Ruth Percik1, Gadi Shlomai2, Amir Tirosh3, Amit Tirosh3, Raya Leibowitz-Amit4, Yael Eshet5, Gahl Greenberg6, Alex Merlinsky7, Ehud Barhod8, Yael Steinberg-Silman9, Tal Sella10. 1. Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: Ruth.percik@sheba.health.gov.il. 2. Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel; Pinchas Burstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 3. Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Nuclear Medicine, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 6. Department of Diagnostic Imaging, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 7. Institute of Clinical Pharmacology and Toxicology, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 8. Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 9. The Ella Lemelbaum Institute for Immuno-Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel. 10. Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Pinchas Burstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract
OBJECTIVE: 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 axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. DESIGN: A retrospective cohort study of a tertiary cancer center. METHODS: 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 < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively. CONCLUSIONS: IAD, 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.
OBJECTIVE: 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 axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. DESIGN: A retrospective cohort study of a tertiary cancer center. METHODS: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 < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively. CONCLUSIONS:IAD, 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.
Authors: Rafael A Schmerling; Antonio C Buzaid; Carolina K Haddad; Fabio Ab Schutz; Fabio R Kater; Juliana Pimenta; Fernando Maluf; William N William; Camila Lopes; Dafne R Bromberg; Ana C Oliveira; Ricardo Golmia; Morton Scheinberg Journal: Future Sci OA Date: 2020-11-23