Vogt–Koyanagi–Harada-like uveitis with severe hyalitis during treatment by anti-programmed death 1 antibody for lung cancer: a case report

Abstract

Background

Vogt–Koyanagi–Harada-like uveitis that presents with severe hyalitis has rarely been reported during anti-programmed death 1 therapy.

Case presentation

A 70-year-old Chinese man presented with bilateral visual disturbances and vomiting after four cycles of serplulimab, an anti-programmed death 1 antibody, for metastatic lung carcinoma. His best corrected visual acuity was measured at 0.04 in the right eye and 0.02 in the left eye. A slit-lamp examination indicated severe hyalitis, while ocular ultrasound revealed focal serous retinal detachment. Magnetic resonance imaging demonstrated choroidal thickening and cerebrospinal fluid analysis indicated a mild lymphocytic elevation. Retinal fluorescein angiography exhibited focal pinpoint leakage and delayed hyperfluorescence at the optic disc. A diagnosis of Vogt–Koyanagi–Harada-like uveitis secondary to anti-programmed death 1 therapy was established. Following the discontinuation of anti-programmed death 1 treatment and 1-month course of oral prednisone at a dosage of 40 mg per day, the patient’s best corrected visual acuity improved to 0.6 in the right eye and 0.4 in the left eye.

Conclusion

Corticosteroid treatment has proven effective for Vogt–Koyanagi–Harada-like uveitis. Currently, the optimal mode and dosage of corticosteroid therapy have not been clearly defined. Gathering more real-world cases of Vogt–Koyanagi–Harada-like uveitis associated with anti-programmed death 1 antibodies would be beneficial in developing therapeutic guidelines.

Background

Programmed death 1 (PD-1) ligands, PD-L1 and PD-L2, are expressed on the surfaces of tumor and immune cells. When these ligands bind to their receptor PD-1, they inhibit T cell activation, allowing tumor cells to evade attacks from T cells. The anti-PD-1 antibodies block the interaction between PD-1 and PD-L1/2, which can boost T cell immune responses against tumor cells and increase survival rates for patients with metastatic cancer [1]. In clinical practice, anti-PD-1 antibodies such as nivolumab, pembrolizumab, and serplulimab are utilized for treating metastatic cancer.

Vogt–Koyanagi–Harada (VKH) disease is characterized by bilateral granulomatous uveitis [2]. The incidence of VKH-like uveitis—a rare ocular adverse effect of anti-PD-1 antibody therapy—is estimated at less than 1%, with cases first documented in 2017 [3, 4]. Following this, a dozen case reports detailing VKH-like uveitis associated with anti-PD-1 antibodies have emerged [5–11]. The latency period between the onset of VKH-like uveitis and the initiation of anti-PD-1 therapy ranges from 10 days to several years [12, 13]. Visual acuity varies significantly, from 1.2 to mere hand motions. Corticosteroid treatment for VKH-like uveitis encompasses local corticosteroids, oral prednisone, intravenous bolus therapy, and intravitreal dexamethasone implants (see Table 1). However, there are no established treatment guidelines for VKH-like uveitis during anti-PD-1 therapy. We report a case of bilateral VKH-like uveitis that arose by serplulimab, a less commonly reported anti-PD-1 antibody for lung cancer. The patient experienced VKH-like posterior uveitis with severe hyalitis, which improved significantly with oral prednisone and the cessation of anti-PD-1 therapy. The aim of this study is to discuss the factors which influence the prognosis of VKH-like uveitis. We found that the severity of VKH-like uveitis and the mode of corticosteroid therapy are two key factors influencing visual outcome of VKH-like uveitis. More real-world cases are necessary to develop guidelines to effectively manage VKH-like uveitis associated with anti-PD-1 antibodies.

Table 1.

Review of the cases of Vogt–Koyanagi–Harada posterior like uveitis reported in literature

Patients (age, sex, type of tumor, references)	PD-1 inhibitor (dosage, cycle, period)	AV initial (right eye (OD), left eye (OS))	Multimodal images (fundi, optical coherence tomography (OCT), fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), magnetic resonance imaging (MRI))	Treatments	AV final (OD, OS)
60 years, female, melanoma [3]	Nivolumab (94 mg/body, 3 cycle, 3 months)	Blurred vision OU	Fundi: red depigmented fundi of both eyes	0.1% betamethasone and nonsteroidal bromfenac eye drops	Complete remission
63 years, F, melanoma [5]	Nivolumab (–, two cycles, about 1 month)	0.7, 0.4	OCT: SRD, wavy RPE; FFA: pinpoints ICGA: choroidal hyperfluorescence, hypofluorescent dark spots	0.1% betamethasone eye drops	1.0, 0.9
61 years, F, ovarian cancer [6]	Nivolumab (2 mg/kg, four cycles, 4 months)	20/100, 20/40	Fundus: optic disk edema, choroidal swelling OCT: choroidal folding and thickening; massive SRF with choroidal folding, hyperreflective points outer nuclear layer; FFA: multiple leakage points, optic disc staining	IV 1 g/day 3 days; oral prednisolone	20/20, 20/20
59 years, M, metastatic melanoma [4]	Pembrolizumab (–, NA, 16 months)	20/20, 20/20	Fundi: bilateral SRD, 360° peripheral choroidal detachment, papillary edema OCT: choroidal folds, SRF FFA: hyperfluorescent optic nerve; ICGA: no abnormality	Methylprednisolone intravenous 1 mg/kg, then oral prednisone 1 mg/kg, subconjunctival and topic corticoid	20/20, 20/20
68 years, F, metastatic melanoma [7]	Pembrolizumab (–, –, 3 months)	0.6, 1.2	Fundi: choroidal folds OU OCT: thickened choroid and choroidal folds, SRD (OD); AS-OCT: ciliary body edema and detachment FFA: spotted hyperfluorescence, leakage of fluorescein from the both optic disks ICGA: hypofluorescent dark area	Oral prednisolone 55 mg/day and topical 0.1% betamethasone	1.0, 1.2
63 years, M, hypopharyngeal cancer [8]	Nivolumab (160 mg, two cycles, –)	10/200, 20/50	Fundi: papilledema and diffuse DSR OU OCT: wavy RPE; SRF; optic disc swelling FFA: leakages of fundi and optic disc; ICGA: leakage, incompetency of the choroidal circulation, hypo fluorescent dark dots	Sub-tenon injections of triamcinolone acetonide without remission; then intravenous 1 g/day 3 days, oral prednisone 50 mg/day	Complete remission
49 years, F, renal cell carcinoma [13]	Nivolumab (–, every 2 weeks, 2 years)	20/200, 20/40	Fundi: creamy, elevated lesion underling choroidal thickening, SRF OCT: bacillary layer detachment, SRF, choroidal thickening and folds FFA: pooling of dye, mottled hypofluorescence and punctate foci of hyperfluorescence ICGA: hypofluorescence	Oral prednisone 60 mg/day	20/40, 20/32
73 years, M, melanoma [9]	Nivolumab (2 mg/kg, four cycles, 12 weeks)	Blurred vision	Fundi: circumference SRD, MRI: diffuse thickening of the choroid	Methylprednisolone intravenous 500 mg/day for 3 days; oral prednisolone 40 mg/day	AV recovered
58 years, M, lung adenocarcinoma [10]	Nivolumab (3 mg/kg, six cycles, 4 months)	0.8, 0.08	OCT: DSR, wavy RPE, and thickening of the choroid FFA: superfluorescence of the optic disc and granular hyperfluorescence ICGA: patchy low fluorescence of the choroid	0.1% betamethasone eye drop; recurrence: hydrocortisone intravenous 150 mg/day for 3 days, oral hydrocortisone 30–20 mg	1.2, 1.2
75 years, F, metastatic melanoma [12]	Nivolumab (–, one cycle, 10 days)	20/170, 20/30	Fundi: reduced retinal pigmentation, macular oedema and optic disc swelling OCT: SRF and multiple hyperreflective inner retinal round foci;	0.1% dexamethasone eye drop;	20/30, 20/30
69 years, M, bladder urothelial carcinoma [11]	Toripalimab (–, 19 cycles, 18 months)	Counting fingers OU	Fundi: edema of the optic disc, peripheral SRD with no retinal tears OCT: swollen choroid, bacillary layer SRD FFA: pin-point hyperfluorescence	Intravitreal implant of dexamethasone, oral prednisone 60 mg/day	20/25, 20/25

AV Acuity visual, VKH Vogt–Koyanagi–Harada, OD right eye, OS left eye, PD programmed death, OCT optical coherence tomography, FFA fluorescein fundus angiography, ICGA indocyanine green angiography, MRI magnetic resonance imaging, VA visual acuity, F female, M masculine, – default, SRD serous retinal detachment, RPE retinal pigment epithelium, IV injection venous, SRF subretinal fluid, OU both eyes, AS-OCT anterior segment OCT

Case presentation

A 70-year-old Chinese male was diagnosed with small-cell lung carcinoma with hepatic metastases on 11 December 2023. He underwent an anti-PD-1 therapy (300 mg serplulimab) administered every 3 weeks for four cycles. At three months post initiation of serplulimab, he experienced significant bilateral visual disturbances and vomiting. He sought ophthalmological evaluation on 22 March 2024.

His best corrected visual acuity (BCVA) scores were 0.04 in the right eye and 0.02 in the left eye. Intraocular pressure recorded 8 mmHg in the right eye and 9 mmHg in the left eye. Slit-lamp examination identified cataracts and quiescent anterior segment. The ocular fundi exhibited dense hyalitis bilaterally (Fig. 1A, B). Ocular ultrasound revealed dense vitreous opacities in both eyes and focal serous retinal detachment (SRD) (Fig. 1C, D). Fluorescein fundus angiography demonstrated focal pinpoint leakage and delayed hyperfluorescence at the optic disc in the late stage (Fig. 1E). Indocyanine green angiography showed hypofluorescent patchy (Fig. 1F). Cerebrospinal fluid (CSF) analysis revealed a mild lymphocytic pleocytosis (13 × 10⁶/L). A cerebral magnetic resonance imaging (MRI) excluded inflammatory and metastatic neuropathies and revealed choroidal thickening (Fig. 1G). A diagnosis of VKH-like uveitis secondary to PD-1 therapy was established. Serplulimab treatment was subsequently discontinued. At 8 days later, his BCVA improved to 0.3 in the right eye and 0.15 in the left eye. He was prescribed oral prednisone at a dose of 40 mg. After 17 days, BCVA further improved to 0.4 in the right eye and 0.3 in the left eye, and the intraocular pressures were 9 mmHg and 10 mmHg, respectively. Ocular ultrasound indicated an improvement in subretinal detachment but persistent vitreous opacities (Fig. 1a–d). Optical coherence tomography (OCT) revealed SRD in the right eye, wavy and granular retinal pigment epithelium (RPE) changes and choroidal thickening in both eyes (Fig. 1e, f). Following a 1-month course of oral prednisone, BCVA reached 0.6 and 0.4 at his final ophthalmologic assessment. The treatment and symptoms of this patient is summarized in Fig. 2.

Fig. 1.

Multimodal images of the case before and after treatment. The fundi and ocular echography revealed severe hyalitis in both eyes (A–D). Ocular echography indicated focal serous retinal detachment in left eye (arrow in C, D). Fluorescein fundus angiographic demonstrated focal pinpoint leakage (arrow in E) hyperfluorescence in optic disc in late phase (head arrows in E). Indocyanine green angiographic showed choroidal hypofluorescent patchy (arrows in F). Ocular magnetic resonance imaging showed thickening of the choroid bilaterally (arrows in G). Following a 2-week treatment period and discontinuation of serplulimab, the fundi and ocular echography revealed the little attenuated hyalitis (a–d). The optic disc margin appears blurred (arrow in b). The serous retinal detachment decreased on echography in left eye (c, d). Optical coherence tomography indicated subretinal fluid (head arrow in e) and thickening of the choroid (white arrows in e) in right eye. The black arrow indicates granular retinal pigment epithelium in both eyes (e, f), consistent with retinal pigmentary alterations

Fig. 2.

The patient’s clinical course after serplulimab treatment. PD-1 programmed death 1, VOD vision of right eye, VOS vision of left eye

Discussion

The underlying mechanism of VKH-like uveitis associated with anti-PD-1 therapy remains undetermined. However, there is consensus regarding the potential pathophysiological process: in genetically predisposed individuals, retinal pigment epithelium (RPE) cells and choroidal melanocytes may express specific epitopes recognized by T cells. The anti-PD-1 antibody alleviates PD-1-mediated inhibition of T cells, resulting in T cell-mediated cytotoxicity against RPE and choroidal melanocytes. This immune infiltration contributes to choroidal thickening, RPE dysfunction, and the accumulation of subretinal fluid (SRF).

The precise modality and dosage of corticosteroid therapy for VKH-like uveitis have yet to be established. Literature indicates that corticosteroid therapy can vary on the basis of the severity of VKH, including local corticosteroid eye drops, periocular injections (subconjunctival, sub-Tenon’s), oral prednisone, intravenous bolus therapy (150 mg to 1 g), or intravitreal dexamethasone implants (Table 1). According to the American Society of Clinical Oncology Clinical Practice Guidelines, posterior uveitis is classified as a grade 3 adverse event, prompting a cessation of anti-PD-1 therapy [14]. Most cases of VKH-like uveitis have led to the discontinuation of anti-PD-1 treatment. However, some VKH-like posterior uveitis was controlled by oral prednisone without discontinuing of anti-PD-1 antibody [15].

From literature, we concluded the character of VKH like uveitis related to anti-PD-1 antibody. The wavy line of RPE is the earliest manifestation on OCT, which was owing to the multifocal choroidal thickening. At this stage, the visual acuity may not be affected. If the condition progresses, OCT scans reveal increased choroidal folding and worsened choroidal thickening, leading to a breakdown of the RPE barrier and SRF [3]. The location of SRF in relation to macula—whether within or adjacent to it—influences visual acuity. At this stage, the prompt discontinuation of anti-PD-1 therapy combined with appropriate steroid treatment could restore visual function [6]. If the treatment is delayed, VKH-like uveitis can result in diffuse choroidal congestion, leading to bullous exudative retinal detachments or peripheral circumferent SRD [16]. Due to gravitational effects, SRD typically occurs in the inferior retina. Approximately 61% of VKH cases with SRD also present with ciliary detachment, which resolves more quickly than SRD [17]. Persistent SRD may require pars plana vitrectomy as a salvage procedure [18].

Should bolus corticoid therapy be administered for severe VKH-like uveitis with SRD? In a documented case of VKH syndrome, initial macular OCT indicated detachment of the bacillary layer, along with exudate and chorioretinal folds. Following 2 months of treatment with oral prednisone at a dosage of 60 mg/day, there was a significant improvement in visual acuity [13]. This suggests that oral prednisone is beneficial for VKH-like uveitis with severe SRD. However, patients with VKH-like uveitis and SRD who received bolus corticoid therapy could achieve complete recovery of visual acuity [4, 6–10]. By contrast, those treated with local eye drops, dexamethasone implants, and oral prednisone experienced only partial recovery of visual acuity [5, 11–13]. It appears that severe VKH-like uveitis may achieve better outcomes with high-dose corticosteroid pulse therapy, provided that the patient’s condition allows for it.

Choroidal metastasis can mimic VKH-like uveitis. In our case, the thickened choroid and severe hyalitis raised suspicions of ocular metastasis, which was ruled out by MRI, retinal angiography and cerebrospinal fluid analysis. In literature, the diffuse uveal melanocytic proliferation might be mistaken for nivolumab-induced VKH syndrome, for which the corticoid was useless. The thickened RPE found in diffuse uveal melanocytic proliferation differentiate from wavy RPE in VKH posterior uveitis [19].

Conclusion

The corticosteroid therapy for VKH-like uveitis is effective, but the mode and dosage of corticoid have not been established. From literature and our case, we conclude that the option of corticosteroid therapy should correlate to clinical demonstrations for VKH-like uveitis. Further scientific researches are needed to determine the precise mechanism and treatment of VKH-like uveitis related to anti-PD-1 therapy.

Abbreviations

PD

Programmed death

VKH

Vogt–Koyanagi–Harada

RPE

Retinal pigment epithelium

SRD

Serous retinal detachment

BCVA

Best corrected visual acuity

MRI

Magnetic resonance imaging

OCT

Optical coherence tomography

FFA

Fluorescein fundus angiography

ICGA

Indocyanine green angiography

CSCR

Central serous chorioretinopathy

SRF

Subretinal fluid

F

Female

M

Masculine

IV

Injection venous

OU

Both eyes

OD

Right eye

OS

Left eye

VOD

Vision of right eye

VOS

Vision of left eye

Author contributions

XL drafted the article. YL gave advice to diagnosis and treatment. PL and YZ reviewed and gave advice on the manuscript. WX interpreted the images and gave final approval of the version to be submitted.

Funding:

Jiangsu Province Social Development Project: BE2023723.

Data availability

The datasets analyzed during the current study are available in Mendeley Data at 10.17632/pgrk43chrc.1

Declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of the First Affiliated hospital of Soochow University, Soochow, China. The performance of this study was followed the tenets of the Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.