Endocrine immune-related adverse effects (irAEs) are recognised complications of checkpoint inhibitor immunotherapies. They typically develop 6-12 weeks after initiation and usually only one endocrine irAE occurs. We present unusual cases of anti-CLTA4 and/or anti-PD-1 associated hypophysitis and thyroiditis presenting either concurrently or consecutively.
Case 1: Concurrent Hypophysitis and Thyroiditis.
One month after commencing nivolumab, a 57-year-old female with metastatic lung adenocarcinoma developed symptomatic hypocortisolism secondary to hypophysitis together with hyperthyroidism which progressed to hypothyroidism (TSH 11.6mIU/L, T4 <5.1pmol/L).
Case 2: Thyroiditis preceding Hypophysitis.
Three months after commencing pembrolizumab, this 22-year-old female with metastatic melanoma developed hyperthyroidism (TSH 0.01mIU/L, T4 19.6pmol/L) which was followed 2 months later by hypothyroidism with concurrent hypophysitis (ACTH 4.3pmol/L, cortisol 37nmol/L).
Case 3: Concurrent Hypophysitis and Thyroiditis followed by Diabetes.
A 57-year-old female with metastatic melanoma was treated with combined ipilimumab and pembrolizumab followed by pembrolizumab monotherapy after 3 months. One month later she developed hypophysitis (cortisol 92nmol/L, ACTH 2.5pmol/L) with concurrent hyperthyroidism (TSH < 0.01mIU/L, T4 21.8pmol/L) followed by hypothyroidism. She developed new GAD antibody-negative diabetes with ketosis 9 months after onset of hypophysitis.
Case 4: Hypophysitis followed much later by Thyroiditis.
A 50-year-old female with metastatic melanoma was treated with combined pembrolizumab and ipilimumab for 3 months, followed by pembrolizumab monotherapy. One month later, she developed hypocortisolism (cortisol < 28nmol/L, ACTH < 1.1pmol/L), followed 12 months later by hypothyroidism(TSH 30mIU/L, T4 9.7pmol/L).
Individuals taking checkpoint inhibitor immunotherapies rarely develop multiple endocrine irAEs, although the risk maybe increased with combination therapy, with thyroiditis typically preceding hypophysitis. These cases demonstrate variations in the temporal presentation of multiple endocrine irAEs within the same patient, with examples of both simultaneous development as well as relatively staggered onsets. Endocrine irAEs may occur synchronously with either single agent or combination immunotherapy.