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

Background Immune 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 methods A 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. Results The 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. Conclusion The etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid

Thermodynamic Measurement of Angular Anisotropy at the Hidden Order Transition of URu2Si2

The heavy fermion compound URu2Si2 continues to attract great interest due to the unidentified hidden order it develops below 17.5 K. The unique Ising character of the spin fluctuations and low-temperature quasiparticles is well established. We present detailed measurements of the angular anisotropy of the nonlinear magnetization that reveal a cos4θ Ising anisotropy both at and above the ordering transition. With Landau theory, we show this implies a strongly Ising character of the itinerant hidden order parameter.RST/Fundamental Aspects of Materials and EnergyLibrary TU Delf