PracticeUpdate: Diabetes

EDITOR’S PICKS 10

PD-1 Inhibitor-Induced Type 1 Diabetes The Journal of Clinical Endocrinology and Metabolism

Take-home message • This systematic review includes 42 published cases of PD-1 inhibitor-induced type 1 diabetes mellitus. Potential patho- genic mechanisms, prognostic markers, clinical presentation, and a treatment and screening protocol are discussed. • Clinicians must be aware of diabetic ketoacidosis as a rare but serious side effect of immunotherapy use. COMMENT By Jason Sloane MD A s more and more case reports surface related to checkpoint inhibitor-induced autoimmune diabetes, this review comes at a fitting time. Although autoimmune diabetes remains one of the rarer immune-related adverse events, it is important to recognize this endocrinopathy as early as possible because acute complications of diabetes can be life-threatening. So far, there have been 42 reported cases of checkpoint inhibitor- associated autoimmune diabetes, and diabetic ketoacidosis (DKA) has been the most common presenting symptom in 30 of those. Most of the reported cases of autoimmune diabetes are asso- ciated with the PD-1 and PD-L1 humanized antibody checkpoint inhibitor cancer drugs. As reported in this review, the proposed mechanism for the induction of autoimmune diabetes is activat- ing T cells and blocking the PD-1 receptor on pancreatic beta cells to eventually induce cell death. Studies have shown that patients with type 1 diabetes mellitus have less PD-1 recep- tor expression on CD4+ T cells, which may contribute to the unchecked immune response that causes beta-cell destruction. It is not surprising that those individuals who have glutamic acid decarboxylase antibodies (GADA) or insulin receptor antibodies (IA2) prior to the initiation of checkpoint inhibitor therapy have a much higher chance of developing autoimmune diabetes and at a much faster rate than those patients without the mutation. This brings us to the most important concept presented in this review, that of establishing screening criteria so that autoim- mune diabetes can be diagnosed early, and hopefully before DKA. Although there are currently no consensus guidelines, I would agree with some of the ideas put forth in this review. Prior to the initiation of checkpoint inhibitor therapy, particularly PD-1 or PD-L1 antibodies, patients should be screened for GADA, IA2, have a baseline HbA1c, and a baseline fasting serum glucose. I would also agree with the review recommendation that patients on checkpoint inhibitor therapy should be screenedwith anHbA1c and fasting serumglucose prior to each cycle of treatment. There should also be education prior to therapy initiation to make sure that patients understand the hallmark symptoms of diabetes. Patients should also be able to check their capillary blood glucose levels at home on a glucometer and have some understanding of what glucose levels should be concerning. Once there are labo- ratory findings or clinical symptoms concerning for diabetes, it is too late to start any immunosuppressive therapy, so it is critical to have a basic understanding of insulin therapy. Oncologists should know it is always acceptable to ask for help if needed from endo- crinology colleagues to coordinate and initiate the proper therapy for diabetes in a timely and safe manner.

Abstract CONTEXT Pembrolizumab (Keytruda) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor which is important in maintaining self-toler- ance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAE) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occur- ring in 0.2% of cases. EVIDENCE ACQUISITION Systematic search of 4 databases (Medline, Embase, Web of Science and Cochrane Library) using the search terms “diabetes” or “ketoacidosis” and “pembrolizumab”, “nivolumab”, “PD-1 inhibitor” or “immunotherapy. Included were articles published in English between January 1, 2012 and January 1, 2018. The search was supplemented by bib- liographic searches of the complete reference lists of all included papers. EVIDENCE SYNTHESIS We provide an overview of all published cases (n=42) of programmed cell death-1 (PD-1) inhibitor induced type 1 diabetes melli- tus to date, including a well-characterized novel case of islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) positive diabetes mellitus, in a patient with a diabetes prone HLA genotype. She presented with diabetic ketoacidosis (DKA) during pembrolizumab therapy for a met- astatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (beta-cell antibod- ies, HLA type), a treatment and a screening protocol. CONCLUSIONS Since the use of immunotherapy will increase, it is essen- tial that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary. Programmed Cell Death-1 (PD-1) Inhibitor Induced Type 1 Diabetes Mel- litus: Mini-Review. J Clin Endocrinol Metab 2018 Jun 27;[EPub Ahead of Print], K Clotman, K Janssens, P Specenier, et al. www.practiceupdate.com/c/70201

PRACTICEUPDATE DIABETES