Eye Pain and Deteriorating Vision After Treatment for Macular Degeneration

What is behind the bilateral eye pain and failing vision affecting a 96-year-old woman with neovascular age-related macular degeneration (nAMD)? That’s what ophthalmologists needed to determine when the patient presented for care after 2 weeks of persistent symptoms, reported Adrian Fung, MBBS, MMed, of the University of Sydney in Australia, and colleagues.

The woman had just started treatment with bilateral intravitreal injections of faricimab (Vabysmo) 18 days previously. However, her medical history included years of receiving treatment for macular degeneration, including 15 ranibizumab (Lucentis) injections followed by 38 aflibercept (Eylea) injections in the right eye, and 21 aflibercept injections in the left eye over 8 years, Fung and colleagues noted in JAMA Ophthalmology.

The patient had no history of intraocular inflammation or systemic autoimmune disease, nor had she required any medications for retinal vasculitis. Her right eye visual acuity (VA) was 20/120 and left eye VA was 1/36 as assessed at the time of receiving her last bilateral faricimab injections.

Fung and team described findings of their ophthalmologic examination when the patient presented for care: “Presenting VA was 20/160 OD [oculus dexter] and counting fingers OS [oculus sinister], with intraocular pressure of 31 mmHg OU, keratic precipitates, and bilateral anterior and posterior vitreous cells. Attenuation of retinal arterioles and veins was associated with 2 blot hemorrhages and pallor of the inferotemporal retina without emboli in the left eye.”

Optical coherence tomography angiography revealed patchy choriocapillaris flow voids, particularly affecting the left eye. “Ultra-widefield fundus fluorescein angiogram (UWF-FFA) demonstrated peripheral retinal venous, arteriolar, and capillary nonperfusion and hyperfluorescent leakage of retinal veins, arteries, and optic discs, with veins more involved than arteries and the left eye more affected than the right,” the authors wrote.

The patient underwent several examinations. Results of chest x-rays and blood tests for syphilis and tuberculosis were all negative, and findings for rheumatoid factor, angiotensin-converting enzyme, antinuclear antibody, and anti-neutrophilic cytoplasmic antibody were also unremarkable.

Because there was only evidence of mild inflammation, clinicians did not perform anterior or vitreous taps to assess for bacterial, fungal, or viral polymerase chain reaction.

They concluded that the patient’s occlusive vasculitis affecting both eyes was associated with the intravitreal faricimab injections she had recently received. The team started her on a 7-week tapering course of oral corticosteroids, at the starting dose of 75 mg, plus topical dexamethasone four times daily and brinzolamide twice daily. After completing 7 weeks of treatment, the patient’s visual acuity remained 20/160 OD and counting fingers OS, with no evidence of intraocular inflammation or exudation. They reported the suspected adverse event to Roche/Genentech, the drug’s developer.

Discussion

“In the present case, faricimab was thought to be the most likely cause for the occlusive retinal vasculitis in these cases, given the time course of onset, the bilateral panuveitic presentation, and absence of other causes, such as prior uveitis or accountable medications,” explained Fung and colleagues.

While there have been anecdotal reports of occlusive retinal vasculitis in patients receiving faricimab, there have been no such reports published in a peer-reviewed journal, they noted.

Intraocular inflammation is a relatively rare complication associated with use of faricimab, which gained approval in the U.S. in 2022 for treatment of nAMD and diabetic macular edema (DME), and in 2023 for retinal vascular occlusion (RVO).

Not including endophthalmitis, the bispecific immunoglobulin G-derived monoclonal angiopoietin 2 and vascular endothelial growth factor A antibody has been linked with intraocular inflammation in 2% of 664 cases of nAMD, 1.3% of 1,262 cases of DME, and 1.4% of 641 cases of RVO, rates which Fung and co-authors noted are numerically higher compared with the aflibercept groups.

Reported rates of intraocular inflammation with other intravitreal agents were:

• Brolucizumab: 4.6%
• Pegcetacoplan: 2.1% to 3.8%
• Aflibercept: 0% to 0.16%
• Bevacizumab (Avastin) : 0.081% to 0.10%
• Ranibizumab: 0.005% to 0.02%

Faricimab injection was associated with three cases of severe acute intraocular inflammation that occurred within 1 month at a single institution; this involved two different lot numbers at three locations.

As a variant of intraocular inflammation, retinal vasculitis has the potential to cause blindness, the authors noted, theoretically due to a type III/IV delayed hypersensitivity reaction. In phase III clinical trials of the drug, no cases of retinal vasculitis were reported.

In August 2023, the company estimated that for every 10,000 faricimab injections, the incidence of vasculitis with or without occlusion was 0.17, and the incidence of occlusive vasculitis was 0.06, which was “equivalent to 26 and 9 patients, respectively, of 1.5 million vials distributed worldwide,” Fung and team wrote.

Roche/Genentech issued a postmarketing safety warning of this risk in November 2023.

Retinal vasculitis, with or without occlusion, has also been associated with intravitreal injection of both brolucizumab and pegcetacoplan. However, the condition may vary in its clinical presentation, progression, and outcomes, due to differing pathogenic mechanisms of the various intravitreal therapies.

For instance, vasculitis developed within 6 months of beginning intravitreal treatment with brolucizumab, and occlusive retinal vasculitis resulted in significant permanent vision loss in five of 23 eyes. Although no cases of vasculitis occurred in the OAKS/DERBY trials for pegcetacoplan, the authors said that after its release on the market, a minimum of 13 cases of retinal vasculitis were reported, all of which occurred after the initial injection.

“Occlusive retinal vasculitis should be recognized as a possible adverse event associated with intravitreal faricimab and support prompt evaluation of patients who experience persistent discomfort or blurred vision following intravitreal injection to exclude IOI [intraocular inflammation] or infection,” Fung and colleagues concluded.

They advised clinicians that UWF-FFA may be useful to assess these patients before starting them on corticosteroid treatment, which may help with visual recovery.

The exact frequency of these relatively rare inflammatory events could be determined through use of large databases, Fung and co-authors noted. “The bilateral involvement in this case emphasizes that risks of bilateral concurrent administration of intravitreal injections need to be balanced against potential advantages of greater convenience and treatment compliance.”

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