Fulminant Type Research Articles

Differences in Immune Cell-Derived Circular RNA Between Fulminant Type 1 Diabetes and Type 1 Diabetes.

Circular RNAs (circRNAs) are associated with fulminant type 1 diabetes (FT1D) and type 1 diabetes (T1D). However, the differences in circRNAs between FT1D and T1D remain unclear. Our objective is to identify peripheral blood mononuclear cells (PBMCs)-derived circRNAs in FT1D and T1D and explore their potential functions. PBMCs were extracted from six patients with FT1D and age-, sex-, and duration-matched T1D patients. The Arraystar Human circRNA Array was utilised to obtain circRNA expression profiles. Seven aberrantly expressed circRNAs were selected for determining expression levels in another independent cohort (FT1D subjects n=35, T1D subjects n=70, and controls n=100) using real-time quantitative PCR (RT-qPCR). Biological functions, circRNA-miRNA-mRNA networks, and the coding potential of circRNAs were predicted through bioinformatics analysis. In total, 145 differentially expressed circRNAs were identified in FT1D and T1D, with 63 upregulated and 82 downregulated circRNAs. Hsa_circRNA_038288, hsa_circRNA_104405, and hsa_circRNA_405498 were successfully validated among the 7 aberrantly expressed circRNAs selected to determine expression levels. Bioinformatics analysis revealed that majority of the parent genes of circRNAs are enriched in signalling pathways such as RNA transport, ubiquitin-mediated proteolysis, and focal adhesion. Hsa_circRNA_038288 appears to play a role in 51 circRNA-miRNA-mRNA signalling pathways associated with immune regulation and diabetes. Additionally, hsa_circRNA_038288 potentially exhibits coding potential and is involved in the progression of both FT1D and T1D. Significant differences in immune cell-derived circRNAs were found between FT1D and T1D patients, offering novel insights into the molecular mechanisms that distinguish FT1D from T1D.

Use pembrolizumab may cause acute and severe adverse reactions: a case report and review

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as pivotal therapeutics for personalized cancer treatment. Programmed death protein receptor 1/ligand 1 (PD-1/PD-L1) inhibitors represent the most extensively utilized immune checkpoint blockade agents. Among these, pembrolizumab has gained approval for advanced cancer management. By engaging with PD-1 on T cells, pembrolizumab orchestrates the immune response against tumor cells; however, it is also associated with a spectrum of adverse events, including an infrequent manifestation of fulminant type 1 diabetes. Case presentation: ICIs-induced fulminant type 1 diabetes mellitus (FT1DM) in breast cancer patients has been rarely documented. To provide further evidence of such adverse events, this paper presents the case of a 58-year-old Chinese patient with breast cancer and multi-organ metastasis, who had no prior history of diabetes. Following five courses of pembrolizumab, she developed severe fulminant type 1 diabetes accompanied by ketoacidosis. Discussion: Pembrolizumab is commonly utilized in the treatment of patients with advanced cancer. While it offers significant benefits to patients, it can also lead to numerous adverse reactions, with immune-related diabetes being the most prevalent among them as a result of pembrolizumab usage. Conclusions: FT1DM complicated with ketoacidosis represents a critical and potentially life-threatening medical condition, necessitating immediate attention. Our case study underscores the inherent risks associated with pembrolizumab administration and offers valuable insights for its safe utilization in patients.

Fulminant type 1 diabetes and autoimmune thyroid disease during treatment with a checkpoint inhibitor

Fulminant type 1 diabetes and autoimmune thyroid disease during treatment with a checkpoint inhibitor

Stevens-Johnson Syndrome/Toxic epidermal necrolysis complicated with fulminant type 1 diabetes mellitus: a case report and literature review

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed β-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported.Case presentationWe present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally.ConclusionsThis rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis.

Snap diagnosis of fulminant type 1 diabetes by the normalized glucose/HbA1c ratio.

Elevated Fulminant Index (FI), [plasma glucose (PG)/glycosylated hemoglobin A1c (HbA1c)], was reportedly a sensitive index to differentiate fulminant type 1 diabetes (FT1D) from non-fulminant T1D (nFT1D). Aim of this study was to describe a better, but simpler index of FT1D. 49 and 52 patients with FT1D and nFT1D, respectively, were registered, and the discriminating ability of the rounded, normalized ratio, [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0], and the original ratio, [PG (mmol/L)]/[HbA1c (%)], was compared. Normalizing the ratio significantly raised its accuracy: area under the curve for receiver operating curve, AUROC (95%CI), 0.927 (0.858-0.964) and 0.851 (0.763-0.910), respectively, with and without the normalization (p < 0.01). Rounding of the figure into [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0] did not significantly sacrifice the discriminating ability of the index. Namely, the optimal cut point of rounded and normalized GAR, 10.0, showed 89.8% sensitivity. In conclusion, rounded, normalized (rn) GAR ≥10 (the rounded optimal cut-off) could be used for the snap diagnosis of FT1D.

One Sugar Too Many: A Rare Case of Fulminant Type 1 Diabetes Following Chemotherapy in Advanced Pancreatic Cancer and Comprehensive Literature Review

One Sugar Too Many: A Rare Case of Fulminant Type 1 Diabetes Following Chemotherapy in Advanced Pancreatic Cancer and Comprehensive Literature Review

Prevalence and prognosis of fulminant type 1 diabetes mellitus in The Middle East: a comparative analysis in a 5-year nationwide cohort

PurposeTo analyze the prevalence and progression of fulminant type 1 diabetes (FT1D) in Qatar.MethodsThis retrospective study analyzed consecutive index- diabetic ketoacidosis (DKA) admissions (2015–2020) among patients with new-onset T1D (NT1D) in Qatar.ResultsOf the 242 patients, 2.5% fulfilled the FT1D diagnostic criteria. FT1D patients were younger (median-age 4-years vs.15-years in classic-T1D). Gender distribution in FT1D was equal, whereas the classic-T1D group showed a female predominance at 57.6% (n = 136). FT1D patients had a mean C-peptide of 0.11 ± 0.09 ng/ml, compared to 0.53 ± 0.45 ng/ml in classic-T1D. FT1D patients had a median length of stay (LOS) of 1 day (1-2.2) and a DKA duration of 11.25 h (11–15). The median (length of stay) LOS and DKA duration in classic-T1D patients were 2.5 days (1-3.9) and 15.4 h (11–23), respectively. The FT1D subset primarily consisted of moderate (83.3%) and severe 916.7%) DKA, whereas classic T1D had 25.4% mild, 60.6% moderate, and 14% severe DKA cases. FT1D was associated with a higher median white cell count (22.3 × 103/uL) at admission compared to classic T1D (10.6 × 103/uL). ICU admission was needed for 66.6% of FT1D patients, compared to 38.1% of classic-T1D patients. None of the patients in the FT1D group had mortality, while two died in the classic-T1D group.ConclusionThis is the first study establishing the existence of FT1D in ME, which presented distinctively from classic-T1D, exhibiting earlier age onset and higher critical care requirements. However, the clinical outcomes in patients with FT1D seem similar to classic T1D.

Fulminant type 1 diabetes, an underrecognized and unique subtype of type 1 diabetes: A case series from Singapore.

Fulminant type 1 diabetes (FT1D) is a unique subtype of type 1 diabetes, characterized by acute absolute insulin deficiency, severe ketosis, and increased risk of hypoglycemia, glycemic variability and microvascular complications. Seven people with FT1D were identified from two tertiary centers in Singapore. Six were Chinese, the mean age was 35 years and all were lean (mean body mass index 20.3 kg/m2). All presented with diabetes ketosis or ketoacidosis and low C-peptide. All but one had low glutamic acid decarboxylase antibodies. Nearly half had a missed/delayed diagnosis of FT1D. Three had frequent hypoglycemia, which improved after transition to continuous subcutaneous insulin infusion therapy. Individuals with FT1D experience unique diagnostic and management challenges associated with rapid absolute insulin deficiency. Greater awareness about this clinical entity is required.

Fulminant Type 1 Diabetes Caused by DIHS Could Be Affected by the Reactivation of HHV-6.

In the previous issue of this journal, we reported that the incidence of fulminant type 1 diabetes (FT1D) due to the drug-induced hypersensitivity syndrome (DIHS) in Japan is higher than that in the general population and is associated with HLAB62. On the other hand, the reactivation of human herpesvirus 6 (HHV-6), which has been reported to be associated with DIHS, was observed at a higher frequency, but its association with the development of FT1D was unclear. We aimed to clarify the relationship between the onset of FT1D and the reactivation of HHV-6. We conducted a literature search for cases of DIHS-induced FT1D in addition to previously reported cases and investigated the changes in the HHV-6 antibody titer before and after the onset of FT1D. The HHV-6 antibody titer was increased just before or after the onset of FT1D in all 8 cases. In 1 case, HHV-6 DNA was also identified shortly before the onset of FT1D. These results indicate for the first time that the reactivation of HHV-6 is associated with the onset of FT1D caused by DIHS.

COVID-19 Vaccination and Its Relation to New-Onset Diabetes: A NarrativeReview.

The COVID-19 vaccination has been effective in preventing a lot of complications caused by SARS-CoV-2 and its variants. Meanwhile, diabetes mellitus, one of the root causes of many co-morbidities, exhibited itself during the COVID-19 pandemic and after COVID-19 vaccination. Diabetes mellitus introduced itself in a new perspective, leading to a variety of presentations and causing a significant number ofemergency admissions. Many of the pre-diabetes patients with no prior history of diabetes developed fulminant type 1 diabetes mellitus (T1DM) after the COVID-19 vaccination. Some cases of conversion of type 2 diabetes mellitus (T2DM) into T1DM were reported. Some prediabetes/diabetes patientspresented with the development of diabetic ketoacidosis after COVID-19 vaccination, whereas some previously healthy people with no relation to diabetes also developed acute exacerbations of new-onset T1DM or T2DM along with lethal ketoacidosis. The purpose of writing this review was to explore what kind of people are more prone to develop new-onset diabetes or diabetic complications, including diabetic ketoacidosis, the typical presentation of these patients, possible mechanisms that lead to these complications occurring after the COVID-19 vaccination, how they can be managed, and whether there is a good prognosis after management or not.

Fulminant type 1 diabetes: Focusing on triggering factors.

Fulminant type 1 diabetes (FT1D) is a novel type of type 1 diabetes that is caused by extremely rapid destruction of the pancreatic β cells. Early diagnosis or prediction of FT1D is critical for the prevention or timely treatment of diabetes ketoacidosis, which can be life-threatening. Understanding its triggers or promoting factors plays an important role in the prevention and treatment of FT1D. In this review, we summarised the various triggering factors of FT1D, including susceptibility genes, immunological factors (cellular and humoural immunity), immune checkpoint inhibitor therapies, drug reactions with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome, pregnancy, viral infections, and vaccine inoculation. This review provides the basis for future research into the pathogenetic mechanisms that regulate FT1D development and progression to further improve the prognosis and clinical management of patients with FT1D.

Metachronous immune-related adverse events involving type 1 diabetes and isolated adrenocorticotropic hormone deficiency associated with pembrolizumab monotherapy for metastatic head and neck cancer: a case report

BackgroundImmune checkpoint inhibitors might cause immune-related adverse events that are still largely unknown.Case presentationAn 80-year-old Asian female was diagnosed with cervical lymph node metastasis from lip cancer (cT1N0M0) and underwent right cervical neck dissection. Subsequently, she developed right cervical lymph node relapse and lung metastasis. The patient was deemed eligible for pembrolizumab owing to unresectable neck recurrence and pulmonary metastasis. The Combined Positive Score of the submandibular lymph nodes was 100. Pembrolizumab monotherapy was initiated, and complete remission was achieved. She developed diabetic ketoacidosis in the eighth month and was diagnosed with fulminant type 1 diabetes mellitus. Insulin induction was performed. The patient developed adrenal insufficiency after 10 months. These were immune-related adverse events, caused by pembrolizumab. The patient has remained in complete remission, and pembrolizumab therapy was continued.ConclusionsThe study presents the first reported case of type 1 diabetes in a patient with head and neck squamous cell carcinoma treated with pembrolizumab monotherapy, in Japan. Efficient interdepartmental collaboration will promote the management of severe immune-related adverse events and improve the quality of life of patients.

CHRONIC INFLAMMATORY DERMATOSIS: ROSACEA, OVERVIEW, DESCRIPTION, PRESENTATION, EPIDEMIOLOGY, PATHOPHYSIOLOGY, TYPES, DIFFERENTIAL DIAGNOSIS, TREATMENT OF THE DISEASE AND ITS ROLE IN PREGNANCY

Introduction: Rosacea is a chronic inflammatory dermatosis involving especially the cheeks, nose, chin and forehead, characterized by repetitive episodes of transient flushing or erythema, persistent erythema, in addition to phymatous changes, papules, pustules and telangiectasias. Objective: to detail the current information related to rosacea, description, presentation, epidemiology, pathophysiology, types, differential diagnosis, treatment of the disease and its role in pregnancy. Methodology: a total of 50 articles were analyzed in this review, including review and original articles, as well as clinical cases, of which 39 bibliographies were used because the other articles were not relevant to this study. The sources of information were PubMed, Google Scholar and Cochrane; the terms used to search for information in Spanish, Portuguese and English were: rosacea, treatment, chronic inflammatory dermatosis. Results: Phymatous changes are not frequent, however they occur primarily in the nose (rhinophyma) and more commonly in men. Rosacea usually begins between 30 and 50 years of age, however it can occur at any age. The approximate population prevalence is between less than 1 to 22%. The neurocutaneous mechanisms in rosacea, reflecting reactivity to temperature change, alcohol, sports, UV rays and spicy foods, may be mediated by the ankyrin and vanilloid subfamilies of the transient receptor potential (TRP). Increased rosacea can occur in pregnancy and multiple cases linked to rosacea fulminans (RF) are reported in the literature. Conclusions: Rosacea is characterized by repetitive episodes of redness, persistent erythema, inflammatory papules-pustules and telangiectasias. Previously rosacea was divided into ocular, phymatous, fulminant and granulomatous types, however there is now a new classification of rosacea. In the treatment the first thing is to identify the trigger, then make some general recommendations on the skin such as the use of sunscreen and finally give treatment that can be both topical and systemic or even to use laser or other procedures. The differential diagnosis of rosacea is broad and should be carefully analyzed. Treatment in pregnant women is a huge challenge, because several of the treatments for rosacea are contraindicated or have limited evidence of probable side effects to the fetus. KEYWORDS: rosacea,treatment,dermatosis,inflammatory.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies

BackgroundWith the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events.MethodsA retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month.Results28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up.ConclusionsIAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Basophil responses in susceptible AKR mice upon infection with the intestinal helminth parasite Trichuris muris.

Intestinal helminth infection promotes a Type 2 inflammatory response in resistant C57BL/6 mice that is essential for worm clearance. The study of inbred mouse strains has revealed factors that are critical for parasite resistance and delineated the role of Type 1 versus Type 2 immune responses in worm clearance. In C57BL/6 mice, basophils are key innate immune cells that promote Type 2 inflammation and are programmed via the Notch signalling pathway during infection with the helminth Trichuris muris. However, how the host genetic background influences basophil responses and basophil expression of Notch receptors remains unclear. Here we use genetically susceptible inbred AKR/J mice that have a Type 1-skewed immune response during T. muris infection to investigate basophil responses in a susceptible host. Basophil population expansion occurred in AKR/J mice even in the absence of fulminant Type 2 inflammation during T. muris infection. However, basophils in AKR/J mice did not robustly upregulate expression of the Notch2 receptor in response to infection as occurred in C57BL/6 mice. Blockade of the Type 1 cytokine interferon-γ in infected AKR/J mice was not sufficient to elicit infection-induced basophil expression of the Notch2 receptor. These data suggest that the host genetic background, outside of the Type 1 skew, is important in regulating basophil responses during T. muris infection in susceptible AKR/J mice.

Development of Fulminant Type 1 Diabetes Mellitus in the Course of Treatment with Atezolizumab for Hepatocellular Carcinoma.

A 71-year-old woman with recurring stage IV hepatocellular carcinoma (HCC) was admitted to our hospital while being treated with atezolizumab and bevacizumab and complained of fatigue, vomiting, and appetite loss. The following were noted on admission: serum glucose level, 633 mg/dL; metabolic acidemia (HCO3- of 19.5 mmol/L); remarkably low serum and urinary C-peptide levels (0.16 ng/mL and ≤1.5 μg/day, respectively); and urinary ketone body level, 4,197 μmol/L. She was diagnosed with atezolizumab-induced fulminant type 1 diabetes mellitus (T1DM), and insulin therapy improved the symptoms. To our knowledge, this a novel report of atezolizumab-induced fulminant T1DM in an HCC patient.

Fulminant Type 1 Diabetes-East and West.

Fulminant type 1 diabetes is a subtype of type 1 diabetes in which beta cells are destroyed within days or a few weeks. The first criterion indicates a rise in blood glucose levels shown in the patient's history. The second suggests that the increase occurs suddenly within a very short period, as shown by the laboratory findings of the discrepancy between the glycated hemoglobin concentration and plasma glucose level. The third indicates a marked reduction in endogenous insulin secretion, which indicates almost complete destruction of beta cells. Fulminant type 1 diabetes is a common subtype in East Asian countries, including Japan, but rare in Western countries. Class II human leukocyte antigen and other genetic factors may have contributed to the skewed distribution. Environmental factors may also be involved including entero and herpes viruses and immune regulation during drug-induced hypersensitivity syndrome; pregnancy may also affect it. In contrast, treatment with an immune checkpoint inhibitor of the anti-programmed cell death 1 antibody induces similar characteristics and incidence of diabetes as fulminant type 1 diabetes. Further studies are needed to clarify the etiology and clinical characteristics of fulminant type 1 diabetes. Although the incidence of this disease differs between the East and West, it is life-threatening; thus, it is important to diagnose fulminant type 1 diabetes without delay and treat it appropriately.

Clinical and HLA genotype analysis of immune checkpoint inhibitor-associated diabetes mellitus: a single-center case series from China.

To investigate the clinical characteristics and HLA genotypes of patients with immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) in China. We enrolled 23 patients with ICI-DM and 51 patients with type 1 diabetes (T1D). Clinical characteristics of the patients were collected. HLA-DRB1, HLA-DQA1, and HLA-DQB1 genotyping was conducted via next-generation sequencing. The ICI-DM patients had a male predominance (70.6%), a mean body mass index (BMI) of 21.2 ± 3.5 kg/m2, and a mean onset of ICI-DM in 5 (IQR, 3-9) cycles after ICI therapy. Most (78.3%) ICI-DM patients were treated with anti-PD-1, 78.3% presented with diabetic ketoacidosis, and all had low C-peptide levels and received multiple insulin injections. Compared to T1D patients, ICI-DM patients were significantly older (57.2 ± 12.4 vs 34.1 ± 15.7 years) and had higher blood glucose but lower HbA1c levels (P<0.05). Only two (8.7%) ICI-DM patients were positive for islet autoantibodies, which was lower than that in T1D patients (66.7%, P<0.001). A total of 59.1% (13/22) of ICI-DM patients were heterozygous for an HLA T1D risk haplotype, and DRB1*0901-DQA1*03-DQB1*0303 (DR9) and DRB1*0405-DQA1*03-DQB1*0401 were the major susceptible haplotypes. Compared to T1D, the susceptible DR3-DQA1*0501-DQB1*0201 (DR3) and DR9 haplotypes were less frequent (17.7% vs 2.3%; P=0.011 and 34.4% vs 15.9%; P=0.025), whereas the protective haplotypes (DRB1*1101-DQA1*05-DQB1*0301 and DRB1*1202-DQA1*0601-DQB1*0301) were more frequent in ICI-DM patients (2.1% vs 13.6%; P=0.006 and 4.2% vs 15.9%; P=0.017). None of the ICI-DM patients had T1D-associated high-risk genotypes DR3/DR3, DR3/DR9, and DR9/DR9. Among the 23 ICI-DM patients, 7 (30.4%) presented with ICI-associated fulminant type 1 diabetes (IFD), and 16 (69.6%) presented with ICI-associated type 1 diabetes (IT1D). Compared to IT1D patients, IFD patients exhibited marked hyperglycemia and low C-peptide and HbA1c levels (P<0.05). Up to 66.7% (4/6) of IFD patients were heterozygous for reported fulminant type 1 diabetes susceptibility HLA haplotypes (DRB1*0405-DQB1*0401 or DRB1*0901-DQB1*0303). ICI-DM shares similar clinical features with T1D, such as acute onset, poor islet function and insulin dependence. However, the lack of islet autoantibodies, the low frequencies of T1D susceptibility and high frequencies of protective HLA haplotypes indicate that ICI-DM represents a new model distinct from classical T1D.

Improving diagnostic accuracy of 3 Screen ICA ELISA kit in the identification of Japanese type 1 diabetes.

This study aimed to investigate the clinical utility of 3 Screen ICA ELISA in identifying immune-mediated type 1 diabetes in Japanese subjects. We compared the positivity of 3 Screen ICA were compared with autoantibodies against GAD, IA-2, and ZnT8 in 638 patients with type 1 diabetes and 159 healthy control subjects. With a cut-off value of 20.0 index, 67.4% of acute-onset type 1 diabetic patients, 71.8% of slowly progressive type 1 diabetic (SPIDDM) patients, and none of the fulminant type 1 diabetic patients showed 3 Screen ICA levels above this threshold. The prevalence of 3 Screen ICA was 14.2% higher in acute-onset type 1 diabetes and 1.6% higher in SPIDDM than in GADA. 3 Screen ICA-positive cases were found in 4.8% of cases of individual autoantibody-negative acute-onset type 1 diabetes and 3.8% of SPIDDM, indicating improved diagnostic sensitivity with the 3 Screen ICA. Among individual autoantibody-negative patients, the sum of each autoantibody level was significantly lower in fulminant type 1 diabetes than in acute onset type 1 diabetes and in SPIDDM (P < 0.0001). Additionally, 84.2% of patients negative for individual autoantibodies but positive for 3 Screen ICA had a sum of individual autoantibody levels of ≥4.7 U/mL. Furthermore, 3 Screen ICA levels were significantly higher in patients with type 1 diabetes with other autoimmune diseases than in those without (P < 0.0001). Our findings suggest that the 3 Screen ICA ELISA may be a valuable screening tool for Japanese patients with type 1 diabetes, potentially increasing the diagnostic sensitivity and accuracy beyond the existing GADA, IA-2A, and ZnT8A tests.

Clinical and immune phenotypes associated with immune checkpoint inhibitor-induced autoimmune diabetes.

2509 Background: ICI-induced autoimmune diabetes (ICI-DM) is an immune-related adverse event (IrAE) that affects approximately 1% of patients who receive ICI. Most reports of ICI-DM suggest that it resembles fulminant type 1 diabetes, with low or absent endogenous insulin production at presentation. However, milder cases have recently been reported, suggesting a more heterogeneous disease. In this study, we identified distinct clinical phenotypes of ICI-DM that may improve individualized approaches to management. Methods: We performed a retrospective chart review of 16,582 patients treated with either anti-PD1, anti- PDL1, anti-CTLA4, or combination between 2010 and 2022 in a multi-centered academic hospital system. We identified patients with ICI-DM as those with a new diagnosis of type 1 diabetes or drug-induced diabetes and a prescription for medium- or long-acting insulin following ICI therapy; cases were confirmed by chart review by two board-certified endocrinologists. To phenotype ICI-DM based on endogenous insulin production, we reviewed all patients with ICI-DM who had a C-peptide level in our system, which allowed us to identify and subdivide 57 cases of ICI-DM. These patients were further characterized at both initial presentation and up to 30 months of follow-up. Results: We identified six distinct groups of ICI-DM based on the presence (A+) or absence (A-) of diabetes-specific autoantibodies, further divided by level of endogenous insulin production, preserved (B+), low (B+/-) or undetectable (B-). In our cohort, A+B- patients showed to have the lowest time to diagnosis (median 45 days) and high rates of both DKA and hospitalization (67%) at presentation. At the other end of the spectrum, A-B+ patients had a longer time to diagnosis (median 176 days) and no evidence of DKA or hospitalization at presentation. Surprisingly, all groups had similar insulin requirements without significant dosage variations at 30-month follow up. Elevated lipase levels varied widely across groups with the highest rate (66.7%) reported in the A+B- cohort. The prevalence of thyroiditis in our cohort was highest in the A-B- group but did not seem to follow any specific distribution. Conclusions: Our study examined the largest data set to date of deep clinical phenotyping of patients with ICI-DM. We define at least three distinct subsets of ICI-DM, with A+B- patients being most similar to the initially described cases of fulminant type 1 diabetes. Patients with negative antibodies seem to have a milder form of the disease. Our findings also suggest significant heterogeneity and distinct underlying mechanisms amongst cases of ICI-DM. Further studies will be needed to elucidate whether these findings could extrapolate to other individual IrAEs, which may also encompass distinct phenotypes with distinct mechanisms.