Various clinical presentations of uveitis associated with durvalumab treatment

Numerous cases of uveitis have been described as consequent on the immune checkpoint inhibitors^{5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15}, with only a few occurring secondary to durvalumab treatment.^{6, 7, 8} This is likely due to both: fewer patients treated with durvalumab in proportion to the other immune checkpoint inhibitors^6,16 and more frequent and severe side effects of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors compared to the PD-1 and PD-L1 inhibitors.⁶

Our search, described in the Methods above, yielded five reports of uveitis secondary to durvalumab treatment. Additionally, two patients presented to our clinic between November 2020 and March 2021 and are added in Table 1. The clinical presentation varies – anterior, intermediate, posterior uveitis, and retinal vasculitis have been described and were managed with a local or a systemic steroid. Immune checkpoint inhibitor was discontinued in four out of seven (57%) cases.

Although rare, various other immune-mediated ocular adverse effects have been linked with durvalumab. Carrera reported a drug-induced myopathy of extraocular muscles in a patient treated with durvalumab and tremelimumab.¹⁷ Optic neuropathy with disc oedema has been described as secondary to durvalumab use by Noble et al.¹⁸ Drug-induced Graves’ orbitopathy has been observed in a patient treated with tremelimumab and durvalumab.¹⁹ Moreover, in one of the largest reviews of databases of ocular adverse events in patients treated with PD-1/PD-L1 inhibitors, Young et al. recently reported two cases of serious ocular adverse events, with no data on the ocular diagnosis available.¹⁶

We report two cases of uveitis secondary to durvalumab treatment. The first patient is a 57-year-old female who presented to our clinic in November 2020 with a one-month history of blurred vision and floaters. Due to ES-SCLC the patient was treated with four cycles of combined chemo-immunotherapy with carboplatin, etoposide, and durvalumab, starting in April 2020 and then continued maintenance durvalumab treatment, receiving a total of eight cycles by November 2020. Both clinical and radiological remissions were achieved. She presented to our clinic after having received the eighth cycle of durvalumab. Her other past medical and ocular history was unremarkable.

Ophthalmic examination revealed aqueous cells 1+ and vitreous cells 1+ as well as bilateral oedema of the optic discs (Figure 1). The best-corrected decimal visual acuity (BCVA) was 0.7 and 0.8 p. for the right and left eye, respectively.

Figure 1

Bilateral optic nerve drusen were revealed on fundus autofluorescence (FAF) and confirmed on ocular ultrasound and optical coherence tomography (OCT) (Figure 2). Fluorescein angiography (FA) was performed (Figure 3), and a diagnosis of intermediate uveitis was made with optic disc drusen as an incidental finding.

Figure 2

Figure 3

No signs of intracranial hypertension were revealed on MRI, nor did it show clear signs of intracranial metastasis or other abnormalities in the course of the optic nerves. After excluding other common uveitic aetiologies (Supplementary File 1. Supplementary Table 1), the ocular inflammation was thought to be consequent to durvalumab treatment. The patient was treated with three applications of intravenous methylprednisolone, receiving 500 mg per day and continued with 48 mg of oral methylprednisolone per day. The dose was then tapered over six weeks. Monthly maintenance treatment with durvalumab was discontinued not only due to uveitic reaction but also due to the progression of the disease.

We observed stable best-corrected visual acuity (BCVA) of the left eye on a five-week follow-up, and a slight improvement of BCVA of the right eye. On ophthalmoscopy, diminishment of inflammation was observed with clear anterior chambers and vitreous cells 0.5 +. In addition, decreased swelling of the optic discs was noted (Figure 4).

Figure 4

The second case was a 55-year old female, sent to our clinic in March 2021 for a complaint of blurry vision that she first noted one week prior to consulting. Her past medical history was significant for K-RAS positive adenocarcinoma in the right middle pulmonary lobe, diagnosed in 2019. She was treated with concurrent radical chemo-radiotherapy. Clinical and radiological remissions were achieved. She then continued with immunotherapy and received 26 applications of durvalumab in the period between January 2020 and January 2021.

The patient had been previously seen at our clinic eight years prior due to peripheral pigmented retinal changes, which were at that time thought to be extensive retinal pigment epithelium (RPE) hypertrophy and small choroidal nevi (Figure 5A). Follow-up was advised, but the patient failed to present for further check-ups.

Figure 5

In March 2021, the patient was diagnosed with bilateral iridocyclitis and prescribed corticosteroid and nonsteroid anti-inflammatory eye drops with the addition of a systemic corticosteroid, 8 mg of oral methylprednisolone daily. By her first consultation at our clinic six days later, her initial BCVA of 0.6 in the right and 0.4 in the left eye improved to 0.7 p. and 1.0, respectively. Slit-lamp examination revealed bilateral aqueous cells 1+ and vitreous cells 2+, blurred papillary margins, and multiple flat, grey-white lesions on the posterior pole with macular and peripapillary predilection (Figure 5B). Hypofluorescent areas in the peripapillary and macular region on indocyanine-green angiography (ICGA) corresponded to the areas of ellipsoid zone loss on OCT (Figure 6A, Figure 7). The patient was diagnosed with bilateral posterior uveitis.

Figure 6

Figure 7

Laboratory and radiological workups were performed to exclude common causes of uveitis (Supplementary File 1. Supplementary Table 2). CT scan of the thorax revealed no progress of the lung cancer, nor did CT scan of the head and ultrasound of the orbits show signs of cranial or orbital metastasis.

Bilateral posterior uveitis was then considered most likely secondary to durvalumab. The patient was treated with 500 mg of intravenous methylprednisolone daily for three consecutive days. She continued with 48 mg of oral methylprednisolone daily, tapered over four weeks until the maintenance dose of 12 mg of oral methylprednisolone per day was reached.

On a three-week follow-up, amelioration of right eye BCVA (0.9) and stable left eye BCVA (1.0 p.) was observed. No aqueous cells were detected while vitreous exudation with cells 1+ in the right and 2+ in the left eye remained without clear dynamics. Diminishment of grey-white lesions on the posterior pole was observed on fundoscopy (Figure 5C) and FAF revealed hyperautofluorescent spots (Figure 8). Due to the current remission of the pulmonary disease, treatment with durvalumab is not foreseen in the near future regardless of the uveitic reaction.

Figure 8

While posterior uveitis secondary to durvalumab has been previously reported⁶, the constellation of uveitis and optic disc oedema consequently to durvalumab treatment has been, to our knowledge, described here for the first time. Uveitis with either optic disc oedema or papillitis was previously linked with the use of other ICIs (Table 2). Even though CTLA-4 inhibitors are deemed to cause more frequent and severe inflammatory ocular side effects than PD-1, and PD-L1 inhibitors⁶, most published cases of uveitis with optic disc oedema or papillitis were secondary to a PD-1 inhibitor (85%), with only one case following the use of CTLA-4 inhibitor. In 7 patients (53%), optic disc oedema occurred with panuveitis. In 5 patients (39%), signs of anterior uveitis with or without vitreous exudation were present, and in 1 patient (8%) optic disc oedema occurred with posterior uveitis and vasculitis. Systemic steroid (with or without a local steroid) was the treatment of choice in 69%, while 31% patients were managed with a local steroid only. Only one case was reported not discontinuing the ICI treatment.