Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer

Abstract

BackgroundAdvances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.Case PresentationA 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.ConclusionNew onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM aft...

Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma

“…However, in that case, testing was performed on pre-treatment frozen blood samples that showed elevated biomarkers despite of there being no other signs or symptoms of diabetes mellitus. [10] It was inferred that initiation of immunotherapy may have exacerbated underlying autoimmune diabetes, leading to DKA. Our patient had no prior diagnosis or testing performed for diabetes and his autoimmune biomarkers were within normal limits.…”

Immune checkpoint inhibitor diabetes mellitus: a novel form of autoimmune diabetes

“…In the subset for whom autoantibodies were present at CPI‐DM diagnosis, it is unknown if they were present preceding treatment, potentially allowing for risk prediction, or whether they have developed during the course of treatment. Pretreatment serum was available for a limited number of cases, and these have had mixed results . It is also unknown if the presence or absence of these autoantibodies represents different forms of CPI‐DM.…”

The evolving role of the rheumatologist in the management of immune-related adverse events (irAEs) caused by cancer immunotherapy

“…While the early clinical series3 18 of rheumatic irAEs failed to demonstrate the presence of autoantibodies in patients with inflammatory polyarthritis, several recent reports suggest that pre-existing autoantibodies such as anticitrullinated protein antibodies5 and diabetes-associated islet antibodies19 may be predictive of new-onset rheumatoid arthritis and type 1 diabetes. Thus, efforts to profile risk for incident irAEs prior to checkpoint therapy need to be explored and specialists such as rheumatologists may be logical partners to monitor and manage such complications before they occur.…”