The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international phase 3 studies and national postmarketing surveillance of nivolumab in Japan.
We analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Secondly, we examined the mRNA and protein expressions of PD-L1 and PD-L2 by RT-PCR and western blotting.
All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed　within 4 weeks from the first administration of nivolumab and normalized within 4 weeks of onset in three of five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism and the other developed mild, transient hypothyroidism. In addition, we verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins.
In our cases, nivolumab-induced thyrotoxicosis seems to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, we verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. It suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. We propose treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.
Thyroid : official journal of the American Thyroid Association. 2017 May 24 [Epub ahead of print]
Ichiro Yamauchi, Yoriko Sakane, Yorihide Fukuda, Toshihito Fujii, Daisuke Taura, Masakazu Hirata, Keisho Hirota, Yohei Ueda, Yugo Kanai, Yui Yamashita, Eri Kondo, Masakatsu Sone, Akihiro Yasoda, Nobuya Inagaki
Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Kyoto, Japan., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; ., Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto, Japan ; .