PD-1 Inhibitor Immune-Related Adverse Events in Patients With Preexisting Endocrine Autoimmunity

Halis Kaan Akturk; Aimon Alkanani; Zhiyuan Zhao; Liping Yu; Aaron W. Michels


J Clin Endocrinol Metab. 2018;103(10):3589-3592. 

In This Article

Abstract and Introduction


Context: Immune checkpoint inhibitors, including monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, have emerged as beneficial cancer immunotherapies. These therapies are known to cause immune-related side effects; however, their role in patients with a preexisting autoimmune disease is not clear.

Case Description: We describe two cases of anti-PD-1 immune-related adverse events. A 52-year-old male with longstanding type 1 diabetes (T1D), long-term stable kidney transplant, and hypothyroidism received two separate anti-PD-1 monoclonal antibodies for metastatic melanoma. The patient developed acute kidney graft rejection requiring hemodialysis and worsening of autoimmune hypothyroidism 3 weeks after starting treatment. He continued anti-PD-1 treatments and remained on hemodialysis and increased levothyroxine dosage. The second case is a 62-year-old male with no previous history of diabetes who received anti-PD-1 treatment and developed severe diabetic ketoacidosis (DKA) 5 days following the start of therapy. Further laboratory testing revealed high titer antibodies directed against glutamic acid decarboxylase. These antibodies, which were of the IgG isotype and involved in memory immune responses, were likely present before anti-PD-1 treatment. He also had human leukocyte antigen genes that confer T1D genetic risk. Despite normal pretreatment blood glucose levels and HbA1c, the patient requires permanent exogenous insulin treatment.

Conclusion: Patients with preexisting endocrine autoimmunity may have more frequent and severe immune-related side effects with anti-PD-1 treatment. Given the morbidity and mortality associated with solid organ transplant rejection and DKA, clinicians caring for patients receiving these state-of-the-art therapies need to be aware of the potential adverse events.


Immunotherapy, including immune checkpoint blockade, is becoming a highly effective treatment of multiple malignancies refractory to conventional chemotherapies. Programmed cell death protein 1 (PD-1) inhibitors inhibit the interaction between PD-1 and its ligand, thereby activating immune responses toward cancer cells. In a normal adaptive immune response, immune checkpoint inhibition is in place to ensure that immune cells do not harm the host when responding to a foreign antigen. Interfering with this mechanism can cause immune-related adverse events directed against self-tissues.[1] Pembrolizumab and nivolumab are two of the most commonly used human monoclonal antibodies directed against PD-1 and are approved by the US Food and Drug Administration to be used in several stage IV cancers, including melanoma.

Clinical trials that led to the US Food and Drug Administration approval of these agents often excluded patients with a known autoimmune disease such as type 1 diabetes (T1D) or an organ transplant.[1,2] Thus, in clinical practice, the potential exists to encounter immune-related adverse events more often than registration trials. Currently, there are no guidelines for the treatment of patients with immune checkpoint inhibitors in the setting of preexisting autoimmunity or a prior organ transplant. We report cases of acute kidney transplant rejection and worsening of autoimmune hypothyroidism in a patient with longstanding T1D having previously stable kidney and thyroid function and a second case of autoimmune diabetes as a rapid consequence of anti-PD-1 treatment of metastatic melanoma.