of brolucizumab-associated vasculitis and other noninfectious vasculitis showed more favorable outcomes when the vasculitis was promptly treated with systemic steroids.^3,12,13 Our patient was treated similarly and rapidly improved, with the resolution of the vasculitis supporting an immune-mediated rather than an infectious cause of inflammation (Figure 1).

Postmarketing reports have shown occlusive and nonocclusive retinal vasculitis associated with intravitreal delivery of newer biologics, such as brolucizumab (Beovu, Novartis) and more recently with the complement inhibitor pegcetacoplan (Syfovre, Apellis).^4,12,14–16 With the increased development and use of similar medications, clinicians must be vigilant in reporting adverse events to the respective manufacturers as well as to medical societies, such as the American Society of Retina Specialists (ASRS). This allows independent review of case findings, verification, and rapid dissemination of warnings. The collaboration provides for case comparisons and, when applicable, may aid in identifying predisposing factors.

Of note, our patient had no history of rheumatologic disease and her review of systems was negative to suggest otherwise. She did, however, have hypothyroidism diagnosed more than 20 years ago. A biopsy was not performed, and we could not confirm whether this resulted from autoimmunity. Our patient had received 7 previous faricimab injections without an inflammatory reaction. Most reported cases of retinal vasculitis after administration of other biologics occurred after the first injection. ⁴ Fortunately, retinal vasculitis after IVT injections is rare. Yet, this can pose a challenge when exploring potential predisposing medical histories, as in this case. Speculation of the role of autoimmunity would be premature without additional data from case comparisons. The medical science team at Genentech and members of the ASRS Research and Safety Therapeutics Committee provided input on navigating this patient’s clinical course. As a result of this collaboration, the faricimab label has been updated to include a warning of potential retinal vasculitis. ¹⁷

After our patient’s recovery, the SRF worsened as a result of her nAMD, posing a dilemma. A repeat faricimab-svoa injection was not advised in case she had indeed developed an immune reaction to this drug. Despite the recommendation of an alternative anti-VEGF agent, the patient initially deferred treatment. After 2 weeks of observation, she began to notice central blurring correlating with worsening SRF. Intravitreal ranibizumab was administered, the topical prednisolone drops were continued as a precaution, and the follow-up intervals were extremely close. The SRF resolved. The patient discontinued the steroids and has had 3 additional injections without incidence.

This is a limited single case, and caution should be exercised in drawing conclusions. An infectious etiology remains a possibility, and the favorable result could have been primarily due to the antibiotic injections while the intravenous steroid merely aided visual recovery. Although the patient’s presentation and response strongly suggest retinal vasculitis of a noninfectious etiology, our standard of care calls for early antibiotic delivery even when an infectious etiology is remote, as in this case. Nevertheless, retina specialists should be aware of the possibility of retinal vasculitis from an intravitreal faricimab injection or any new biologic. When inflammatory vasculitis is suspected, FA should be considered as well as immediate treatment with high-dose systemic steroids and coverage for potential infectious etiologies. Finally, reporting to safety monitoring boards for case verification and case comparison may help identify those at risk for this potentially devastating complication when new biologics are injected.