Autoimmune-Related Primary Hypoparathyroidism Possibly Induced by the Administration of Pembrolizumab: A Case Report

Umeguchi, Hitomi; Takenoshita, Hiromasa; Inoue, Hiroshi; Kurihara, Yuki; Sakaguchi, Chihiro; Yano, Shunsuke; Hasuzawa, Nao; Sakamoto, Shohei; Sakamoto, Ryuichi; Ashida, Kenji

doi:10.1200/jop.18.00076

Cited by 20 publications

(24 citation statements)

References 5 publications

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“…14 20 Although rare, autoimmune hypoparathyroidism can also manifest following the use of ICIs for the treatment of cancer. [9][10][11] Here, we report a patient with metastatic melanoma who developed hypocalcemia resulting from autoimmune hypoparathyroidism following ICI treatment. The case described demonstrates a cause of hypoparathyroidism that is likely immune-mediated secondary to ICIs, given the temporal proximity of hypoparathyroidism to the initiation of treatment without other mechanism for acute injury to the parathyroid glands.…”

Section: Case Presentationmentioning

confidence: 96%

“…5 6 Hypoparathyroidism is exceedingly rare. [9][10][11] Here, we describe the long-term follow-up of a patient who developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab combination for the treatment of metastatic melanoma. A possible autoimmune etiology of the patient's hypoparathyroidism was investigated.…”

Section: Introductionmentioning

confidence: 99%

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Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Dadu

Rodgers

Trinh

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented.Case and methodsA 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively.ResultsThe patient’s symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient’s hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient’s clinical course of hypoparathyroidism. CaSR antibodies purified from the patient’s serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1.ConclusionThe etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.

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Section: Case Presentationmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Dadu

Rodgers

Trinh

et al. 2020

J Immunother Cancer

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“…While it is possible that hypoparathyroidism induced by ICIs results from inflammation in the parathyroid glands, the number of cases reported to date is small and there is no histological evidence showing the presence of such inflammation. There is evidence that patients treated with an anti-PD-1 antibody alone or in combination with anti-CTLA-4 antibodies developed hypoparathyroidism 1-4 months after the initiation of the drugs [24][25][26][27]. Because serum calcium levels can be affected by advanced malignancies per se or by treatment, evaluation of serum calcium levels, intact PTH, 25-OH vitamin D, phosphorus, and magnesium, as well as urinary excretion of calcium and magnesium should be performed for differential diagnosis.…”

Section: Overviewmentioning

confidence: 99%

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society

et al. 2019

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Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

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“…Among the included 26 RCTs, only one trial 18 involved ICI‐related hypocalcemia. Thus far, only 5 case reports mentioned hypocalcemia and low parathyroid hormone (PTH) levels caused by ICIs 46–50 . The mechanism of hypocalcemia still remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Endocrine Adverse Events Caused by Different Types and Different Doses of Immune Checkpoint Inhibitors in the Treatment of Solid Tumors: A Meta‐Analysis and Systematic Review

Yang

Liu

Yang

et al. 2021

The Journal of Clinical Pharma

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The aim of this meta-analysis was to assess the risks of endocrine adverse events in patients with malignancies treated with different types and different doses of immune checkpoint inhibitors (ICIs). PubMed and Embase were searched for randomized controlled trials on ICIs and endocrine adverse events since 2000, and meta-analysis was carried out. Twenty-six randomized controlled trials comprising 13 824 patients with malignancies were included. Compared with the other tumor therapies (used as a control group), patients treated with programmed death-1 inhibitors appeared to be at higher risks of hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis or hypopituitarism, and type 1 diabetes mellitus, while there was no difference in the risk of primary adrenal insufficiency. It was also found that patients treated with cytotoxic T-lymphocyte-associated protein-4 inhibitors were at higher risk of hypophysitis or hypopituitarism, primary adrenal insufficiency, and hypothyroidism. In comparison, patients treated with programmed death-ligand 1 inhibitors were at higher risk of hyperthyroidism and hypothyroidism. Compared with the control group, both low-dose and high-dose ICI groups were at higher risk of hypothyroidism and hyperthyroidism, and the low-dose group had increased risk of thyroiditis and primary adrenal insufficiency. There was no significant difference in the risk of type 1 diabetes between the low-dose group and the high-dose group. The risk of hypophysitis or hypopituitarism in the high-dose group (relative risk, 20.12; 95% confidence interval, 8.02-50.46) was significantly higher than that in the low-dose group (relative risk, 4.92; 95% confidence interval, 2.11-11.47). The risk of endocrine adverse events was increased in patients treated with ICIs. Different types and doses of ICIs have varying characteristics of endocrine adverse events.

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Autoimmune-Related Primary Hypoparathyroidism Possibly Induced by the Administration of Pembrolizumab: A Case Report

Cited by 20 publications

References 5 publications

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society

Endocrine Adverse Events Caused by Different Types and Different Doses of Immune Checkpoint Inhibitors in the Treatment of Solid Tumors: A Meta‐Analysis and Systematic Review

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