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

Inaba, Hidefumi; Kaido, Yosuke; Ito, Saya; Hirobata, Tomonao; Inoue, Gen; Sugita, Takakazu; Yamamoto, Yuki; Jinnin, Masatoshi; Kimura, Hiroaki; Kobayashi, Tomoko; Iwama, Shintaro; Arima, Hiroshi; Matsuoka, Taka‐aki

doi:10.3803/enm.2021.1282

“…However, other authors have also described an overrepresentation of T1DM protective haplotypes in patients with DM-ICIs (such as DR7, DR11 o DR15), which casts doubt on the real role of genetic predisposition in the pathogenesis of DM-ICIs [21]. This position is reinforced by the fact that DR9 (an HLA-II haplotype associated with Asian Fulminant Diabetes (AFD), which has a similar course to that of DM-ICIs) has not been found to be overrepresented [19,20,37]. Some authors have suggested the existence of different subtypes of DM-ICIs depending on the clinical and biochemical profile at the onset [25].…”

Section: Discussionmentioning

confidence: 99%

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Vera-Gómez

¹

,

Piñar-Gutiérrez

²

,

Guerrero-Vázquez

³

et al. 2022

Journal of Diabetes Research

4

1

0

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Objectives. The aim of this study is to investigate in depth diabetes mellitus associated with immune checkpoint inhibitors (DM-ICIs) by analysing a case series. We also evaluated the clinical impact of flash glucose monitoring (FGM) systems in the management of this entity. Methods. We conducted an observational cohort study of DM-ICIs diagnosed in two hospitals in Seville (Spain). Patients with a new diagnosis of diabetes mellitus (DM) or with sudden worsening of preexisting DM after starting treatment with ICIs, with a random 5 hour-postprandial C-peptide value of <0.6 nmol/L and without possibility of subsequent withdrawal of insulin treatment, were included. Results. A total of 7 cases were identified, mostly males ( n = 6 ; 85.7%), with a mean age of 64.9 years. The mean glycated hemoglobin (HbA1c) upon diagnosis was 8.1%, with diabetic ketoacidosis (DKA) observed in 6 cases (85.7%). Subcutaneous flash glucose monitoring (FGM) systems were used in six cases, with a mean follow-up period of 42.7 weeks. During the first 90 days of use, mean average glucose was 167.5 mg/dL, with a coefficient of variation (CV) of 34.6%. The mean time in the range 70-180 mg/dL (TIR) was 59.7%, with a mean time above range (TAR) 181-250 mg/dL of 27.8% and a mean TAR > 250 mg / dL of 10.2%. The mean time below range (TBR) 54-69 mg/dL was 2%, while the mean TBR < 54 mg / dL was 0.3%. The mean glucose management indicator (GMI) was 7.3%. No significant differences were observed in FGM values for the following 90 days of follow-up. A progressive improvement in all parameters of glycaemic control was observed between the first month of FGM use and the sixth month of FGM use. Of note, there was a decrease in mean CV (40.6% to 34.1%, p = 0.25 ), mean TAR 181-250 (30.3% to 26%, p = 0.49 ), mean TAR > 250 mg / dL (16.3% to 7.7%, p = 0.09 ), mean TBR 54-69 mg/dL (5.2% to 2%, p = 0.16 ), and mean TBR < 54 mg / dL (1.8% to 0.2%, p = 0.31 ), along with an increase in mean values of TIR 70-180 mg/dL (46.5% to 60.5%, p = 0.09 ). The lack of statistical significance in the differences observed in the mean FGM values over the follow-up period may be related to the small sample size. Conclusion. DM-ICI is recognised by a state of sudden-onset insulinopenia, often associated with DKA. The use of FGM systems may be a valid option for the effective management of DM-ICIs and for the prevention of severe hyperglycaemic and hypoglycaemic episodes in this condition.

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“…In comparison with our previous study (5), the current study was conducted on a larger scale with confirmation of HLA-DPB1*05:01 predominance in ICI-T1DM than those of general controls and ICIcontrols with the same ethnic background. Current study may also support other reports describing that HLA-DR4 alleles are increased in patients with ICI-T1DM in the United States (21,22), although these studies are not at the detailed allelic levels.…”

Section: Discussionmentioning

confidence: 79%

“…Immune-checkpoint inhibitors (ICIs) are effective agents in various cancers; however, immune-related adverse events (irAEs) often occur during treatment with ICIs (1)(2)(3)(4)(5). Major endocrine irAEs include pituitary irAE (3), thyroid irAE (4), and ICI-induced type 1 diabetes mellitus (ICI-T1DM).…”

Section: Introductionmentioning

confidence: 99%

“…Major endocrine irAEs include pituitary irAE (3), thyroid irAE (4), and ICI-induced type 1 diabetes mellitus (ICI-T1DM). ICI-T1DM is an especially critical irAE due to the possibility of acute damage to pancreatic bcells (5). Qiu et al reported that anti-insulin antibody was observed in 7 patients with ICI-T1DM (3 patients with fulminant type 1 diabetes, and 4 patients with acute type 1 diabetes) (6).…”

Section: Introductionmentioning

confidence: 99%

“…Major endocrine irAEs include pituitary irAE ( 3 ), thyroid irAE ( 4 ), and ICI-induced type 1 diabetes mellitus (ICI-T1DM). ICI-T1DM is an especially critical irAE due to the possibility of acute damage to pancreatic β-cells ( 5 ). Qiu et al.…”

Section: Introductionmentioning

confidence: 99%

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Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

Inaba

¹

,

Morita

²

,

Kosugi

³

et al. 2023

Self Cite

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IntroductionImmune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear.MethodsWe examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules.Results and DiscussionTwelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

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Clinical characteristics and human leukocyte antigens in patients with immune checkpoint inhibitor-induced type 1 diabetes and pituitary dysfunction: a single center prospective study

Hara

¹

,

Suwanai

²

,

Yakou

³

et al. 2023

Endocrine

3

0

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Immune checkpoint inhibitor (ICI)-induced type 1 diabetes and pituitary dysfunction are life-threatening adverse events, yet there is little clinical data available. We aimed to investigate the clinical characteristics of patients with these adverse events and report their human leukocyte antigen (HLA) pro le to determine its relevance. MethodsThis is a single-center prospective study. We collected clinical and biochemical data and extracted DNA from blood samples. HLA typing was performed using next-generation sequencing. We compared our results with those previously reported in healthy controls and investigated the correlation between HLA and the occurrence of ICI-induced type 1 diabetes and pituitary dysfunction. ResultsWe identi ed 914 patients treated with ICI in our facility from 1st September, 2017 to 30th June, 2022. Six of these patients developed type 1 diabetes and 14 developed pituitary dysfunction. The duration from the initiation of ICI treatment to the onset of type 1 diabetes or pituitary dysfunction averaged 492 ± 196 days and 191 ± 169 days, respectively. Among the six patients with type 1 diabetes, two were positive for anti-GAD antibody. The frequencies of HLA-DR11, -Cw10, -B61, -DRB1*11:01, and -C*03:04 were signi cantly higher in patients with ICI-induced type 1 diabetes than in controls. The frequencies of HLA-DR15 and -DRB*15:02 were signi cantly higher in patients with ICI-induced pituitary dysfunction than in controls. ConclusionThis study revealed the clinical characteristics of type 1 diabetes and pituitary dysfunction induced by ICI and the association between speci c HLAs and these adverse events.

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

Cited by 20 publications

References 36 publications

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Flash Glucose Monitoring and Diabetes Mellitus Induced by Immune Checkpoint Inhibitors: An Approach to Clinical Practice

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

Clinical characteristics and human leukocyte antigens in patients with immune checkpoint inhibitor-induced type 1 diabetes and pituitary dysfunction: a single center prospective study

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