Background: Pembrolizumab is a monoclonal antibody that blocks the immune inhibitory effects of the programmed cell death protein-1 (PD-1) resulting in the enhanced effects of T cells which are beneficial in multiple conditions including malignancies but consequently could have serious autoimmune complications.

Objectives: We aim to highlight the mechanism of Pembrolizumab-induced autoimmune conditions and focus on identifying susceptible patients while emphasizing the essential role of physicians in informed patient decision-making regarding whether to continue the medication once the autoimmune condition resolves.

Case Presentation: A 69-year-old male presenting with progressive lethargy for 1 week associated with fatigue, shortness of breath, and excessive thirst without complaints of nausea or vomiting, abdominal pain, weight loss, polyuria, lightheadedness, or focal neurologic deficits.

Past Medical History of Graves’ Disease status post total thyroidectomy now on Levothyroxine, Stage IV Non-Small Cell Lung Carcinoma of the right upper lobe with metastasis to the bones and adrenals, treated with a combination of Carboplatin, Paclitaxel, and Pembrolizumab. No prior personal or family history of diabetes mellitus.

In the emergency department, Vital signs Temp 36.7, BP 150/90, RR 30s, HR 120s. On physical examination, the patient was lethargic but arousable without focal neurologic deficits and appeared cachectic with dry skin and oral mucosa with noticeable rapid shallow breathing. Diagnostic tests showed serum Glucose 829, Beta-hydroxybutyrate 11.5, urinalysis ++ketones, ABG pH 6.9, Bicarbonate 23, Anion Gap 20, lactate 3.50, Creatinine 2.2 from baseline of 0.86, K 7.7, EKG with peaked T waves with no QRS widening or PR prolongation, other tests including Head CT and Chest X-ray imaging studies were normal.

The patient was immediately given intravenous fluids and bicarbonate, was started on insulin drip, hyperkalemia was temporized with calcium gluconate, and adjunctively given albuterol nebulization with close monitoring of blood glucose and electrolytes. Endocrinology was consulted, and tested for C peptide level (0.22 ng/mL) and Anti-GAD-65 (<5 IU/mL) which were both low. Oncology was also consulted for which they recommended stopping Pembrolizumab for now.

Throughout his hospital stay, his symptoms and blood glucose improved and his Anion Gap normalized, later tolerated oral diet, was successfully transitioned to subcutaneous basal-bolus insulin, and was eventually discharged with strict outpatient endocrinology and oncology follow-up.

Discussions/Conclusion: The primary function of the programmed cell death protein-1 (PD-1) is to down-regulate the immune system preventing damage to self-antigen. Pembrolizumab is a monoclonal antibody that blocks the binding of the PDL1 ligand to its receptor causing enhanced T cell response resulting in better tumor killing with consequent increased risk of adverse autoimmune effects such as hyper and hypothyroidism, colitis, nephritis, with type 1 diabetes accounting for only 0.1% of the patients.

Pembrolizumab added to a standard chemotherapy regimen has shown longer overall and progression-free survival than chemotherapy alone and this is likely the reason why Pembrolizumab-induced autoimmune conditions have been increasing for the past couple of years.

The predisposing factors for the development of Pembrolizumab-induced type 1 diabetes (T1DM) is not well known. However, previous studies support that patients with a history of autoimmune diseases are more susceptible to develop this complication which was consistent with our patient’s prior history of Graves’ disease.  Pembrolizumab-induced T1DM can present with classic symptoms of diabetes but on rare occasions, it can initially present with diabetic ketoacidosis as evident in our patient. Unlike the classic T1DM where at least one autoantibody is present in 98% of patients, Pembrolizumab-induced diabetes had lower levels which was evident in our patient.

In one meta-analysis, the onset of Pembrolizumab-induced diabetes varied and ranged from one cycle to as long as 19 cycles and most studies showed that continuation of Pembrolizumab after initial treatment of diabetes ketoacidosis was still possible with initiation of basal-bolus insulin regimen since stopping Pembrolizumab in the setting of advanced malignancies, where only a few treatment options are available, is not always possible, and the overall prognosis of malignancies treated with Pembrulizumab did not seem to change even if they develop endocrinopathies. Hence, an informed decision by the patient with a transparent and collaborative effort between healthcare providers is of utmost importance, zeroing in on the risks and benefits of continued treatment.