Checkpoint Inhibitor Associated Autoimmune Diabetes and Hashimoto's Thyroiditis

1. Abstract

1.1. Background: Anti-PD-1 antibodies have activity across many cancers. Changes in the balance of the immune system may lead to some autoimmune manifestations, also referred to as immune-related adverse events (IRAEs). These adverse events were described affecting different systems of the body, including the endocrine system.

1.2. Case Presentation: A 61-year-old patient was treated with Pembrolizumab and developed autoimmune DM and Hashimoto's thyroiditis.

1.3. Conclusion: To our knowledge, this is the first reported case of a patient who developed autoimmune diabetes and Hashimoto's thyroiditis, likely as a consequence of PD-1 inhibition with pembrolizumab.

2. Key words

Checkpoint inhibitors; Hashimoto’s thyroiditis; Autoimmune DM; IRAEs

3. Introduction

The field of tumor immunology significantly developed and changed therapeutic options for many malignancies, especially using immune checkpoint inhibitors [1]. The latter enhance the activation of the immune system to control tumor growth. Antibodies targeting programmed death 1 (PD-1) receptor or programmed death ligand 1 (PDL-1) have shown clinical responses in multiple tumor types [2]. Immune checkpoints are crucial for maintaining self–tolerance and regulating the immune system, preventing it from attacking cells in a random manner [3]. By unbalancing the immune system, immune check-point blockade favors the development of autoimmune manifestations, also referred to as immune-related adverse events (IRAEs) [4]. Pembrolizumab and Nivolumab are humanized monoclonal antibody against PD-1 receptor. These agents are associated with adverse effects that can affect multiple organs of the body and are most commonly seen in the skin, GI tract, lungs, endocrine system etc [5]. As for endocrinopathies, hypothyroidism is the most common adverse event (~7%). Other auto-immune endocrine disorders described in patients treated with PD-1 inhibitors include: hyperthyroidism (3.2%), hypophysitis (1.1%), but also primary adrenal insufficiency and insulin-deficient diabetes mellitus (DM) in smaller number of events[6]. Recently, immune-related hypoparathyroidism was also described in this context and seems even rarer [7]. Here, we describe a case of new onset autoimmune polyendocrinopathy which appeared shortly after starting PD-1 inhibitors therapy and synchronously associated hashimoto’s thyroiditis with hypothyroidism and positive Glutamic Acid Decarboxylase (GAD) antibody-related insulin deficient diabetes in a post-menopausal woman with no autoimmune background.

4. Case Presentation

A 61-year-old female was addressed to the Emergency Room (ER) at our institution due to weight loss, polydipsia, polyuria and fatigue in the last few days. Her past medical history was significant for an endometrial adenocarcinoma of uterus and ovary diagnosed four years before her admission. Initially, there was no evidence of systemic involvement. She was treated surgically with no adjuvant therapy. Seven months before her admission, a hormonal therapy with Tamoxifen and Megestrol was initiated due to lymph nodes metastases. A month later, the therapy was switched to anti- PD1 immunotherapy with Nivolumab. Three months before admission, the treatment was switched again to Pembrolizumab. There was a significant response to the treatment with elimination of the lymphadenopathy. The patient was on regular follow-up at the oncology outpatient clinic. was measured at the general practitioner clinic whereas her fasting blood glucose was always strictly normal in the previous blood tests. Metformin was initiated. However, because of high glucose levels and continuation ofsymptoms, she was addressed to the ER. At presentation, physical examination revealed a thin woman, with stable hemodynamic status (blood pressure 108/60 mmHg, pulse 56 bpm, room air saturation 100%, body temperature 36.5℃ ), BMI 24 kg/m2, and no abnormal finding was detected. Laboratory data showed hyperglycemia and high anion-gap metabolic acidosis with respiratory compensation, with elevated urinary ketones, compatible with Diabetic Keto-Acidosis (DKA) (Table 1).

5. Discussion

In this case report, we describe a patient several months after initiation of immunological treatment with PD-1 inhibitor for endometrial carcinoma. At first, the patient presented to her GP with severe hyperglycemia and was treated with Metformin. Her advanced age probably suggested that the patient had new onset type 2 DM. A week later, the patient presented with a DKA event. Retrospectively, high levels of GAD antibodies are suggestive of autoimmune DM. A differential diagnosis for the etiology of autoimmune DM in this patient includes late-onset auto-immune diabetes of the adult (LADA)/type 1 DM, and adverse event of PD-1 inhibitor treatment. The acute presentation and the need for insulin treatment one week after presentation of hyperglycemia are not compatible with the indolent presentation of LADA [8]. It would be reasonable to assume that the development of DM was secondary to the immunological treatment. There is limited amount of data regarding the incidence of autoimmune DM in patient received PD-1 inhibitors. Among patients treated with all kinds of checkpoint inhibitors, 0.2% developed autoimmune DM [6]. As for treatment with PD-1 inhibitors, a review reported 5 cases of patients who developed severe hyperglycemia or DKA 1 week to 5 months after initiation of PD-1 inhibitor therapy [9]. 3 additional cases were published with a similar clinical presentation [10, 11]. However, some cases of checkpoint inhibitors-related DM were reported to be unrelated to the occurrence of typical T1DM antibodies, raising the possibility of a more complex pathophysiology [12].

The reasons for differential autoimmune involvement of the endocrine glands between patients and different treatment regimens are not entirely clear [15]. Further investigation should be made in order to understand the specific pathophysiology of the different adverse effects This case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Physicians must be aware of these adverse events in order to avoid morbidity and mortality of patients. New onset of DM during checkpoint inhitor therapy should be actively screened, and if diagnosed, should prompt initiation of insulin therapy rather than oral anti-diabetic medications to avoid potentially lethal complications as DKA.

Reference

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Citation:

Tiram Y. Checkpoint Inhibitor Associated Autoimmune Diabetes and Hashimoto's Thyroiditis. Annals of Clinical and Medical Case Reports 2020