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

Abstract

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.

Development and validation of a novel immune-related prognostic model in hepatocellular carcinoma

“…Research progress discovery that programmed cell death-1 (PD-1) pathway is a new target for HCC immunotherapy [17]. As an anti-PD-1 monoclonal antibody, nivolumab can block PD-1 and restore the body's anticancer immune response by interfering with the signaling pathway, thereby preventing T cell activation [18]. In HCC, nivolumab showed significant benefits in objective response rates and overall survival [19].…”

A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia

“…Given the patient's CPR level of 5.92 ng/mL, his ability to secrete insulin appeared to be preserved at the time of his first visit, which might have caused us to overlook the onset of FT1DM. Table 3 summarizes previously published case reports on PD-1 inhibitor-related T1DM, including DKA and changes in the serum level of CPR (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Most previously reported patients had depleted insulin secretion or DKA at their initial visit; 2 patients reported by Matsumura et al and Saito et al had preserved CPR levels without DKA (20,21).…”

Lesions in endocrine glands as a complication of immunotherapy in the practice of oncologist

“…Как ипилимумаб [37], так и ниволумаб [38,39] могут вызвать инсулинит и острое развитие гипергликемии и кетоацидоза (фульминантный СД), требующих введения инсулина.…”

“…Необходимо также отметить, что нередко у пациента может быть зарегистрировано одновременное или последовательное поражение нескольких эндо-кринных желез на фоне терапии ниволумабом [38,39], ипилимумабом [37] или комбинацией этих препаратов. Так, в описанном F. Gunwan и соавт.…”