Journal Article

Checkpoint Inhibitor–Associated Autoimmune Diabetes Is Distinct From Type 1 Diabetes

Guminski, Alexander D, Scolyer, Richard A, Long, Georgina V, McGrath, Rachel T, Menzies, Alexander M, Clifton-Bligh, Roderick J, Tsang, Venessa H M, Jakrot, Valerie

2019

Overview

Abstract Context Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. Case Series Description Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. Conclusion CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure. CIADM represents a new class and increasingly common cause of autoimmune diabetes that is distinct from T1D in onset and cause; it is characterized by sudden complete β-cell failure after immune checkpoint inhibitor therapy.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Adult / Aged / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents, Immunological - adverse effects / Antineoplastic Agents, Immunological - therapeutic use / Apoptosis / Autoantibodies / Autoimmune diseases / Autoimmunity / Beta cells / Blood Glucose / Cell death / Dextrose / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 1 - blood / Diabetes Mellitus, Type 1 - chemically induced / Diabetes Mellitus, Type 1 - diagnosis / Diagnosis / Drug therapy / Female / Glucose / Glutamate decarboxylase / Glutamic acid / Glycosylated hemoglobin / Haplotypes / Hemoglobin / Histocompatibility antigen HLA / Humans / Hypoglycemic agents / Immune checkpoint / Immunotherapy / Inflammation / Insulin / Ipilimumab / Male / Melanoma / Melanoma - drug therapy / Metastases / Metastasis / Middle Aged / Nivolumab - adverse effects / Nivolumab - therapeutic use / PD-1 protein / Peptides / Retrospective Studies / Skin Neoplasms - drug therapy / Type 1 diabetes / Type 2 diabetes