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Primary adrenal insufficiency (PAI) is most often caused by an autoimmune destruction of the adrenal cortex resulting in failure to produce cortisol and aldosterone. The aetiology is thought to be a combination of genetic and environmental risk factors, leading to breakdown of immunological tolerance. Regulatory T cells (Tregs) are deficient in many autoimmune disorders, but it is not known whether they contribute to development of PAI. We aimed to investigate the frequency and function of naive and expanded Tregs in patients with PAI and polyendocrine syndromes compared to age- and gender-matched healthy controls. Flow cytometry was used to assess the frequency and characterize functional markers of blood Tregs in PAI (N = 15). Expanded Treg suppressive abilities were assessed with a flow cytometry based suppression assay (N = 20), while bulk RNA-sequencing was used to examine transcriptomic differences (N = 16) and oxygen consumption rate was measured by a Seahorse cell metabolic assay (N = 11). Our results showed that Treg frequency and suppressive capacity were similar between patients and controls. An increased expression of killer-cell leptin-like receptors and mitochondrial genes was revealed in PAI patients, but their expanded Tregs did not display signs of mitochondrial dysfunction. Our findings do not support a clear role for Tregs in the contribution of PAI development. Regulatory T cells (Tregs) are involved in the initiation or progress of many autoimmune disorders. Here, we describe number and function of Tregs in the endocrine autoimmune disorder primary adrenal insufficiency (PAI). Tregs from PAI patients were adequate in number and in functional cell assays, but had an increase in mitochondria and killer receptors in transcriptomic assays, and showed a higher proliferation capacity, which might point to a higher turnover of these suppressive cells. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Dogs with eunatremic, eukalemic hypoadrenocorticism (EEH) typically show signs of chronic gastrointestinal disease (CGD). Previous glucocorticoid administration (PGA) can give false‐positive results on the ACTH stimulation test (ACTHst). Hypothesis/Objectives: To determine the prevalence of EEH in dogs with signs of CGD, and to identify clinical and clinicopathological features for EEH and PGA. Animals: One hundred twelve dogs with CGD (101 non‐PGA and 11 PGA), 20 dogs with EEH. Methods: Multicenter prospective cohort study. Basal serum cortisol (BSC) concentration was measured in dogs with signs of CGD. When BSC was <2 μg/dL and in PGA dogs, ACTHst plus measurement of endogenous ACTH (eACTH) were performed. Records of dogs with EEH from 2009 to 2021 were reviewed. Results: The BSC concentration was <2 μg/dL in 48/101 (47.5%) non‐PGA and in 9/11 (82%) PGA dogs. EEH was diagnosed in 1/112 dog (prevalence 0.9%; 95% CI, 0.1%‐4.8%); the ACTHst provided false‐positive results in 2/11 PGA dogs. PGA dogs showed lower C‐reactive protein‐to‐haptoglobin ratio (median 0.01, range 0.003‐0.08; P =.01), and higher haptoglobin (140, 26‐285 mg/dL; P =.002) than non‐PGA dogs (0.04, 0.007‐1.5; 38.5, 1‐246 mg/dL, respectively). eACTH was higher (P =.03) in EEH (396, 5‐>1250 pg/mL) than in non‐PGA dogs (13.5, 7.3‐46.6 pg/mL). Cortisol‐to‐ACTH ratio was lower (P <.0001 and P =.01, respectively) in EEH (0.002, 0.0002‐0.2) than in non‐PGA (0.1, 0.02‐0.2) and PGA dogs (0.1, 0.02‐0.2). Conclusions and Clinical Importance: The prevalence of EEH in dogs with signs of CGD was lower than previously reported. The clinical and clinicopathological features herein identified could increase the index of suspicion for EEH or PGA in dogs with an unclear history of glucocorticoid administration. [ABSTRACT FROM AUTHOR]

Case Description: An 18‐month‐old spayed female domestic short haired cat was presented for poor appetite, lethargy, exaggerated swallowing, and regurgitation 2 weeks after endoscopic retrieval of gastric foreign material. Clinical Findings: The cat was quiet with tacky mucous membranes on physical examination. Point‐of‐care blood testing identified mild azotemia, moderate hypercalcemia, and a sodium‐to‐potassium ratio of 26. An ultrasound examination the next day identified moderate to marked bilateral adrenomegaly. Cytology of a fine needle aspirate of the adrenal glands was consistent with necrosis and associated inflammation. Hypoadrenocorticism was diagnosed by a confirmatory adrenocorticotropic hormone stimulation test. Treatment and Outcome: The cat normalized both clinically and biochemically after treatment with prednisolone and desoxycorticosterone pivalate. Clinical Relevance: Acute adrenal necrosis has been well documented in human medicine after anesthetic events. To our knowledge, hypoadrenocorticism caused by cytologically confirmed acute adrenal necrosis has not been previously reported in dogs and cats. [ABSTRACT FROM AUTHOR]

Patients with adrenal insufficiency (AI) have been found to have increased cardiovascular morbidity, partly associated with nonphysiologic glucocorticoid replacement. We included two separate cohorts (cohort 1 n=384 patients, cohort 2 n=180 patients) of patients with chronic primary and secondary AI under standard replacement therapy and compared them to two age- and sex-matched population-based studies (SHIP-TREND/DEGS). Odds ratios with 95% CI for hypertension, hyperlipidemia/HLP, type 2 diabetes/T2DM, obesity, and hospitalization with adjustment for confounders were evaluated by logistic regression. Patient cohort 1 had significantly lower ORs for obesity [0.4 (0.3–0.6), p<0.001] and hypertension [0.5 (0.3–0.6), p<0.001] compared to SHIP-TREND and for obesity [0.7 (0.5–0.9), p=0.01], hypertension [0.4 (0.3–0.5), p<0.001] and HLP [0.4 (0.3–0.6), p<0.001] compared to DEGS. In cohort 2, ORs were significantly lower for HLP compared to both SHIP-TREND [0.4 (0.2–0.7), p=0.001] and DEGS [0.3 (0.2–0.5), p<0.001] and for hypertension [0.7 (0.4–0.9), p=0.04] compared to SHIP-TREND. In patients with SAI from cohort 2, ORs for DM2 [2.5 (1.3–4.9) p=0.009], hypertension [2.5 (1.4–4.5), p=0.002] and obesity [1.9 (1.1–3.1), p=0.02] were significantly higher compared to DEGS, whereas ORs for HLP were significantly lower compared to both SHIP [0.3 (0.1–0.6), p=0.002] and DEGS [0.3 (0.1–0.6), p<0.001]. In most of our AI patients treated with conventional glucocorticoid doses, the risk for T2DM, obesity, hypertension, and HLP was not increased. The number of hospitalizations was significantly higher in AI patients compared to controls, which might reflect increased susceptibility but also a more proactive management of concomitant diseases by physicians and patients. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (AI) is an endocrine disorder in which hormones of the adrenal cortex are produced to an insufficient extent. Since receptors for adrenal steroids have a wide distribution, initial symptoms may be nonspecific. In particular, the lack of glucocorticoids can quickly lead to a life-threatening adrenal crisis. Therefore, current guidelines suggest applying a low threshold for testing and to rule out AI not before serum cortisol concentrations are higher than 500 nmol/l (18 μg/dl). To ease the diagnostic, determination of morning cortisol concentrations is increasingly used for making a diagnosis whereby values of>350 nmol/l are considered to safely rule out Addison's disease. Also, elevated corticotropin concentrations (>300 pg/ml) are indicative of primary AI when cortisol levels are below 140 nmol/l (5 μg/dl). However, approximately 10 percent of our patients with the final diagnosis of primary adrenal insufficiency would clearly have been missed for they presented with normal cortisol concentrations. Here, we present five such cases to support the view that normal to high basal concentrations of cortisol in the presence of clearly elevated corticotropin are indicative of primary adrenal insufficiency when the case history is suggestive of Addison's disease. In all cases, treatment with hydrocortisone had been started, after which the symptoms improved. Moreover, autoantibodies to the adrenal cortex had been present and all patients underwent a structured national education program to ensure that self-monitored dose adjustments could be made as needed. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis is a complex autoimmune disease associated with chronic systemic keratinization and inflammation, which can affect the skin, joints, and oral cavity. Xerostomia is a subjective feeling of oral dryness that impairs patient comfort and lowers the quality of life. The aim of this case report is to describe the clinical mechanism of xerostomia in a psoriasis patient with multiple systemic diseases.Case Report: A 51-year-old inpatient man with psoriasis vulgaris was referred to the Oral Medicine Department with complaints of difficulty swallowing due to a sore throat and dry tongue since last week. The patient had psoriasis vulgaris 15 years ago, chronic adrenal insufficiency, psoriatic arthritis, acute circulatory collapse, anemia of inflammation, acute kidney injury, dehydration, gastritis, urinary tract infections, and malnutrition. A complete anamnesis and oral examination were done. The patient was diagnosed with severe xerostomia, a fissured tongue, exfoliative cheilitis, angular cheilitis, and gingivitis by the Oral Medicine Department.Case Management: The patient was treated with petroleum jelly, chlorine dioxide mouthwash, miconazole cream, and benzydamine HCl lozenges.Conclusion: Based on case reports and reviews, multiple systemic diseases may not only increase the risk of xerostomia but also aggravate its severity. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome type 2 (APS-2) is the coexistence of Addison disease and at least one of the disorders like autoimmune thyroid diseases and/or type 1 diabetes mellitus. We discuss the case of 16.5-year-old girl who had been diagnosed with APS-2 at the early age of 13.5 years. The girl presented recurrent abdominal pain and emesis for about 3 years, occurring about every 6 months. Moreover, in physical examination, characteristic skin hyperpigmentation furrows in the hands, nipples, and mucosa in the oral cavity were noticed. Due to the clinical picture and laboratory data, autoimmune thyroiditis and primary adrenal insufficiency were diagnosed. After initiating substitution treatment, the girl developed full-blown diabetes mellitus, probably masked earlier after primary adrenal insufficiency. It should be kept in mind that during the diagnosis of autoimmune disease, other autoimmune disorders may coexist; thus, such patients should be under specialists' close supervision. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60–74.7%), North American (51–86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care. [ABSTRACT FROM AUTHOR]

Addison’s disease is a rare, autoimmune condition leading to the destruction of the adrenal gland. Autoimmune conditions are known to commonly co-occur. When Addison’s disease presents in the setting of autoimmune thyroid disease and/or type 1 diabetes, this condition is termed autoimmune polyendocrine syndrome type II, a rare endocrinopathy found in roughly 1.4-4.5 per 100,000 individuals. Here, we describe a clinical case presenting with hypotension refractory to fluid resuscitation and electrolyte derangements later diagnosed as autoimmune polyendocrine syndrome type II.

Abstract Background Primary hypoadrenocorticism in dogs is thought to be multifactorial with roles for both genetic and environmental factors. The contributions of environmental factors remain unexplored. Objective Identify environmental and lifestyle exposures associated with primary hypoadrenocorticism in 2 dog breeds with high risk of developing the disease. Animals Animals were not used in this study. Owners of Standard Poodles (STPDs) and Portuguese water dogs (POWDs) participated in a survey. Methods Retrospective case‐control study. Dog owners were invited to participate in an online survey through convenience sampling. Questions regarded the demographics, health histories, and indoor/outdoor environments in which their dogs live and play. Responses for dogs with primary hypoadrenocorticism were compared to those without the disease using univariate and multivariate logistic regression models. Results Five thousand forty‐seven responses (358 cases, 4689 controls) met initial inclusion criteria. Significant associations with modest effect size were found for community type, ingestion of canned food, and use of lawn fertilizer in some analysis models. Reproductive (spay/neuter) status exhibited the strongest association with high effect size across all models with adjusted odds ratio (OR) 2.5 (95% confidence interval [CI], 1.4‐4.5; P = .003) for spayed females and 6.0 (95% CI, 2.6‐13.9; P

Background: There is no consensus strategy for mineralocorticoid (MC) therapy titration in patients with primary adrenal insufficiency (PAI). W e aim to measure serum fludrocortisone (sFC) and urine fludrocortisone (uFC) levels and to determine their utility, alongside clinical/biochemical variables and treatment adherence to guide MC replacement dose titration. Methods: Multi-centre, observational, cross-sectional study on 41 patients with PAI on MC replacement therapy. sFC and uFC levels (measured by liquid chr omatography-tandem mass spectrometry), plasma renin concentration (PRC), electrolytes (Na+, K+), mean arterial blood pressure (MAP), total daily glucocorticoid (dGC) and MC (dMC) dose, and assessment of treatment adherence were incorporated into statis tical models. Results: We observed a close relationship between sFC and uFC ( r = 0.434, P = 0.005) and between sFC and the time from the last fludrocortisone dose ( r = −0.355, P = 0.023). Total dMC dose was related to dGC dose ( r = 0.556, P < 0.001), K+ (r = −0.388, P = 0.013) as well as sFC (r = 0.356, P = 0.022) and uFC (r = 0.531, P < 0.001). PRC was related to Na+ (r = 0.517, P < 0.001) and MAP (r = −0.427, P = 0.006), but not to MC dose, sFC or uFC. Regression analyses did not support a role for sFC, uFC or PRC measurements and confirmed K+ (B = −44.593, P = 0.005) as the most important variable to guide dMC titration. Of the patients, 32% were non-adherent with replacem ent therapy. When adherence was inserted into the regression model, it was the on ly factor affecting dMC. Conclusions: sFC and uFC levels are not helpful in guiding dMC titration. T reatment adherence impacts on clinical variables used to assess MC replacement and should be included as part of routine care in patients with PAI.

Objective: Patients with primary adrenal insufficiency (PAI) are thought to be particularly vulnerable to coronavirus disease 2019 (COVID-19); however, little is known about its true impact on this group. We assessed morbidity and health promotion attitudes during the pandemic amongst a large cohort of patients with PAI. Design: Cross-sectional, single-centre study. Methods: In May 2020, COVID-19 advice on social distancing and sick-day rules was distributed to all patients with PAI registered with a large secondary/tertiary care centre. A semi-structured questionnaire was used to survey patients in early 2021. Results: Of 207 contacted patients, 162 responded (82/111 with Addison’s disease, AD; 80/96 with congenital adrenal hyperplasia, CAH). Patients with AD were older than those with CAH (median age 51 vs 39 years; P < 0.001) and had more comorbidities (Charlson comorbidity index ≥2 47.6% vs 10.0%; P < 0.001). By the time of the survey, 47 patients (29.0%) had been diagnosed with COVID-19, the second commonest cause of sick-day dosing during the study and the leading trigger of adrenal crises (4/18 cases). Patients with CAH had a higher risk of COVID-19 compared to AD (adjusted odds ratio 2.53 (95% CI 1.07–6.16), P = 0.036), were less inclined to have the COVID-19 vaccine (80.0% vs 96.3%; P = 0.001), and were less likely to have undergone hydrocortisone self-injection training (80.0% vs 91.5%; P = 0.044) or wear medical alert jewellery (36.3% vs 64.6%; P = 0.001). Conclusions: COVID-19 was a principal trigger for adrenal crises and sick-day dosing in patients with PAI. Despite a higher risk of COVID-19, patients with CAH showed less engagement with self-protective attitudes. Significance statement: We conducted a cross-sectional study on a large and well-characterised group of patients with PAI and demonstrated that COVID-19 was a leading cause of morbidity during the early phases of the pandemic. Patients with AD were older and had a greater burden of comorbidity than those with CAH, including non-adrenal autoimmune disorders. However, patients with CAH were more likely to develop COVID-19 and demonstrated reduced engagement with healthcare services and health promotion strategies.

Autoimmune Addison’s disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

(1) Background: Patients with primary adrenal insufficiency (PAI) suffer from a reduced quality of life. However, clinical factors associated with this impairment remain unclear. The aim of this study was to assess the health-related quality of life (HRQoL) and to evaluate the associations with clinical and hormonal parameters in a group of patients with PAI. (2) Methods: The study included 32 patients with autoimmune PAI, who answered the quality of life in Addison's disease questionnaire (AddiQoL). Clinical data and hormonal measurements were collected from the patients. (3) Results: The total AddiQoL score of males was significantly higher than that of females (p = 0.011). Furthermore, males reached significantly higher scores in each of the four subscales (fatigue—p = 0.013, emotional sphere—p = 0.048, adrenal insufficiency symptoms—p = 0.039, and miscellaneous questions—p = 0.034). There was a negative correlation between HRQoL and gonadotropin levels (FSH and fatigue r = (−)0.38, p = 0.032; FSH and emotional sphere r = (−)0.416, p = 0.018). This study found no significant associations between AddiQoL scores and the presence of autoimmune comorbidities; only fatigue scores were worse in the presence of autoimmune thyroiditis (p = 0.034). The doses of hydrocortisone and fludrocortisone in the replacement therapy were not associated with AddiQoL scores. AddiQoL scores correlated negatively with the age of diagnosis (p = 0.015). (4) Conclusions: Female sex, higher gonadotropins level, and older age at diagnosis were associated with impaired HRQoL in the studied group of patients with PAI. [ABSTRACT FROM AUTHOR]

Patients diagnosed with Type 1 Diabetes Mellitus (T1DM) can sometimes manifest as part of broader clinical presentations known as Autoimmune Polyglandular Syndromes (APS). APS refers to a group of rare autoimmune disorders in which multiple endocrine glands are affected by autoimmune attacks. There are four types of APS described so far, including APS1, APS2, APS3 and APS4. In contrast to APS1 and APS2, APS3 does not involve the adrenal cortex. In APS3, autoimmune thyroiditis occurs with other organspecific autoimmune diseases, excluding Addison’s disease. A 20-year-old female with a known case of T1DM, Chronic Kidney Disease (CKD), hypothyroidism, and hypertension recently presented with a hypertensive emergency. On further evaluation, she was also diagnosed as a possible case of APS3 with a rare presentation of hypercortisolism instead of Addison’s disease. Various challenges were faced while managing her diabetes due to the brittle diabetes pattern she showed, and also there was a dilemma in the conclusive diagnosis of hypercortisolism in this patient due to the co-existing CKD. [ABSTRACT FROM AUTHOR]

Chronic adrenal insufficiency is an endocrine disease caused by insufficient secretion of adrenal hormones due to dysfunction of one or more links of the hypothalamic-pituitary-adrenal axis. The highest prevalence has been documented in Scandinavian countries: 15–22 people per 100,000 population, while other European countries report 10 cases per 100,000 population. Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in adults, and it can be either alone (40 %) or a component of autoimmune polyglandular syndromes (60 %). The etiologic factors of primary adrenal insufficiency include tuberculosis or AIDS. These causes of adrenal cortical insufficiency are particularly relevant in Ukraine. The article describes a clinical case of a patient with both primary adrenal insufficiency and Werlhof’s disease. The prevalence of adrenal insufficiency and etiologic factors of primary adrenal insufficiency are highlighted. A detailed differential diagnosis of primary adrenal insufficiency with other diseases that could cause clinical symptoms such as hypoglycemic states, severe weight loss, hypotension, severe muscle weakness, hyponatremia, hyperkalemia is performed. The basic principles of diagnosis, treatment, and prognosis in primary adrenal insufficiency are discussed. Despite typical, specific manifestations of adrenal insufficiency, diagnosis in real clinical practice is difficult. Awareness and vigilance of doctors regarding the symptoms of adrenal insufficiency is necessary. Late detection of chronic adrenal insufficiency can lead to complications. Timely diagnosis and treatment of chronic adrenal insufficiency improves disease prognosis and quality of life. [ABSTRACT FROM AUTHOR]

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Purpose: The purpose of this study was to check the efficacy and safety of a novel tear substitute containing hyaluronic acid and low-dose hydrocortisone in the treatment of moderate dry eye disease. Methods: In this prospective randomized study, 38 patients with moderate dry eye disease were divided into two treatment groups: Group 1 received one drop of 0.2% sodium hyaluronate and 0.001% hydrocortisone four times daily for 3 months, while Group 2 received 0.15% sodium hyaluronate and 3% trehalose at the same dosage. OSDI and SANDE questionnaires, Non-Invasive Break-Up time (NIBUT), Tear Meniscus Height (TMH), meibography, Lipid Layer Thickness (LLT), Tear Break-Up Time (TBUT), Corneal Staining Score (CFS), and Intraocular Pressure (IOP) were evaluated at baseline and after 1, 2, and 3 months of treatment. Results: During the treatment period, Group 1 showed statistically significant improvement in OSDI score (p = 0.002), SANDE score (p = 0.01), NIBUT (p < 0.0001), LLT (p < 0.0001), TBUT (p = 0.01), and CFS (p = 0.02). In Group 2, significant improvement was observed only in the TBUT score (p < 0.05). Comparison of the two groups showed that NIBUT and LLT were significantly different at the end of treatment (p = 0.001 for both comparisons), with more favorable results for sodium hyaluronate and hydrocortisone than for sodium hyaluronate and trehalose. No significant variations in intraocular pressure were observed in either group during the treatment period (p > 0.05). Conclusions: The study confirms that a 3-months treatment with hyaluronic acid 0.2% in combination with low-dose hydrocortisone 0.001% improves the signs and symptoms of moderate DED and that a low-dosage 0.001% hydrocortisone can be helpful in preventing the progression to chronic stages of DED. [ABSTRACT FROM AUTHOR]

Introduction: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. Methods: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing’s syndrome (BADx), 21 with Addison’s disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. Results: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. Discussion: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) is a rare cause of primary amenorrhea in adolescents. For young women with uncertain etiology of POI, genetic and autoimmune testing may be recommended to assist in treatment and management decisions. This report presents a case of POI in a 16-year-old adolescent with both poly-autoimmune disease and a heterozygous missense variant in the bone morphogenic factor 15 (BMP15) gene, both potentially involved in the pathogenesis of POI. Accurately distinguishing between autoimmune and genetic causes is crucial for effective treatment and counseling. In addition, given the significant psychological impact and the need for reproductive options counseling, a multidisciplinary approach that includes psychological support is highly recommended. [ABSTRACT FROM AUTHOR]

Addison's disease (AD) entails a chronic insufficient production of gluco- and mineralocorticoids. Fatigue and decreased quality of life are frequently reported symptoms, but little is known about its effects on cognition. This study aims to explore the existence of cognitive impairment in patients with AD and the influence of treatment regimens. We conducted a systematic review. Inclusion criteria were met by 10 articles, most of them ranked as intermediate quality. Three studies analyzed the relationship between AD and cognitive impairment; one explored the effect of delaying treatment showing no effect on cognitive performance, and another one studied the effect of fludrocortisone treatment. Episodic memory was the most frequent cognitive domain impaired across studies, in comparison to healthy controls. Two papers investigated the relationship between impaired sleep quality and poor cognitive performance. Two studies related cognitive impairments with hypocortisolism-derived brain neuroglycopenia. Two studies investigated the effect of DHEA substitution. In conclusion, patients exhibit a moderately reduced performance in verbal learning. The pathophysiology of this impairment is likely multifactorial. Future studies should include larger sample sizes, the use of comprehensive and multi-domain neuropsychological and behavioral protocols, and neuroimaging. [ABSTRACT FROM AUTHOR]

Background: Primary hypoadrenocorticism in dogs is thought to be multifactorial with roles for both genetic and environmental factors. The contributions of environmental factors remain unexplored. Objective: Identify environmental and lifestyle exposures associated with primary hypoadrenocorticism in 2 dog breeds with high risk of developing the disease. Animals: Animals were not used in this study. Owners of Standard Poodles (STPDs) and Portuguese water dogs (POWDs) participated in a survey. Methods: Retrospective case‐control study. Dog owners were invited to participate in an online survey through convenience sampling. Questions regarded the demographics, health histories, and indoor/outdoor environments in which their dogs live and play. Responses for dogs with primary hypoadrenocorticism were compared to those without the disease using univariate and multivariate logistic regression models. Results: Five thousand forty‐seven responses (358 cases, 4689 controls) met initial inclusion criteria. Significant associations with modest effect size were found for community type, ingestion of canned food, and use of lawn fertilizer in some analysis models. Reproductive (spay/neuter) status exhibited the strongest association with high effect size across all models with adjusted odds ratio (OR) 2.5 (95% confidence interval [CI], 1.4‐4.5; P =.003) for spayed females and 6.0 (95% CI, 2.6‐13.9; P <.001) for neutered males. Conclusions and Clinical Importance: The large effect size for reproductive status reflects its high potential clinical relevance, whereas modest effect sizes for other environmental variables suggest lower potential clinical relevance. These findings are associations and do not necessarily imply causation. Before any actionable recommendations are warranted, additional evidence regarding biological mechanisms is needed. [ABSTRACT FROM AUTHOR]

Background: Patients with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy can present with early neurological deterioration, but rapidly progressive respiratory failure is rarely reported. We present the cases of two patients with autoimmune GFAP astrocytopathy who experienced rapid progression to respiratory failure and were effectively treated using plasma exchange therapy. Case report: Two patients were diagnosed with autoimmune GFAP astrocytopathy. Their initial symptoms were consistent with those of previously observed cases of autoimmune GFAP astrocytopathy. However, they experienced rapid progression to respiratory failure due to their lesion location. Specifically, case 1 had lesions in the medulla oblongata, and case 2 had lesions in the high cervical spinal cord, which are both common sites of lesions causing respiratory failure. The patients did not respond well to intravenous methylprednisolone and intravenous immunoglobulin initially and could not be withdrawn from ventilator support. Fortunately, subsequent plasma exchange therapy led to significant clinical improvements and successful withdrawal from ventilator support. Discussion: Patients with autoimmune GFAP astrocytopathy can present with rapidly progressive respiratory failure. Early treatment with plasma exchange can be beneficial in withdrawing patients from ventilator support. [ABSTRACT FROM AUTHOR]

In male dogs, long-acting gonadotropin-releasing hormone (GnRH) analogs are widely accepted as an alternative to surgical castration but are also used to suppress and induce estrus in bitches (off label). Behavioral changes reported in bitches in association with the use of long-acting GnRH analogs have included male-like behavior associated with triggered estrus, increased food intake, enlargement of mammary glands and milk production, pseudopregnancy, and urinary incontinence. In male dogs, intra-species and rarely inter-species aggression may occur during the flare-up effect. However, at the time of downregulation, this behavior should no longer occur if it is testosterone dependent. An intact, three-year-old female cocker spaniel with Addison’s disease was admitted to our clinic for consultation on spaying options because of pseudopregnancies followed by mastitis, which had to be treated with antibiotics, after her heat cycles. The owners were hesitant about surgical sterilization and therefore, deslorelin implant was inserted. Approximately one month after implantation, owners observed the onset of aggressive behavior, including incessant barking, extreme irritability, and aggression toward other dogs and towards family members. The behavior problems started to escalate and the owners were not able to handle her anymore. After removal of the implant, the observed aggression ceased, and the bitch returned to normal behavior. Although aggressive behavior toward other dogs and sometimes even toward owners has been observed after neutering or insertion of a deslorelin implant, this is the first report of extremely aggressive behavior toward owners and other dogs in a female dog after insertion of a 4.7 mg deslorelin implant. [ABSTRACT FROM AUTHOR]

Objective: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison’s disease (AAD), but pathomechanisms are poorly understood. Design: Cross-sectional study. Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Results: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = −0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (−0.15 normalized protein expression [NPX], P = .0001, and −0.25 NPX, P = .0003, respectively)Conclusions: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small. [ABSTRACT FROM AUTHOR]

Since individuals with Addison’s disease (AD) present considerable co-occurrence of additional autoimmune conditions, clustering of autoimmunity was also predicted among their relatives. The study was aimed to assess circulating autoantibodies in first-degree relatives of patients with AD and to correlate them with the established genetic risk factors (PTPN22 rs2476601, CTLA4 rs231775, and BACH2 rs3757247). Antibodies were evaluated using validated commercial assays, and genotyping was performed using TaqMan chemistry. The studied cohort comprised 112 female and 75 male relatives. Circulating autoantibodies were found in 69 relatives (36.9%). Thyroid autoantibodies, that is antibodies to thyroid peroxidase (aTPO) and thyroglobulin (aTg), were detectable in 25.1 and 17.1% relatives, respectively. Antibodies to 21-hydroxylase (a21OH) were found in 5.8% individuals, and beta cell-specific antibodies to ZnT8, GAD, and IA2 were found in 7.5, 8.0, and 2.7%, respectively. The prevalence of a21OH (P = 0.0075; odds ratio (OR) 7.68; 95% CI 1.903–36.0), aTPO (P < 0.0001; OR 3.85; 95% CI 1.873–7.495), and aTg (P < 0.0001; OR 7.73; 95% CI 3.112–19.65), as well as aGAD (P = 0.0303; OR 3.38; 95% CI 1.180–9.123) and aZnT8 (P = 0.032; OR 6.40; 95% CI 1.846–21.91), was significantly increased in carriers of rs2476601 T allele. Moreover, T allele appeared to be a risk factor for multiple circulating autoantibody specificities (P = 0.0009; OR 5.79; 95% CI 1.962–15.81). None of the studied autoantibodies demonstrated significant association with rs231775 in CTLA4 (P > 0.05), and only weak association was detected between BACH2 rs3757247 and circulating aTPO (P = 0.0336; OR 2.12; 95%CI 1.019–4.228). In conclusion, first-degree relatives of patients with AD, carriers of the PTPN22 rs2476601 T allele, are at particular risk of developing autoantibodies to endocrine antigens.

There is a number of systemic diseases affecting the cornea. These include endocrine disorders (diabetes, Graves' disease, Addison's disease, hyperparathyroidism), infections with viruses (SARS-CoV-2, herpes simplex, varicella zoster, HTLV-1, Epstein-Barr virus) and bacteria (tuberculosis, syphilis and Pseudomonas aeruginosa), autoimmune and inflammatory diseases (rheumatoid arthritis, Sjögren's syndrome, lupus erythematosus, gout, atopic and vernal keratoconjunctivitis, multiple sclerosis, granulomatosis with polyangiitis, sarcoidosis, Cogan's syndrome, immunobullous diseases), corneal deposit disorders (Wilson's disease, cystinosis, Fabry disease, Meretoja's syndrome, mucopolysaccharidosis, hyperlipoproteinemia), and genetic disorders (aniridia, Ehlers-Danlos syndromes, Marfan syndrome). Corneal manifestations often provide an insight to underlying systemic diseases and can act as the first indicator of an undiagnosed systemic condition. Routine eye exams can bring attention to potentially life-threatening illnesses. In this review, we provide a fairly detailed overview of the pathologic changes in the cornea described in various systemic diseases and also discuss underlying molecular mechanisms, as well as current and emerging treatments.

ObjectiveTo describe the semiquantitative acid-base status of dogs with untreated naturally occurring typical hypoadrenocorticism and to compare this to the status determined by traditional acid-base analysis.DesignRetrospective study.SettingUniversity teaching hospital.AnimalsThirty-three dogs with newly diagnosed typical hypoadrenocorticism between 2000 and 2017.InterventionsNone.Measurements and main resultsDogs were included if they had newly diagnosed hypoadrenocorticism, post-ACTH stimulation serum cortisol concentration

Pneumomediastinum and subcutaneous emphysema usually result from alveolar rupture and rarely from colonic perforation. Although steroid use has been shown to increase the risk of complicated diverticulitis, there is limited data on the role Addison's disease may play in the development of colonic perforation. We present a rare case of a patient with Addison's disease who presented with hoarseness and was found to have massive subcutaneous emphysema, pneumomediastinum, and pneumoretroperitoneum secondary to complicated diverticulitis. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APCED) syndrome is a rare autosomal recessive syndrome. There is a loss of function mutation in the autoimmune regulator (AIRE) gene. It is characterized by two of the following conditions: chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison's disease. Here, we describe one such mysterious case of APCED syndrome, which posed a diagnostic challenge. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndromes (APS) are rare disorders involving multiple endocrine and non-endocrine organs. These are often difficult to diagnose, as the clinical presentation of these is insidious. We present a case where a 29-year-old man presented to the Emergency Department in a state of altered sensorium with a history of focal seizures. His clinical presentation further included hypotension, malaise, and diplopia. A detailed workup revealed multiple endocrine gland involvement, and a diagnosis of APS was made.

IntroductionPatients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency.MethodsThis cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing’s syndrome (BADx), 21 with Addison’s disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated.ResultsThe percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected.DiscussionIn patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Introduction: MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we report the case of a girl with MIRAGE syndrome who presented with adrenal insufficiency and chronic diarrhea. Case presentation: The patient was born at 29 + 6 weeks of gestational age with a birth weight of 656 g (<3p). Her height and head circumference were also <3p. At birth, she presented with respiratory distress, meconium staining, and pneumomediastinum, which were managed with high-frequency ventilation and empirical antibiotics. Physical examination showed generalized hyperpigmentation and normal female genitalia. A few days after birth, polyuria and hypotension developed, and laboratory findings revealed hypoglycemia, hyponatremia, and hyperkalemia. Plasma adrenocorticotropic hormone levels were elevated with low serum cortisol levels and high plasma renin activity, which were suggestive of adrenal insufficiency. Hydrocortisone and fludrocortisone were introduced and maintained, and hyperpigmentation attenuated with time. Both kidneys looked dysplastic, and adrenal glands could not be traced on abdominal ultrasound. From the early days of life, thrombocytopenia and anemia were detected, but not to life-threatening level and slowly recovered up to the normal range. Despite aggressive nutritional support, weight gain and growth spurt were severely retarded during the hospital stay. Additionally, after introducing enteral feeding, she experienced severe diarrhea and subsequent perineal skin rashes and ulcerations. Fecal calprotectin level was highly elevated; however, a small bowel biopsy resulted in non-specific submucosal congestion. The patient was diagnosed with MIRAGE syndrome with SAMD9 gene mutation. She was discharged with tube feeding and elemental formula feeding continued, but chronic diarrhea persisted. By the time of the last follow-up at 15 months of corrected age, she was fortunately not subjected to severe invasive infection and myelodysplastic syndrome. However, she was dependent on tube feeding and demonstrated a severe developmental delay equivalent to approximately 5-6 months of age. Conclusion: The early diagnosis of adrenal crisis and hormone replacement therapy can save the life of -patients with MIRAGE syndrome; however, chronic intractable diarrhea and growth and developmental delay continue to impede the patient's well-being. [ABSTRACT FROM AUTHOR]

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1–31·8; 149 [52%] of 284 died) versus 13·3 months (10·5–16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46–0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2–8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3–6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42–0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1–9·3) and overall survival of 15·1 months (11·3–18·7). The most common grade 3–4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi. [ABSTRACT FROM AUTHOR]

Background: Although a potentially life‐threatening endocrine emergency, if diagnosed promptly and treated appropriately, the majority of acute Addisonian crises represent very rewarding cases to treat. A complete review of the diagnosis and management of acute and chronic hypoadrenocorticism (including atypical Addison's disease) was published in In Practice (Spence and others 2018). Aim of the article: This article aims to supplement the previously published review with some additional considerations in the management of acute Addisonian crises. [ABSTRACT FROM AUTHOR]

A 32‐year‐old nulliparous woman with premature ovarian insufficiency POI and autoimmune polyglandular syndrome type 2 (APS‐2), presented to our fertility center with a 2.5‐year history of amenorrhoea. Controlled ovarian hyperstimulation (COH), with high dose gonadotropins, failed to promote antral follicle growth. The patient was given a short, 4‐week course of 2 mg dexamethasone prior to a repeat COH cycle, which resulted in the retrieval of good oocyte numbers and eventual live birth from a thawed embryo transfer. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD. Design: Case-control study on patients with AAD and healthy controls. Methods: Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls. Results: With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10-44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLADQB1* 02:01 (P = 9 × 10-63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD. Conclusions: We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles. [ABSTRACT FROM AUTHOR]

Background: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. Case presentation: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. Conclusions: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison’s disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNwAbs or AIRE mutations (Ferre-Lionakis criteria). Patients and methods: We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms. Results: Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic L-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome. Conclusion: Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED. [ABSTRACT FROM AUTHOR]

Aim: We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS‐CoV‐2 (PIMS‐TS) and examine the association between steroid therapy and key clinical markers of severity. Methods: We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS‐TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo‐pituitary‐adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2/day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. Results: Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2/day (interquartile range 232.5–355.5) and treatment length of 26.0 days (interquartile range 19.0–32.0). Dosing regimens predominantly involved a short course of high‐dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). Conclusion: Prolonged, high‐dose steroid therapy is often used in the management of severe PIMS‐TS with the potential for HPA axis suppression and should be withdrawn carefully. [ABSTRACT FROM AUTHOR]

Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. Results: The genetic susceptibility to AAD—quantified using PRS—was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e − 16), and 1.2 SD higher in the young patients compared with the old (p = 3e − 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. Conclusions: The PRS performed well for case‐control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndromes (APSs), also called autoimmune polyglandular syndromes, are a group of autoimmune diseases characterized by the co-occurrence of dysfunctions of several (at least two) endocrine glands. They develop under the influence of environmental factors in genetically predisposed people. Autoimmune polyendocrine syndromes may accompany autoimmune rheumatic diseases and worsen their course - APS-2 and APS-3 are the most common. The APS-2 includes the coexistence of, e.g. Hashimoto's disease, celiac disease and rheumatoid arthritis (RA). In APS-3, rheumatic diseases such as RA, systemic lupus erythematosus, and Sjögren's syndrome may coexist with Hashimoto's disease, type 1 diabetes and hypogonadism or other endocrinopathies. Undiagnosed endocrine diseases may be the reason for the intensification of metabolic disorders observed in the course of rheumatic diseases, cause the ineffectiveness of rheumatological treatment and also increase the frequency of bone fractures due to osteoporosis, cardiovascular complications and even miscarriages when coexistent, e.g. Hashimoto's disease with hypothyroiditis, which increases the risk of pregnancy loss. It is important to be able to conduct an extensive interview, paying attention to the symptoms of possible endocrinopathy as well as the features of other autoimmune disorders in the physical examination (e.g. vitiligo or darkening of the skin in Addison's disease). Depending on the history and physical examination, screening for various APSs is advised. [ABSTRACT FROM AUTHOR]