Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors

Fujita, Yasunori; Kamitani, Fumika; Yamamoto, Masaaki; Fukuoka, Hidenori; Hirota, Yushi; Nishiyama, Nobuharu; Goda, Naho; Okada, Yuko; Inaba, Yuiko; Nakajima, Hiroki; Kurematsu, Yukako; Kanie, Keitaro; Shichi, Hiroki; Urai, Shin; Suzuki, M.; Yamamoto, Naoki; Bando, Hironori; Iguchi, Genzo; Suto, Hirotaka; Funakoshi, Yohei; Kiyota, Naomi; Takahashi, Yutaka; Ogawa, Wataru

doi:10.1210/jendso/bvad002

Cited by 3 publications

(1 citation statement)

References 43 publications

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“…A total of 84 PD-1/L1-irH cases were extracted from 55 case reports (9-63) and 11 case series [64][65][66][67][68][69][70][71][72][73][74]. The patients' information were summarized in Table 2.…”

Section: Descriptive Analysismentioning

confidence: 99%

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

Chen,

Ouyang,

et al. 2024

DD&T

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PD-1/PD-L1 inhibitors, hypophysitis, disproportionality analysis, characteristic, managements To get a thorough understanding of PD-1/L1 inhibitor-related hypophysitis (PD-1/L1-irH), we utilized a combination of disproportionality analysis and case analysis to comprehensively characterize the clinical features of PD-1/L1-irH. Significant signals of hypophysitis were detected for all PD-1/PD-L1 inhibitors in the FAERS (FDA Adverse Event Reporting System). As revealed by both FAERS and the case analysis, PD-1/L1-irH occurred more commonly in males, PD-1 inhibitors users and patients older than 65 years. The median onset time was 101 days in FAERS and 8 cycles in the case analysis. In the case analysis, eight late-onset PD-1/L1-irHs occurred even after a discontinuation of several months (4-15 months). As revealed in FAERS, the outcome of PD-1/L1-irH tended to be poor, generally resulting in 64.66% hospitalization and 12.59% death. Fatigue was the most prominent symptom of PD-1/L1-irH, followed by anorexia, hyponatremia, and hypotension, as revealed by the analysis of 84 cases. Meanwhile isolated adrenocorticotropic (ACTH) deficiency was particularly prevalent for PD-1/L1-irH (85.71%), while gonadal hormones or posterior pituitary hormones deficiencies were rare. Glucocorticoids were administered to almost all cases (81/84), with a physiologic or stress dosage in 61.9% of cases, and a high-dose in 26.2% of cases. Most cases (58.3%) showed a favorable tumor response before diagnosis of PD-1/L1-irH. PD-1/L1-irH may occur throughout the whole therapy period even after discontinuation. Clinicians should pay more attention to PD-1 inhibitor users, males and older patients. Early diagnosis and prompt managements are crucial for PD-1/L1-irH as its potentially life-threatening nature.

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Section: Descriptive Analysismentioning

confidence: 99%

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

Chen,

Ouyang,

et al. 2024

DD&T

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HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis

Ono,

Nagao,

Takeuchi

et al. 2024

European Journal of Endocrinology

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Objective Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with both conditions. Methods HLA signatures were examined for their frequencies of occurrence in 22 patients with ICI-T1D without concurrent IAD, including 16 patients from nationwide reports (ICI-T1D group) and 14 patients with ICI-IAD without concurrent T1D (ICI-IAD group). The HLA signatures were also compared for their respective frequencies in 11 patients with ICI-T1D and ICI-IAD, including eight from nationwide reports (ICI-T1D/IAD group). Results In the ICI-T1D group, HLA-DRB1*09:01-DQB1*03:03 and DQA1*03:02, which are in linkage disequilibrium with DRB1*09:01-DQB1*03:03 and DRB1*13:02-DQB1*06:04, were susceptible to ICI-T1D, whereas DRB1*15:02-DQB1*06:01 was protective against ICI-T1D. In the ICI-IAD group, DPB1*09:01, C*12:02-B*52:01, and DRB1*15:02-DRB1*06:01, which are in strong linkage disequilibrium, were associated with susceptibility to ICI-IAD. Moreover, DRB1*15:02-DRB1*06:01 was not detected in the ICI-T1D/IAD group. Conclusions This study revealed specific HLA signatures associated with ICI-T1D and ICI-IAD. Moreover, HLA-DRB1*15:02-DRB1*06:01, an ICI-IAD-susceptible HLA haplotype, coincides with the ICI-T1D-protective HLA haplotype, suggesting that the presence of DRB1*15:02-DRB1*06:01 may protect against the co-occurrence of T1D in patients with ICI-IAD.

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Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB104:05-DQB104:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes

Yabuki,

Hirai,

Moriya

et al. 2024

Front. Endocrinol.

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Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

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Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors

Cited by 3 publications

References 43 publications

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis

Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB104:05-DQB104:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes

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Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors

Cited by 3 publications

References 43 publications

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

PD-1/PD-L1 inhibitors associated hypophysitis: An analysis from the FAERS database and case reports

HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis

Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes

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Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB104:05-DQB104:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes