Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α

Abstract

Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known β cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

“…Twenty-seven studies with detailed patients’ features have been published from 2013 to 2022 and are included in Table 1 [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. These studies describe a total of 29 patients who experienced PAI following ICI therapy for various types of malignancy.…”

“…The ICI-induced PAI was diagnosed from 10 days to 1 year post ICI initiation. In four cases, PAI was also associated with other autoimmune endocrinopathies such as DM and thyroiditis, leading to a diagnosis of autoimmune polyendocrine syndrome type 2 (APS-2) [ 13 , 16 , 17 , 28 ]. The majority of these reported cases (20/27, 74.1%) presented with severe or life-threatening symptoms (grade III/IV).…”

“…The assessment of antibodies was inconsistently reported throughout the studies. Six cases out of 10 [ 13 , 17 , 23 , 26 , 28 , 39 ] presented positive 21-hydroxylase antibodies (21-OHAbs), while antibodies were negative in four cases [ 20 , 29 , 35 ]. The 21-OHAbs and adrenal cortex antibodies (ACA) were both positive in two cases [ 13 , 23 ].…”

“…In the rest of the cases with confirmed cortisol deficiency, the diagnosis of PAI was established mainly based on elevated ACTH or plasma renin activity or concentration in combination with low serum aldosterone concentration and electrolyte disturbances. It is worthwhile noting that, in a few cases [ 16 , 27 , 28 , 30 , 36 , 37 ], the authors concluded a PAI diagnosis without providing data of the “classical” tests which are mandatory for the establishment of PAI.…”