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.

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.

Atypical presentation of autoimmune polyglandular syndrome type 1 in the fifth decade.

A 45-year-old woman presented to us with a short-term history of nausea, vomiting and giddiness. On arrival at our hospital, examination revealed postural hypotension. Fluid resuscitation with intravenous normal saline was commenced. She also had chronic mucocutaneous candidiasis and nail changes suggestive of ectodermal dystrophy. Detailed history taking revealed that she had never attained menarche. Serum biochemistries showed hyponatraemia, hyperkalaemia, and hypocalcaemia (sodium, 127 mEq/L; potassium, 6 mEq/L; and albumin-corrected calcium, 6 mg/dL). Adrenocorticotropic hormone-stimulated cortisol (16.7 mcg/dL) was suboptimal favouring adrenal insufficiency. She was started on hydrocortisone and fludrocortisone supplementation. Additionally, the parathyroid hormone was inappropriately low (3.8 pg/mL) confirming hypoparathyroidism. Oral calcium and active vitamin D supplementation were added. With the above clinical and biochemical picture, namely, clustering of primary amenorrhoea, adrenal insufficiency and hypoparathyroidism, the diagnosis pointed towards autoimmune polyglandular syndrome. Genetic workup revealed a deletion in exon 8 of the autoimmune regulator gene confirming the diagnosis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy/autoimmune polyglandular syndrome type 1 .

Typical and reverse Takotsubo syndromes as initial manifestations of consecutive Addisonian crises in a 38-year-old patient: the heart has its reasons!

We report an interesting case of a 38-year-old woman presenting with reverse Takotsubo syndrome (TTS) secondary to an Addisonian crisis, her second such episode. A few years prior, she had presented with typical TTS in the setting of Addisonian crisis; diagnostic work-up revealing Auto-Immune Polyglandular Syndrome Type II (APS II). We believe this to be the first case report of typical and variant phenotypes of TTS in a patient with APS II. The pathogenic link between these two conditions is explored. In patients presenting with Addisonian crises and refractory shock, the possibility of concurrent TTS should be considered. TTS muddies the diagnostic waters and poses therapeutic challenges as outlined.

A case of eosinophilic esophagitis with autoimmune polyendocrine syndrome type 2, including autoimmune gastritis.

Both eosinophilic esophagitis (EoE) and autoimmune polyendocrine syndrome (APS) are relatively rare diseases in Japan. We herein report a case of EoE with APS in a 67-year-old Japanese man who presented with chest pain and dysphagia. On the basis of endoscopic findings and histological analysis, we diagnosed the patient with EoE along with autoimmune gastritis. Additional serological examinations revealed the presence of Hashimoto's thyroiditis and type 1 diabetes, which led to the final diagnosis of APS. His symptoms did not respond to treatment with a proton-pump inhibitor but improved with topical steroid therapy. This case of coexisting EoE and APS-2 is quite rare and has several implications for the pathogenesis of both conditions.

Rituximab as Maintenance Therapy in Type 1 Autoimmune Pancreatitis: An Italian Experience.

OBJECTIVE: Rituximab (RTX) has been proposed for the induction of remission and maintenance therapy in relapsing type 1 autoimmune pancreatitis (AIP). The aim of the study was to describe the use of RTX as maintenance therapy for patients with type 1 AIP. METHODS: Patients with type 1 AIP based on the International Consensus Diagnostic Criteria and treated with RTX were selected from our database. Two doses of RTX (1000 mg each) were administered 15 days apart and repeated after 6 months. RESULTS: Eighteen patients were treated with RTX as maintenance therapy. Of these, the involvement of other organs was observed in 16 patients (89%). Eight of the 18 patients (44%) relapsed during follow-up. Median time to relapse after the last infusion was 30 months (range, 12-35 months). No disease relapse was observed in the first year after the last infusion. Probability of disease relapse was 80% between 1 and 3 years from initial treatment. No adverse effects were observed. CONCLUSIONS: Rituximab seems be safe and effective for maintenance therapy of type 1 AIP during the first year after completing RTX infusion. However, the probability of disease relapse is high within 1 and 3 years from the last infusion.

[Type 1 diabetes mellitus and Graves Basedow's disease, a case of Autoimmune Polyglandular Syndrome]. / Diabetes mellitus tipo 1 y enfermedad de Graves Basedow, un caso de Síndrome Poliglandular Autoinmune.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is one of the most frequent autoimmune diseases in childhood. Its diagnosis requires the search for other autoimmune diseases. OBJECTIVE: to present the case of a pediatric patient with two rare concomitant autoimmune endocrine diseases. CLINICAL CASE: A 12-year-old male with no significant morbid history, is hospitalized due to a 3-month clinical pic ture of fatigue, eye pain, intermittent eyelid edema, goiter, polyphagia, polydipsia, polyuria, and weight loss (12 kilograms), compatible with T1DM and Graves-Basedow disease. It was confir med by laboratory tests which showed elevated glycemia (207 mg/dL, HbA1C 10.9%), suppressed TSH (< 0.01 uIU/mL), elevated FT4 (6.99 ng/dL), and the presence of anti-autoantibodies thyroid peroxidase, antithyroglobulin, and anti-TSH receptor, along with suggestive ultrasound findings. Therefore, we established the diagnosis of autoimmune polyglandular syndrome (APS) 3A and initiated treatment with insulin, propranolol, and thiamazole. The patient evolved satisfactorily and was discharged with outpatient follow-up. CONCLUSION: We present the case of an adolescent who presented APS due to T1DM and hyperthyroidism. This APS may be more common than is reported in clinical practice. The alteration of two or more endocrine glands or other autoimmune diseases should make us suspect its diagnosis, with important clinical implications, such as co morbidity and quality of life prognosis.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model.

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.