Case Presentation: We are presenting a case of a 71-year-old male patient with a history of hypertension, non-insulin dependent type 2 diabetes mellitus (DM) well controlled on metformin, and non-invasive high grade urothelial bladder cancer diagnosed in 2014 treated with transurethral resection of the prostate and intravesicular mitomycin. In 2016, his bladder cancer has progressed to become invasive reaching the muscularis mucosa (stage T2) for which the patient received neoadjuvant chemotherapy. His disease persisted despite treatment; thus, pembrolizumab was initiated and he received 2 doses total prior to August 2017.The patient’s diabetes was well controlled with an average glycosylated hemoglobin (HbA1c) of 6.6 % and he never experienced an episode of diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). On August 2017, he presented to the emergency department with fatigue, dizziness, shortness of breath, polyuria and polydipsia. He was diagnosed with DKA for which he was treated in the intensive care unit. During the workup, the patient was found to have an HbA1c of 9 % and further investigations detected an elevated glutamic acid decarboxylase-65 (GAD-65 )(>250 IU/ML) and low C-peptide (0.26 ng/ml), which are usually diagnostic for type 1 DM. This case is one of the few reported cases of DKA as an autoimmune complication of Pembrolizumab.
Discussion: Pembrolizumab is a humanized monoclonal antibody directed against programmed death-1(PD-1), acting as an immune checkpoint inhibitor (ICI), reversing T cell exhaustion and reinforcing antitumor response. After several trials, it was approved for the treatment of cisplatin-ineligible metastatic bladder cancer, for progression after cisplatin therapy, and for metastatic urothelial carcinoma.
Despite being a new landmark in cancer treatment, ICI are associated with many immune related adverse events (irAEs) due to the disinhibition of the host immune homeostasis affecting mainly the skin, liver, gastrointestinal tract and endocrine system. Most of these irAEs are reversible with supportive treatment, however others are life-threatening such as severe skin reactions, type 1 DM and rhabdomyolysis.
In our patient, Pembrolizumab is highly suspected to be the cause of his presentation as it was started 1 month prior to the episode of DKA, accompanied by new findings of high GAD-65 and low C-peptide. In addition, HbA1c on presentation was 9 % compared to 6.6 % 8 weeks prior and values of 6.2%, 6.7%, and 6.5 % over the last 18 months.
A recent literature review revealed that type 1 DM and DKA have been reported in 6 (0.2%) of 2799 patients who received Pembrolizumab after performing 3 randomized, open-label, active-controlled clinical trials. Furthermore, a total of 12 cases of PD-1 associated type 1 DM are reported,1 week to 12 months after starting immunotherapy and most presented with DKA.
Conclusions: ICI are a breakthrough in the treatment of cancer. However, clinicians should have a high index of suspicion for its irAEs, especially autoimmune diabetes as it usually presents as DKA and can be life-threatening.