AIM search for new genetic predictors of autoimmune adrenal insufficiency (AAI). MATERIALS AND METHODS : In n=54 patients with AAI (isolated and as part of type 2 autoimmune polyglandular syndrome (APS-2; group 1)) and n=32 healthy individuals (group 2) we analyzed polymorphisms in IL28B (rs12979860, rs8099917), TLR9 (rs5743836, rs352140), TLR2 (rs5743708). RESULTS : In group 1, compared with group 2, a predominance of CT genotype of rs12979860 polymorphism of IL28B (p=0.024), and T allele of rs5743836 polymorphism of TLR9 (p=0.044) was revealed. The allele C of rs5743836 polymorphism of TLR9 (p=0.044) was more common in group 2 than in group 1. With respect to other genotypes, alleles and haplotypes, no significant differences (or differences at the level of statistical trend) were found between groups 1 and 2. CONCLUSION : Thus, it is possible that the CT genotype according to the polymorphic locus rs12979860 of the IL28B gene and the allele T of the rs5743836 polymorphism of the TLR9 gene are prognostic markers that increase the likelihood of developing AAI due to violation the peripheral immune tolerance (IT), whereas the allele C of the rs5743836 polymorphism of the TLR9 gene performs a protective role in this disease in the Russian population.

Introduction: The addition of immunotherapy to neoadjuvant treatment for early triple-negative breast cancer (TNBC) has been adopted in clinical practice in France since March 2022, with little real-world data published on the topic. The aim of this study was to evaluate real-world data on treatment feasibility, efficacy, and related toxicities, with a specific focus on immune-related adverse events (irAEs). Methods: We conducted a retrospective analysis of patients who completed at least the neoadjuvant sequence of pembrolizumab combined with chemotherapy for early-stage TNBC at Montpellier Cancer Institute from April 2022 to July 2024. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The pathological complete response (pCR) was defined as the absence of residual invasive disease in the breast and axillary lymph nodes (ypT0/Tis ypN0). Results: We reviewed data from 92 patient records. The median age at diagnosis was 50 years (range: 27-76). The history of autoimmune disease was noted in 3.2% of patients. Grade 3-4 irAEs were observed in 20% of patients and included hepatitis (8.6%), colitis (3.3%), skin toxicity (2.1%), myocarditis (2%), arthralgia (1%), autoimmune hemolytic anemia (1%), hypothyroidism (1%), and adrenal insufficiency (1%). No treatment-related deaths were reported. Immunotherapy was discontinued due to irAEs in 29.3% of patients in the study population. The pCR rate was 61,1%, with no significant association between the number of neoadjuvant pembrolizumab cycles and the pCR rate (p = 0.7). Patients experiencing grade 3-4 irAEs had a pCR rate of 80%, compared to 56.7% in those without such toxicities (p = 0.079). Initial positivity of antinuclear antibodies (ANA) was not associated with an increased incidence of irAEs. Conclusions: The immune-related adverse events and efficacy data observed in our cohort were broadly comparable to those reported in the KEYNOTE-522 trial, with no treatment-related deaths. Patients with grade 3-4 irAEs tended to have higher pCR rates.

Disclosure: F. Abdulle: None. H. Dave: None. A. Abushamma: None. A. Diwakar: None.Hypoglycemia is defined as blood glucose BG levels below 60 mg/dL and is considered a serious medical emergency. It requires immediate treatment, as untreated, it may lead to neurological deficits. While hypoglycemia in non-diabetic patients is rare, certain medications contribute. Doxycycline, a broad-spectrum tetracycline, commonly prescribed for pneumonia. We present a case of a non-diabetic male who developed hypoglycemia following treatment with oral doxycycline for suspected community-acquired pneumonia. A 66-year-old male with a past medical history of diastolic heart failure and obstructive sleep apnea presented with dyspnea. He was admitted to the inpatient hospital floor for acute hypoxic respiratory failure, likely in the setting of heart failure. CT revealed mild infiltrates, and IV ceftriaxone and oral doxycycline 100 mg were initiated. After the second dose of doxycycline, the patient became acutely diaphoretic, with a BG reading of 20 mg/dL and a (POC) point-of-care glucose of 40 mg/dL. Vitals were stable. Doxycycline was discontinued, he was managed with a D10 drip and transferred to the intensive care unit. Management continued with a D10 boluses, and POC checks hourly; ranging between 48-136 mg/dL. Endocrinology were consulted. Possible causes of hypoglycemia, including insulin autoimmune hypoglycemia, insulinoma, sulfonylureas, hypothyroidism, and adrenal insufficiency, were ruled out. The latter was confirmed with a negative cosyntropin stimulation test, showing an appropriate cortisol response (basal 11.7 µg/dL, 30 minutes 21.7 µg/dL, 60 minutes). C-peptide levels were found to be 0.8 ng/mL and insulin antibodies were negative. The patient was transferred to a regular nursing floor and discharged without further hypoglycemic events. Hypoglycemia in non-diabetic patients is a rare occurrence. Drug-induced hypoglycemia is the most common etiology. Limited case reports have described doxycycline-induced hypoglycemia in non-diabetics. Further, these document hypoglycemic events after six days of doxycycline use. The elimination half-life of doxycycline is estimated between 15 and 20 hours. Our patient received the first dose on 11/14/2024 at 15:30 and second dose on 11/15/2024 at 06:30. He developed hypoglycemia two hours after the second dose, with symptoms resolving by 12:20. This timeline suggests that the first dose of doxycycline was likely the cause. Our case is the first reported doxycycline-induced hypoglycemia occurring within 24 hours, which is consistent with the drug’s half-life. The mechanism by which doxycycline causes hypoglycemia remains unclear, but theories suggest it may increase insulin sensitivity or prolong insulin half-life by inhibiting its degradation in the liver. Given that doxycycline is commonly prescribed in outpatient settings, it is vital for clinicians to be aware of this rare but potentially serious side effect.Presentation: Saturday, July 12, 2025

Disclosure: L. Walfish: None. L. Feldman: None. O. Ajise: None. J.A. Rivera: None.Background: Adrenal tumors can be seen in inadequately treated patients with congenital adrenal hyperplasia (CAH), thought to result from chronic adrenocorticotrophic hormone (ACTH) overstimulation. In patients with CAH, a characteristic finding of poor control is elevated 17-hydroxyprogesterone (17-OHP). Similarly, it has been documented that some non-secreting adrenal adenomas can be 21-hydroxylase deficient and, therefore, also produce 17-OHP under ACTH stimulation. Scarce data exists describing autoimmune adrenalitis associated with adrenal masses and elevated 17-OHP. Case Presentation: A previously healthy 17-year-old female presented to her primary care physician for a 1-year history of secondary amenorrhea after discontinuing oral contraceptives. Progesterone challenges were negative. Notable laboratory investigations included an elevated 17-OHP at 117 nmol/L (ref. 0.6-8.0nmol/L). An abdominal pelvic ultrasound revealed a 2.7 cm right adrenal tumor. Upon presentation to endocrinology, history and physical examinations showed no signs or symptoms of adrenal hormone overproduction. Further biochemical assessment of adrenal hyperfunction was also negative. Other than an elevated renin at 464.8 ng/L (ref. 3.3-6.1) with a low normal aldosterone, the rest of her hormonal work up showed no abnormalities. Genetic analysis showed no mutation in a 12-genes CAH panel. On further questioning, the patient admitted to salt craving, morning nausea, fatigue, and spontaneous skin darkening in comparison to her twin sister. A morning cortisol resulted at 76 nmol/L (ref.120-535), ACTH > 440pmol/L (ref. 1.6-13.9), with presence of adrenal autoantibodies. She was diagnosed with autoimmune primary adrenal insufficiency (AI) and started on hydrocortisone and fludrocortisone replacement. An abdominal MRI demonstrated a 2.5x1.4x1.8cm right adrenal, well-circumscribed tumour, isointense in T2, hypointense in T1, with no loss of signal on the out-of-phase T1 sequences, in keeping with a lipid-poor lesion. A PET scan demonstrated the mass to be FDG avid at 19.4 SUV. The patient is currently waiting for laparoscopic right adrenalectomy. Conclusion: This case highlights a potential relationship between adrenal masses and primary autoimmune adrenalitis that has not been described before. Most reported cases of this type of co-occurrence have been related to adrenal lymphoma or CAH. The elevated plasma 17-OHP in our case is unusual and is suspected to originate from the adrenal tumor’s expected decreased 21-hydroxylase expression. Such deficiency would otherwise go unnoticed but has become evident under strong ACTH stimulation from the primary AI. The strong ACTH stimulation may also explain the high FDG uptake, contrasting with surrounding ongoing adrenalitis. Nevertheless, surgical removal is indicated given the lipid-poor nature of the lesion.Presentation: Monday, July 14, 2025

Abstract Disclosure: F. El Sayed: None. K. Estrada: None. Background: Autoimmune polyglandular syndrome type 2 (APS-2) is a rare condition characterized by the coexistence of autoimmune adrenal insufficiency (Addison's disease), autoimmune thyroid disease, and often type 1 diabetes mellitus. Viral infections are known to trigger autoimmune diseases, with some studies suggesting an increased risk of autoimmune conditions following infections, including SARS-CoV-2. However, the direct association between COVID-19 and APS-2 remains underexplored. Case Description: A 47-year-old male with a history of gastroesophageal reflux disease (GERD) and Raynaud’s disease presented with dizziness, hypotension, unintentional weight loss, increased salt cravings, and dyspnea on exertion. His daughter’s pediatrician observed skin hyperpigmentation, prompting further evaluation. He had a history of SARS-CoV-2 infection six months prior and had received a 5-day course of steroids. Family history was notable for scleroderma and possible thyroid disease in his mother.The primary care provider measured an 8 am cortisol, which was low (4.1 µg/dL), alongside an elevated TSH (13.48 uIU/L) and low free T4 (0.91 ng/dL), prompting referral to endocrinology. On exam, he was hypotensive (90/60 mmHg), tachycardic (pulse 112), and had diffuse skin hyperpigmentation but was not in acute distress.Laboratory findings showed hyponatremia (sodium 133 mmol/L), high-normal potassium (4.7 mmol/L), suppressed aldosterone (<3 ng/dL), elevated renin (701.1 pg/mL), elevated ACTH (1,370 pg/mL), and low morning cortisol (2.1 µg/dL), suggestive of Addison’s disease. Testing for 21-hydroxylase antibodies was positive. Thyroid tests revealed elevated TSH (17.62 uIU/mL), low free T4 (0.49 ng/dL), and positive thyroid peroxidase antibodies (92 IU/mL), confirming autoimmune hypothyroidism. Screening for type 1 diabetes was positive for GAD65 antibodies (120 IU/mL) and a hemoglobin A1c of 5.6%, indicating latent autoimmune diabetes (LADA). Diagnosis and Management: The patient was diagnosed with Autoimmune Polyglandular Syndrome Type 2, consisting of Addison’s disease, autoimmune hypothyroidism, and stage 1 LADA. He was started on hydrocortisone, fludrocortisone, and levothyroxine. His glucose and hemoglobin A1c are being monitored. Discussion and Conclusion: This case suggests a possible link between SARS-CoV-2 and APS-2. Viral infections, including COVID-19, may trigger autoimmune responses in genetically predisposed individuals. The patient’s history of COVID-19, followed by multiple autoimmune conditions, supports this hypothesis. This case contributes to the growing literature on post-viral autoimmune diseases and highlights the need for further research into SARS-CoV-2 as an autoimmune trigger. Clinicians should be vigilant in recognizing and managing post-COVID autoimmune endocrinopathies. Presentation: Sunday, July 13, 2025

Disclosure: M.D. Balina: None. J. Uy-Ho: None. H. Yao: None. S. Reburiano: None. E. David: None. F. Sorsona: None.Background: Autoimmune Polyglandular Syndromes (APS) are groups of 2 or more autoimmune endocrine and non-endocrine disorders that occur in discreet patterns. APS type 2, considered to be the most common form, is composed of primary adrenal insufficiency, type 1 diabetes mellitus, and autoimmune thyroid disease. Recognition of signs and symptoms of adrenal insufficiency before management of a diagnosed thyroid disease is of utmost importance. Case: This is a case of a 58-year-old female who was referred to endocrine service due to nodular goiter. Additional physical examination showed areas of hyperpigmentation, particularly sun-exposed areas, gums, and ears, which developed gradually over 3 years. On further probing, the patient reported brief episodes of lightheadedness, easy fatigability, and weight loss. She was initially diagnosed with hypothyroidism and tested positive for anti-thyroid peroxidase antibodies. She had mild hyponatremia with normal potassium and blood sugar levels. Further endocrine work-up showed low fasting 8 am serum cortisol levels at 1.99 mcg/dL associated with elevated ACTH of 1488 pg/mL. A tuberculosis infection was also ruled out. Ideally, 21-hydroxylase antibody testing should be done to diagnose autoimmune adrenal insufficiency. However, it was not available in our country. Anti-glutamic acid decarboxylase was negative. The adrenal CT scan result was also unremarkable. She was started on a physiologic dose of prednisone 5mg tab once daily and eventually given levothyroxine replacement for Hashimoto’s thyroiditis. On her latest follow-up, she reported significant improvement in daily activities and showed no signs of steroid excess. Conclusion: This case underscores the importance of the ability to diagnose clinical syndromes. Starting a patient on a thyroid hormone replacement for autoimmune thyroiditis without suspecting the presence of possible adrenal insufficiency will lead to worsening of the patient’s symptoms. Early recognition and intervention are crucial in preventing complications and improving the quality of life for affected individuals while also being able to anticipate the future development of associated disorders. Recommendation: Active screening for the development of type 1 diabetes mellitus in the future for our patient is recommended. Relatives should be advised of the early symptoms and signs of the principal component disease and should undergo screening every 3-5 years.Presentation: Monday, July 14, 2025

Adrenal gland transplantation has only been performed in rare cases, with variable results in terms of functional activity. Consequently, there is a lack of evidence in endocrine management and tapering hormone replacement therapy after such transplantations. We report on a simultaneous pancreas-kidney and adrenal gland allotransplantation in a 48-year-old female patient with type 1 diabetes and severe autoimmune adrenal insufficiency. Surgery was uneventful, without major surgical morbidity. Pancreas and kidney graft function were excellent from the beginning. Adrenal graft function was difficult to assess and steroid tapering was not well tolerated and hampered clinical recovery. Despite the evidence of adequate graft perfusion and initially even measurable levels of cortisol production, persistent adrenal graft function was not obtained, and the patient remained on hormone replacement therapy. Simultaneous pancreas-kidney and adrenal gland transplantation is technically safe, without the need for major surgical modifications or adjustments in immunosuppression. However, it should only be performed in combination with a kidney or pancreas-kidney transplant, which justifies the lifelong immunosuppression. The major challenge remains the postoperative endocrine management, with steroid tapering and adequate assessment of adrenal graft function. Patients should be followed by an interdisciplinary team involving endocrinologists, nephrologists and transplant surgeons.

Schmidt's syndrome combines several autoimmune diseases, including Addison's disease, thyroiditis and peripheral gonadal insufficiency. A 21-year-old female presented 15 days prior to admission with a digestive complaint of nausea, vomiting, generalised asthenia and epigastric pain, all evolving in a context of weight loss. Clinical examination revealed an altered patient, hypotensive to 80/60 mmHg, normocardial to 70 bpm. Paraclinical examinations revealed acute renal failure, hyperkalaemia (8 mmol/l) and hyponatraemia (124 mmol/l). Given the hyperkalaemia without electrical signs on ECG, the patient was treated with Kayxalate and calcium gluconate and hydration with saline and sodium; the blood ionogram improved. In the face of chronic constipation, a TSH was performed, returning to 11 uui/ml with antiTPO antibodies at 1000. An ultrasound scan revealed thyroiditis, and the patient was put on levothyrox 50ug/d. The patient continued to suffer from profound asthenia and also reported secondary amenorrhoea for 4 months with negative BHCG and a hypophysiogram showing hypergonadotropic hypogonadism in favour of primary ovarian failure. On re-examining the patient, our attention was drawn to the presence of hyperpigmentation of the skin and slate- coloured patches, slate-coloured patches in the oral mucosa. The diagnosis of Addison's disease was suspected. A cortisol assay was ordered, which came back collapsed at 0.01μg/dl with ACTH elevated to 199pg/ml with anti-21-hydroxylase antibodies at 5.0U/ml (VN<0.4) confirming the diagnosis. The patient was started on intravenous hydration and hydrocortisone, with marked improvement in clinical and paraclinical parameters and restoration of menstrual cycles, followed by oral hydrocortisone and fludrocortisone. As part of the etiological diagnosis, an adrenal CT scan revealed adrenal atrophy (absence of visible adrenal parenchyma). Other autoimmune disorders in the context of polyendocrinopathy were ruled out in our patient. Adrenal insufficiency is most often caused by an autoimmune disease. Autoantibodies to steroidogenic enzymes in the adrenal cortex are present in 86% of patients with primary autoimmune adrenal insufficiency, the most common antibody being anti-21- hydroxylase.

Adrenal insufficiency presents a significant clinical challenge due to its diverse etiologies and potentially life-threatening consequences. This review highlights the spectrum of adrenal insuf- ficiency, focusing on primary adrenal insufficiency (PAI). Childhood PAI, predominantly con- genital, presents unique diagnostic and management considerations. An aspect of this review is the discussion of PAI related to non-congenital adrenal hyperpla- sia, particularly adrenocorticotropic hormone (ACTH) resistance syndromes and autoimmune adrenal insufficiency. The clinical presentation, diagnosis, and treatment management of these rare childhood PAI types are assessed through 5 case studies. Despite advancements in genetic understanding, some cases are unsolved and remain diag- nostic mysteries. There is a need for further research and elucidation of molecular etiopatho- genesis in adrenal insufficiency. Clinicians are pivotal in identifying these rare diseases and providing lifesaving outcomes.

Abstract Introduction Diabetic ketoacidosis (DKA) has been linked to insulin deficiency or increased insulin resistance or requirements due to stressors such as infection or trauma. However, with the advent of immune checkpoint inhibitors (ICIs) like nivolumab, a new etiology for DKA has emerged: Immune-related adverse events (irAEs). We are reporting a case of a young patient developing DKA following nivolumab treatment. Case Presentation A 20-year-old male with a medical history of a recently diagnosed stage IIIc melanoma of the left calf was admitted with ongoing vomiting, shortness of breath, and fatigue with polyuria and polydipsia. Eight days prior to admission, he received his 2nd cycle of nivolumab as part of his ongoing adjuvant therapy following primary tumor resection. Labs revealed anion gap metabolic acidosis with a pH of 7.08, bicarbonate of 9 mEq/L, anion gap of 29 mEq/L, and blood glucose of 467 mg/dL. Beta-hydroxybutyrate was elevated to 8.4 mg/dL, and urine showed 4+ glucosuria and ketonuria. Prior glucose levels were normal, but hemoglobin A1c at admission was 6.8%. He was diagnosed with diabetic ketoacidosis and treated with fluids, insulin, and electrolyte monitoring with resolution of metabolic derangements. No other precipitating factors were identified, and the patient was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab given undetectable C-peptide levels and significantly elevated glutamic acid decarboxylase 65 antibody (GAD-65 > 250 IU/ml). Unfortunately, without a pre-nivolumab C-peptide and anti-GAD antibody level, we could not establish whether our patient was seroconverted before or during nivolumab therapy. He was started on insulin with a plan for lifelong hormone substitution and endocrinology follow-up. Oncology continued the patient on nivolumab as systemic adjuvant therapy was necessary, and an alternate regimen (dabrafenib plus trametinib) was not an option given the BRAF WT mutation of melanoma. Discussion Nivolumab, an ICI, has been shown to trigger autoimmune side effects, including pneumonitis, thyroid dysfunction, and adrenal insufficiency, but is less commonly known to cause DKA. The underlying pathophysiology involves the autoimmune destruction of pancreatic beta cells, which mirrors the process seen in idiopathic type 1 diabetes mellitus. The rapid development of DKA following nivolumab administration highlights the need for close glucose monitoring in patient's receiving ICIs. Management of nivolumab-induced DKA generally follows conventional DKA treatment protocols. However, multidisciplinary collaboration involving oncologists and endocrinologists is crucial in determining the continuation or discontinuation of ICI therapy, as the patients may still benefit from continued treatment due to better cancer outcomes.

The Autoimmune Regulator, AIRE, acts as a transcriptional regulator in the thymus, facilitating ectopic expression of thousands of genes important for the process of negative T-cell selection and immunological tolerance to self. Pathogenic variants in the gene encoding AIRE are causing Autoimmune polyendocrine syndrome type 1 (APS-1), defined by multiorgan autoimmunity and chronic mucocutaneous candidiasis. More recently, Genome Wide Association Studies (GWAS) have also implicated AIRE in several common organ-specific autoimmune diseases including autoimmune primary adrenal insufficiency, type 1 diabetes and pernicious anemia. We developed a highly sensitive cell-system approach based on HEK293FT cells transfected with AIRE that allowed us to characterise and functionally evaluate the transcriptional potential of genetic variants in the AIRE gene. By utilizing RNAseq with an average read depth of 100 million reads and 12 replicates per condition we have the statistical power and sensitivity to characterize the AIRE induced transcriptome in depth. We confirm that our cell system recapitulates the expression of the vast majority of known AIRE induced genes including well-characterised tissue restricted antigens (TRAs). Our approach also increases the total number of identified AIRE induced genes by an order of magnitude compared to previously published strategies, including a comprehensive number of clinically relevant autoantigens. Our cell-system approach differentiates between categories of AIRE variants on the transcriptional level, including the nonsense variant p.R257* (near complete loss of function), the p.C311Y variant associated with dominantly inherited APS-1 (severely impaired function), and the polygenic risk variant p.R471C (slightly increased function) linked to common organ-specific autoimmunity. The increased activity of p.R471C compared to wildtype indicates different molecular mechanisms for monogenic and polygenic AIRE related autoimmunity. We find that AIRE induced expression is characterised by a small absolute increase in expression levels of genes of both high and low tissue specificity.

Autoimmune polyglandular syndrome type 1 (APS1) is characterized by chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal insufficiency and sporadically by other autoimmune conditions including thyroiditis and diabetes mellitus. APS1 is usually caused by recessive mutations in the AIRE gene, though rare dominant mutations can result in mild, late-onset clinical manifestations. Whether and to what extent autoimmune diabetes is present in these latter forms has been poorly addressed. Genetic testing for monogenic diabetes in an Italian child with early onset diabetes (at the age of 18 months), positive IA2 antibodies and negative insulin GAD antibodies was performed by Next Generation Sequencing, using direct Sanger sequencing as a confirmatory test. A heterozygous AIRE inframe likely pathogenic deletion (c.64_69del, p.Val22_Asp23del, rs752303080 in exon 1; NM_000383.4) was identified. The proband's father carried the same AIRE mutation and presented with subclinical hypothyroidism and coeliac disease but normal glucose level. To the best of our knowledge this is the first case of early onset diabetes as the only autoimmune manifestation related to AIRE heterozygous variants. In a broader context, our report indicates the need for genetic testing in individuals with isolated autoimmune hyperglycemia whose very early onset makes the diagnosis of type 1 diabetes unlikely. Our finding also highlights the heterogeneity of clinical expression of AIRE heterozygous variants, with two carriers of the same pedigree showing different organs involved and age of disease onset, in the absence of the most typical APS1 clinical abnormalities.

The primary outcome was the evaluation of the T-cell phenotype in autoimmune primary adrenal insufficiency (PAI). Secondary outcomes included the evaluation of the CD4+CD25+Foxp3+ Treg population and the gene expression levels of IL-6, IL-17A, cyclooxygenase (COX)-2, heat shock proteins (HSP)-70, indoleamine-2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1), inducible nitric oxide synthase (iNOS), and thioredoxin (TXN)-1. We prospectively included 15 patients with PAI on conventional glucocorticoid (GC) replacement therapy, 15 switched to dual-release hydrocortisone (DR-HC), and 20 healthy controls. Serum inflammatory parameters and peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and after 12 months of treatment. At baseline, significantly higher CD4+ and CD8+ (both p < 0.001) T-cell percentages, a lower CD4+/CD8+ ratio (p < 0.05), and higher CD25+ and CD4+/CD25+ T cells (both p < 0.001) were observed in PAI compared to controls. After 12 months of DR-HC treatment, we found significantly lower IL-6 (p = 0.019), IL-17A (p = 0.046), COX-2 (p < 0.001), HSP-70 (p = 0.006), and TXN-1 (p = 0.008) and higher PD-L1 (p < 0.001) and IDO (p < 0.001) mRNA values compared to baseline. After 12 months of DR-HC treatment, a significant increase in CD4+ T cells (p = 0.012), PD-L1 (p = 0.003), and IDO (p < 0.001) and a decrease in CD8+ T cells (p < 0.001), IL-6 (p = 0.003), IL-17A (p = 0.0014), COX-2 (p < 0.001), HSP-70 (p = 0.005), and TXN-1 (p = 0.0008), as well as a significantly higher conversion in the CD4+/CD8+ ratio (p = 0.033), were observed compared to conventional GCs. The switch from conventional GCs to DR-HC treatment altered the T lymphocyte phenotype and CD4+/CD8+ ratio in a Treg-independent manner, inducing significant improvements in the immune and inflammatory profile in PAI.

Addison's disease, a rare endocrine disorder affecting approximately 1 in 100,000 individuals, is characterized by adrenal insufficiency due to adrenal cortex dysfunction. Initially described by Thomas Addison in 1855, the disease's etiology has shifted from infectious causes, such as tuberculosis, to autoimmune mechanisms, especially in industrialized countries. In children, congenital adrenal hyperplasia (CAH) is a common cause, while autoimmune destruction dominates in adults. Autoimmune adrenal insufficiency is associated with various other autoimmune disorders, often manifesting as polyglandular syndromes. The disease leads to insufficient cortisol and aldosterone production, resulting in symptoms like fatigue, hyperpigmentation, hypotension, gastrointestinal issues, and salt cravings. Diagnosis involves measuring serum cortisol, ACTH levels, and performing the cosyntropin stimulation test. Treatment requires lifelong hormone replacement with glucocorticoids (prednisone or hydrocortisone) and mineralocorticoids (fludrocortisone). Despite advances in research, the condition remains incurable, with management focusing on symptom control and preventing adrenal crises. Moreover, patients require ongoing monitoring for comorbid autoimmune conditions. This review explores the pathophysiology, diagnosis, and multidisciplinary management of Addison's disease, emphasizing the significance of oral manifestations and the need for continuous care. Keywords: Addison's disease, adrenal insufficiency, autoimmune adrenalitis, cortisol deficiency, and adrenal glands.

Autoimmune adrenal insufficiency (AAI) is a rare disease. This research evaluates three patients with AAI, including autoimmune polyglandular syndrome (APS) type 2. Two patients had APS or AAI during childhood, and one had a history of endocrine autoimmune disease, indicating a possible hereditary basis of the condition. Trio-based exome sequencing and high-resolution HLA typing were employed to analyze patients and their parents. Benign or likely benign variants of the AIRE gene were identified in all participants of the study. These variants, coupled with clinical data and the results of antibody studies to type I interferons, helped to exclude APS-1. Patients with APS-2, in contrast to patient with AAI, inherited distinct variants of unknown significance in the CLEC16A gene, which is associated with autoimmune diseases, including AAI. Various risk alleles in other genes associated with autoimmunity were identified in all patients. HLA typing of class II loci revealed alleles related to APS. Nevertheless, the frequencies of the haplotypes identified are substantial in the healthy Russian population. Immunological tests can detect antibody carriers and assess the risk of autoimmune disease development. In the future, to identify genetic predictors of autoimmune endocrinopathies, it is recommended to analyze the whole genome of patients and their relatives, examining clinically relevant variants in non-coding regions.

BackgroundWe report a rare case of new onset autoimmune adrenal insufficiency in childhood, presenting with severe shock requiring mechanical circulatory support. In the current era of readily available imaging, laboratory and other diagnostic investigations, medical history and careful physical exam can often provide valuable diagnostic information for timely therapy.Case presentationA 7-year-old boy with a history of mild intermittent asthma, presented with severe cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO). Bronzing of his entire body was noted on physical exam. Stress dose hydrocortisone was given for suspected adrenal insufficiency. After weaning from ECMO and extensive rehabilitation, the patient recovered and was discharged home.ConclusionPrimary adrenal insufficiency (PAI) should be considered in the context of physical exam and laboratory findings, even in the presence of circulatory shock.

Abstract Disclosure: J. Naredo Rojas: None. B. Udegbe: None. I. Remba-Shapiro: None. S.L. Stockman: None. L.B. Nachtigall: None. Background: The adrenal glands express angiotensin converting enzyme and transmembrane serine protease 2 receptors for SARS-CoV-2 protein S, facilitating viral entry. Cortisol levels are decreased in COVID-19 infection in correlation with disease severity. A number of potential mechanisms could relate autoimmune adrenal insufficiency (AI) to COVID-19, but whether or not SARS-CoV-2 infection plays a direct role in the autoimmune pathogenesis of primary AI is unknown. Furthermore, while single cases have been reported, autoimmune-mediated primary adrenal insufficiency following COVID-19 illness has not been formally studied. Purpose: To determine the association and clinical presentation of primary autoimmune adrenal insufficiency in patients with COVID-19 disease. Methods: A retrospective chart review was performed on patients presenting to Massachusetts General Hospital (MGH) with primary AI in the setting of recent COVID-19 illness. Review of the literature was performed to identify additional cases. Clinical, biochemical and radiographic characteristics, and interval between the diagnosis of COVID-19 and primary AI diagnosis were evaluated. Criteria for inclusion were biochemical confirmation of AI, clinical signs and/or symptoms of adrenal insufficiency within 6 months of COVID-19 illness, and evidence of autoimmune etiology of AI. Results: Five novel cases of COVID-19 associated primary autoimmune-mediated adrenal insufficiency from our Center were identified. Review of the literature yielded five additional cases. This series combines our Center’s experience, and the cases reported to date, including a total of 10 patients, 6 men and 4 women. All men (6/6) and 2 women (2/4) were &amp;lt; 30 years old. Patients demonstrated clinical evidence of adrenal insufficiency in a median time frame of 14 days (IQR 8.5-23.3) after SARS-CoV-2 infection. Vomiting, hypotension, and hyponatremia were present in all (N=10). Other common symptoms were nausea (90%), fatigue (70%), hyperpigmentation (70%) and hyperkalemia (50%). Nine (90%) had a positive past medical and/or family history of autoimmune disease. Nine (90%) had positive 21-hydroxylase antibodies. The median serum morning cortisol level was 1.1μg/dL with an IQR of 0.7-3.0 μg/dL. The mean ACTH level was 1235.2 pg/mL with a SD of 580.1 pg/mL. The mean ACTH was 19.3 x ULN with a SD of 10.0. Adrenal imaging did not show hemorrhage or necrosis but showed atrophy in 50%. Conclusions: This series reveals that autoimmune-mediated primary adrenal insufficiency may be diagnosed in the aftermath of COVID-19 illness. Age under 30, family history and/or past medical history of autoimmune disease may be associated. Future prospective studies are needed to determine causality. Presentation: 6/1/2024

Abstract Disclosure: E.M. Niedzialkowska: None. D. Shelden: None. Introduction: Autoimmune polyglandular syndrome type 2 (APS2) is a rare endocrinopathy with co-occurrence of autoimmune adrenal insufficiency, autoimmune thyroiditis and/or type 1 diabetes. In rare cases, APS2 can predispose patients to recurrent pericardial effusion and tamponade. Case presentation: 32 y.o male with medical history of hypothyroidism on replacement therapy diagnosed 2 weeks prior to admission presented with progressive dyspnea and hypotension. The patient was found to have pericardial effusion with tamponade requiring pressor support. Initial lab tests showed TSH 148.7 uIU/ml (N 0.4-4.5), free t4 0.7 ng/dl(N 0.7-1.5 ), free t3 2 pg/ml (N 1.7-3.5), Hb a1c 4.7% (N &amp;lt;5.6%), thyroglobulin antibody 851 IU/ml (N &amp;lt;20), TPO antibody &amp;gt;1 000 IU/ml (N&amp;lt;=35), TSI 0.1 IU/l (&amp;lt;0.1), sodium 127 mmol/l (N 135-145), and a negative adrenal antibody panel. The patient was started on IV levothyroxine (400 mcg daily) and stress dose steroids in the setting of shock requiring 4 pressors. Shock resolved after pericardiocentesis and the patient was weaned off pressor support. Pericardial fluid showed neutrophil predominance and was negative for an infectious process, lab tests showed negative ANA, ANCA and GBM. The day following admission lab tests showed TSH of 23.86 uIU/ml, ft4 1.3 ng/dl, the patient was transitioned to oral levothyroxine 125 mcg and the steroid regimen was tapered and discontinued. Follow up tests showed normal TSH and resolution of pericardial effusion. Four weeks after initial admission the patient was readmitted due to hypotension. Laboratory tests showed random cortisol &amp;lt;1.0 ug/dl (N 2.9-19.4), ACTH 17 pg/ml (N 6-48), adrenal antibody titers 1:20 (N &amp;lt; 1:10), cosyntropin stimulation test was positive for adrenal insufficiency and the patient was started on steroid regimen with symptomatic improvement. He was diagnosed with APS type 2 based on his constellation of endocrinopathies. Repeat echocardiogram was negative for pericardial effusion. Two months later, the patient presented with chest pain. Imaging was positive for recurrent pericardial effusion requiring pressor support and pericardiocentesis. The patient was subsequently started on colchicine. Infectious and rheumatologic workup continued to be negative. The patient did not exhibit symptoms of connective tissue disease. Seven months after the initial presentation the patient was readmitted with COVID-19 infection complicated by hypotension and a small pericardial effusion. Symptoms improved after initiation of stress dose steroids. Conclusion: Cardiac tamponade is a rare presentation of APS2 with 9 cases reported in the literature up to date. Increased incidence of pericardial effusion is presumed to be a result of autoimmune inflammation leading to fluid accumulation. The patients are prone to tamponade due to intravascular volume depletion, decreased vascular tone and impaired stress response. Presentation: 6/3/2024

Abstract Disclosure: A. Calderon: None. E. Calderon-Martinez: None. J. Shakil, MD: None. A. Kansara: None. Immunechekpoint inhibitors (ICI)-related Primary Adrenal Insufficiency (PAI) is an uncommon entity. Compared to other endocrine-related adverse effects (irAES), antibody detection is less consistent. TPO and GAD65 antibodies are usually present in about 40-80% of the cases with hypothyroidism, hyperthyroidism, and diabetes. On the contrary, case reports and series for PAI seldom report the presence or absence of 21OH antibodies. We present a case and perform a literature review of PAI, in a patient who received pembrolizumab and developed PAI with 21 hydroxylase antibodies. A 62-year-old man with history HIV on ART (last CD4 count 590 cells/mm3) and locally advanced urothelial cancer on Pembrolizumab, presented with nausea, vomiting, abdominal pain, and decreased urine output. He was noted to be confused, and in hypoactive delirium. On admission, his chemistry panel he was noticed to have normal sodium and potassium levels. The CT scan of the abdomen revealed regional enteritis and was started on IV fluid therapy. His adrenal glands were described as normal on imaging. On the 16th day of hospitalization, the patient became unresponsive and hypotensive. He was transferred to the ICU. His sodium level was 132 mEq/L and potassium level was 6.1 mEq/L, bicarbonate level was 18 mEq/L, calcium of 10.3 mg/dl, and eosinophils of 15%. Random cortisol levels measured before administration of steroids were undetectable twice, 9 hours apart, with an ACTH level of 94. He underwent an ACTH stimulation test with cosyntropin 250 mcg IV with resulting undetectable cortisol levels after 30 and 60 minutes. CT and MRI of the brain showed no signs of hypophysitis. He was started on high-dose hydrocortisone with improvements in his mental status, hypotension, and gastrointestinal symptoms. He was discharged on hydrocortisone. His 21-Hydroxylase antibody was later found out to be positive. After combination immunotherapy regimens, CTLA-4 inhibitors are the most common to cause any irAE, however endocrine irAE particularly are mostly associated with PD-1 inhibitors. Among these, thyroid and pituitary disorders are the most common ones. Reports show that about 10% of patients receiving immunotherapy will develop endocrinopathy. ICI-induced PAI has been reported to occur in 7.6% of patients receiving combination therapy, and 2% of patients receiving Pembrolizumab. It has been reported that only 15% of patients will recover adrenal function. A meta-analysis that gathered 15 cases of ICI-induced PAI, found that only 2 cases had positive 21-hydroxylase antibodies. In our presented case, we have robust biochemical confirmation of PAI, with positive 21 hydroxylase antibody, after being on pembrolizumab for 9 months. Further information is needed to establish the pathophysiology, presentation, and prognosis of ICI-related PAI when anti adrenal antibodies are positive. Presentation: 6/1/2024

Abstract Polyglandular autoimmune syndrome type 2 involving autoimmune primary adrenal insufficiency and autoimmune hypothyroidism is rare. Fatigue and tiredness are common overlapping symptoms between the two conditions. Initiating levothyroxine in a patient with underlying adrenal insufficiency may precipitate a severe adrenal crisis. Here, we report a case of a 21-year-old lady who presented with an adrenal crisis with hypercalcemia after levothyroxine initiation. This case highlights the importance of taking a proper detailed history and diligent physical examination which can direct the appropriate diagnosis and avoid the preventable consequence.