This is an intriguing aspect of nivolumab-induced Graves’-like hyperthyroidism in our patient, but is in line with the debated role of thyroid autoantibodies in the pathogenesis of PD-1 inhibitor-induced thyroid dysfunction. levels of TSH, FT4 and FT3 were in the normal range; assessments for anti-thyroglobulin (TgAb) and anti-thyroid-peroxidase (TPO-Ab) antibodies were negative. After the second administrations of nivolumab, the patient complained of palpitations and tremors. Biochemical assessment showed an undetectable serum TSH ( 0.01 mU/L) associated with elevated levels of FT3 (5.71 pg/ml; n.r. = 2.0C4.4). The serum level of FT4 was in the upper-normal range (FT4 1.36 ng/dl; n. r. = 0.89C1.76). Assessments for TRAb, TPO-Ab and Tg-Ab were unfavorable. In the month before, the patient did not receive any iodinated contrast media nor corticosteroid therapy. In basal conditions, other pituitary and peripheral hormones (ACTH, cortisol, GH, IGF-1, PRL, FSH, LH, testosterone) were normal. Adrenal stimulation with 1-24 ACTH (250 mcg i.v.) yielded a normal increase in serum cortisol levels (basal = 6.1 mcg/dl; 30 min = 16.4 mcg/d; 60 min = 21.3 mcg/dl). Thyroid ultrasound showed a multinodular goiter (estimated volume = 34 ml) with a normo-echoic pattern of the parenchyma and a normal pattern of vascularization. Fine-needle aspiration was performed on the two dominant nodules which yielded cytological benign findings. The patient was initially treated with Syringic acid beta-blocker drugs only, but in the subsequent follow-up a worsening T3-toxicosis was evident. At this time, a 99 mTc scintigraphy revealed a diffuse thyroid uptake of the radionuclide suggesting Graves’-like hyperthyroidism. Methimazole (MMI) therapy was started at a dose of 15 Syringic acid mg/day. In the subsequent 3 months, the MMI dose was tapered and the patient is currently euthyroid under a maintenance dose of 7.5 mg/day of the drug. TRAb assessments remained persistently unfavorable. The thyroid hormone profiles of the patient are shown in Figure ?Physique2.2. Nivolumab therapy was continued and is still ongoing with no further progression of the neoplastic disease. Open in a separate window Physique 2 Thyroid hormone profile of Case 2. Written informed consent was obtained from both patients for the publication of this case reports. Discussion The unusual case histories of two patients who developed thyroid dysfunction while receiving nivolumab therapy for metastatic lung cancer are reported. The development of thyroid dysfunction in patients receiving anti-cancer treatment with nivolumab has been repeatedly reported. As reviewed by Barroso-Sousa et al. (1), the prevalence of hypothyroidism in nivolumab treated patients is as high as 6.5% and a low serum level of TSH, suggesting thyrotoxicosis, is reported in nearly 2.5% of them. When the cause of low serum TSH was specifically investigated, as in the study by Yamauchi et al. (4) reporting five such patients, destructive (painless) thyroiditis was found to be responsible for the thyrotoxic state. A similar diagnosis was rendered in other isolated case reports (1, 2, 5). Although clearly described, hypophysitis in the course of nivolumab treatment is usually less frequently reported, with prevalence of 0.3% of treated patients as assessed by a further analysis of reviewed series (1). However, it should be emphasized that, at difference with the hypophysis-thyroid and -gonadal axes, the isolated hypophysis-adrenal axis failure secondary to ICIs is usually rarely reversible, requiring appropriate treatment (6). The clinical presentation of the first patient was particularly intriguing due to the concomitant occurrence of destructive thyroiditis and hypophysitis. Indeed, after the initial thyrotoxic phase, the course of FT4, being characterized by a transient reduction (hypothyroidism) followed by a complete normalization in the absence of any specific treatment, was common of destructive thyroiditis. However, serum TSH did not increase during the hypothyroid phase, reasonably due to a concomitant pituitary failure. This case highlights how nivolumab-induced irAEs may simultaneously involve more than one endocrine gland. Indeed, the concomitant presence of primary hypothyroidism and secondary adrenal failure was previously described in several case reports (5, 7C10). The second reported patient demonstrates that nivolumab can also induce Graves’-like hyperthyroidism. To the best of our knowledge, this is the first description of such an occurrence. The development of Graves’ disease was previously reported in a patient treated with ipilimumab, which, unlike nivolumab, is usually a CTLA-4.every 2 weeks) was started. levels of TSH, FT4 and FT3 were in the normal range; assessments for anti-thyroglobulin (TgAb) and anti-thyroid-peroxidase (TPO-Ab) antibodies were negative. After the second administrations of nivolumab, the patient complained of palpitations and tremors. Biochemical assessment showed an undetectable serum TSH ( 0.01 mU/L) associated with elevated levels of FT3 (5.71 pg/ml; n.r. = 2.0C4.4). The serum level of FT4 was in the upper-normal range (FT4 1.36 ng/dl; n. r. = 0.89C1.76). Assessments for TRAb, TPO-Ab and Tg-Ab were unfavorable. In the month before, the patient did not receive any iodinated contrast media nor corticosteroid therapy. In basal conditions, other pituitary and peripheral hormones (ACTH, cortisol, GH, IGF-1, PRL, FSH, LH, testosterone) were normal. Adrenal stimulation with 1-24 ACTH (250 mcg i.v.) yielded a normal increase in serum cortisol levels (basal = 6.1 mcg/dl; 30 min = 16.4 mcg/d; 60 min = 21.3 mcg/dl). Thyroid ultrasound showed a multinodular goiter (estimated volume = 34 ml) with a normo-echoic pattern of the parenchyma and a normal pattern of vascularization. Fine-needle aspiration was performed on the two dominant nodules which yielded cytological benign findings. The patient was initially treated with beta-blocker drugs only, but in the subsequent follow-up a worsening T3-toxicosis was evident. At this time, a 99 mTc scintigraphy revealed a diffuse thyroid uptake of the radionuclide suggesting Graves’-like hyperthyroidism. Methimazole (MMI) therapy was started at a dose of 15 mg/day. In the subsequent 3 months, the MMI dose was tapered and the patient is currently euthyroid under a maintenance dose of 7.5 mg/day of the drug. TRAb tests remained persistently negative. The thyroid hormone profiles of the patient are shown in Figure ?Figure2.2. Nivolumab therapy was continued and is still ongoing with no further progression of the neoplastic disease. Open in a separate window Figure 2 Thyroid hormone profile of Case 2. Written informed consent was obtained from both patients for the publication of this case reports. Discussion The unusual case histories of two patients who developed thyroid dysfunction while receiving nivolumab therapy for metastatic lung cancer are reported. The development of thyroid dysfunction in patients GU2 receiving anti-cancer treatment with nivolumab has been repeatedly reported. As reviewed by Barroso-Sousa et al. (1), the prevalence of hypothyroidism in nivolumab treated patients is as high as 6.5% and a low serum level of TSH, suggesting thyrotoxicosis, is reported in nearly 2.5% of them. When the cause of low serum TSH was specifically investigated, as in the study by Yamauchi et al. (4) reporting five such patients, destructive (painless) thyroiditis was found to be responsible for the thyrotoxic state. A similar diagnosis was rendered in other isolated case reports (1, 2, 5). Although clearly described, hypophysitis in the course of nivolumab treatment is less frequently reported, with prevalence of 0.3% of treated patients as assessed by a further analysis of reviewed series (1). However, it should be emphasized that, at difference with the hypophysis-thyroid and -gonadal axes, the isolated hypophysis-adrenal axis failure secondary to ICIs is rarely reversible, requiring appropriate treatment (6). The clinical presentation of the first patient was particularly intriguing due to the concomitant occurrence of destructive thyroiditis and hypophysitis. Indeed, after the initial thyrotoxic phase, the course of FT4, being characterized by a transient reduction (hypothyroidism) followed by a complete normalization in the absence of any specific treatment, was typical of destructive thyroiditis. However, serum TSH did not increase during the hypothyroid phase, reasonably due to a concomitant pituitary Syringic acid failure. This case highlights how nivolumab-induced irAEs may simultaneously involve more than one endocrine gland. Indeed, the concomitant presence of primary hypothyroidism and secondary adrenal failure was previously described in several case reports (5, 7C10). The second reported patient demonstrates that nivolumab can also induce Graves’-like hyperthyroidism. To the best of our knowledge, this is the first description of such an occurrence. The development of Graves’ disease was previously reported in a patient treated with ipilimumab, which, unlike nivolumab, is a CTLA-4 inhibitor, and in another case receiving tremelilumab, another CTLA-4 inhibitor (11C13). In contrast with these previous observations, in which Graves’ disease was accompanied by positive tests for TRAb, this antibody was persistently negative in our patient. This is an intriguing aspect of nivolumab-induced Graves’-like hyperthyroidism in our patient, but is in line with the debated role of thyroid autoantibodies in the pathogenesis of PD-1 inhibitor-induced thyroid dysfunction. Indeed, some studies report a close relationship between thyroid antibodies and PD-1 inhibitor-induced thyroid dysfunction (13) while others do not (14, 15). Studies in larger series will.