check point inhibitor hypophysitis

Although any organ system can be affected, endocrinopathies are frequently encountered. The most common, and one of the most concerning, endocrine toxicity with ipilimumab is hypophysitis, in which the pituitary gland is the target of immunologic injury. The pathogenesis of ipilimumab-induced hypophysitis is a type II hypersensitivity reaction that occurs on the basis of anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA4) antibody binding to antigens on pituitary cells. The consequence of this is complement activation and destruction of the pituitary gland.

A characteristic presentation is of multiple endocrine deficiencies. This patient’s nausea, vomiting, and orthostasis are consistent with the secondary adrenal insufficiency that results from the hypophysitis. The elevated temperature in the context of a normal WBC count is reflective of the association of adrenal insufficiency with the production of IL-6 as a fever mediator. Not explained on the basis of adrenal insufficiency is the patient’s bradycardia. This finding is consistent with the hypothyroid state that occurs because of the pituitary insult from ipilimumab.

This patient’s diffuse erythematous macular rash is not consistent with cellulitis but is explainable on the basis of the immune-mediated inflammatory reaction of his skin as an immunologic organ that is targeted by immune checkpoint blockade. The minor elevation in his temperature along with the normal WBC count are not strongly suggestive of sepsis.

In addition to endocrinopathies, other organ systems commonly impacted by irAEs include the GI tract, liver, and skin. The patient’s nausea and vomiting could be on the basis of such immune-related injury. The patient does have orthostatic findings, but they are mild. His BUN and creatinine are not supportive of significant hypovolemia. If this was the presentation of profound intravascular volume depletion on the basis of excessive GI loss, one would expect a heart rate greater than the 62/min manifested by this patient.

As a paraneoplastic endocrine syndrome resulting from hormone production by the tumor, syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described in patients with melanoma. With this disorder, patients have hypoosmotic euvolemic hyponatremia. This patient’s orthostatic vital signs in the setting of his hyponatremia argue against a euvolemic state. The BUN >10 mg/dL (3.57 mmol/L) and the plasma uric acid >4 mg/dL (0.24 mmol/L) do not conform to the supplemental criteria for diagnosing SIADH.12345

A 61-year-old man with metastatic melanoma is treated with the combination of the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab and the programmed cell death receptor 1 antibody nivolumab. Eleven weeks after beginning therapy, he begins experiencing fatigue and generalized weakness. Over the next 5 days, his symptoms progress, and he begins having nausea and vomiting. Because of inability to eat or drink over the next 3 days, he presents to the ED after having a syncopal event at home. He is acutely ill, with BP of 86/56 mm Hg supine and 72/44 mm Hg standing and heart rates of 58/min and 62/min, respectively. His temperature is 37.7°C. Exam is otherwise unremarkable except for a diffuse erythematous macular rash. Notable laboratory data are sodium 126 mEq/L (126 mmol/L), potassium 4.8 mEq/L (4.8 mmol/L), chloride 88 mEq/L (88 mmol/L), bicarbonate 24 mEq/L (24 mmol/L), BUN 24 mg/dL (8.57 mmol/L), creatinine 1.8 mg/dL (159.12 μmol/L), WBC count of 7,800/µL (7.8 x 109/L) with a normal differential. Uric acid is 6 mg/dL (0.36 mmol/L).

On the basis of this clinical presentation, what is the most likely diagnosis in this patient?

Footnotes

  1. SEEK Questionnaires ↩

  2. Byun DJ, Wolchok JD, Rosenberg LM, et al. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017;13(4):195-207. PubMed ↩

  3. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. PubMed ↩

  4. Rosner MH, Dalkin AC. Electrolyte disorders associated with cancer. Adv Chronic Kidney Dis. 2014;21(1):7-17. PubMed ↩

  5. Snyders T, Chakos D, Swami U, et al. Ipilimumab-induced hypophysitis, a single academic center experience. Pituitary. 2019;22(5):488-496. PubMed ↩