Autoimmune Endocrine Diseases Research Articles

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

Interleukin (IL)-23, IL-31, and IL-33 Play a Role in the Course of Autoimmune Endocrine Diseases.

Interleukins (IL)-23, 31, and 33 are involved in the regulation of T helper 17 (Th17)/regulatory T (Treg) cells balance. The role of IL-23, 31 and 33 in non-endocrine autoimmune diseases has been confirmed. Data on the involvement of these cytokines in endocrine autoimmune diseases are limited. This study aimed to determine the involvement of cytokines regulating the T helper 17 (Th17)/regulatory T (Treg) cells axis in the course of autoimmune endocrine diseases. A total number of 80 participants were divided into 4 groups: the autoimmune polyendocrine syndrome (APS) group consisting of APS type 2 (APS-2) and type 3 (APS-3) subgroups, the Hashimoto's thyroiditis (HT) group, the Graves' disease (GD) group and the control (C) group. Fifteen cytokines related to Th17 and Treg lymphocytes were determined in the serum of all participants. Higher levels of IL-23 and IL-31 were found in the APS, GD, and HT groups compared to the C group. Higher levels of IL-23 and IL-31 were also observed in the APS-2 group, in contrast to the APS-3 group. Correlation analysis of variables in the groups showed a statistically significant correlation between the cytokines IL-23, IL-31, and IL-33 in the APS and APS-2 groups, but no correlation in the APS-3 and C groups. IL-23 and IL-31 are independent factors in the course of HT, GD, and APS-2, in contrast to APS-3. The positive correlation between IL-23 and IL-31, IL-23 and IL-33, and between IL-31 and IL-33 in the APS, APS-2 groups, but the lack of correlation in the APS-3 and C groups may further suggest the involvement of these cytokines in the course of Addison's disease.

Systematic immune cell dysregulation and molecular subtypes revealed by single-cell RNA-seq of subjects with type 1 diabetes

BackgroundType 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document} cells. A comprehensive immune cell phenotype evaluation in T1DM has not been performed thus far at the single-cell level.MethodsIn this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (stage 3) cases and 31 matched controls.ResultsWe surprisingly detected profound alterations in circulatory immune cells (1784 dysregulated genes in 13 immune cell types), far exceeding the count in the comparator systemic autoimmune disease SLE. Genes upregulated in T1DM were involved in WNT signaling, interferon signaling and migration of T/NK cells, antigen presentation by B cells, and monocyte activation. A significant fraction of these differentially expressed genes were also altered in T1DM pancreatic islets. We used the single-cell data to construct a T1DM metagene z-score (TMZ score) that distinguished cases and controls and classified patients into molecular subtypes. This score correlated with known prognostic immune markers of T1DM, as well as with drug response in clinical trials.ConclusionsOur study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes, and has the potential to guide non-invasive test development and patient stratification.

Prevalence of autoimmune diseases in functional neurological disorder: influence of psychiatric comorbidities and biological sex

BackgroundFunctional neurological disorder (FND) is a common and disabling neuropsychiatric condition, which disproportionally affects women compared with men. While the etiopathogenesis of this disorder remains elusive, immune dysregulation is emerging...

Autoimmune Polyendocrine Syndromes in Adult Italian Celiac Disease Patients.

Celiac disease (CD) is frequently associated with other autoimmune disorders. Different studies have explored the association between CD and single autoimmune endocrine disease (AED), especially autoimmune thyroiditis (AIT) and type-1 diabetes mellitus (T1DM). Data about CD as a component of autoimmune polyendocrine syndrome (APS) are scant. We analyzed a large dataset including prospectively collected data from 920 consecutive adult CD patients diagnosed in a third-level Italian institution in the 2013-2023 period, The prevalence of isolated autoimmune endocrine diseases and APS were collected. A total of 262 (28.5%) CD patients had at least one associated AED, with AIT (n = 223, 24.2%) and T1DM (n = 27, 2.9%) being the most frequent conditions. In most cases (n = 173, 66%), AEDs were diagnosed after CD. Thirteen patients (1.4%) had at least two of the requested three endocrinopathies, satisfying the diagnosis of type 2 APS. APS-2 is a rare but not exceptional occurrence among Italian CD patients, underscoring the intricate and multifaceted nature of autoimmune disorders. Periodic evaluations of thyroid function and glycaemia should be recommended after the diagnosis of CD together with testing for autoantibodies that may be helpful in assessing disease risk before disease onset. Likewise, implementation of a systematic screening for CD amongst T1DM and other autoimmune endocrine diseases are paramount.

Late manifestation of autoimmune polyglandular syndrome type 1 with hypoparathyroidism and autoimmune thyroiditis

Autoimmune polyglandular syndrome type 1 (APS 1) is a rare genetic disorder caused by a mutation in the autoimmune regulator AIRE gene. The diagnosis is usually based on the combination of at least two components of the classic triad: mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Other autoimmune disorders, including thyroid diseases, also occur and may manifest before the primary components. The disease is more likely to manifest during infancy, but some components may develop in adult patients. As the components of the syndrome do not occur simultaneously, verification of the diagnosis is often delayed. A significant challenge in the management of patients with APS 1 is the selection of optimal drug doses due to polypragmasy and the frequent presence of autoimmune disorders and/or candidiasis of the gastrointestinal tract. We present a clinical case of a patient with an atypical course of APS 1, in whom the first endocrine components (hypoparathyroidism and hypothyroidism) were diagnosed in adulthood. This case highlights the phenotypic diversity of APS 1, and the difficulties in selecting therapy when several autoimmune endocrine diseases are combined.

Monoclonal Gammopathy of Undetermined Significance and the Risk of Thrombotic Events: Results from Istopmm, a Population-Based Screening Study in Iceland

Introduction: Multiple myeloma (MM), Waldenström's macroglobulinemia (WM), and related disorders have been associated with excess risk of thrombosis. Furthermore, medications used to treat these disorders, in particular immunomodulatory agents, have been associated with excess thrombotic risk. Monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor of MM, WM, and related disorders, has also been associated with arterial and venous thrombosis. However, prior studies have been based on cohorts where MGUS was diagnosed as part of the work-up for other unrelated medical disorders. We have shown that these cohort have biased selection of individuals with chronic disease, including autoimmune disease, heart failure, endocrine disorders and more. This selection bias may have led to false associations or overestimation of the relationship of MGUS and thrombotic events. Aim: To evaluate the relationship of MGUS and thrombosis in a screened cohort of individuals with MGUS. Methods: Data were obtained from the Iceland screens, treats, or prevents multiple myeloma study (iStopMM), a population-based screening study for MGUS and a randomized trial of follow-up strategies with the aim of evaluating the benefits and harms of MGUS screening. As part of the study 75,422 Icelandic residents 40 years and older (54% of the underlying population) have provided their informed consent for the study and were screened by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. The cohort was crosslinked to population-based Icelandic government registries that includes all diagnoses made in the universal healthcare system, recorded as international classification of diseases (ICD) 10 codes. The study exposure was MGUS at screening and the outcome was venous and arterial thrombosis, defined as recorded ICD-10 codes. Events recorded within 90 days of each other were considered the same event. We further analyzed subgroups of M protein isotype and light chain (LC) MGUS. We followed participants prospectively after the date of screening to arterial and venous thrombosis as the endpoint and censoring at death, progression to MM, WM, and related disorders, or end of follow-up. Hazard ratios (HR) for time to first thrombotic event were estimated using Cox regression models, while hazard ratios for recurrent thrombotic events were estimated using mixed-effects Cox regression models with a random intercept. Both prospective analyses were adjusted for age as a non-linear variable and sex. In a secondary analysis, M-protein concentration was included as a non-linear variable into similar models that were restricted to those with MGUS with an M-protein. Results: Of the 75,422 screened, 3,353 had MGUS with an M-protein, here termed heavy chain (HC) MGUS, and 315 had LC MGUS. Over a median follow-up of 3.67 to 3.90 years, depending on the outcome of interest, 263 and 3,557 arterial events (20.4 and 13.5 per 1,000 person years) and 260 and 3,092 venous events (20.2 and 11.7 per 1,000 person years) were observed in those with and without MGUS respectively. MGUS was found to be associated with venous thrombotic events (HR: 1.31; 95% CI: 1.08-1.57), in particular deep vein thrombosis (HR:1.46; 95% CI: 1.12-1.90). Of the different MGUS subtypes, this association was only observed in non-IgM MGUS. The results were similar in the recurrent events analysis. IgM MGUS was found to be associated with a higher of peripheral arterial embolic events (HR: 2.86; 95% 1.04-7.85) but this association was not observed in the recurrent event analysis. M-protein concentration was not correlated with the risk of thrombotic events. Discussion: In this large population-based study including more than 75,000 individuals screened for MGUS, we found that MGUS, and particularly non-IgM MGUS, was associated with venous thrombotic events. Interestingly, the size of the M-protein spike was not associated with a higher risk for thromboembolic events. Further studies are needed to identify the underlying mechanisms with the goal of identifying subgroups of the MGUS population that may require interventions to prevent thrombotic events, potentially improving the survival and quality of life of those with MGUS.

Influence of the transferred coronavirus infection on diseases of the endocrine system in athletes

Purpose: to study the effect of the transferred viral (on the example of COVID‑19) infection on the endocrine system of athletes.Materials and methods: the data of 1114 athletes (average age 22.23 ± 4.18 years) who underwent in‑depth medical examination in the period 2021–2022 were analyzed. The examination included an analysis of sports and infectious anamnesis, the results of hormonal, biochemical and instrumental studies.Results: coronavirus infection was suffered by the majority of athletes — 724 people (65 %) — in the vast majority of cases (91 %), their disease was asymptomatic or mild. 390 athletes (35 %) had no history of infection. There was a significant increase in the incidence of hypothyroidism, thyrotoxicosis, insulin‑dependent diabetes mellitus, autoimmune thyroiditis among athletes who had a coronavirus infection when compared with athletes who were not ill. The development of endocrine diseases did not depend on the severity of the infection and was most often detected with its mild and asymptomatic course. During the examination, six cases of newly diagnosed type 1 diabetes mellitus and eight cases of thyrotoxicosis were detected among athletes who had a coronavirus infection. The development of these conditions did not depend on the severity of the infection. At the same time, only 1 case of thyrotoxicosis was registered in athletes who were not ill, no new cases of type 1 diabetes mellitus were diagnosed. In the present study, no association was found between the transmitted coronavirus infection and an increase in the number of cases of nodular goiter, hyperprolactinemia and type 2 diabetes mellitus.Conclusion: the results of the study showed that in the long‑term period after COVID‑19, autoimmune endocrine diseases, such as primary hypothyroidism, diffuse‑toxic goiter with thyrotoxicosis, autoimmune thyroiditis, type 1 diabetes mellitus, were significantly more often manifested in athletes, which is probably associated with a cross‑lesion of autoimmunity against a background of viral infection.

Correction: Serological Screening for Celiac Disease and Gastrointestinal Absorption Disorders in Patients with Autoimmune Endocrine Diseases.

Correction: Serological Screening for Celiac Disease and Gastrointestinal Absorption Disorders in Patients with Autoimmune Endocrine Diseases.

FRI258 A Diagnostic Journey To Autoimmune Polyendocrine Syndrome Type 2

Abstract Disclosure: S. Amankwah: None. H.K. Driscoll: None. C. Muojieje: None. M. Sanati: None. Background: Approximately 50-65% of patients with autoimmune adrenal insufficiency have one or more autoimmune endocrine disorders. This case demonstrates the importance of considering autoimmune polyendocrine syndrome (APS) when a patient presents with more than one autoimmune endocrine disorder. Case: A 29-year-old woman with history of idiopathic intracranial hypertension, hypothyroidism on levothyroxine 50 mcg daily, endometriosis, and chronic migraines complained of fatigue, word finding difficulty, misspeaking of words, and staring spells. An MRI of the brain w+wo IV contrast revealed hypo-enhancing appearance of the pituitary gland. The patient was referred to endocrinology by neurology. Hormonal work up was performed checking for prolactin, ACTH, morning cortisol, TSH, Free T4, FSH, LH, IGF-1 and a serum chemistry panel. Thyroid antibodies were also ordered to help understand the etiology of her hypothyroidism. Pituitary hormones were normal except elevated TSH and borderline low serum cortisol. Subsequently a co-syntropin stimulation test resulted in inadequate cortisol rise. ACTH level measured inappropriately low normal. The patient then started steroid replacement therapy. Thereafter, 21-hydroxylase antibodies, serum renin and aldosterone were checked to screen for Addison Disease. Her 21-hydroxylase antibody was positive, aldosterone level low, and renin elevated pointing to autoimmune adrenalitis etiology. Her thyroid antibodies were also positive indicating autoimmune thyroid disease. Considering these results, the condition of APS came into question. Hence, the patient was screened for type 1 diabetes mellitus which was positive for glutamic acid decarboxylase 65 antibody but negative for insulin and pancreatic islet cell antibodies. Her hemoglobin A1c was 5.0%. Due to her history of gluten intolerance, she was screened for celiac disease which was negative for t-Transglutaminase antibody. The patient’s fatigue improved on steroid replacement therapy. She became euthyroid after increasing her levothyroxine dose to 75 mcg daily, and repeated MRI a year later did not show pituitary abnormalities. Discussion: APS type 2 is a polygenic inherited disorder associated with HLA-DR3 and DR4 that affects adult females more than males. The syndrome is characterized by type 1 diabetes mellitus, autoimmune thyroid disease and Addison disease. Associated nonendocrine autoimmune syndromes include celiac disease, pernicious anemia, and atrophic gastritis. These characteristics overlap with APS type 1 except for autoimmune thyroid disease that presents with type 2. It should be noted that thyroxine therapy can precipitate a life-threatening Addison crisis in a patient with untreated adrenal insufficiency and hypothyroidism. Therefore, it is necessary to evaluate adrenal function in all hypothyroid patients in whom APS is suspected. Presentation: Friday, June 16, 2023

Serological Screening for Celiac Disease and Gastrointestinal Absorption Disorders in Patients with Autoimmune Endocrine Diseases.

Celiac disease (CD) accompanying autoimmune endocrine diseases (AED) is generally asymptomatic. This study aimed to evaluate the frequency of clinically overt or silent CD in patients diagnosed with autoimmune endocrinopathy and the clinical effects of silent CD in these endocrinopathies. The study included 166 patients with known or newly diagnosed mono-/polyglandular AED and 90 age- and gender-matched healthy controls. The patients were classified into four groups: type 1 diabetes mellitus (DM) (n=44), Hashimoto's thyroiditis (HT) (n=68), Addison's disease (AD) (n=17), and autoimmune polyglandular syndrome (APS) (n=37). All subjects were serologically screened for tissue transglutaminase antibody (tTG) IgA and IgG. In addition, to evaluate the possible systemic consequences of CD, serum parathormone (PTH), 25-hydroxicholecalsiferol (25-OH-Vit D), vitamin B12, folic acid, iron, iron-binding capacity (IBC), and ferritin levels were measured. In the total series, 193 (75.4%) individuals were females, and 63 (24.6%) were males. TTG IgA antibody positivity was found in 23 among 166 patients, while no positivity was encountered in the healthy control group. The highest rates of positive tTg IgA frequency were detected in AD, with 29.4% (5/17). Serum 25-OH-Vit D, vitamin B12, folic acid, iron, and ferritin levels were significantly lower in AEDs compared to controls (p<0.001), and the lowest these parameters were detected in patients with AD. The serologic CD prevalence is higher in autoimmune mono-/and polyglandular endocrine diseases than in the control group. The data support recommends regular screening for CD in all patients with AEDs.

FRI540 A Novel, Rapid, Sensitive Bioassay For Thyrotropin Receptor Stimulatory Antibodies Improves Diagnosis &amp; Management Of Autoimmune Thyroid Disease

Abstract Disclosure: G.J. Kahaly: None. M.A. Lupo: None. A.T. Bossowski: None. L. Frommer: None. B. Hatun: None. A. George: None. J. Wolf: None. Background: Autoantibody mimicry of hormone action at the thyrotropin receptor (TSH-R) and aberrant signaling of TSH-R by autoantibodies (TSH-R-Ab) causes autoimmune thyroid disease (AITD), hyperthyroidism and hypothyroidism, both of which affect millions of patients worldwide. In this multicenter, single blind study, the specificity, sensitivity and performance of a novel bioassay for stimulatory TSH-R-Ab were tested. Methods: TSH-R-Ab were measured in a blinded manner with a TSH-R binding immunoassay (Cobas e411, Roche), and both stimulatory (TSAb) and blocking (TBAb) bioassays with luciferase release as readout (Thyretain®, Quidel) according to manufacturer’s instructions. TSH-R-Ab was also measured using the new TSAb bioassay (TurboTM). TurboTM utilizes a cAMP biosensor that is an engineered form of firefly luciferase in which the cAMP-binding domain of protein kinase A is fused between the N- and C-termini such that the luciferase is inactive until cAMP binds to the cAMP binding site. Using this biosensor, luciferase activity is proportional to intracellular cAMP levels. TurboTM detects TSAb in serum at room temperature, in a real-time homogeneous format, which delivers results in 60 minutes. It does not require cell culture, sample dilution, washing or cell lysis steps. Results: Eight-hundred forty-four samples of unselected, consecutive AITD patients and control subjects, devoid of autoimmune endocrine and thyroid disorders, were included. Mean age (SD) was 49 (14.7) years, range 1-89 years. Female: male sex ratio was 3.7:1. The four TSH-R-Ab assays were negative in all 174 controls. In contrast, the Turbo TSAb, Thyretain® TSAb and the binding assays detected TSAb in 557 of 670 (83%), 526/670 (78%) and 430/637 (67%) AITD samples, respectively (TurboTM bioassay versus binding immunoassay, chi-square test p&amp;lt;0.001). The results of the Turbo bioassay highly correlated with both thyroid function in Graves’ hyperthyroidism as well as with the clinical activity and severity of associated thyroid eye disease (p&amp;lt;0.001). Inter- (two users) and intra- (two lots) assay comparison for the Turbo bioassay showed coefficient of variations of only 4%, 3%, and 2%, respectively. The two TSAb bioassays, TurboTM and Thyretain®, correlated (Spearman’s r =0.7, p&amp;lt;0.001). Furthermore, the magnitude of serum levels in both TSAb bioassays correlated with TSH-R-Ab binding (both p&amp;lt;0.001). Finally, seventeen AITD samples showed dual TSH-R-Ab positivity in the TBAb and TSAb bioassays. Conclusions: The novel, rapid, easy-to-perform, sensitive and specific TurboTM bioassay performs better than the established TSH-R-Ab binding immunoassay and the Thyretain® bioassay. It provides clinically useful information for the accurate diagnosis and management of AITD patients. Presentation: Friday, June 16, 2023

FRI537 Thyrotropin Receptor Blocking Antibodies - A Multicenter, 4-Assay Comparison

Abstract Disclosure: A. George: None. A.T. Bossowski: None. B. Hatun: None. J. König: None. M.A. Lupo: None. L. Frommer: None. J. Wolf: None. G.J. Kahaly: None. Background: Thyrotropin receptor (TSH-R) blocking autoantibodies (TBAb) are present in 10-15% of patients with autoimmune thyroid disease (AITD). TBAb are functional, impact thyroid function, and are clinically relevant. This multicenter study compares, in a large collective of AITD subjects, the sensitivity and specificity of four immunoassays for the measurement of TBAb and introduces a novel and ultra-rapid TBAb bioassay. Methods: Serum samples from AITD patients were tested with a TSH-R binding immunoassay (Cobas e411, Roche, Penzberg, Germany), an established cell-based TBAb reporter bioassay (Thyretain®, Quidel, San Diego, USA) with expression of a Luciferase transgene as readout and a new “TurboTM” TBAb bioassay (Quidel) with a readout that is based on a cyclic AMP-activated luciferase. A Passing-Bablok regression and intra- and inter-assay validations were performed. All samples were also tested for stimulating TSH-R-Ab (TSAb, Thyretain®, Quidel). Results: Of 1011, unselected, consecutive AITD patients (Graves’ disease and Hashimoto thyroiditis), 132 patients and 212 samples were TBAb positive. Median age was 32 years (25/75 percentile 13.25/46.5 years) and female: male ratio was 2.86:1. Of 212 samples, 149 (70.3%), 47 (23,1%) and 16 (7,5%) were hypothyroid, euthyroid and hyperthyroid, respectively. Thyroperoxidase and thyroglobulin antibodies were present in 136 (64.15%) and 70 (33.02%) samples, respectively. The four TSH-R-Ab assays were negative in 90 control subjects devoid of autoimmune thyroid and endocrine disorders. In contrast, the TurboTM cAMP TBAb, Luciferase TBAb and the Cobas binding assays detected TBAb in 212 (100%), 168 (79%) and 137/180 (76%) samples, respectively (Chi-square test p&amp;lt;0.001). The TurboTM TBAb bioassay highly correlated with thyroid function (p=0.007). Furthermore, the magnitude of percentage inhibition in both TurboTM and Luciferase TBAb bioassays correlated with TSH-R-Ab binding assay positivity (both p&amp;lt;0.001). Seventeen of 212 (8%) samples showed dual TSH-R-Ab positivity in the Turbo TBAb and TSAb bioassays, while 13 (6.1%) samples showed dual positivity for TSAb and TBAb in all three bioassays. The two TBAb bioassays correlated (Spearman’s r =0.59, p&amp;lt; 0.001). Single-user testing and intra-assay validation demonstrated adequate precision with very low coefficient of variation (CV 0.05) and low CV (0.14) at 92% and 44% inhibition (serum TBAb positivity), respectively. Conclusions: This is the largest reported collective of TBAb-positive samples in AITD patients, measured with four different immunoassays. TBAb markedly affects thyroid function. The novel, easy-to-perform, rapid and reliable TurboTM blocking bioassay detected significantly more TBAb than the established immunoassays demonstrating both its higher analytical performance and clinical utility in the management of AITD patients. Presentation: Friday, June 16, 2023

Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects

Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.

Protocol for a double-blinded randomised controlled trial to assess the effect of faecal microbiota transplantations on thyroid reserve in patients with subclinical autoimmune hypothyroidism in the Netherlands: the IMITHOT trial

BackgroundHashimoto’s thyroiditis (HT) is a common endocrine autoimmune disease affecting roughly 5% of the general population and involves life-long treatment with levothyroxine, as no curative treatment yet exists. Over the...

#6130 COMMON VARIABLE IMMUNODEFICIENCY WITH A TNFRSF13B GENE MUTATION IN A KIDNEY AND PANCREAS TRANSPLANT RECIPIENT: WHAT SHOULD WE AIM FOR?

Abstract Background and Aims Common Variable Immune Deficiency (CVID) is a primary immunodeficiency disorder, where genetic defects are commonly present, with hypogammaglobulinemia (typically IgG) and increased susceptibility to recurrent infections, autoimmune disorders, granulomatous diseases and malignancy. It can also potentially lead to nephropathy, with increased risk of proteinuria and metabolic acidosis, higher risk of acute tubular injury caused by Immunoglobulin replacement therapy, and the data available in current literature shows a higher incidence of tubulointerstitial nephritis and membranous glomerulopathy, with IgG deposits on immunofluorescence in most cases. Our aim is to report the challenges of a kidney and pancreas transplant in a recipient with chronic kidney disease and a primary immunodeficiency disorder, to outline an immunosupression strategy with potential alternatives, and to report on the short-term outcomes. Case Report Here-in, we report the case of a 27-year-old patient, with type 1 diabetes mellitus, diagnosed with end-stage chronic kidney disease, who has a history of chronic inflammatory response dysregulation, with chronic monoarthritis, persistent elevation of inflammation markers, recurrent infections and low IgG levels. Genetic screening revealed a heterozygous pathological mutation in TNFRSF13B gene, and a Variant of Uncertain Significance (VOUS) in BACH2 gene. At 24 years-old, she experienced a high-risk pregnancy with HELLP syndrome, and serum creatinine and non-nephrotic proteinuria progressively worsened after postpartum. A native kidney biopsy revealed diabetic nephropathy, with C3 and IgG pseudolinear deposits on immunofluorescence. Eventually, disease progression led to hemodialysis induction. 10 months later, she received a kidney and pancreas cadaveric transplant from a standard criteria donor (SCD). Serum baseline donor creatinine was 0.9 mg/dL, and cause of death was a hemorrhagic stroke. Both donor and receptor had blood group type A (ABO system) and positive cytomegalovirus (CMV) IgG levels. Compatibility analysis showed donor Histocompatibility Leukocyte Antigens (HLA) class I: A 01,32; B08,64; C07,08; and class II: DR 17,07; DQ 02,02; DP 03,45; and receptor HLA class I: A 02,02; B 35,44; C 04,05; and class II: DR 03,04. Flow cytometry showed no receptor class I or class II anti-HLA antibodies. Panel Reactive Antibodies (PRA) test score was 0%, and flow cytometry cross-match (FCCM) was negative. Immunosuppression induction regimen included thymoglobulin, mycophenolate mofetil, tacrolimus and methylprednisolone, with optimal pancreatic graft function. Creatinine at discharge was 2.1 mg/dL. After discharge, maintenance immunosuppression protocol included tacrolimus, mycophenolate mofetil and prednisolone, and pancreas and renal graft function remained successfully stable, with no serious infections until current date. Discussion Common variable immunodeficiency with a heterozygous TNFRSF13B gene mutation is associated with increased risk of hypogammaglobulinemia, lymphoma, gastrointestinal cancer and autoimmunity. The VOUS BACH2 gene is also likely pathological, since there have been BACH2 polymorphisms associated with autoimmune endocrine diseases, including Addison's disease, Graves’ disease and type 1 diabetes mellitus. A hyper-regulated inflammatory state can accelerate kidney function deterioration, but chronic treatment with corticosteroids should be cautious due to the underlying diabetic nephropathy. After transplantation, recipients with CVID are at higher risk of atypical infections, autoimmune complications and disease recurrence with suboptimal long term graft survival. The evidence of current immunosuppression maintenance regimens is weak due to the paucity of CVID cases described in current literature. In the future, we believe that belatacept could offer benefits in terms of reducing the risk of graft loss or the incidence of serious infectious in a transplant recipient with a primary immunodeficiency disorder. Nevertheless, therapy management should be accomplished in a patient-to-patient basis.

Genome-wide association studies reveal shared genetic haplotypes of autoimmune rheumatic and endocrine diseases with psychiatric disorders.

Several studies have shown that autoimmune diseases are associated with psychiatric diseases like depression and psychosis. Genetic evidence supports this association. The aim of this study was to investigate if genetic variants predisposing to autoimmune diseases and psychiatric disorders are genetically linked, constructing the common haplotypes. All registered single nucleotide polymorphisms (SNPs) in the Genome-wide association studies ("GWAS catalog") having been associated with autoimmune rheumatic and endocrine diseases were investigated for being in linkage disequilibrium with any psychiatric disorders' associated SNPs. Analysis was performed by the LDtrait and LDhap bioinformatics tools. Multiple chromosomal regions have been detected containing rheumatic/endocrine diseases' predisposing SNPs and psychiatric disorders' predisposing SNPs. The genetic haplotypes have been constructed for some of these genetic regions. Six of the autoimmune rheumatic and endocrine diseases examined here share a common haplotype with psychiatric diseases at the HLA locus 6p21-22. Our study shows that autoimmune diseases and psychiatric diseases are genetically linked. Genetic haplotypes have been constructed, showing in detail this genetic linkage.

A case of doxorubicin and cyclophosphamide therapy-induced type 1 diabetes: a case report

BackgroundPatients receiving immune checkpoint inhibitors have been reported to develop autoimmune endocrine diseases, including type 1 diabetes, although few drugs have been shown to induce type 1 diabetes. Additionally, it is important to note that drugs other than immune checkpoint inhibitors could lead to the development of type 1 diabetes.Case presentationA 54-year-old Filipino female patient underwent surgery for left-sided breast cancer. Postoperative chemotherapy was initiated, including doxorubicin (Adriamycin) and cyclophosphamide therapy. The patient was brought to our hospital by ambulance after consciousness disturbance following three courses of doxorubicin and cyclophosphamide therapy and was hospitalized. Her blood glucose and hemoglobin A1c levels were 1661 mg/dL and 11.9%, respectively. The patient was diagnosed with diabetic ketoacidosis after arterial blood gas analysis indicated a blood pH of 7.120. Her insulin secretion was impaired, and her anti-glutamic acid decarboxylase antibody test result was significantly positive.ConclusionsThe present case shows that doxorubicin and cyclophosphamide therapy may cause unexpected adverse responses, such as type 1 diabetes, though rarely, and highlights the importance of careful patient follow-up. This report is the first to present a case of type 1 diabetes that suddenly developed after doxorubicin and cyclophosphamide treatment.

Seasonality of month of birth in patients with autoimmune endocrine diseases: A systematic review

BackgroundExposure to seasonal environmental factors during gestation or early in the postnatal period could influence the development of autoimmunity, determining a seasonality in the month of birth (MOB). There are studies evaluating this potential seasonality in patients with type 1 diabetes (T1D), autoimmune thyroid diseases (AITD), and Addison's disease (ADD), but results have been controversial. MethodsSystematic review according to PRISMA guidelines, using PubMed, Web of Science and WorldCat databases (2005–2020) of studies that explored the association between the seasonality of the MOB and T1D, AITD and ADD. Information on sex and age, location, methodology and internal quality, seasonal patterns, hypotheses and other factors proposed to explain seasonality were extracted. Differences in season and month of birth were further discussed. ResultsThe initial search retrieved 300 articles, and after further screening, 11 articles fulfilled inclusion criteria and were finally selected and reviewed. 73% found a seasonal pattern and 64% showed birth peaks in spring and/or summer. Hashimoto's thyroiditis and women exhibited a higher seasonality. Ultraviolet radiation, Vitamin D levels and viral infections were identified as influencing factors. ConclusionsThe effect of certain seasonal factors during foetal development, reflected by the seasonal differences in the MOB, could contribute to the development of endocrine autoimmune diseases in predisposed patients. Further research is needed to elucidate the mechanisms underlying the observed seasonality.

Evaluation of IL-10, MCP-1, IFN gamma, and protectin D1 levels in patients with Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) is one of the most prevalent autoimmune endocrine diseases and caused by the loss of immune tolerance for the thyroid gland. Many pathophysiological mechanisms were speculated about the development of HT. In our study, we aimed to reveal the relationship between HT and IL-10, MCP-1, IFNɤ, and PD1 levels and compare them with control subjects. We collected 37 patients with HT and 25 controls referred to our outpatient clinic. The diagnosis of HT was based on the detection of circulating antibodies to thyroid antigens and decreasing echogenicity on thyroid USG in patients with appropriate clinical characteristics. Serum IL-10, MCP-1, IFNɤ, and PD1 levels were detected using an ELISA KIT (96T) method according to the manufacturer's instructions. All subjects were euthyroid (median TSH level was 1.68mU/L in HT vs 1.83mU/L in the controls, p = 0.672). Twenty-three of 37 patients with HT were taking L-thyroxin replacement. Levels of serum IL-10, IFNɤ, and PD1 in patients with HT were higher than the controls, but the differences were not statistically significant (p = 0.393, p = 0.495, and p = 0.052 respectively). The serum levels of MCP-1 in HT patients were statistically different and higher than the controls (p = 0.018). Correlation analysis displayed significant associations between IL-10, MCP-1, IFNɤ, and PD1 levels. Our study demonstrated that serum MCP-1 levels in HT patients were significantly increased; on the other hand, significant difference was not found between HT patients and the controls in terms of serum IL-10, IFNɤ, and PD1 levels.