Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1 Diabetes

Miyoshi, Yuka; Ogawa, Osamu; Oyama, Yu

doi:10.1620/tjem.239.155

Cited by 84 publications

(36 citation statements)

References 14 publications

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“…HLA typing of our patient revealed HLA-I A30 and HLA-II DR9 (Table 1); neither is a high risk haplotype associated with the development of T1DM. In contrast to our findings, several case reports have shown an established high risk allele for T1DM (HLA-II DR4 haplotype) present in the majority of patients for whom HLA typing was available [5, 7, 8, 10] while other case reports did not observe an association between HLA and the development of ICI associated T1DM [4, 6, 9]. …”

Section: Discussioncontrasting

confidence: 99%

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

Godwin¹,

Jaggi²,

Sirisena³

et al. 2017

j. immunotherapy cancer

108

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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...

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Section: Discussioncontrasting

confidence: 99%

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

Godwin¹,

Jaggi²,

Sirisena³

et al. 2017

j. immunotherapy cancer

108

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show abstract

“…The cases with HbA1c levels of < 8.7% are therefore marked by an asterisk in the literature of Table 3 and 4. Nine cases of anti-PD-1 therapy-induced type 1 diabetes mellitus with negative islet-related autoantibodies (autoantibodies to glutamic acid decarboxylase, insulinomaassociated antigen-2 or insulin) have been reported in the literatures (Table 3) (Gaudy et al 2015;Hughes et al 2015;Mellati et al 2015;Hofmann et al 2016;Kong et al 2016;Miyoshi et al 2016;Okamoto et al 2016;Munakata et al 2017). Seven of these nine cases showed HbA1c levels of < 8.7%, indicating that these seven cases had fulminant type 1 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab

Sakurai

Niitsuma

Sato

et al. 2018

Tohoku J. Exp. Med.

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The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrinerelated adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 μU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.

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“…If not promptly treated, an increased risk of complications with about 88.9% of chance of having a stillbirth may happen [10]. Japan has reported a number of patients who developed fT1D after anti-PD-1 drug therapy, which may be due to inappropriate activation of T cells in a population of HLA haplotype DRB1*04:05-DQB1*04:01 [11–13]. …”

Section: Discussionmentioning

confidence: 99%

A Case of Fulminant Type 1 Diabetes with Gastric and Urinary Retention

2018

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Fulminant type 1 diabetes (fT1D) is a severe subtype of type 1 diabetes which progresses rapidly with islet cells destroyed almost completely within a short period of time. It is often characterized by flu-like or gastrointestinal symptoms at the onset with negative islet-associated autoantibodies, resulting in an absolute deficiency of endogenous insulin secretion. Poor prognosis can be caused by the significantly higher incidence of metabolic disorders (such as severe ion disorders and elevated serum pancreatic enzymes), acute and chronic complications if not diagnosed and treated in a timely manner. We herein describe an fT1D patient with gastric and urinary retention along with severe ion disturbance, whose laboratory tests revealed diabetic ketoacidosis, peripheral neuropathy, retinopathy, nephropathy, and hypoproteinemia.

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Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1 Diabetes

Cited by 84 publications

References 14 publications

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

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

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab

A Case of Fulminant Type 1 Diabetes with Gastric and Urinary Retention

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