For patients who developed hypothyroidism, the onset occasions were comparable between combination therapy and monotherapy groups (Fig. respectively. In the combination therapy and monotherapy groups, the median occasions to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either antiCPD-1 or combination antiCPD-1 and antiCCTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and development of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Introduction Immune checkpoints are cell surface proteins expressed on T lymphocytes and other immune cells (1). Inhibition of immune checkpoints has shown antitumor efficacy across a spectrum of solid and hematologic malignancies in clinical studies (2C5). A common feature of immune checkpoint inhibition is usually that it may also lead to immune-related adverse events (irAE; refs. 6C8). Endocrinopathies, such as hypophysitis and thyroid disorders, are among the most common irAEs (9C11). Hypophysitis is usually more commonly associated with CTLA-4 inhibition, whereas thyroid disorders are more common in patients receiving antiCPD-1 therapy (2, 7, 12, 13). Even though clinical manifestations of immune checkpoint inhibition-related hypophysitis have been well described in several large case series (9C11, 14), few studies have characterized the nature and progression of immune checkpoint inhibition-related thyroid disorders. Clinical trials have found that the incidence of thyroid disorders is usually high in antiCPD-1 treatment, 5% to 9.5% with pembrolizumab treatment (3, 15) and 8.6% with nivolumab treatment (16). A single institution retrospective review found an incidence of hypophysitis of 8% and of main hypothyroidism/thyroiditis of 6% in patients receiving ipilimumab (antiCCTLA-4) therapy (11). In the same study, the incidence of thyroid disorders was higher (22%) with combination CTLA-4 and PD-1 blockade, even (R)-BAY1238097 though the incidence of hypophysitis was 9%, comparable to that of antiCCTLA-4 monotherapy (11). Prompt identification and proper management of immune-mediated thyroid disorders will help to avoid severe effects, such as life-threatening thyroid storm or myxedema coma. Here, we analyzed the dynamic development of thyroid disorders associated with antiCPD-1 monotherapy or combination antiCCTLA-4 and antiCPD-1 therapy in 45 patients. Materials and Methods Study design Patients with immune checkpoint inhibition-related thyroid disorders were evaluated clinically in the outpatient endocrinology medical center of (R)-BAY1238097 Brigham and Womens Hospital and received continued longitudinal clinical care. This cohort analysis was performed retrospectively by collecting relevant data from chart reviews with removal of individual identifiers. The period for this study was from December 21, 2010 to May 9, 2016. Institutional Review Table approval was obtained for the study. We analyzed the type of checkpoint inhibition therapy, initial presentations of the thyroid disorder, time to onset after treatment initiation, and time for development from thyrotoxicosis to hypothyroidism. The patients received either combination therapy or monotherapy. Combination therapy was comprised of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks for up to 4 doses followed by nivolumab monotherapy (3 mg/kg) every 2 weeks. Patients on monotherapy received either pembrolizumab (2 mg/kg every 3 weeks, = 6; 10 mg/kg every 3 weeks, = 3; 200 mg/infusion every 2C3 weeks, = 5) or nivolumab (3 mg/kg every 2 weeks, = 4). Definition of thyrotoxicosis and hypothyroidism Thyrotoxicosis was diagnosed based on low thyrotropin (TSH) in conjunction with elevation of at least one of Cd200 three thyroid hormones: total thyroxine (T4), free T4, or free triiodothyronine (FT3). We use the term thyrotoxicosis rather than hyperthyroidism in this study because hyperthyroidism is usually defined as overproduction of thyroid hormone by the thyroid gland, as occurs in Graves disease, harmful nodular goiter, or TSH-driven hyperthyroidism, whereas thyrotoxicosis is usually defined as any cause of thyroid hormone extra. Indeed, previous studies (R)-BAY1238097 have suggested that thyroiditis is the most common type of immune checkpoint blockade-related thyroid disorder (11, 17). Hypothyroidism was diagnosed based on an elevated TSH with a low or normal total or free T4 and/or FT3. Definition of times to onset Thyroid function assessments were performed before each immune checkpoint inhibitor treatment, which was given every 2 to 3 3 (R)-BAY1238097 weeks. Time to onset of thyrotoxicosis was defined as the number of days between the administration of the first dose of nivolumab or pembrolizumab in patients receiving monotherapy, or the first dose of ipilimumab and nivolumab in patients receiving combination therapy, and the date of the first biochemical paperwork of thyrotoxicosis. Time from the onset of thyrotoxicosis to the onset of hypothyroidism was defined as the number of days between the initial biochemical.