Occlusive Retinal Vasculitis After a Single Injection of Pegcetacoplan

Abstract

Purpose: To describe a patient with retinal vasculitis after a single intravitreal injection (IVI) of pegcetacoplan. Methods: A case and its findings were analyzed. Results: An 80-year-old woman was treated with pegcetacoplan for subfoveal geographic atrophy. Ten days later, the patient noted “purple iridescent waves” but did not immediately report it. On day 18, she presented with pain and decreased visual acuity from 20/80 (pinhole) preinjection to 20/150 postinjection. No signs of inflammation were observed, and she was treated for high intraocular pressure (30 mm Hg). On day 23, iritis was noted. The fluorescein angiogram showed severe occlusive vasculitis involving all quadrants and the macula. The vasculitis/neuroretinitis laboratory panels were negative, and no contributing systemic features were identified other than well-controlled diabetes. Conclusions: In this patient, occlusive retinal vasculitis occurred shortly after a single IVI of pegcetacoplan.

Introduction

Pegcetacoplan (Syfovre, Apellis Pharmaceuticals) was ap-proved by the US Food and Drug Administration in February 2023 for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). ¹ Pegcetacoplan is a polyethylene-glycolylated complement C3 inhibitor that downregulates the cascade of the 3 complement pathways, thus decreasing disease activity. ² In the phase 3 OAKS and DERBY clinical trials, investigators reported a rate of infectious endophthalmitis of 0.034% per injection and a rate of noninfectious intraocular inflammation of 0.24% per injection (ie, 24 cases per 1000 injections), with no cases of occlusive vasculitis or retinitis. ³

Following the approval of pegcetacoplan, ophthalmologists have reported the occurrence of intraocular inflammation-associated occlusive and nonocclusive retinal vasculitis to the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee. The ReST Committee recently reported 14 eyes of 13 patients with retinal vasculitis, of which 11 eyes had occlusive retinal vasculopathy. Cases presented a median of 10.5 days after pegcetacoplan treatment, and all cases occurred after the first injection. ⁴

We report a case of retinal vasculitis after a single intravitreal injection (IVI) of pegcetacoplan. We also provide images of the tempo of the GA progression, including the pretreatment optical coherence tomography (OCT) images of both eyes and the photography and autofluorescence images of the left eye, which was ultimately treated with pegcetacoplan.

Case Report

An 80-year-old woman presented in November 2021 for evaluation of GA resulting from AMD. Her ocular history was significant for an intraocular pressure (IOP) spike to 76 mm Hg in the right eye 9 years previously after macular hole surgery performed elsewhere. She had no known history of an ocular or systemic inflammatory process. Personal medical antecedents included diabetes mellitus type 2, hypothyroidism, and systemic hypertension, all well controlled medically.

At presentation, the corrected visual acuity (VA) was 20/70 OD and 20/80 OS. Fundus photography of the left eye (Figure 1A) and OCT of both eyes (Figure 1, B and C) were consistent with GA. The cup-to-disc ratios were graded as 0.6 in the right eye and 0.5 in the left eye. The baseline OCT showed temporal thinning of the retinal nerve fiber layer (average thickness, 79 µm) in the right eye and normal thickness in the left eye (average thickness, 91 µm). Fundus autofluorescence was not obtained at this visit.

Figure 1.

(A) Color fundus photography of the left eye in November 2021 shows GA and extensive drusen. The appearance of the fundus in the right eye was similar. (B) OCT of the right eye in November 2021 shows an irregular inner retinal contour resulting from previous macular hole surgery. There is foveal thinning and GA. (C) OCT of the left eye in November 2021 shows GA. There are central drusenoid changes and foveal thinning.

Abbreviations: GA, geographic atrophy; OCT, optical coherence tomography.

In May 2023, 18 months later, the corrected VA was 20/80 OD and 20/150 OS, improving with pinhole to 20/80. Autofluorescence of the left eye (Figure 2A) and OCT of both eyes (Figure 2, B and C) showed stability of the GA in the right eye and superior and nasal progression of the GA in the left eye. Fundus photography was not obtained at this visit.

Figure 2.

(A) Autofluorescence of the left eye in May 2023. Compared with the color photograph (Figure 1A) in November 2021, there is superior and nasal progression of the GA. (B) OCT of the right eye in May 2023 shows stability of the GA on the infrared image. (C) OCT of the left eye in May 2023 is stable centrally; however, the infrared image shows superior and nasal progression of the GA.

Abbreviations: GA, geographic atrophy; OCT, optical coherence tomography.

After appropriate informed consent was obtained from the patient, the left eye was treated with pegcetacoplan. The medication was drawn up with the 19-gauge needle provided in the kit by the manufacturer. Ten days after injection, the patient noted a visual disturbance in the left eye described as “purple iridescent waves” but did not immediately report it. On day 18 postinjection, a Sunday, she presented emergently with left ocular pain and decreased VA to 20/150 (pinhole testing not done). A slitlamp examination of the left eye showed mild conjunctival injection, a mid-dilated pupil, and no signs of inflammation. The etiology of this IOP spike was unknown but was thought possibly to be related to the IOP spike she previously experienced after macular hole surgery in the fellow eye. She was treated with timolol twice daily for high IOP (30 mm Hg).

On day 22 postinjection, the VA in the left eye remained 20/150 without improvement with pinhole and the IOP was 27 mm Hg. No inflammation was noted in the aqueous or vitreous; however, 2 hemorrhages were noted in the retinal midperiphery. On day 23 postinjection, the VA remained 20/150 without improvement with pinhole. Iritis was noted with 1+ cells in the anterior chamber as well as increased conjunctival injection and persistent elevated IOP (31 mm Hg). A fundus examination and color photography (Figure 3A) showed posterior pole and midperipheral retinal hemorrhages along with vascular attenuation and segmentation in the left eye. Fluorescein angiography of the left eye (Figure 3B) showed occlusive vasculitis to the central 20 degrees with marked vascular leakage and optic disc staining. The patient was started on prednisolone acetate 1% every 2 hours overnight. This was tapered to 4 times daily the next day and then to twice daily over the next few weeks.

Figure 3.

(A) Color fundus photography of the left eye on day 23 postinjection of pegcetocoplan shows posterior pole and midperipheral retinal hemorrhages with flame-shaped hemorrhages on the optic nerve. Compared with the baseline examination (Figure 1A), venous caliber is irregular and there is arteriolar attenuation. Focal areas of retinal whitening are seen superior and supertemporal to the foveal center. (B) Fluorescein angiography of the left eye (1 minute 25 seconds) on day 23 postinjection of pegcetacoplan. There is widespread occlusion of arteries and venules affecting all 4 quadrants and the macula. The central macula is affected within 5 degrees of the foveal center. The large venules appear dilated with stippled hyperfluorescence. The optic nerve leaks fluorescein.

On day 69 postinjection, the VA in the left eye remained 20/150 without improvement with pinhole and the IOP was 23 mm Hg on timolol twice daily and prednisolone acetate twice daily. A laboratory workup found negative or normal Treponema pallidum antibodies, Toxoplasma immunoglobulin (IgG), cytomegalovirus IgG, Lyme antibodies, Bartonella henselae IgG and IgM, Bartonella quintana IgG and IgM, QuantiFERON, angiotensin-1 converting enzyme, myelin oligodendrite glycoprotein antibody, homocysteine, and C-reactive protein (sedimentation rate was not obtained). The lupus anticoagulant/cardiolipin antibody panel was negative except for the dilute Russell viper venom time screen, which was elevated at 52 seconds (normal ≤45 seconds) but was considered a false positive by the laboratory. Because there was no response to topical steroids and the IOP had improved, the patient consented to injection of an intravitreal dexamethasone implant (Ozurdex, Allergan).

On day 97 postinjection of pegcetacoplan and day 28 postinjection of dexamethasone, the VA in the left eye was 20/200 without improvement with pinhole and the IOP was 17 mm Hg on timolol twice daily. There were no aqueous cells on prednisolone acetate twice daily; however, there were vitreous cells and strands with mild vitreous haze. Fundus photography of the left eye (Figure 4A) documented the 0.7 mg dexamethasone implant, retinal vascular attenuation, and peripheral retinal hemorrhages. Autofluorescence of the left eye (Figure 4B) showed stable GA compared with preinjection and a shadowing defect from the dexamethasone implant. OCT of the left eye (Figure 4C) showed stable GA. The patient was observed with monthly follow-up.

Figure 4.

(A) Color fundus photography of the left eye on day 97 postinjection of pegcetacoplan shows increased retinal vascular attenuation and occlusion, especially inferiorly. There are new retinal hemorrhages. Areas of ischemic retinal whitening have resolved. The optic nerve is pale, and the central vessels appear narrower. There is a clump of vitreous cells and strands over the optic nerve and mild diffuse vitreous haze. A 0.7 mg dexamethasone implant is visible inferiorly. (B) Autofluorescence of the left eye on day 97 postinjection of pegcetacoplan shows stability of the GA. There is blockage by the retinal hemorrhages and shadowing from the vitreous opacities and the dexamethasone implant. (C) Optical coherence tomography on day 97 postinjection of pegacetacoplan shows GA.

Abbreviation: GA, geographic atrophy.

On day 223 postinjection of pegcetacoplan, the VA in the left eye was 20/350 without improvement with pinhole and the IOP was 32 mm Hg on dorzolamide–timolol twice daily. Iris and angle neovascularization were noted. The patient was treated with off-label bevacizumab (Avastin, Genentech) injected into the anterior chamber followed by panretinal photocoagulation. A plan was made for close follow-up.

Conclusions

A temporal association of retinal vascular occlusion after IVI of pegcetacoplan does not confirm drug-related or injection-related toxicity. Reporting similar cases to the manufacturer, Medwatch, and the ASRS ReST Committee will help further investigations into the etiology. Until further information is available, physicians who use pegcetacoplan may wish to discuss the few reported cases of retinal vascular occlusion with patients during the informed consent process.