Ipilimumab is an anti-CTLA-4 monoclonal antibody licensed for metastatic melanoma.
A 70-year-old female with metastatic malignant melanoma presented with anorexia, malaise and confusion two weeks after her fourth dose of Ipilimumab. She had a low serum sodium of 124 pmol/L on proton pump inhibitor and selective serotonin reuptake inhibitors, which were stopped and she was fluid restricted to 1.5 litres/day. Her urinary sodium was elevated 65 mmol/L. Serum cortisol was 19 nmol/L with no history of steroid use. A short synacthen test demonstrated a baseline cortisol of 18 nmol/L rising to 176 nmol/L at 90 minutes, and glucagon stimulation test baseline cortisol of 19 nmol/L to only 20 nmol/L at 120 minutes, GH rose to maximum <0.3 mIU/L. Her FSH and LH were low at 5.8 mIU/ml /0.4 mIU/ml respectively, oestradiol undetectable, TSH inappropriately low at 0.5 IU/ml for T4 of 6.1 pmol/L. ACTH was 3.2 pmol/L range (1.113.2). MRI pituitary was normal.
She was commenced on dexamethasone 0.75 mgs od and is currently well and continues on 0.75 mgs to date. 6 months later TSH has returned to normal 0.71 IU/ml (T4 19.2 pmol/L), Na 137 pmol/L.
Ipilimumab inhibits CTLA-4 receptors on T-cells, enhancing immune response and has been associated with immune related adverse events (irAEs). Hypophysitis accounts for 16% of Ipilimumab associated irAEs with some studies showing anterior pituitary antibodies in the serum of patients that developed ipilimumab induced hypophysitis (IIH). Measurement of these antibodies may help early diagnosis. Caturegli et al analysed autopsy pituitary samples of six patients treated with anti-CTLA-4. All samples expressed CTLA-4. The highest expression was found in the patient who had a pre-mortem diagnosis of IIH. Individuals with high pituitary expression of CTLA-4 may have a higher risk of anti-CTLA-1 hypophysitis.
There are currently no available tests to identify these individuals.