**Patient Information**
This report describes two adolescent individuals with autoimmune polyendocrine syndrome type 1 (APS-1) who developed stage 2 type 1 diabetes (T1D). The first individual, who was not initially diagnosed with APS-1, presented with symptoms prompting early investigation. She exhibited multiple autoimmune features including hypoparathyroidism, adrenal insufficiency, alopecia, and chronic mucocutaneous candidiasis. Her genetic background included compound heterozygous mutations (796C>T and 1337G>A) in the AIRE gene.
The second individual had a pre-existing diagnosis of APS-1, confirmed by homozygosity for the 796C>T mutation in AIRE. She demonstrated diverse autoimmune manifestations such as hypoparathyroidism, enteritis, vitiligo, hypothyroidism, and adrenal insufficiency.
Both patients were on various medications to manage their autoimmune conditions, detailed in supplementary materials. Laboratory evaluation revealed the presence of islet autoantibodies, though the antibody profiles varied between the two individuals.
Diagnosis
Both patients exhibited oral glucose tolerance test (OGTT) results consistent with stage 2 T1D, characterized by abnormal glucose regulation without complete dependence on exogenous insulin. The diagnosis of autoimmune T1D in the context of APS-1 was supported by autoantibody positivity and clinical presentation.
Differential Diagnosis
Differential diagnosis considered other causes of hyperglycemia such as monogenic Diabetes Mellitus and secondary causes due to other autoimmune or genetic syndromes. However, the presence of islet autoantibodies and the clinical setting supported diagnosis of autoimmune T1D associated with APS-1. Treatment and Management
Given the autoimmune nature of the disease and the experimental context, both patients received a 14-day course of teplizumab, an anti-CD3 monoclonal antibody known for prolonging β-cell function in early T1D. The first individual was not yet diagnosed with APS-1 at the time of treatment but displayed features suggestive of impending diabetes. The second individual had a confirmed diagnosis of APS-1.
Fig. Individual characteristics and responsiveness to teplizumab dosing. A: APS-1 manifestations in each individual. B: Autoantibody status of each individual. C: OGTTs indicated abnormal 60-min glucose tolerance (normal <155 mg/dL) in individual 1 and 120-min (normal <140 mg/dL) glucose tolerance in both individuals, indicative of stage 2 T1D. D: Absolute lymphocyte counts during the 14 day teplizumab infusion indicated a nadir at day 5 in both individuals, with an increase thereafter. E: Treatment-related adverse events for both individuals included a rash on individual 1 and elevated liver enzyme levels in individual 2. Individual 2 also was treated with insulin due to abnormal glucose results from CGM data observed on review of the prior 3 days during day 1 of infusion. JDF, Juvenile Diabetes Federation; N.D., not detected; Ref, reference; yo, years old.
Prior to treatment, individual 2 was started on insulin therapy due to elevated glucose levels. Post-treatment, insulin was discontinued by day 11, and patients were monitored with continuous glucose monitoring (CGM) and oral glucose tolerance testing (OGTT) at scheduled intervals.
In individual 1, OGTT normalized to stage 1 diabetes at 3, 6, and 12 months post-intervention. Individual 2 demonstrated marked improvement: reduced time in hyperglycemia, a decrease in hemoglobin A1c to 6.0% at 9 months, and sustained normoglycemia on CGM data. These findings suggest preservation or recovery of endogenous insulin secretion.
Additional assessments included pancreatic imaging and spectral immune cell phenotyping. Magnetic resonance imaging (MRI) indicated a transient increase in pancreatic volume post-treatment in individual 1. Immunophenotyping analysis revealed phenotypic shifts in T cell populations, notably a reduction in markers associated with T cell homing and senescence, such as CCR7, CXCR4, and CD127, and alterations in CD57+ T cell populations.
**Outcome and Prognosis**
Both individuals experienced improved glycemic control following teplizumab therapy. Individual 1 showed a reversion from stage 2 to stage 1 T1D, with normalized OGTT results over a year. Individual 2 achieved insulin independence and maintained lower glucose levels with improved CGM metrics over 9 months.
Both patients showed no change in other APS-1 manifestations or autoantibody titers, indicating the specificity of the intervention’s effect on pancreatic β-cell function. The transient increase in pancreatic volume and immune cell phenotypic shifts suggest mechanisms involving immune modulation and tissue response.
**Discussion**
This case series provides preliminary evidence that teplizumab may be beneficial in modulating autoimmune T1D associated with APS-1, potentially delaying or reversing disease progression. The phenotypic immune changes observed mirror those seen in idiopathic early T1D responders, supporting the immunomodulatory role of anti-CD3 therapy.
The findings are significant given the rarity of APS-1 and the limited data on immune intervention in this population. Larger studies are necessary to establish efficacy, durability, and mechanistic details, including tissue-specific immune responses.
This report underscores the promise of targeted immunotherapy for autoimmune endocrine diseases, especially in genetically susceptible individuals. Future exploration may include combination therapies and personalized approaches based on immunophenotyping.
**References**
Wilson CS, Falk A, Williams JM, et al. Use of Teplizumab to Modulate Stage 2 Type 1 Diabetes in Two Individuals With Autoimmune Polyendocrine Syndrome 1. Diabetes Care. 2026 Jan 1;49(1):111-117. doi: 10.2337/dc25-1444 IF: 16.6 Q1 . PMID: 41223156 IF: 16.6 Q1 .
