Intrinsic insulin secretion capacity might be preserved by discontinuing anti-programmed cell death protein 1 antibody treatment in 'anti-programmed cell death protein 1 antibody-induced' fulminant type 1 diabetes.

Intrinsic insulin secretion capacity may be preserved by discontinuing anti-PD-1 antibody treatment in 'anti-PD-1 antibody-induced'fulminant type 1 diabetes.

Fulminant type 1 diabetes has been described as a subtype of type 1 diabetes characterized by accelerated progression and without the presence of islet‐associated autoantibody. Thus far, several reports have documented the occurrence of type 1 diabetes, including the fulminant type, after anti‐programmed cell death protein 1 (PD‐1) antibody treatment for malignant tumors1. T cells are deactivated by inhibitory signals, such as those produced by PD‐1 and the ligand PD‐L12, and PD‐1 inhibition by anti‐PD‐1 antibody probably triggers an autoimmune phenomenon through the reduction of the immune checkpoint function of T cells.

Previously, we reported a case of fulminant type 1 diabetes that developed after the treatment of a malignant melanoma with the anti‐PD‐1 antibody, nivolumab3. A 63‐year‐old Japanese woman with melanoma received eight courses of anti‐PD‐1 immunotherapy, which was discontinued 6 weeks before the onset of fulminant type 1 diabetes. Laboratory data at the onset of fulminant diabetes were as follows: plasma glucose 661 mg/dL, pH 6.95, total ketone body 8,477.5 μmol/L, glycated hemoglobin 8.6%, serum C‐peptide 0.08 ng/mL, elastase 1 1100 ng/dL and CRP 1.89 mg/dL. We recently evaluated the human leukocyte antigen type in this patient and found that she had an HLA‐DRB1*09:01 genotype, which is a susceptible human leukocyte antigen type in Japanese type 1 diabetes patients.

Although previous reports have documented similar cases1, 2, we believe no report has described the changes in intrinsic insulin secretion capacity; that is, C‐peptide level, after the onset of fulminant type 1 diabetes caused by anti‐PD‐1 antibody treatment.

The present patient was followed up without using anti‐PD‐1 antibody after the onset of fulminant type 1 diabetes, because the treatment was ineffective against malignant melanoma.

As shown in the Figure 1, the serum C‐peptide level was relatively higher (range 0.12–0.37 ng/mL) than that seen in typical fulminant type 1 diabetes4. Furthermore, even 10 months after the onset, C‐peptide was still detected (0.17 ng/mL). During this time‐course, the patient's glycated hemoglobin ranged 7.0–8.6%, postprandial plasma glucose level 145–348 mg/dL and insulin dose 46–48 units/day.

Figure 1

Changes in the C‐peptide (CPR) and plasma glucose (PG) level after the onset of fulminant type 1 diabetes in the present case. C‐peptide levels were examined in postprandial condition. The x‐axis shows the number of visits to our outpatient clinic (Saitama Medical University, Moroyama, Saitama, Japan) (duration of visit interval: 4–6 weeks).

A reason for the residual β‐cell function in the present case might be the effect of intensive insulin therapy, especially at the onset of fulminant type 1 diabetes. Nevertheless, we suspect that not only the intensive insulin therapy, but also the discontinuation of anti‐PD‐1 antibody treatment, might have prevented the β‐cell destruction after the onset of fulminant type 1 diabetes caused by anti‐PD‐1 antibody treatment.

If the prognosis will be worsened by the discontinuation of the anti‐PD‐1 antibody treatment, we might have to continue the treatment throughout the patient's life. However, if there is an alternative treatment choice for the malignancy, the discontinuation of anti‐PD‐1 antibody treatment might be the one of choice, because this could help preserve pancreatic β‐cell function in the patient.

We should monitor changes in the intrinsic insulin secretion capacity; that is, C‐peptide level, of patients with ‘anti‐PD‐1 antibody‐induced’ fulminant type 1 diabetes, and discuss whether treatment discontinuation can be considered by accumulating and analyzing reports of similar cases henceforth.

Disclosure

AS has received lecture fees from Novo Nordisk Pharma, Sanofi and Eli Lilly Japan. MN has received lecture fees from Sanofi, Novo Nordisk Pharma, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Eli Lilly Japan, MSD, Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Astellas, Kowa Pharmaceutical Co. Ltd, Taisho Toyama Pharmaceutical Co. Ltd, Kissei Pharmaceutical Co. Ltd, Meiji Seika Pharma Co. Ltd, Kyowa Hakko Kirin Co. Ltd, ABBVie Inc. Johnson & Johnson K.K., Novartis Pharma K.K. and Shionogi & Co., Ltd., and has received research grants from AstraZeneca, Takeda Pharmaceutical Co. Ltd, Daiichi Sankyo, Mitsubishi Tanabe Pharma and Kyowa Hakko Kirin Co. Ltd. GS, DS, RN, MH, YN, SK, SK and II declare no conflict of interest.