Increased frequency of microalbuminuria in patients with type 3 autoimmune polyglandular syndrome (APS) compared to isolated autoimmune type 1 diabetes mellitus: A real-life study.

AIM OF THE STUDY: The primary aim of the study was to evaluate the differences in metabolic control and chronic microvascular complications in patients with type 3 autoimmune polyglandular syndrome (APS3), compared to type 1 diabetes mellitus (T1DM) alone. Secondary aims were to evaluate the age of autoimmune thyroid disease (AIT) onset and the effects of levothyroxine treatment on metabolic control in patients with APS3. MATERIAL AND METHODS: We retrospectively reviewed 276 patients with T1DM alone and 214 patients with APS3 and evaluated clinical and metabolic parameters and microvascular complications. RESULTS: Patients with T1DM showed a longer duration of diabetes (p = 0.001) and lower age of diabetes onset (p = 0.020) compared to patients with APS3. Female gender (p = 0.001) and microalbuminuria (p = 0.006) were significantly more frequent in patients with APS3 compared to T1DM. In addition, patients with APS3 showed higher AIT onset frequency in the 16-30 quartile age-range. Furthermore, APS3 patients treated with levothyroxine showed significantly better HbA1c values than non-treated patients (p = 0.001). CONCLUSIONS: We found that patients with APS3 showed positive microalbuminuria, earlier than T1DM. Patients with APS3 showed higher frequency of AIT age of onset in the 16-30 age-range and those treated with levothyroxine had better metabolic control, than untreated ones.

The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Challenges in autoimmune polyendocrine syndrome type 2 with the full triad induced by anti-programmed cell death 1: a case report and review of the literature.

Background: Immune checkpoint inhibitors (ICPis) induce autoimmune diseases, including autoimmune polyendocrine syndrome type 2 (APS-2), which is defined as a combination of at least two of the following endocrinopathies: autoimmune thyroid disease, type 1 diabetes, and Addison's disease. Cases with the full triad are rare. We present a case of an elderly woman who developed APS-2 with the complete triad shortly after starting anti-programmed cell death 1 (anti-PD1) treatment and review the related literature. Case: A 60-year-old woman, without any personal or family history of autoimmune and endocrine diseases, started the immunotherapy of anti-PD1 (camrelizumab) for squamous cell carcinoma of the urethral meatus. She developed primary hypothyroidism with elevated antibodies to thyroid peroxidase and thyroglobulin after 25 weeks of treatment, and developed primary adrenal insufficiency with adrenal crisis and fulminant type 1 diabetes with ketoacidosis after 45 weeks. Therefore, this patient met the diagnosis of APS-2 and was given multiple hormone replacement including glucocorticoid, levothyroxine and insulin therapy. Continuous improvement was achieved through regular monitoring and titration of the dosage. Conclusions: Different components of APS-2 may appear at different time points after anti-PD1 administration, and can be acute and life-threatening. A good prognosis can be obtained by appropriate replacement with multiple hormones. Insights: With the clinical application of ICPis to APS-2, the complexity of its treatment should be paid enough attention.

Association of latent autoimmune diabetes of adults with type 3 polyglandular autoimmune syndrome-a diagnostic challenge.

Autoimmune polyendocrine syndromes (APS) encompass m ultiple e ndocrin e gland ins ufficiencies asso ci ated wit h auto immune disease. This c as e report underscores the importance of recognising the association between latent auto immune di a betes of ad ults (LADA) and type 3 polyglandular syndrome. A 42-year-old man belonging to R awalpi ndi, Pakistan, p resented to th e out patient department (OPD) of Ali Medi cal Centre, Islamab ad, i n Januar y 2023 with the complaints o f e xtreme thirs t and frequent urination. The patient reported consistently raised app etite an d eating four to five meals a day along with abrupt weight loss, dry mouth, fatigue occasional dizziness, an d dyspnoea. He was diagno s ed with type 3 polygla ndular syndrome w ith associat io n of LADA. Daily administration of 10 units of glargine insulin, along with six units of rapid-acting insulin, was prescribed. The patient's H bA1c level reduce d in a few months afte r succe ssive follow-up. Patients who exhi bit uncontrol led diabe tes despite dietar y and oral hypoglycaemic management should be further investigated for multiple au toimmune endocrine disorders.

Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital.

BACKGROUND: Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM: To improve overall understanding of this disease's diagnosis and prognosis. METHODS: We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS: Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin's lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION: Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.

Long-term remission of candidiasis with fermented lingonberry mouth rinse in an adult patient with APECED.

We report a long-term remission in candidiasis in a 57-year-old Finnish female with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) suffering from recurrent oral, esophageal, gastric, vaginal, and anal candidiasis since childhood. Candidiasis treatment with antifungal medicines fluconazole, itraconazole, posaconazole, voriconazole, caspofungin, nystatin, or amphotericin-B during 2008-2021 had variable effects and intermittent development of antifungal resistance and hospital periods. The patient started using fermented lingonberry juice (FLJ) as a mouth rinse daily in April 2021. No symptoms or mucosal signs of candidiasis in any part of the digestive system or vaginal area have been noticed during this exceptionally long-term 2 ½ year remission in candidiasis without antifungal medications.

A case report of anti-GAD65 antibody-positive autoimmune encephalitis in children associated with autoimmune polyendocrine syndrome type-II and literature review.

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

Ruxolitinib Rescues Multiorgan Clinical Autoimmunity in Patients with APS-1.

Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.

Successful live birth following a short course of glucocorticoid suppression in a patient with autoimmune polyglandular syndrome type 2 and premature ovarian insufficiency: A case report.

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.

A Case of Autoimmune Poly Glandular Glandular Syndrome Type 2 (Schmidt's Syndrome).

INTRODUCTION: Autoimmune polyendocrine syndrome (APS) type II (Schmidt's syndrome) is defined by the coexistence of autoimmune Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus. Patients also present with other organ specific autoimmune disorders like hypergonodotropic hypogonadism, vitiligo, chronic atrophic gastritis, pernicious anaemia, autoimmune chronic hepatitis and celiac disease. Many circulating organ-specific antibodies directed against endocrine organs. MATERIALS: A 40 year old female presented to the casualty with multiple episodes of vomiting and giddiness. Patient known case of hypothyroidism since past 4 years but was not on medications recently 1 month back patient was started on Thyroxine supplementation. History of menopause 8 years back present (premature). On examination patient had cold clammy extremity with signs of dehydration. Hyperpigmentation of face and gums was noted. PR -120/min thready pulse BP- 70/50 mmhg. Blood pressure was stabilised with fluid resuscitation. On investigation hyponatremia with hyperkalemia was present. In view of adrenal insufficiency co-syntropin stimulation test was done which came in favour of PRIMARY ADRENAL INSUFFICIENCY. TSH > 100 and anti TPO was positive suggesting AUTOIMMUNE THYROIDITIS. FSH was elevated and estradiol was reduced in favour of HYPERGONADOTROPIC HYPOGONADISM.ANA IF was positive. Therefore diagnosis of APS type 2 was made and appropriate substitution therapy was initiated. RESULT: Autoimmune endocrine gland disorders may regularly coexist with other endocrine autoimmune diseases. Neufeld and Blizzard organized and classified these clinical conditions and defined them as polyglandular autoimmune diseases or autoimmune polyendocrine syndromes (APS). Oegle first reported the association between Addison's disease, caused by bilateral tuberculous destruction of the adrenal glands, and diabetes mellitus in 1886. Schmidt's excisional biopsy detected lymphocytic infiltration of the adrenal cortex and thyroid gland in a patient who died from adrenal insufficiency in 1926. From that time, the coexistence of Addison's disease and autoimmune thyroid disease has been known as Schmidt's syndrome. APS II typically occurs in early adulthood with a peak onset during the third or fourth decades and is three times more common in females than in males. CONCLUSION: Autoimmune poly glandular syndrome can be treated with respective substitution therapy. Thyroxine therapy when initiated first may precipitate Addisonian crisis in patients with Schmidt's syndrome through increasing cortisol clearance and metabolic rate as evident in our case. Early detection of the disease and appropriate management may reduce morbidity and mortality significantly in the patients with autoimmune poly glandular syndrome.

Autoimmune polyglandular syndrome type 2 in an HIV-positive man managed at the University Teaching Hospitals Lusaka, Zambia: a case report.

Autoimmune polyglandular syndromes (APS) are rare autoimmune endocrinopathies characterized by the coexistence of at least two endocrine gland insufficiencies developed from autoimmune mechanisms. APS may also be associated with non-endocrine immune diseases. In HIV infection, antiretroviral therapy can improve the quality of life to reduce the incidence of opportunistic infections, malignancies, and death. HIV disease may also be associated with complications, such as immune reconstitution inflammatory syndrome (IRIS) presenting as infections, malignancies or autoimmune diseases. We here report the clinical case of an HIV-infected man receiving antiretroviral therapy, who subsequently developed APS type II, characterized by Grave's disease, type 1 diabetes mellitus. He complained of a mass in his anterior neck, diarrhea, weight loss, palpitations, hand tremors and excessive sweating. Six months before he had been diagnosed with type 1 diabetes mellitus. The patient had a diffusely enlarged thyroid on ultrasound, elevated random blood glucose of 14.0 mmol/l; elevated free T4 at 5.03 ng/dL and suppressed thyroid-stimulating hormone (TSH) at <0.05 micro-IU/mL. The patient was treated with carbimazole and propranolol for Graves' thyrotoxicosis and basal bolus insulin regimen (actrapid and protaphane) for hyperglycemia. At monthly follow-up assessments he was euthyroid and 2-hour postprandial blood glucose test was normal. The goitre had markedly reduced in size. This screening for APS in HIV patients with autoimmune IRIS as well as patients with autoimmune endocrinopathies in order to allow for early diagnosis and prompt initiation of treatment to reduce the risk of morbidity and mortality.

[The efficacy of alemtuzumab for pure red cell aplasia associated with autoimmune polyendocrine syndrome type 1].

We present a case of a 41-year-old woman who was diagnosed with autoimmune polyendocrine syndrome type 1 (APS-1) at the age of 2. She developed severe anemia and was diagnosed with pure red cell aplasia (PRCA) and T-cell large granular lymphocyte leukemia at the age of 34. The pathogenesis of APS-1 is based on the presence of an inactive mutation in the autoimmune regulator gene on thymic medullary epithelial cells. It is thought that the autoimmune T cells generated by impaired negative selection in the thymus induce PRCA. The patient was treated with immunosuppressive therapy (ciclosporin, antithymocyte globulin, prednisolone, and cyclophosphamide) for a long time by her previous doctor. After a long period of remission and exacerbation, she became dependent on blood transfusion approximately at the age of 40 and was transferred to our hospital. At our hospital, alemtuzumab treatment resulted in the disappearance of large granular lymphocytes and improvement of anemia. We report this case as a valuable demonstration of the efficacy of alemtuzumab for treating PRCA associated with APS-1.

Oral manifestations of autoimmune polyglandular syndrome type 1.

AIMS: Autoimmune polyglandular syndrome type I (APS-I) is a rare condition of autosomal recessive and monogenic inheritance, which is characterized clinically by at least two signs of the classic triad: mucocutaneous candidosis, hypoparathyroidism, and Addison's disease. This study aims to report the oral manifestations of APS-I in a 42-year-old woman, who attended the Special Care Dentistry Center. METHODS AND RESULTS: The patient presented with hypoparathyroidism, diabetes mellitus, and autoimmune hepatitis. Chronic hyperplastic candidosis (CHC) was the main oral manifestation and it was diagnosed based on clinical and cytologic characteristics. Microstomia, angular cheilitis, xerostomia, enamel hypoplasia, and microdontia were also present. CONCLUSIONS: CHC was treated with topical nystatin and oral fluconazole, resulting in a significant improvement of the lesions.

Successful Pregnancy Outcome in a Lady with Polyglandular Autoimmune Syndrome Type II.

We report a case of a lady who had polyglandular autoimmune syndrome type II (hypothyroidism, Addison's disease, vitiligo), who completed a successful pregnancy. Addison's disease (AD) was confirmed by the presence of anti-adrenal antibodies and hyponatremia. The patient had pre-pregnancy counselling about the need of antepartum, intrapartum and postpartum steroids. The pregnancy was managed with endocrinologist and obstetrician inputs, and appropriate follow-ups. Her pregnancy was completed with no complications. Labour was complicated by hyponatremia, secondary to nausea and vomiting that needed anaesthesia consultation. The patient delivered by vaginal delivery with no perinatal or early neonatal complications. The fetal growth was at 90th centile. Management in pregnancy, labour and postnatal period requires multidisciplinary care by the endocrinologist, obstetrician, midwife, anaesthetist and neonatologist. Key Words: Addison's disease, Hypothyroidism, Hyponatremia, Labour, Pregnancy.

Case Report: A Rare Case of Coexisting of Autoimmune Polyglandular Syndrome Type 3 and Isolated Gonadotropin-Releasing Hormone Deficiency.

APS (autoimmune polyglandular syndrome) is defined as the coexistence of at least two kinds of endocrine autoimmune diseases. APS type 3 comprises autoimmune thyroid diseases and other autoimmune diseases but does not involve autoimmune Addison's disease. So far, APS-3 combined with isolated gonadotropin-releasing hormone (GnRH) reduction caused by the suspected autoimmune hypothalamic disease has not been reported. We recently received a 43-year-old woman with a one-year history of Graves' disease (GD) and a four-month history of type 1 diabetes presented with hyperthyroidism and hyperglycemia. After the GnRH stimulation test, she was diagnosed with secondary amenorrhea attributed to suspected autoimmune Hypothalamitis and APS type 3 associated with Graves' disease and Latent Autoimmune Diabetes (LADA). According to this case, the hypothalamus cannot be spared from the general autoimmune process. It is recommended to carry out the GnRH stimulation test when encountering APS patients combined with secondary amenorrhea.

Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity.

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.

SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients.

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.

Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center.

INTRODUCTION: Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center. METHODS: Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10). RESULTS: Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23-73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation. DISCUSSION: Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.

AIRE Gene Mutation Presenting at Age 2 Years With Autoimmune Retinopathy and Steroid-Responsive Acute Liver Failure: A Case Report and Literature Review.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an AIRE gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an AIRE gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and AIRE gene mutations.