Nivolumab-associated immune-related filamentary keratitis

Abstract

A woman in her late 50s presented to the ophthalmology clinic having bilateral eye pain and discharge for the last month. Her medical history was significant for lung adenocarcinoma, for which she was being treated with nivolumab. Filamentary keratitis was evident at the slit-lamp examination. Regardless of ophthalmic reasons, nivolumab was suspended. Prednisolone ointment was started, with a complete remission. We present a case of steroid-responsive filamentary keratitis triggered by nivolumab. We aim to highlight the importance of prompt ophthalmology referral and the use of therapies targeting ocular surface inflammation in immune checkpoint inhibition therapy.

Background

Immune checkpoint inhibitors are a class of immunotherapy that uses the body’s immune system in the management of malignancies. They prevent ligation between T-cell immune checkpoint proteins and their targets. Nivolumab is a monoclonal antibody that blocks the transmembrane receptor programmed death protein 1 (PD-1) on T-cells and tumour-associated macrophages. The cancer cells lose their ability to downregulate T-cells through PD-1/PD-L1 (programmed death-ligand 1) interaction and, conversely, the immune response against malignancy is stimulated.¹

Nivolumab was first approved for the treatment of unresectable, metastatic melanoma. Since then, a growing number of indications have emerged, including progressive, metastatic non-small-cell lung carcinoma.¹

Derived from its immunomodulated mechanism of action, it was proposed that T-cell hyperstimulation could induce toxic side effects throughout the body. The most common immune-related adverse events (irAEs) include pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis.² Ocular irAEs have been reported with nivolumab use. According to recent reviews, they occur in approximately 1%–7% of patients, within the first weeks to months of starting therapy. Dry eye, uveitis and ophthalmoplegia are the most frequently described ocular irAEs. Typically, they respond well to conservative treatment with corticosteroids and only uncontrolled cases may require discontinuation of immunotherapy.^1–4

Case presentation

A woman in her late 50s presented with a 1-month history of bilateral eye pain and discharge, worse on the left eye. Besides presbyopia corrective spectacles, she denied any previous ocular history. She was an active smoker of 30 pack-year units. Her medical history was positive for stage IIIb lung adenocarcinoma, with cervical and mediastinal lymphadenopathy and central nervous system involvement. After an incomplete response to chemoradiation, she was proposed for immunotherapy with nivolumab. She had been receiving it for the past 2 years (comprising 47 cycles), with disease stabilisation since then.

On ophthalmic examination, her best-corrected visual acuity was 20/20 and intraocular pressure was 21 mm Hg in both eyes. Slit-lamp findings included bilateral mucopurulent discharge in the inferior fornices, bulbar hyperaemia, diffuse strands of degenerated epithelial cells and mucus filaments firmly adherent to the corneal surface. Fluorescein stained diffuse punctate keratopathy. Break-up time and Schirmer without anaesthetic were within normal limits. The anterior chamber and lens were clear and no abnormalities were found on the dilated posterior segment funduscopy.

Differential diagnosis

Filaments of mucoepithelioid debris adherent to the corneal surface are pathognomonic for filamentary keratitis. The differential diagnosis for the underlying aetiology includes tear film and lid abnormalities, often related, previous ocular surgery, superior limbic keratoconjunctivitis (SLK), systemic conditions or medications affecting the ocular surface health.

Dry eye disease is one of the most common irAEs reported with nivolumab use, however, the characteristic punctate epithelial erosions involving the lower third of the cornea were absent. The external eye examination excluded lid malpositioning and the patient denied a history of ocular surgery. SLK is a bilateral inflammation of the superior tarsal and bulbar conjunctiva that occurs more frequently in women with thyroid eye disease. Our patient had a predominantly inferior to central staining associated with filaments in coils and there was no history of thyroid disease, and directed laboratory investigation was normal (Thyroid stimulating hormone [TSH] 1.90 μUI/L, Thyroxine [T4] 16.4 pmol/L).

After excluding the aforementioned differentials, in a female patient on nivolumab, we hypothesised immune-related filamentary keratitis. Our clinical diagnosis was later confirmed by a striking response to corticosteroids and nivolumab suspension.

Treatment

The patient was first started on ofloxacin drops (3 mg/mL, four times per day), vitamin A ointment (250 IU/g, three times per day) and preservative-free artificial tears (minimum four times per day), targeting control of the punctate superficial keratopathy.

Five days later, slit-lamp examination showed less conspicuous punctate keratopathy, which permitted the addition of topical fluorometholone (1 mg/mL, four times per day), as supported by the literature.

There was no significant objective improvement at the slit-lamp after 5 days (figure 1). The patient reported relief when applying fluorometholone drops. At this time, the treatment plan was changed to a combined chloramphenicol and prednisolone ointment (10 mg/mL and 2.5 mg/mL, respectively, three times per day), combined with oral acetylcysteine (1.2 g a day), vitamin A ointment and artificial tears, targeting filamentary keratitis pathogenesis. Nivolumab was stopped by decision of her oncology team, independently of ocular effects.

Figure 1.

Anterior segment slit-lamp photograph showing staining of interpalpebral punctate epithelial defects and brighter dispersed mucoepithelioid strands, after fluorescein instillation (superior panel, right eye; inferior panel, left eye).

The following week, the patient felt significantly better and the slit-lamp examination showed an improved ocular surface with a slight interpalpebral punctiform keratopathy, without the filamentary component. Topical treatment was maintained for 2 weeks.

Outcome and follow-up

On follow-up, 2 weeks later, the patient denied ocular complaints and the slit-lamp exam was normal (figure 2). Antibiotic and steroid coverage were stopped and she was advised to keep vitamin A ointment at night and frequent preservative-free artificial tears.

Figure 2.

Anterior segment slit-lamp photograph exhibiting a normal corneal fluorescein staining after treatment (right and left eye, respectively).

One year after nivolumab was stopped, there was no progression of the lung adenocarcinoma or secondary lesions, and the patient was kept on surveillance by the oncology team.

Discussion

This case emphasises the challenge in diagnosing and managing nivolumab-associated steroid-responsive filamentary keratitis. In the era of emerging immunotherapy, the ophthalmologist must become acquainted with these therapeutic agents’ side effects, particularly ocular irAEs.

To the best of our knowledge, there are seven case reports of nivolumab-associated corneal irAEs in the literature to date (table 1). The majority describe corneal ulcerations,^5–9 but some refer to keratitis,^8–10 which was responsive to corticosteroid therapy and ciclosporin A. A case of chronic corneal graft rejection refractory to steroids was found.¹¹

Table 1.

Summary of case reports addressing corneal irAEs associated with nivolumab use

Reference	Patient age and sex	Oncology diagnosis	Ophthalmology diagnosis	Time to occurrence	Treatment (besides lubrification)	Nivolumab treatment status	Additional information
5	60-year-old man	Metastatic melanoma	Bilateral ulcerative keratitis, evolving to corneal perforation	5–12 days	Bilateral lamellar minikeratoplasty, after failure of topical anti-inflammatory therapy and cyanoacrylate glue	Stopped 4 months after keratoplasty due to disease stabilisation	Combination of ipilimumab and nivolumab
6	80-year-old woman	Metastatic melanoma	Corneal ulcer in the left eye	4 months	Topical steroid, after unsuccessful conjunctival flap procedure and antiviral and antibiotic therapy	Stopped 2 months after resolution of eye disease because of other systemic side effects	–
7	34-year-old man	Metastatic melanoma	Bilateral ulcerative keratitis	5–10 months	Topical steroid, after failed antiviral topical and oral therapy	Continued throughout ocular management, unknown afterwards	After disease stabilisation, punctal plugs were inserted and topical intermittent steroid therapy was synchronised with nivolumab infusions
8	49 year-old man	Metastatic colorectal cancer	Bilateral ulcerative keratitis	2 months	Topical steroid and autologous serum, after failed antibiotic and neurotrophic treatment	Temporary suspension during 1-month treatment period	Combinantion of regorafenib and nivolumab. After nivolumab reinsertion, the patient developed corneal ulceration with perforation, treated with multilayered amniotic membrane filling and steroids.
9	58-year-old man	Metastatic melanoma	Severe bilateral dry eye, evolving to right eye corneal perforation	3–6 months	Bilateral punctum plugs, topical cyclosporine and steroid, oral doxycycline and vitamin C	Discontinued due to corneal perforation	Nivolumab was resumed after ocular surface stabilisation, combined with a topical steroid and cyclosporine regimen
9	46-year-old woman	Metastatic melanoma	Bilateral punctate keratitis	1.5–3 months	Topical cyclosporine	Held 8 weeks during ocular treatment	Regular use of topical cyclosporine in subsequent nivolumab infusions
10	92-year-old woman	Metastatic melanoma	Bilateral keratitis and uveitis	1.5–3 months	Topical cycloplegic, steroid and antibiotic therapy	Switched to a kinase inhibitor 3 months after control of eye disease for medical reasons independent of ocular course	Tapering of steroid drops coordinated with posterior nivolumab infusions
11	58-year-old woman	Squamous non-small-cell lung cancer	Chronic corneal graft rejection in the left eye	4.5 months	Refractory to intravenous, oral and subconjunctival steroids	Discontinued at presentation	–

irAEs, immune-related adverse events.

The exact mechanism underlying nivolumab-associated corneal irAEs is still unknown. It is hypothesised that overstimulation of T-cell response may play a role. Blockage of the PD-1 pathway shifts the T-cells to a proinflammatory Th1/Th17 phenotype, capable of cross-reacting with corneal antigens.¹² Such autoimmune reaction could take place at a systemic level, with T-cell invasion of the corneal stroma and/or be produced in situ by keratocytes. This hypothesis is supported by evidence of elevated inflammatory cytokines and matrix metalloproteinases in the tear fluid after nivolumab use.⁷ Corneal immune privilege breakdown may also play a role. In vitro studies found that PD-L1 mRNA is present in corneal epithelial, stromal and endothelial cells, and the PD-L1 protein is constitutively expressed in the epithelium and endothelium.¹³ PD-L1 interaction with PD-1 on the T-cell surface is capable of downregulating inflammatory T-cell activity on the cornea.¹ The immune privilege could be hampered during nivolumab with PD-1/PD-L1 blockage.

Regardless of understanding autoimmunity as the driver for nivolumab-associated filamentary keratitis, the contribution of dry eye cannot be ignored. Our patient developed punctate epithelial keratitis during the follow-up, which could be attributed to nivolumab-induced dry eye (either by autoimmune-mediated corneal and/or lacrimal gland inflammation), ocular toxicity from the topical therapy prescribed or simply any other cause of keratoconjunctivitis sicca, given its widespread prevalence in the general population.

Concerning disease presentation, the patient’s chief complaint, that motivated the first visit, was eye pain. Filamentary keratitis can present with significant ocular pain because of the firm attachment between the mucoepitheliod strands and the innervated corneal epithelium.

The majority of case reports support nivolumab continuation throughout ocular treatment because there is resolution, or at least improvement, despite its use.3 5–7 10 Refractory chronic corneal graft rejection and corneal perforation were the reasons that motivated discontinuation in three of those cases.^{8 9 11} In our patient, nivolumab was stopped during ocular management independently of ocular irAEs, but by the decision of the oncology team. As the filamentary keratitis was controlled with topical corticotherapy, nivolumab could have been continued if it was in the patient’s best interest. Additionally, pretreatment steroid drop pulsing followed by a taper or cyclosporine regimens could have been considered, as suggested by some of the case reports.^{7 9 10}

Both in our case and in the literature, cessation of nivolumab is predominantly related to medical non-ophthalmological reasons, including systemic irAEs.^{6 11} Corneal disease anticipated such events. For this reason, corneal irAEs, including filamentary keratitis, could be considered a warning sign or a prelude to the development of more serious, life-threatening complications. The appearance of ocular irAEs should motivate an active search for these systemic complications, with referral to the appropriate specialties (oncology, general medicine).

Despite the exposure-cessation effect, our patient presented relatively late after nivolumab initiation. The literature reports a broad range of time to occurrence of corneal irAEs, from early weeks to late months, in some cases almost reaching a year.^{1 3 4}

Increasing awareness of the significance of ocular irAEs in immunotherapy shall determine the pertinence of including routine ophthalmological evaluation in nivolumab’s protocol. At least, all general clinicians should be able to seek proper ophthalmological referral in patients with vision changes or eye-related complaints being treated with nivolumab. Although not recommended specifically for keratitis, ophthalmological referral is already recognised in the American Society of Clinical Oncology guidelines for the management of iRAEs in patients treated with immune checkpoint inhibitor therapy.¹⁴

Learning points.

• Vision changes or eye-related complaints should be taken seriously in patients under immunotherapy. Prompt observation by ophthalmology is required.

• Filamentary keratitis may present as a nivolumab-associated corneal immune-related adverse event (irAE).

• Topical steroid responsiveness suggests that targeting ocular surface inflammation/autoimmunity is important in controlling corneal related-irAE.

• A multidisciplinary approach is essential to acknowledge ocular complaints, monitor other systemic irAEs and decide whether to maintain or suspend the immunotherapy (lifesaving therapy vs irreversible corneal perforation).

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).