Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution

Guaraldi, Federica; Selva, Roberta La; Samà, Maria Teresa; D’Angelo, Valentina; Gori, Davide; Fava, Paolo; Fierro, Maria Teresa; Savoia, Paola; Arvat, Emanuela

doi:10.1007/s40618-017-0772-1

Cited by 49 publications

(37 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thyroid autoantibodies have been suggested as biomarkers to predict the development of ICI-related thyroiditis, but some studies do not support this suggestion (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). In the current study, we found that 42% of tested patients had positive TPOAb.…”

Section: Discussionmentioning

confidence: 99%

The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor–Related Thyroid Disorders

Hodi

Giobbie‐Hurder

et al. 2019

Cancer Immunology Research

View full text Add to dashboard Cite

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)-induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7-85) and 42 (range, 14-273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14-169) and 42 days (range, 14-315) days, the median time to onset of hypothyroidism: 63 (range, 21-190) and 63 (range, 14-489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4-2.3) mg/kg/day, and 1.3 (range, 0.3-2.5) mg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3-5.2) mIU/L and 1.7 (range, 0.5-4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P ¼ 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor–Related Thyroid Disorders

Hodi

Giobbie‐Hurder

et al. 2019

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…Phase 3 studies of nivolumab therapy for malignant melanoma and non-squamous non-small cell lung cancer ( 4 ) have reported a frequency for hypothyroidism of 5.6–6.6% and for thyrotoxicosis of 1.4–1.9% respectively. Noteworthy, the risk of thyroid abnormalities increases substantially when patients are treated with a combination of PD-1 and CTLA-4 (cytotoxic T-lymphocyte antigen-4) inhibitors ( 14 , 15 ) or when PD-1 inhibitor follows CTLA-4 therapy, such as ipilimumab, especially when the wash-out period is <4 weeks ( 15 ). The most commonly described types of nivolumab-related thyroid dysfunction are either a transient thyrotoxic phase, which tends to resolve spontaneously and is often followed by hypothyroidism ( 11 ) or development of isolated hypothyroidism, both caused by painless thyroiditis ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Thyrotoxicosis tends to occur within 6 weeks after the first administration of nivolumab. However, the time to onset of hypothyroidism ranges from 4 days to months following initiation of immunotherapy, making it very difficult to predict the occurrence time ( 11 , 12 , 14 , 15 ). Finally, it has been suggested that new occurrence of thyroid and extra-thyroid autoimmune disorders may be associated with a better treatment response to PD-1 inhibitors ( 13 , 15 ), but this finding needs to be studied further.…”

Section: Discussionmentioning

confidence: 99%

Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis

Tzoulis

Corbett

Ponnampalam

et al. 2018

Endocrinology, Diabetes &Amp; Metabolism Case Reports

View full text Add to dashboard Cite

SummaryFive days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy.Learning points:Nivolumab can induce fulminant type 1 diabetes, resulting in DKA.Nivolumab is frequently associated with thyroid dysfunction, mostly hypothyroidism.Nivolumab-treated patients should be monitored regularly for hyperglycaemia and thyroid dysfunction.Clinicians should be aware and warn patients of potential signs and symptoms of severe hyperglycaemia.

show abstract

“…В проспективном исследовании с медианой наблюдения 9 лет установлено, что субклинический гипертиреоз в анамнезе достоверно повышает относительный риск развития злокачественных новообразований любой локализации в 1,34 раза (95 % ДИ 1,06-1,69), при этом рака легких -в 2,34 раза, рака предстательной железы -в 1,97 раза, колоректального рака -в 1,34 раза [10]. Терапия противоопухолевыми и/или иммунопрепаратами, например интерлейкином 2-го типа, интерферонами [5], ингибиторами тирозинкиназы [15] и ингибиторами контрольных точек иммунного ответа [9], достаточно часто приводит к снижению функции щитовидной железы -у 14-85 % пациентов, по данным разных авторов [5,9,15]. При этом во многих исследованиях продемонстрированы увеличение уровня объективных ответов и/или улучшение показателей суррогатных маркеров выживаемости (продолжительность безрецидивного периода, продолжительность времени до прогрессирования) у онкологических больных [15].…”

Section: обсуждение полученных результатовunclassified

Effect of altered thyroid status on the incidence of colon tumors induced by methylnitrosourea in rats

Glushakov

Иванович²,

Tolkach

et al. 2019

Rev Clin Pharm Drug Ther

View full text Add to dashboard Cite

Aim. The present study was designed to determine whether medically induced hyper- and hypothyroidism effect on incidence of colon tumors induced by methylnitrosourea (MNU) burden in rats. Methods. Female rats (n = 88) were randomly divided into four groups: I (euthyroid-control), II (hyperthyroid caused by liothyronine), III (hyperthyroid caused by L-thyroxine) and IV (hypothyroid caused by propylthiouracil (PTU), also 11 rats were intact control. Colon carcinogenesis was induced with a four intrarectal instillation of MNU (4 mg in 0.5 ml saline solution) one time per week. Liothyronine (100 ± 10 µg per 100 g of animal weight 1 time per day), L-thyroxin (100 ± 10 µg per 100 g of animal weight 1 time per day) and propylthiouracil (PTU, 2,0 ± 0,15 mg per 100 g of animal weight 1 time per day) were administered intragastrically through an atraumatic probe daily, starting from the day of the last intrarectal instillation of MNU. Rats were sacrificed at 216 days after experiment beginning, and the total colon were excised, fixed for histology and analyzed. Results. Drug inhibition of thyroid hormone function by PTU resulted in a decrease in the incidence of MNU-induced colon tumors and amounted to 27.3%. The incidence of colon tumors in the hyperthyroid group caused by L-thyroxine was 70.0% (F-test – 0.012, χ2 – 7.67; p < 0.05 compared with the hypothyroid group).

show abstract

Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution

Abstract: Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.

Cited by 49 publications

References 22 publications

The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor–Related Thyroid Disorders

The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor–Related Thyroid Disorders

Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis

Effect of altered thyroid status on the incidence of colon tumors induced by methylnitrosourea in rats

Contact Info

Product

Resources

About