A UNIQUE CASE OF ATEZOLIZUMAB-INDUCED AUTOIMMUNE DIABETES

Abstract

Objective:

Immunotherapy is a novel treatment that can cause autoimmune diabetes in rare cases. More cases occur following use of the inhibitor to the protein programmed cell death-1 rather than the inhibitor to programmed cell death-ligand 1.

Methods:

We report a unique case of autoimmune diabetes following atezolizumab use.

Results:

A 55-year-old, Aboriginal Australian female with no prior history of diabetes was commenced on atezolizumab for recurrent squamous cell lung carcinoma. Two months following its commencement, there was the onset of fatigue, polyuria, polydipsia, and new hyperglycemia. Subsequently she was found to have a borderline-low C peptide level of 0.6 nmol/L (reference range is 0.5 to 1.0 nmol/L), and positive zinc transporter-8 antibodies. Following the diagnosis of autoimmune diabetes, 5 units of glargine insulin was commenced which maintained euglycemia and resolved her symptoms of hyperglycemia.

Conclusion:

There are few case reports of atezolizumab-induced autoimmune diabetes. We present the first case associated with zinc transporter-8 antibodies, and a unique case of autoimmune diabetes in a patient of Aboriginal Australian background.

INTRODUCTION

Immunotherapy is a novel way of managing hematological and solid organ cancers. Neoplastic cells can express programmed cell death-ligand 1 (PD-L1), which when it interacts with programmed cell death-1 (PD-1) on T cells, generates an inhibitory T cell signal and allows neoplastic cells to evade immune recognition. Targeted therapies to PD-1 and PD-L1 have been developed to help prevent immune escape of neoplastic cells. Atezolizumab is an immunoglobulin G1 monoclonal antibody which targets PD-L1 and can be used to treat non-small cell lung cancer and urothelial carcinoma (1,2).

Due to increased immune activity with immunotherapy, its use is associated with autoimmunity. Typically auto-immunity occurs in the first few weeks to months following commencement of therapy and can affect any organ system (1). The risk of autoimmune diabetes mellitus (DM) is quite low, occurring in only 0.2 to 1.0% of patients (3–5). Furthermore most cases of autoimmune DM occur following PD-1 inhibition rather than PD-L1 inhibition (6). Here we present a unique case of autoimmune DM following PD-L1 inhibitor use with atezolizumab.

CASE REPORT

A 55-year-old, Aboriginal Australian female with a background remarkable for smoking, chronic obstructive lung disease, and hypertension developed recurrent squamous cell lung carcinoma. Prior to the commencement of 1,200 mg atezolizumab taken every 3 weeks starting in June of 2018, she had no history of DM, autoimmune conditions, or thyroid disease. Hemoglobin A1c prior to the commencement of atezolizumab was 5.1% (32 mmol/mol), with random blood sugar levels ranging between 4.8 to 7.9 mmol/L.

After the commencement of atezolizumab therapy, in August of 2018 she developed symptoms of fatigue, polyuria, polydipsia, and new-onset hyperglycemia, with random blood sugar levels peaking up to 10.9 mmol/L. Investigations showed a borderline-low C peptide level of 0.6 nmol/L (reference range is 0.5 to 1.0 nmol/L), zinc transporter-8 (ZnT8) antibodies were 30 U/mL (reference range is <15 U/mL), and glutamic acid decarboxylase (GAD) and islet tyrosine phosphatase-2 (IA2) antibodies were undetectable.

Following a diagnosis of autoimmune DM, 5 U daily of glargine insulin were commenced which maintained fasting blood sugar levels between 5 to 7 mmol/L and resolved her hyperglycemia. Although atezolizumab was thought to have led to the development of her autoimmune DM, treatment was initially continued with close oncology and endocrinology follow up. However, after receiving 11 cycles of atezolizumab treatment, she developed progressive disease and therefore atezolizumab treatment was ceased.

DISCUSSION

We have described a case of autoimmune DM following atezolizumab use in a patient with no prior history of DM. Two months following atezolizumab commencement, the patient experienced the onset of fatigue, polyuria, polydipsia, and hyperglycemia. Her low basal insulin requirement, borderline-low C peptide level, and positive ZnT8 antibodies are in keeping with autoimmune DM.

Based on our literature review of atezolizumab-induced autoimmune DM, we found only 5 prior reported cases (Table 1) (4,7–10). Two cases were associated with GAD antibodies (8,9). Lanzolla et al (7) reported a case in the setting of atezolizumab-induced polyglandular syndrome type 2, though both IA2 and GAD antibodies were negative. Two other reports presented cases of diabetic ketoacidosis following atezolizumab use, with the absence of antibodies (4,10). Our case is unique, as it is the first report of atezolizumab-induced autoimmune DM with ZnT8 antibodies.

Table 1.

Prior Case Reports of Autoimmune Diabetes Mellitus Following Atezolizumab Use

	Year of publication	Age in years, sex	Primary diagnosis	Presentation	Autoantibodies
Lanzolla et al (7)	2019	60, male	NSCLC	Hyperglycemia	GAD negative, IA2 negative
Patti et al (4)	2018	70, female	NSCLC	Diabetic ketoacidosis	GAD negative
Way et al (8)	2017	Unknown age, male	Urothelial carcinoma	Hyperglycemia	GAD positive
Kapke et al (9)	2017	63, female	Urothelial carcinoma	Diabetic ketoacidosis	GAD positive
Hickmott et al (10)	2017	57, male	Urothelial carcinoma	Hyperglycemia	GAD negative, islet cell antibody negative

Abbreviations: GAD = glutamic acid decarboxylase; IA2 = islet tyrosine phosphatase-2; NSCLC = non-small cell lung carcinoma.

ZnT8 antibody levels (especially the arginine variant), in contrast to GAD and IA2 antibodies, are positively associated with C peptide levels and β-cell function (11,12), which is consistent with our case where mild hyperglycemia was observed. It is possible that prior cases may have been underrecognized, and therefore we suggest testing for ZnT8 antibodies if there is clinical suspicion of autoimmune DM and GAD and IA2 antibodies are negative.

The assessment of ZnT8 antibodies has been shown to improve sensitivity for β-cell autoimmunity from 67 to 76% (13), and has been detected in 60 to 80% of Caucasian patients with type 1 DM (14). As ZnT8 antibodies can appear years before clinical diagnosis of DM, their measurement can improve accuracy of disease risk prediction (15,16). There may also be limited reports of atezolizumab-induced autoimmune DM due to the clinical application of atezolizumab, as it is indicated in patients with metastatic lung and urothelial cancer whom have previously trailed chemotherapy (2,10).

Furthermore, this case is also unique in that it occurred in an Aboriginal Australian patient. Wright et al (3) retrospectively investigated cases of DM that had been reported following checkpoint inhibitor use between 2014 to 2018, and they found that 45.2% of cases were from America, 26.2% from Europe, 25.1% from Asia, and only 3.5% of cases were from Oceania. Based on our literature search there appears to be no prior case of an Aboriginal Australian developing autoimmune DM from immunotherapy.

Among Aboriginal Australians, there is a high prevalence of metabolic syndrome and type 2 DM. Compared to non-Aboriginal Australians, autoimmune disease is infrequent, with the exception of increased risk for rheumatic fever, post-streptococcal glomerulonephritis, and systemic lupus erythematosus (17). Aboriginal Australians have restricted and unique polymorphisms of the major histo-compatibility complex, and it is unclear if this contributes to their reduced susceptibility to autoimmune disease. They also have lower lymphocyte counts (17), which may contribute to their lower rates of autoimmune disease.

There is currently a paucity of literature regarding the underlying pathophysiology of autoimmune DM following targeted therapy. Autoreactive T cells appear to play a role. It is thought that PD-L1 expression on pancreatic islet cells is protective against autoreactive T lymphocytes, and with immunotherapy this inhibitory signal is lost (18). Mouse models have confirmed the importance of the interaction of PD-1 and PD-L1 in pancreatic islet cells, with PD-1 and PD-L1 blockade precipitating the onset of DM (19).

CONCLUSION

Autoimmune DM is a rare complication of immunotherapy, and most cases have been reported following inhibition of PD-1 rather than PD-L1. There are few case reports following atezolizumab use, and we report a unique case occurring in an Aboriginal Australian patient. Assessment of ZnT8 antibodies may be important for the diagnosis of autoimmune DM in these cases.

Abbreviations

DM

diabetes mellitus

GAD

glutamic acid decarboxylase

IA2

islet tyrosine phosphatase-2

PD-1

programmed cell death-1

PD-L1

programmed cell death-ligand 1

ZnT8

zinc transporter-8