Cemiplimab-Induced Vogt-Koyanagi-Harada-Like Syndrome in a Patient With Cutaneous Squamous Cell Carcinoma of the Lower Back

Abstract

Cemiplimab is a programmed death receptor-1 inhibitor that has been approved for the treatment of advanced cutaneous squamous cell carcinoma (CSCC). The immune-related adverse events most commonly reported with cemiplimab are thyroiditis, pneumonitis, and hepatitis. Ocular adverse events have been rarely reported. We present a rare case of Vogt-Koyanagi-Harada (VKH)-like syndrome in a patient with CSCC being treated with cemiplimab. A 53-year-old woman presented with bilateral progressive visual disturbances, eye pain, and headache for 4 weeks after 4 cycles of neo-adjuvant cemiplimab therapy for stage IV CSCC of the lower back. The detailed ophthalmologic evaluation established the diagnosis of VKH-like syndrome with panuveitis, subretinal fibrosis, and exudative retinal detachment. The patient received high-dose intravenous and topical steroids followed by a gradual taper of oral steroids over 6 months. Cemiplimab was discontinued. There was significant improvement in her symptoms with the resolution of subretinal fluid, choroidal elevations, and retinal detachment. VKH-like syndrome is an immune-mediated disorder that affects pigmented structures and is a significant cause of noninfectious uveitis. Drug-related uveitis has been seen more commonly with immune checkpoint inhibitors than with other drug classes and can occur anytime during the treatment. The mainstay of treatment of VKH-like syndrome is high-dose intravenous corticosteroids. In resistant cases, immunosuppressive therapies and biological agents are beneficial. This case highlights the importance of prompt recognition of VKH-like syndrome associated with cemiplimab, enabling timely intervention to prevent permanent vision loss.

Introduction

Cemiplimab is an immune checkpoint inhibitor (ICI) that targets programmed death receptor-1 (PD-1). Cemiplimab is approved for the treatment of advanced cutaneous squamous cell carcinoma (CSCC) in patients who are not candidates for curative surgery or radiation. ¹ Despite critical clinical benefits, ICIs are associated with immune-related adverse events (irAEs), including dermatologic, gastrointestinal, hepatic, and endocrine. ²

The ocular adverse events are uncommon, reported with an incidence rate of <1%, and may include dry eyes, conjunctivitis, uveitis, retinal detachment, vasculitis, keratitis, episcleritis, and choroidopathy. ³ Ocular adverse events may be vision-threatening and can cause significant morbidity. ⁴

The most-reported irAEs with cemiplimab are thyroiditis, pneumonitis, and hepatitis. ¹ Ocular adverse events associated with cemiplimab have been reported as case reports.^5,6 We hereby describe a case of Vogt-Koyanagi-Harada (VKH)-like syndrome in a patient with advanced CSCC of the lower back during treatment with cemiplimab. In the best of our knowledge, this is the second case of cemiplimab-induced VKH-like syndrome in the literature.

Case Presentation

A 53-year-old woman with a medical history of diabetes mellitus and stage IV well-differentiated CSCC of the lower back was started on neo-adjuvant cemiplimab therapy (Figure 1a). The patient received 4 cycles of cemiplimab every 3 weeks over 3 months. After 4 cycles, the patient presented to the oncology clinic with progressive headaches, bilateral eye pain, and visual disturbances for 4 weeks. An urgent ophthalmologic evaluation was done. The external ocular examination was normal. However, the fundus examination with optical computed tomography and fluorescein angiography revealed bilateral anterior uveitis, scleritis, subretinal fibrosis, and exudative retinal detachment (Figure 1b). The magnetic resonance imaging of the orbits revealed abnormal T1-weighted and T2-weighted hypointensity in both globes, suggestive of bilateral vitreous hemorrhage or detachment. These findings were consistent with the diagnosis of VKH-like syndrome. The laboratory investigations revealed a normal complete blood count and renal and hepatic functions. The autoimmune workup was negative. The patient was admitted for systemic high-dose corticosteroids and received intravenous methylprednisolone 1 g over 3 days, along with topical steroids. The patient reported improvement in symptoms after initiation of treatment. Upon discharge, the patient was started on oral prednisone with a slow taper over 6 months with outpatient follow-up. Cemiplimab was discontinued. The patient had progression of squamous cell carcinoma for which she was started on a combination of paclitaxel, carboplatin, and cetuximab. After 6 months of oral and topical steroids, there was a significant improvement in her symptoms of VKH-like syndrome along with the resolution of subretinal fluid, choroidal elevations, and exudative retinal detachment. At the time of the last follow-up, the patient was undergoing chemotherapy and cetuximab with minimal disease response. The patient is under regular follow-up with oncology and ophthalmology.

Figure 1.

(a) Cutaneous squamous cell carcinoma of the lower back. (b) Fundus picture showing multiple pockets of subretinal fluid with subretinal fibrosis and exudative retinal detachment.

Discussion

VKH-like syndrome is an uncommon, immune-mediated disorder affecting pigmented structures, including the eye, inner ear, meninges, and skin. This syndrome is characterized by bilateral panuveitis and extraocular symptoms of sensorineural hearing loss, meningismus, and skin depigmentation. VKH-like syndrome is primarily a T CD4+ Th1 lymphocyte-mediated aggression against melanocytes in individuals with a genetic predisposition, particularly those with the HLA-DRB1*0405 allele. This syndrome is an important cause of noninfectious uveitis, causes an acute onset of bilateral blurred vision, and has been reported more frequently in women than men. The mainstay of treatment for VKH-like syndrome is prompt, high-dose systemic corticosteroids, followed by slow tapering of oral corticosteroids over a minimum of 6 months. Immunosuppressive drugs such as azathioprine, methotrexate, cyclosporine, and mycophenolate mofetil are given to prevent recurrences in patients with resistant disease and those unable to tolerate steroids. ⁷ In patients who are resistant to first-line immunosuppressive therapies, tumor necrosis factor inhibitors, for example, adalimumab, have been found to be effective. ⁸

Drug-related uveitis has been seen more commonly with ICIs than with other drug classes. Among ICIs, ipilimumab, and ipilimumab/nivolumab combination have been found to be associated with anterior uveitis. However, VKH-like uveitis is significantly associated with PD-1/PD-L1 inhibitors due to the expression of PD-L1 in the cornea and retinal epithelium. Patients on ICI therapy are often diagnosed to have drug-related uveitis if infectious and autoimmune causes are ruled out. ⁹

A challenging case of cemiplimab-induced VKH-like syndrome was reported earlier by Huang et al. ⁶ A 53-year-old woman with a history of squamous cell carcinoma and melanoma in-situ status post resection involving the back and lower extremities, received cemiplimab to prevent additional skin cancer. The patient developed acute eye pain, bilateral blurred vision, and photosensitivity 14 months after starting cemiplimab therapy. In addition, the patient also had vitiligo and hair loss. VKH-like syndrome was diagnosed. Autoimmune workup revealed positive HLA-B51 allele. Cemiplimab was discontinued, and oral prednisone was started at a dose of 80 mg daily. Due to the recurrence of symptoms on tapering steroid doses, azathioprine started with poor tolerance. Azathioprine was stopped, and adalimumab was started at a dose of 40 mg subcutaneous injection every 2 weeks. The patient showed improvement in her symptoms. ⁶

ICI-related ocular adverse events can occur either during or after the cessation of treatment. However, most adverse events typically occur within 2 months of initiating therapy.^3,10 The patient described here developed VKH-like syndrome after 3 months of cemiplimab, whereas the one described by Huang et al developed the syndrome after 14 months.

VKH-like syndrome has been reported mainly in patients with metastatic melanoma treated with ICIs. ¹¹

Conclusion

VKH-like syndrome is a rare, vision-threatening autoimmune disorder that may develop at any time during cemiplimab therapy. Early diagnosis and prompt management are paramount to prevent permanent vision loss.