Challenges in autoimmune polyendocrine syndrome type 2 with the full triad induced by anti-programmed cell death 1: a case report and review of the literature

Abstract

Background: Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at least two of the following endocrinopathies: autoimmune thyroid disease, type 1 diabetes, and Addison's disease. Cases with the full triad are rare. We present a case of an elderly woman who developed APS-2 with the complete triad shortly after starting anti-programmed cell death 1 (anti-PD1) treatment and review the related literature.

Case: A 60-year-old woman, without any personal or family history of autoimmune and endocrine diseases, started the immunotherapy of anti-PD1 (camrelizumab) for squamous cell carcinoma of the urethral meatus. She developed primary hypothyroidism with elevated antibodies to thyroid peroxidase and thyroglobulin after 25 weeks of treatment, and developed primary adrenal insufficiency with adrenal crisis and fulminant type 1 diabetes with ketoacidosis after 45 weeks. Therefore, this patient met the diagnosis of APS-2 and was given multiple hormone replacement including glucocorticoid, levothyroxine and insulin therapy. Continuous improvement was achieved through regular monitoring and titration of the dosage.

Conclusions: Different components of APS-2 may appear at different time points after anti-PD1 administration, and can be acute and life-threatening. A good prognosis can be obtained by appropriate replacement with multiple hormones.

Insights: With the clinical application of ICPis to APS-2, the complexity of its treatment should be paid enough attention.

Keywords: adrenal crisis; adrenal insufficiency; anti-programmed cell death protein 1; autoimmune polyendocrine syndrome type 2; hypothyroidism; type 1 diabetes mellitus.

Figure 1

Ultrasound showing normal thyroid and parathyroid glands.

Figure 2

Ultrasound showing normal bilateral adrenal glands.

Figure 3

MRI with contrast showing a normal-sized pituitary and normal enhancement.

Figure 4

Mechanism of immune checkpoints and immune checkpoint inhibitors. Immune checkpoint inhibitors are monoclonal antibodies that target the CTLA-4 and PD-1 receptors and the PD-1 ligand PD- L1.T cell activation requires two signals: first, antigen recognition by the T cell receptor (TCR) following antigen presentation by major histocompatibility complex (MHC) class II molecules on the surface of antigen- presenting cells(APC); and, second, signal modulation by CD80 or CD86 binding to the CD28 receptor. CTLA-4 expressed on conventional T-cells interacts with its ligands CD80 and CD86 to initiate inhibitory signalling, enhance adhesion, and compete with CD28 to block interaction between CD28 and CD80/CD86.CTLA-4 inhibitors block CTLA-4 binding to CD80 or CD86 to promote T-cell activation PD-1 is a surface receptor that is expressed by T cells and promotes apoptosis of antigen- specific T cells and reduces apoptosis of regulatory T cells through its interaction with its ligand, PD- L1, which is expressed by tumour cells. Engagement of PD-1 with PD-L1 induces an intracellular inhibitory pathway to inhibit costimulatory CD28-activated PI3K pathways, leading to T-cell exhaustion. PD-1 and PD- L1 inhibitors block the PD-1–PD- L1 interaction, facilitating T cell activation.