ISOLATED AUTOIMMUNE ADRENOCORTICOTROPHIC HORMONE DEFICIENCY: FROM A RARE DISEASE TO THE DOMINANT CAUSE OF ADRENAL INSUFFICIENCY RELATED TO IMMUNE CHECK POINT INHIBITORS
- Ruth Percik, Israel
Abstract
Background and Aims
Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal (HPA) axis diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of HPA axis endocrinopathies.
Methods
A retrospective cohort study all patients who received immunotherapy (Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Avelumab and/or Durvalumab) between January 2015 and October 2018 in a large tertiary cancer center. Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis.
Results
Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p<0.001] and 3.67 [95% CI 1.13-11.84, p=0.03]), respectively.
Conclusions
Isolated ACTH Deficiencty, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.