Internal Medicine The Japanese Society of Internal Medicine
[ CASE REPORT ]
Nivolumab-induced Vogt-Koyanagi-Harada-like Syndrome and Adrenocortical Insufficiency with Long-term Survival in a Patient with Non-small-cell Lung Cancer
Ryota Ushio’, Masaki Yamamoto’, Atsushi Miyasaka1, Tatsuya Muraoka1, Hiromi Kanaoka’, Hironori Tamura’, Ayami Kaneko’, Ami Izawa’, Nobuyuki Hirama’, Shuhei Teranishi’, Saki Manabe ’, Tatsuya Inoue2, Kunihiko Shibata3, Yasuyuki Sugiura4, Makoto Kudo1 and Takeshi Kaneko5
Abstract:
A 58-year-old man was diagnosed with lung adenocarcinoma with a tumor proportion score of 10%. After six cycles of second-line chemotherapy with nivolumab, he achieved a complete response (CR) but developed uveitis and sensorineural hearing disorder, which were consistent with Vogt-Koyanagi-Harada (VKH)-like syndrome. Simultaneously, pituitary adrenocortical insufficiency was identified. Nivolumab discontinuation and systemic corticosteroid administration resolved these immune-related adverse events (irAEs). The patient has maintained a CR without any chemotherapy for approximately two years. We herein report a patient with a long-term progression-free survival despite chemotherapy discontinuation due to irAEs, including VKH-like syndrome, which were appropriately managed.
Key words: non-small-cell lung cancer, immune-related adverse events, Vogt-Koyanagi-Harada-like syndrome, adrenocortical insufficiency, HLA-DR4
(Intern Med 60: 3593-3598, 2021) (DOI: 10.2169/internalmedicine.6410-20)
Introduction
The advent of immune checkpoint inhibitors, such as nivolumab and pembrolizumab [anti-programmed cell death protein 1 (PD-1) antibodies] and ipilimumab [anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody], has revolutionized the treatment of cancers including malignant melanoma, non-small-cell lung cancer, renal cell carcinoma, microsatellite instability-high carcinoma, and Hodgkin lym- phoma (1-3). In addition to monotherapy, combination che- motherapy has successfully improved the survival rate of pa- tients with lung cancer. However, immune checkpoint inhibi- tors have unique side effects, called immune-related adverse
events (irAEs), which can occur in all body organs. IrAEs occur in 70-80% of patients receiving anti-PD-1 antibodies and in up to 90% of patients receiving anti-CTLA-4 anti- bodies (4-6). IrAEs often lead to treatment discontinuation; therefore, appropriate management of these adverse events is important.
Vogt-Koyanagi-Harada (VKH) disease is a multisystem autoimmune disease with multiple clinical manifestations that can occur in the eyes, inner ear, central nervous system, hair, and skin melanocytes. Immune checkpoint inhibitors have been reported to cause VKH-like syndrome in rare cases.
We herein report a patient with lung cancer who devel- oped various irAEs, including VKH-like syndrome, and
1 Respiratory Disease Center, Yokohama City University Medical Center, Japan, 2Ophthalmology Department, Yokohama City University Medical Center, Japan, 3 Otolaryngology, Head and Neck Surgery Department, Yokohama City University Medical Center, Japan, 4Endocrinology Diabe- tes and Metabolism Department, Yokohama City University Medical Center, Japan and 5Department of Pulmonology, Yokohama City University Graduate School of Medicine, Japan
Correspondence to Ryota Ushio, rushio@yokohama-cu.ac.jp
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maintained a long-term complete response (CR) without chemotherapy, even after drug discontinuation.
Case Report
A 58-year-old man visited our hospital with a right femo- ral fracture. Computed tomography (CT) showed a 36-mm- diameter mass on the middle lobe of the right lung and mul- tiple bone metastases to the sternum, pelvis, and right femur. The patient underwent open reduction and internal fixation of the right femoral fracture. A histological examination of the femoral bone revealed lung adenocarcinoma. The clinical stage was cT3N2M1c, stage IVB (7), with the patient test- ing negative for EGFR, ALK, ROS-1, and BRAF V600E mu- tations. His PD-L1 tumor proportion score (TPS) was 10%.
The patient received first-line chemotherapy with car- boplatin (area under the curve=6, day 1), pemetrexed (500 mg/m2, day 1), and bevacizumab (15 mg/kg, day 1). New metastatic lesions appeared in the bilateral adrenal glands, bladder, and abdominal lymph nodes immediately after four cycles of the first-line chemotherapy. Bleeding from the bladder lesion induced urinary retention and acute kidney injury. After transurethral resection of the bladder tumor, second-line chemotherapy with nivolumab (3 mg/kg, day 1) was administered. After six cycles of the second-line chemo- therapy, a marked response was observed on CT, which was consistent with a CR, according to the Response Evaluation Criteria in Solid Tumors (Fig. 1) (8). However, the patient
experienced severe visual impairment and was diagnosed with uveitis approximately four months after the initiation of nivolumab.
His decimal best-corrected visual acuity (BCVA) scores were 0.8 and 0.08 in the right and left eyes, respectively. Furthermore, intraocular pressures were 16 and 17 mmHg in the right and left eyes, respectively. Optical coherence to- mography confirmed serous retinal detachment, wavy retinal pigment epithelium, and thickening of the choroid in both eyes (Fig. 2A, B). Fluorescein angiography revealed super- fluorescence of the optic disc and granular hyperfluores- cence centered on the posterior pole (Fig. 3A, B). Indocy- anine green fluorescence angiography showed patchy low fluorescence of the choroid (Fig. 3C, D).
In addition to nivolumab discontinuation, a topical steroid (betamethasone sodium phosphate, 0.1%) was initiated 6 times a day. Two weeks after starting the topical treatment, the patient’s decimal BCVA scores recovered to 1.2 and 1.0 in the right and left eyes, respectively. Furthermore, the serous retinal detachment almost disappeared (Fig. 2C, D). However, 3 weeks after starting the topical treatment, the decimal BCVA of his left eye decreased to 0.4, and serous retinal detachment reappeared in the left eye (Fig. 2E, F). During the same period, he developed hearing loss, tinnitus, nausea, vomiting, and diarrhea. An audiometric evaluation revealed bilateral sensorineural hearing loss with a down- ward slope configuration (Fig. 4A). He had no cutaneous manifestations. Human leukocyte antigen (HLA) serological
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DR typing revealed that the patient was DR4-positive (SRL, Tokyo, Japan); his cerebrospinal fluid cell count increased to 16/uL. These findings were consistent with VKH-like syn- drome. Furthermore, his baseline serum cortisol levels were 0.6 ug/dL (range, 3.0-19.6 µg/mL), with no response to adrenocorticotropic hormone (ACTH) stimulation. Although his prolactin, luteinizing hormone, follicle-stimulating hor- mone, thyroid-stimulating hormone, triiodothyronine, and thyroxine levels showed normal responses in a triple stimu- lus test (insulin, thyrotropin-releasing hormone, and luteiniz- ing hormone-releasing hormone), his ACTH and cortisol lev- els did not show any response. Specifically, the patient’s baseline ACTH and cortisol levels were less than 1.0 pg/mL (range, 7.2-63.3 pg/mL) and 0.4 ug/mL (range, 3.0-19.6 µg/ mL) with peak values of 1.9 pg/mL and 0.3 ug/mL, respec- tively. These findings indicated primary and pituitary adrenocortical insufficiency, which was considered to be the cause of nausea, vomiting, and diarrhea.
Systemic corticosteroid therapy was administered (150 mg intravenous hydrocortisone daily for 3 days, followed by 30 and 25 mg oral hydrocortisone daily for 3 days each, and 20 mg daily as a maintenance dose). His nausea and vomiting disappeared rapidly (Fig. 5). After 3 months of systemic
corticosteroid therapy, the patient’s decimal BCVA improved to 1.2 in both eyes, and the serous retinal detachment disap- peared (Fig. 2G, H). Similarly, the audiometric test findings improved to almost normal (Fig. 4B).
Since nivolumab treatment discontinuation, a CR has been maintained without chemotherapy for approximately two years thus far.
Discussion
Some reports have suggested a correlation between irAEs and efficacy of nivolmab in patients with non-small-cell lung cancer (9-11). Proper management of irAEs is essential for maximizing the therapeutic effect of immune checkpoint inhibitors.
The HLA system is a locus of genes encoding the major histocompatibility complex, a set of cell surface molecules that mediate leukocyte interactions (12). Therefore, HLA plays an important role in not only the functioning of the immune system but also the pathogenesis of autoimmune diseases, including VKH (13). the HLA-DR4 serotype has been reported to be frequently observed in VKH disease pa- tients (14). DR4 has been further classified into several sub-
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types, and some HLA-DRB1*04 sub-alleles, including HLA- DRB1*0404, 0405, and 0410, have been shown to increase the risk of VKH. Certain ethnic groups are known to have a genetic predisposition to develop VKH, especially those with Mongoloid ancestry (15), and among such populations,
very strong correlations have been found with HLA-DRB1* 0405 and 0410 in Japan (16). Although the frequency of HLA-DRB1*0405 is about 12% in Japan, VKH disease itself is a rare disease. Most Japanese with HLA-DRB1*0405 are expected to go their entire lives without developing VKH
| Reference | Age | Sex | Cycles | Ocular Complication | Neurological and auditory symptom | HLA class II examination | Other irAE | Systemic Corticosteroids |
|---|---|---|---|---|---|---|---|---|
| Our case | 58 | M | 6 | P | Hearing loss | DR4 | Adrenal insufficiency | P (start with 150 mg of hydrocortisone) |
| 18 | 69 | M | 2 | P | N | DR4 (DRB1*0405) DR9 (DRB1*0901) | - | P (start with 1,000 mg of mPSL) |
| 19 | 55 | M | 1 | P | N | DR4 (DRB1*0410) DR4 (DRB1*0406) | - | N (only topical treatment) |
| 20 | 60 | F | 2 | P | Headache | - | - | P (start with 30 mg of PSL) |
| 21 | 73 | M | 1 | P | Hearing loss | DR4 (DRB1*0405) | - | P (start with 500 mg of mPSL) |
| 35 | F | 8 | P | Headache Hearing loss | DR4 (DRB1*0405) | Severe erythema exudative multiforme | P (start with 500 mg of mPSL) | |
| 22 | 64 | F | 6 | P | - | - | N | P (start with 500 mg of mPSL) |
| 23 | 63 | F | 2 | P | - | - | - | N (only topical treatment) |
F: Female, M: Male, P: Positive, N: Negative, -: not described, mPSL: Methylprednisolone, PSL: Prednisolone, irAE: Immune-related adverse event
Symptom
Visual impairment
Hearing loss
Nausea and diarrhea
Immune checkpoint inhibitor
Nivolumab (3mg/kg)
Steroids
hydrocortisone (mg/day)
150
Systemic steroid
30
20
Topical steroid (betamethasone)
-5 Months
-1 Months
Day 0 (admission)
Day 3
Day 6
disease (17). Although we were unable to determine the HLA-DR4 subtype in the present case, patients with HLA genotypes at risk for VKH may develop VKH-like syn- dromes after receiving immune checkpoint inhibitors. Thus far, seven patients with the HLA-DR4 subtype have been re- ported to have experienced nivolumab-induced VKH-like uveitis, similar to the present patient (Table). However, whether or not there is an association between HLA types
and the effects of immune checkpoint inhibitors - and thus the risk of VKH-like irAEs - remains unclear; therefore, fur- ther investigations are required.
In a previous report, one patient with VKH disease-like uveitis as an irAE without symptoms of other organs was treated with only topical steroid. However, the standard treatment for VKH disease is high-dose systemic corticoster- oids, which was administered to six other patients (Ta-
ble) (18-23). In the present case, the irAE uveitis appeared initially and was successfully treated with a topical steroid; however, the patient sequentially developed hearing loss and adrenal insufficiency, thus requiring systemic corticosteroid therapy. The treatment had to be interrupted because of vari- ous adverse events; however, corticosteroid therapy relieved his irAEs, which led to his long-term disease-free survival.
To our knowledge, this is the first report describing the si- multaneous development of VKH-like syndrome and adreno- cortical insufficiency in a patient. Furthermore, after immune checkpoint inhibitor discontinuation, the patient has main- tained a long-term progression-free survival despite his low TPS and high tumor burden. This case suggests the impor- tance of appropriately managing irAEs and the need for bet- ter biomarkers to more accurately predict therapeutic effects.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Mark Abramovitz, PhD, for editing a draft of this manuscript.
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