Anti-programmed cell death protein 1 (anti-PD1) immunotherapy induced autoimmune polyendocrine syndrome type II (APS-2): a case report and review of the literature

Abstract

Background Autoimmune polyendocrine syndrome type II (APS-2) is a rare constellation of autoimmune hypoadrenalism, thyroid dysfunction and/or type 1 diabetes (T1DM), usually occurring in the 3rd or 4th decades and associated with a human leukocyte antigen (HLA) DR3 or DR4 serotype. We detail the first report of an elderly woman developing the full triad of APS-2 shortly after commencing anti-programmed cell death protein 1 (anti-PD1) immune checkpoint inhibition for unresectable melanoma and review the literature for similar presentations secondary to anti-PD1 axis therapy. Case A 78-year-old female with advanced unresectable BRAF wild-type melanoma was treated with pembrolizumab (2 mg/kg 3-weekly). Three weeks following the first dose she developed fulminant autoimmune diabetes, with an initially low C-peptide denoting rapid destruction of ß-islet cells. Following stabilisation of her diabetes, two further doses of pembrolizumab was administered. She then represented with symptomatic hypoadrenalism and hypothyroidism, consistent with APS-2. Her HLA class II genotype was HLA-DRB1*04.16 (DR4 serotype), a recognised association with this syndrome. Her melanoma responded rapidly to anti-PD1 therapy, and a complete response (CR) was attained after four doses of pembrolizumab. Treatment was discontinued and her CR is ongoing. Conclusion This is the first report of the full triad of APS-2 developing in a genetically susceptible individual at the age of 78 after treatment with an anti-PD1 agent. Although scarcely reported, a literature review of similar reports seems to indicate a predilection for this syndrome in patients with HLA-DR4 serotypes. HLA Class II typing is not routinely recommended, but may provide useful predictive information for patients at risk of poly-endocrinopathy even in patients without a relevant personal or family history. Additional studies are required to determine if such testing would be useful and/or cost effective. Electronic supplementary material The online version of this article (10.1186/s40425-019-0713-y) contains supplementary material, which is available to authorized users.

NF-κB: At the Borders of Autoimmunity and Inflammation

“…Interestingly, administration of an immunotoxin consisting of an anti-PD-1 single chain variable fragment coupled to a Pseudomonas exotoxin selectively kills PD-1 expressing cells and delay diabetes onset in a mouse model of autoimmune diabetes (120). However, PD-1 immunotherapy is better known for inducing or precipitating autoimmune diseases (121,122).…”

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

“…Several patients had an HLA-genotype associated with autoimmune endocrinopathies. Many cases displayed other organ-specific autoimmune diseases, most often autoimmune thyroid disease, but sometimes also T1D (103).…”

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

“…Only a few cases of ICI-related autoimmune polyendocrine syndrome (APS) have been reported thus far. Most cases, where PAI typically occurred with APS-2, were treated with anti-PD-1 or anti-PD-L1 antibodies ( 26 , 132 , 140 ). HLA typing revealed haplotypes, which were associated with increased susceptibility to ‘classic’ T1DM and APS-2 ( 141 ).…”

“…The patient was positive for 21-hydroxylase and pituitary antibodies and negative for islet cells antibodies ( 26 ). In a case report by Gunjur et al , a 78 year-old female receiving pembrolizumab presented with a typical APS-2 triad of PAI, T1DM, and hypothyroidism ( 140 ). The patient was positive for anti-islet antibodies.…”