Graves' Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review)

Abstract

Thyrotoxicosis is an adverse event associated with immune checkpoint inhibitors (ICPis) that occurs in 0.6 to 3.2% of treated patients, depending on ICPi class. Presentation usually consists of a biphasic thyroiditis with transient thyrotoxicosis and secondary hypothyroidism. ICPi-induced Graves' disease (GD), due to the stimulating activity of TSH-receptor autoantibodies (TRAb), is extremely rare. The aim of this retrospective study was to describe the characteristics and evolution of GD during ICPi therapy. Five among 243 patients followed for ICPi-induced thyrotoxicosis showed TRAb positivity (2% of the cohort). GD occurred quickly after initiation of ICPis; its course was typical for two patients, with prolonged requirement for antithyroid drug treatment (ATD). The three other patients experienced biphasic thyroiditis with secondary hypothyroidism requiring long-term substitution. Three other patients had a diagnosis of GD before starting ICPis; they evolved toward hypothyroidism with early cessation of ATD and long-term substitution treatment during ICPi treatment. None developed significant Graves' orbitopathy. ICPi treatment was not interrupted for thyroid dysfunction. In conclusion, GD is a rare, immune-related adverse event of ICPis with an unusual course and frequent evolution to biphasic thyroiditis. In the case of ICPi-induced thyrotoxicosis in the presence of TRAb, observing the spontaneous evolution and performing a scintigraphy are useful before starting ATD treatment. Pre-existing GD is not exacerbated by ICPis and tends to evolve towards hypothyroidism. ICPi treatment can be maintained with adequate biochemical surveillance.

Keywords: Graves’ disease; endocrine toxicities; immune checkpoint inhibitors; immune-related adverse event; thyroid dysfunction.

Figure 1

Flow chart. ICPis: immune checkpoint inhibitors; TRAb: TSH-receptor autoantibodies.

Figure 2

Evolution of thyroid dysfunction. (A) Patient no. 1; (B) Patient no. 3; (C) Patient no. 6. TSH: thyroid stimulating hormone; FT4: free thyroxine; ICPi: immune checkpoint inhibitor; ATD: antithyroid drug therapy; irAE: immune-related adverse event; GC: glucocorticoids; TRAb: TSH-receptor autoantibodies; LVT: levothyroxine.