Endocrinol Metab.  2022 Feb;37(1):84-95. 10.3803/EnM.2021.1282.

Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors

• Inaba H
• Kaido Y
• Ito S
• Hirobata T
• Inoue G
• Sugita T
• Yamamoto Y
• Jinnin M
• Kimura H
• Kobayashi T
• Iwama S
• Arima H
• Matsuoka T

• KMID: 2527140
• DOI: http://doi.org/10.3803/EnM.2021.1282

Abstract

Background
Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear.
Methods
In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021.
Results
Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset.
Conclusion
Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

Keyword

Immune checkpoint inhibitors; Immune-related adverse events; Diabetes mellitus, type 1; Biomarkers; Cytokines; Chemokines

Figure

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  Fig. 1 (A) Glycemic changes in patients with immune-checkpoint inhibitor (ICI)-induced type 1 diabetes mellitus are shown. (B) Casual plasma glucose levels are indicated with changes in the last 6 weeks until the onset.

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  Fig. 2 Rate of changes in values for each factor for 6 weeks until the onset of immune-checkpoint inhibitor-induced type 1 diabetes mellitus. In box-and-whisker plots, minimum, lower quartile, median, upper quartile, and maximum levels are shown as indicated. Average levels are shown as ‘x.’ The rate of change in values (each value/baseline value: 0 week), and shown on the y-axis. A significant change between 6 weeks before and at the onset was seen in levels of (A) absolute neutrophil count, (B) relative neutrophil count, (C) absolute lymphocyte count, (D) absolute eosinophil count, (E) relative eosinophil count, (F) neutrophil-lymphocyte rate, and (G) neutrophil-eosinophil rate. A significant change between 3 weeks before and at the onset was observed in levels of (H) albumin, and (I) potassium (K). aP<0.05.

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