Case Report: A Variety of Immune-Related Adverse Events Triggered by Immune Checkpoint Inhibitors in a Subject With Malignant Melanoma: Destructive Thyroiditis, Aseptic Meningitis and Isolated ACTH Deficiency

Abstract

Recently, immune checkpoint inhibitors have been drawing much attention as cancer immunotherapy, but it has been shown that various immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors in various organs, which has become one of the serious issues at present. A 58-year-old Japanese male with malignant melanoma was treated with nivolumab and/or ipilimumab. During the period of treatment, he suffered from various irAEs. Firstly, about 1 month after starting nivolumab monotherapy, destructive thyroiditis was induced, and so we started replacement therapy with levothyroxine. Secondly, about 1 month after starting nivolumab and ipilimumab combination therapy, aseptic meningitis was induced. We stopped both drugs and started steroid therapy with prednisolone. Finally, about 9 months after restarting nivolumab, isolated adrenocorticotropic hormone (ACTH) deficiency was induced, and so we started replacement therapy with hydrocortisone. Taken together, we should bear in mind the possibility of a variety of irAEs when we use immune checkpoint inhibitors.

Long-term nivolumab treatment possibly associated with aseptic meningitis.

“…However, as stated earlier, Mikami et al described an incidence as high as 5.3% with anti-PD-L1 inhibitors, suggesting that this condition is becoming more common, especially with the rise of immune therapy 3. Not only neurological irAEs have been reported in the literature, but also endocrinopathies such as hypopituitarism and adrenal cortex dysfunction 6…”

“…Regarding the treatment of irAEs, steroids have been proposed with a dose of prednisone of 1 mg/kg/day. We did not use steroids for this patient due to spontaneous clinical improvement, but a similar case used intravenous prednisolone (1 mg/kg/day), achieving rapid clinical improvement 6. Shields et al state treatment plans can also include high-dose corticosteroids as well as intravenous immunoglobulins (IVIGs) and plasmapheresis in severe cases 11.…”

“…However, Katakura et al describe a case of a patient with malignant melanoma with multiple metastases to the lung and liver 6. The patient was started on nivolumab and later ipilimumab.…”

Immune-related aseptic meningitis and strategies to manage immune checkpoint inhibitor therapy: a systematic review

“…In 11 articles, 40 cases of immune-related meningitis or meningoencephalitis (with at least signs of meningitis on lumbar puncture) were reported [10][11][12][13][14][15][16][17][18][19][20][21][22] (Tables 1 and 2). An overview of the results is presented in Fig.…”

“…New irAEs were reported in three patients after reintroduction, all of whom had received the same ICI. One patient developed interstitial lung disease and meningitis relapse, and the other two developed adrenal insufficiency [11,21,28]. Takamasu et al reported that a patient with stage IV renal cell carcinoma achieved a complete response owing to the combination of ipilimumab 1 mg/kg and nivolumab 3 mg/kg, despite irAE reoccurrence [28].…”