Abstract
BackgroundTreatment with a combination of PD-1 and CTLA-4 targeted checkpoint inhibition has improved outcome of melanoma patients and led to durable remissions but is also associated with significant toxicities. Endocrinopathies such as thyroiditis and hypophysitis are often seen, but other, rarer disturbances have also been described. Endocrinopathies affecting the parathyroid gland are rarely reported and no clear pathomechanism has been proposed.Case presentationHere, we report a case of severe hypocalcemia due to an antibody-mediated hypoparathyroidism as an immune-related adverse event (irAE) in a patient who was treated with the anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab. Hypocalcemia was rapidly corrected by substitution, but the endogenous serum parathyroid hormone (PTH) remained low. The patient demonstrated a rapid and profound tumor response to the combination immune checkpoint blockade, but developed a severe colitis that required high-dose intravenous corticosteroid and anti-TNFα therapy. During this strong immunosuppression the PTH level normalized and the calcium levels were stable without substitution. However, during tapering of immunosuppressants, the PTH and calcium levels decreased again to a level requiring calcium substitution.ConclusionOur report demonstrates a rare endocrinopathy as a complication of combined PD-1 and CTLA-4 blockade. In addition, it provides evidence from the course of the disease that inflammation within the parathyroid gland is involved in the mechanism.
Highlights
Treatment with a combination of Programmed Death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) targeted checkpoint inhibition has improved outcome of melanoma patients and led to durable remissions but is associated with significant toxicities
Our report demonstrates a rare endocrinopathy as a complication of combined PD-1 and CTLA-4 blockade
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]
Summary
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]. The patient was diagnosed with acute symptomatic hypocalcemia most likely due to immune-mediated hypoparathyroidism and hospitalized for further treatment He was given a total of 4 g calcium gluconate in divided doses and 3 g of magnesium sulfate (corresponding 12,15 mmol) intravenously. When we analyzed control patients that had undergone immunotherapy with nivolumab and ipilimumab for melanoma, similar levels of auto-antibodies against CaSR were found, suggesting that the detected antibody concentrations were probably not pathogenic and the test for such low concentrations is most likely unspecific.
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