Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma

Yano, Shunsuke; Ashida, Kenji; Nagata, Hiromi; Ohe, Kenji; Wada, Naoko; Takeichi, Yukina; Hanada, Yuki; Ibayashi, Yuta; Wang, Lixiang; Sakamoto, Shohei; Sakamoto, Ryuichi; Uchi, Hiroshi; Shiratsuchi, Motoaki; Furue, Masutaka; Nomura, Masatoshi; Ogawa, Yoshihiro

doi:10.1186/s12902-018-0267-x

Cited by 15 publications

(7 citation statements)

References 33 publications

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“…Augmentation of bands observed differently; this would be in contrast to systemic activated immunoreactivity if all four bands were augmented. In addition, we verified that Interestingly, patients without TPOAb and TgAb at the development of thyroid irAEs are frequently observed (3,15,16). For example, of 17 patients with thyroid irAEs in our previous study, 7 patients were double positive, 5 were double negative, and 5 were exclusively positive for TgAbs, while no patients were exclusively positive for TPOAbs (3).…”

Section: Discussionsupporting

confidence: 79%

“…The procedure was based on the following findings. Firstly, antibodies related to thyroid irAEs might be different from those of other types of thyroiditis, such as anti-thyroperoxidase antibodies (TPOAbs) and antithyroglobulin antibodies (TgAbs), as some patients with thyroid irAEs were double negative for them (3,15,16). Secondly, endocrine-related irAEs including ACTH deficiency and type 1 diabetes as well as thyroid irAEs are commonly associated with severe or null hormonal deficiency.…”

Section: Introductionmentioning

confidence: 99%

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Novel Thyroid-Specific Autoantibodies in Patients with Immune-Related Adverse Events Involving the Thyroid Gland

Yamauchi

Yasoda

Hakata

et al. 2021

Preprint

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AimsProgrammed cell death-1 (PD-1) blockade therapy frequently results in immune-related adverse events involving the thyroid gland (thyroid irAEs). Although clinical features of thyroid irAEs are known, the mechanisms remain unclear. Here, we conducted a pilot study to investigate mechanisms of thyroid irAE development from the perspective of autoantibodies.MethodsWe performed immunoprecipitation-based assays using sera of 3 patients who developed thyroid irAEs with PD-1 blockade therapy by nivolumab and HEK293T cell lysates, including overexpressed proteins of interest (NKX2-1, PAX8, FOXE1, and HHEX; thyroid-specific transcriptional factors). The pellets were analyzed by western blot to detect the HiBit tag attached to the C-terminus of the proteins.ResultsRelevant changes to NKX2-1 bands were not seen in all 3 patients, but PAX8 bands were augmented in patient 2 with lung cancer and patient 3 with renal cell carcinoma. In addition, FOXE1 bands were augmented in patient 1 with malignant melanoma and patient 3, and a HHEX band was augmented in patient 3. Thus, we revealed novel thyroid-specific autoantibodies, PAX8Ab, FOXE1Ab, and HHEXAb. Expression patterns of the antigens recognized by these antibodies were not identical to the primary sites, so autoimmune responses in thyroid irAE may originate from the thyroid gland, and not the malignancy. Considering that TPOAb rather than TgAb is often negative in patients with thyroid irAEs, other mechanisms such as cytotoxic T cell and antigenicity of thyroglobulin may be involved.ConclusionsAlthough the significance of these novel autoantibodies needs further examination, the present study provides new insights for thyroid autoimmunity.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Novel Thyroid-Specific Autoantibodies in Patients with Immune-Related Adverse Events Involving the Thyroid Gland

Yamauchi

Yasoda

Hakata

et al. 2021

Preprint

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“…yrotoxicosis associated with PD-1 inhibitors is caused by destructive thyroiditis or autoimmunity, destroying thyroid follicular epithelial cells and the release of reserved thyroid hormones, characterized by hyperthyroidism. PD-1 transmembrane receptor in hypothyroidism is an immune checkpoint receptor that can act on activated T cells, B cells, natural killer cells, and macrophages, thus improving the tolerance of the body to autoimmunity [32]. PD-1 can bind to PD-L1 and PD-L2, thus down-regulating the effect of self-antigen on the body and producing tolerance.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Thyroid Dysfunction in Patients with Advanced Non-Small-Cell Lung Cancer Treated with PD-1 Antibody

Zhang

Lou

2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To analyze the health status of thyroid function in patients with advanced non-small-cell lung cancer cured with PD-1 antibody and to explore the risk factors of thyroid dysfunction. Methods. 100 patients from Hunan Provincial People’s Hospital with advanced non-small-cell lung cancer hospitalized from January 2021 to March 2022 were selected. All patients were treated with a PD-1 antibody. The differences in sex, age, operation history, chemotherapy history, radiotherapy history, and thyroid nodules between patients with abnormal thyroid function and normal thyroid function after treatment were compared. Moreover, the risk factors of thyroid dysfunction were analyzed. Results. The proportion of women in the normal thyroid function group was lower compared to the abnormal thyroid function group. And the proportion of patients with the course of the disease within 1 year in the normal thyroid function group was higher compared to the abnormal thyroid function group. The incidence of thyroid color ultrasound nodules in the normal thyroid function group was remarkably higher compared to the abnormal thyroid function group ( P < 0.05 ). The proportion of patients with nodules in the abnormal thyroid function group was remarkably higher compared to the normal thyroid function group. Among the 36 patients who developed abnormal thyroid function, the incidence of hyperthyroidism (hyperthyroidism) and subclinical hyperthyroidism (subclinical hyperthyroidism) was 33.33%. The incidence of hypothyroidism (hypothyroidism) and hypothyroidism (subclinical hypothyroidism) was 66.66%. The cumulative incidence rates after 3 cycles, 6 cycles, and 12 cycles were 63.88%, 83.33%, and 94.44%, respectively. T4 and FT3 levels decreased more than the normal group following therapy. The results showed that females, course of disease more than one year, and thyroid nodule were independent risk factors of thyroid dysfunction. Conclusion. Female gender, disease duration of more than 1 year, and thyroid nodules were independent risk factors for thyroid dysfunction after PD-1 antibody therapy. Therefore, clinical treatment should focus on patients with the above factors, and early intervention should be implemented to avoid the occurrence of thyroid dysfunction after PD-1 antibody treatment.

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“…Osorio et al describe that their onset coincided with the development of thyroid dysfunction (7/11 anti-thyroid antibodies developed during pembrolizumab treatment, of which 6/7 with onset of transient hyperthyroidism) [37]. According to yet other authors, thyroid autoantibodies are absent in patients with thyroid dysfunction [38,39]. It remains to be determined whether the pre-existence of subclinical thyroid autoimmunity can be reliably detected through thyroid autoantibodies at baseline and subsequently confers a risk for developing thyroid dysfunction in this population.…”

Section: Fdg Compatiblementioning

confidence: 99%

Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms

et al. 2022

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Background Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy. Case presentation A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0. She developed thyrotoxicosis followed by hypothyroidism induced by consolidation immunotherapy with durvalumab (anti-PD-L1). Analysis of the human leukocyte antigen (HLA) region showed HLA-DR4 (susceptible) and DR13 (protective). The possible mechanisms are subsequently discussed in detail. Conclusions The case of a patient with thyroiditis associated with the PD-L1 inhibitor durvalumab is described, highlighting the need for proactive monitoring of thyroid hormone levels. Identifying biomarkers associated with an increased risk of ICI-induced side effects (such as HLA) is of interest for better patient selection, optimal management and improved understanding of the mechanisms involved.

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Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma

Cited by 15 publications

References 33 publications

Novel Thyroid-Specific Autoantibodies in Patients with Immune-Related Adverse Events Involving the Thyroid Gland

Novel Thyroid-Specific Autoantibodies in Patients with Immune-Related Adverse Events Involving the Thyroid Gland

Risk Factors for Thyroid Dysfunction in Patients with Advanced Non-Small-Cell Lung Cancer Treated with PD-1 Antibody

Durvalumab-induced thyroiditis in a patient with non-small cell lung carcinoma: a case report and review of pathogenic mechanisms

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