Nivolumab, a programmed cell death protein 1 (PD-1) antibody, and ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, are immune checkpoint inhibitors (ICI) which have emerged as first- and second-line therapy of stage IV melanoma [1, 2]. However, they can induce immune-related adverse events (irAEs) involving a range of organs similar to auto-immune diseases [1, 3, 4]. The endocrine system is often affected [1, 3, 4], with disturbances of the thyroid and the pituitary gland being the most common endocrinopathies [1]. Inflammation of the thyroid gland can often lead to an initial hyperthyroidism and subsequent hypothyroidism. Inflammation of the pituitary gland can lead to insufficiencies of the thyroid, adrenal and gonadal axis. Also, rarer endocrinopathies such as adrenalitis have been described, but the course of such inflammations and also the pathomechanisms are less well-known.

Here, we report on a 53-year old patient with stage IV melanoma who was admitted to the hospital after he presented with generalized paresthesia, stiffness in both hands, a feeling of obstruction in his throat and mild dizziness. He had metastases in the liver, spleen, lung and bones but not in the brain (Fig. 1a). Treatment of his melanoma with nivolumab 1 mg/kg and ipilimumab 3 mg/kg was started 4 weeks earlier and two doses had been given before the time point of presentation. He reported a significant worsening of symptoms over the past few days. His medical history included arterial hypertension treated with valsartan and bisoprolol and intermittent stomach complaints treated with pantoprazole. He had no known auto-immune disorders before the treatment with nivolumab and ipilimumab was started. Serologies for hepatitis B and C virus were negative before the start and serum levels of TSH and free T4 were within the normal limits. At presentation, his vital signs showed no abnormalities. Physical examination was unremarkable with negative Chovestek’s and Trousseau’s signs. ECG showed a prolonged corrected QT interval (493 ms). Laboratory testing revealed hypocalcemia (calcium 1,35 mmol/l [normal range 2.10–2.65], albumin 38 g/l [normal range 35–52], ionized calcium 0,7 mmol/l [normal range 1,15-1,3]), marginal hypomagnesemia (0,69 mmol/l [normal range 0,70-1,00]) and hyperphosphatemia (1,75 mmol/l [normal range 0,8-1,5]. Intact parathyroid hormone (iPTH) level was inadequately low (7,2 pg/ml [normal range 15–65]), 25-hydroxy vitamin D₃ level was just above normal range (121 nmol/l [normal range 13.2–118]), venous blood gas showed normal pH of 7.418. There was no clinical sign of other auto-immune endocrinopathies, thyroid hormone and cortisol levels were normal.Fig1Fig. 1

Clinical response to nivolumab and ipilimumab. a, Lung lesion before the treatment with anti-CTLA-4 and anti-PD-1 antibodies and after 8 weeks. There was a marked regression with 8 weeks of the treatement. b, After 16 weeks of treatment, a complete metabolic response was observed in the ¹⁸FDG-PET/CT scan

Immune checkpoint inhibitors provide a promising treatment of various cancer entities by enhancement of a patient’s antitumor immunity but are associated with inflammatory side effects. The incidence of any grade irAEs in patients on therapy with ICI is reported to range from 15 to 90% [1, 3, 4]. Immune-mediated endocrinopathies are among the most common irAEs. The most frequently reported immune-mediated endocrinopathies are hypophysitis and thyroid dysfunction while type 1 diabetes mellitus and adrenal insufficiency are less commonly reported [1]. Hypocalcemia has been found to be significantly associated with PD-1 inhibitor pembrolizumab treatment in a recent meta-analysis by Manohar et al. [5], notably as rare (11 out of 604 patients) grade 1–3 adverse events, but the pathomechanism is usually unknown. To our knowledge, there are only two case reports to date on severe hypocalcemia with confirmed hypoparathyroidism - one in a melanoma patient associated with nivolumab/ipilimumab treatment [6] and another in a small cell lung cancer patient on nivolumab treatment [7].

Normally, the calcium sensing receptor (CaSR) of parathyroid glands stimulate the release of PTH by the parathyroid glands upon sensing of low blood calcium. PTH in turn increases renal tubular Ca²⁺ reabsorption, enhances 1,25(OH)₂D₃ synthesis and increases Ca²⁺ release from bone, thus restoring normal calcium levels. CaSR autoantibodies and CaSR-activating autoantibodies have previously been identified in patients with idiopathic hypoparathyroidism and autoimmune polyendocrine syndrome type 1 (APS1) [8] and have also been described in a patient treated with nivolumab [7]. Various pathomechanisms of irAEs have been described and proposed [4, 9]. One prominent mechanism is the loss of peripheral tolerance to autoantigens where, for example, T cell clones react against antigens in tumors that are also present in healthy tissue [10, 11]. This putative mechanism includes cross-presentation of tumor-antigens that leads to expansion of T cell clones, which then infiltrate healthy tissue and cause inflammation [9]. Also, autoantibodies have been found in irAEs induced by ICI therapy including in a patient with cerebral vasculitis [12], or autoimmune bullous skin disorders [13]. Autoimmune hypoparathyroidism can be caused by either immune-mediated destruction or by hyperactivation of the CaSR by activating autoantibodies. Interestingly, we find that the hypoparathyroidism in the described patient was dependent on immune-suppressive medication and therefore was rather inflammation-mediated. Since we could not detect significant titers of anti-CaSR antibodies in our patient, it seems the pathomechanism is probably distinct from the one seen in sporadic hypoparathyroidism.

This case describes a rare immune-related endocrinopathy in a patient treated with combination immune checkpoint blockade for melanoma. Therefore, physicians caring for cancer patients treated with ICI should be aware of such irAEs. We also demonstrate that this patient has an inflammation -driven and not an autoantibody-mediated irAE. Our case report therefore also provides a new insight into the pathomechanism of this rare side effect of ICI treatment.