SAT-429 Systemic Safety Analysis of Mycophenolate in Graves’ Orbitopathy

Abstract Context The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves’ orbitopathy (GO). Methods The safety data, which is of utmost importance in immunomodulation, from the two major randomized mycophenolate trials [“Chinese trial” (1) and “European Group on Graves’ Orbitopathy (EUGOGO) trial” (2)] and the original database of the EUGOGO trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of clinical disease activity and severity were also compared. Results A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenou…

Quality of Life in a German Graves Orbitopathy Population

To evaluate the validity and responsiveness of a German-language version of the disease-specific Graves orbitopathy quality-of-life questionnaire (GO-QOL).Prospective cross-sectional study.At a multidisciplinary university orbital center, 310 consecutive unselected Graves orbitopathy outpatients answered the GO-QOL before undergoing complete ophthalmic and endocrine assessment. The main outcome measures were the GO-QOL and its 2 subscales, Visual Functioning and Appearance.The QOL scores for the subscales Visual Functioning and Appearance were (mean ± SE) 72.5 ± 1.4 and 71.3 ± 1.5, respectively. Visual Functioning and Appearance were higher in mild (82.2 ± 2.2 and 86.0 ± 17.6) than in moder…

Eye Muscle Antibodies in Endocrine Exophthalmos

Serum samples were obtained from 65 patients with endocrine exophthalmos class I-V. In 33/65 patients who were treated either with prednisone or with ciclosporin, blood was sampled before, during and after therapy. Antibodies against eye muscle were determined during the course of immunosuppressive therapy in order to have an objective parameter of the therapeutic effect. To ascertain the specificity of the reaction both eye and abdominal muscles were used as antigens in an ELISA system. Both IgG and IgM antibodies were detected. In 45/65 patients (71%) eye muscle antibodies were positive before starting therapy. Antibodies were mostly detected in patients with active disease. Patients with…

Das polyglanduläre Autoimmunsyndrom – Lebensqualität und familiäre Beteiligung

Hintergrund und Fragestellung: Fur Patienten mit einem Polyglandularem Autoimmunsyndrom (PGA) und ihre Angehorigen liegen keine Daten zur familiaren Beteiligung und zur Lebensqualitat vor. Daher erfolgte eine Erhebung in einer reprasentativen Gruppe. Patienten und Methoden: Im Rahmen einer prospektiv angelegten und kontrollierten Studie wurden klinische und serologische Untersuchungen an 75 konsekutiv aufgenommenen Patienten mit PGA (mittleres Alter 47,5  ±  15,3 Jahre; 65,3 % Frauen) mit 108 Angehorigen (mittleres Alter 33,13 Jahre  ± 20,08 Jahre; 65,7% Frauen) durchgefuhrt. Drei validierte Messinstrumente (Short Form 36 [SF-36], Hospital Anxiety and Depression Scale [HADS] und Giesener Be…

Endokrine Orbitopathie 1998

Die haufigste extrathyreoidale Manifestation der autoimmunen Thyreopathie ist die endokrine Orbitopathie. Das Charakteristikum dieser Autoimmunerkrankung ist die entzundliche Volumenzunahme des peri- und retrobulbaren Gewebes, die zur klinischen Symptomatik nichtinfiltrativer Lidaffektionen, Protrusio bulbi, Augenmuskelparesen und bis hin zum Visusverlust fuhren kann. Die pathologischen Veranderungen der endokrinen Orbitopathie sind gekennzeichnet durch immunologisch vermittelte Entzundungsreaktionen im Retrobulbarraum, in deren Verlaufes zur lymphozytaren Infiltration und Einlagerung von Glykosaminoglykanen in das orbitale Muskel-, Binde- und Fettgewebe kommt. Trotz verschiedener neuer dia…

Public Health Relevance of Graves' Orbitopathy

Disfiguring proptosis and functional impairment in patients with Graves' orbitopathy (GO) may lead to impaired earning capacity and to considerable indirect/direct costs.The aim of the study was to investigate the public health relevance of GO.This cross-sectional study was performed between 2005 and 2009 at a multidisciplinary university orbital center.A total of 310 unselected patients with GO of various degrees of severity and activity participated in the study.We conducted an observational study.We measured work disability and sick leave as well as the resulting indirect/direct costs of GO-specific therapies.Of 215 employed patients, 47 (21.9%) were temporarily work disabled, and 12 (5.…

Type 1 diabetes associated autoimmunity.

Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid disease, Addison's dise…

Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity.

Abstract Context The structure of the human leucocyte antigen (HLA) peptide-binding clefts strongly contributes to monoglandular and polyglandular autoimmunity (AP). Objective To investigate the impact of amino acid polymorphisms on the peptide-binding interactions within HLA class II and its association with AP. Design Immunogenetic study. Setting Tertiary referral center for autoimmune endocrine diseases. Subjects 587 subjects with AP, autoimmune thyroid disease (AITD), type 1 diabetes (T1D), and healthy unrelated controls were typed for HLA class II. Methods Amino acids within the peptide binding cleft that are encoded by HLA class II exon 2 were listed for all codon positions in all sub…

In vitro synthesis of glycosaminoglycans in endocrine ophthalmopathy

The effects of humoral and cell-mediated immunity on the glycosaminoglycan synthesis of retrobulbar fibroblasts was evaluated in patients with endocrine ophthalmopathy. After incubation with IgG and sera, secreted glycosaminoglycans, radiolabeled with D-6-3H-glucosamine and 35sulfate, were precipitated with cetylpyridinium chloride and ethanol. Hyaluronic acid synthesis of human retrobulbar fibroblasts after incubation with sera and IgG and after co-culture with lymphocytes was assessed by means of a radiometric test. Patients' IgG, compared to controls', accounted for a higher secretory stimulation of porcine retrobulbar fibroblasts (as measured by cetylpyridinium chloride precipitation) a…

2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism.

Graves' disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during p…

Response to methimazole in Graves' disease

Summary OBJECTIVE A variety of regimens continue to be used In the treatment of Graves' disease with antithyrold drugs. We have lnvestigated the factors which determine the initial response to methimazole (time until euthyroidism Is achieved) In Graves' disease. PATIENTS Five hundred and nine patients with Graves' disease in different European countries with normal and subnormal iodine supply. Patients were randomized to treatment with either 10 or 40mg of methimazole per day for one year, with levothyroxine supplementation as required to maintain euthyroidism. Investigations were carried out before treatment and at 3 and 6 weeks and 3, 6, 9 and 12 months. MEASUREMENTS Response was assessed…

The 2015 European Thyroid Association Guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism

Endogenous subclinical hyperthyroidism (SHyper) is caused by Graves' disease, autonomously functioning thyroid nodules and multinodular goitre. Its diagnosis is based on a persistently subnormal serum thyroid-stimulating hormone (TSH) level with free thyroid hormone levels within their respective reference intervals. In 2014 the European Thyroid Association Executive Committee, given the controversies regarding the treatment of Endo SHyper, formed a task force to develop clinical practice guidelines based on the principles of evidence-based medicine. The task force recognized that recent meta-analyses, including those based on large prospective cohort studies, indicate that SHyper is associ…

Triiodothyronine alongside levothyroxine in the management of hypothyroidism?

The current guideline-based management of hypothyroidism recommends monotherapy with levothyroxine (LT4), titrated to maintain the level of thyrotropin within a euthyroid reference range. This has been successful for most people with hypothyroidism, but a substantial minority still report symptoms of hypothyroidism unexplained by a comorbid medical condition. LT4 is essentially a prodrug for triiodothyronine (T3), the thyroid hormone that acts on target tissues in the brain and the periphery. Thyroid hormone replacement with LT4 alone does not restore physiological tissue levels of thyroid hormones, particularly T3. During the last two decades, much interest has focussed on the potential of…

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

<b><i>Background:</i></b> Both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders. <b><i>Summary:</i></b> Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin…

OR18-03 Functional TSH Receptor Antibodies Are a Biomarker for Graves’ Disease - a Prospective Trial

Abstract Objective We aimed to evaluate the clinical utility and predictive value of stimulatory (TSAb) and blocking (TBAb) TSH receptor antibodies in the management of Graves’ disease (GD). Methods Hundred well-defined, consecutive, unselected, untreated hyperthyroid patients with GD were enrolled in a prospective two-year trial. Methimazole (MMI) was administered for 24 weeks according to baseline serum concentrations of free T3/free T4. Starting dose was 5–30 mg/day. Through a titration regimen, this dose was respectively tapered or increased at each subsequent study visit as the patient became euthyroid or remained hyperthyroid. Goals of therapy were to maintain normal fT4 and TSH level…

Proteomics Differentiate Between Thyroid-Associated Orbitopathy and Dry Eye Syndrome.

PURPOSE: In patients with thyroid-associated orbitopathy (TAO), the dry eye syndrome occurs frequently, and symptoms and signs of both disorders overlap making early and accurate differential diagnosis difficult. A differentiation via specific markers is warranted. METHODS: Tear fluid samples of 120 subjects with TAO, TAO + dry eye, dry eye, and controls were collected. The samples were measured using matrix-assisted laser desorption ionization mass spectrometry. The identified proteins were tested with antibody microarrays. RESULTS: Proteomics identified deregulated proteins in TAO and dry eye. Compared with dry eye, proline-rich protein 1 (PROL1, P = 0.002); uridine diphosphate (UDP)-gluc…

Relation of endocrine and cardiac findings in acromegalics

Cardiac involvement in 32 acromegalics was related to endocrine parameters, clinical score and duration of the disease as well as compared to that of 50 controls free of cardiac disease. Stress ECG, 24h Holter monitoring and echocardiography revealed that supraventricular premature complexes did not occur more often in acromegalics than in controls, both prevalence and severity of ventricular arrhythmia, however, were higher in patients compared to controls: 15/32 (48%) acromegalics had complex ventricular arrhythmia as compared with 6/50 (12%) normal subjects (p less than 0.01). Repetitive ventricular arrhythmia was manifest in 10/32 (31%) patients but only in 4/50 (8%) controls (p less th…

Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy.

Abstract Glucocorticoids are usually given for management of Graves' ophthalmopathy (GO), but they may cause side effects. By comparison, intravenous administration of immunoglobulins resulted in clinical improvement and decreased antibody titres in a large number of autoimmune diseases. Therefore, a randomized trial was done, in which 19 patients with active GO were treated with a 20-week course of oral prednisolone (P, starting dose 100 mg/day), and 21 received 1 g immunoglobulin/kg body weight for 2 consecutive days every 3 weeks. The immunoglobulin course was repeated six times. Before and at the end (20 weeks) of immunomodulating therapy, ophthalmological investigation and quantitative…

Exophthalmos and basilar impression. A contribution to differential diagnosis of endocrine orbitopathy.

We report on a male patient with exophthalmos of unclear etiology, basilar impression, syringohydromyelia and type II Arnold-Chiari malformation. Two diseases involving the orbital region were to be considered in differential diagnostic terms: endocrine orbitopathy and osseous orbit dysplasia. The typical physical appearance associated with basilar impression as well as suppurative keratitis in Lagophthalmos was striking. Tetraspasticity with pareses, bulbar symptoms, proximally pronounced muscular atrophy as well as a left hemihypesthesia was shown neurologically. Although the orbit CT was normal, sonography revealed thickened ocular muscles. There was euthyroidism in diffuse goiter with n…

Response, Letter to the Editor: Author Response to Mustafa Sahin.

A Novel Long-Term Graves’ Disease Animal Model Confirmed by Functional Thyrotropin Receptor Antibodies

<b><i>Introduction:</i></b> A novel long-term murine model for Graves’ disease (GD) using repeated, long-term immunizations with recombinant adenovirus expressing the extracellular A-subunit of the human thyrotropin receptor (Ad-TSHR) was applied to evaluate the functional anti-TSHR-antibody (TSHR-Ab) profile. <b><i>Methods:</i></b> BALB/c mice received 7 immunizations with either 10<sup>10</sup> plaque-forming units of Ad-TSHR or control Ad-GFP. Naïve (nonimmuized native) mice were also studied. Three 3-weekly immunizations were followed by 4-weekly boosts until the 7th immunization. Blocking (TBAb) and stimulating (TSAb) TSHR-Ab …

Glycosaminoglycan Antibodies in Endocrine Ophthalmopathy

An increased accumulation of glycosaminoglycans (GAG) in the orbita has been reported in endocrine ophthalmopathy (EO). In this study we investigated whether antibodies directed against GAG are present in the sera of 52 EO patients and 47 healthy controls. Three out of 52 patients exhibited low titers of antinuclear antibodies and all patients were negative for antibodies against extractable nuclear antigens. Isotype IgG antibodies were detected by means of an ELISA using hyaluronic acid and dermatan sulfate as antigens. Values were expressed as optical density at 405 nm. In comparison to the control group (0.445, 0.364, 0.588; median, 25th, 75th percentile) significantly (p < 0.001) higher…

Thyrotropin Receptor Blocking Antibodies.

AbstractAutoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were u…

2021 European Thyroid Association Guidelines for the Management of Iodine-Based Contrast Media-Induced Thyroid Dysfunction

Given the fact that a large number of radiological examinations using iodine-based contrast media (ICM) are performed in everyday practice, clinicians should be aware of potential ICM-induced thyroid dysfunction (TD). ICM can induce hyperthyroidism (Hyper) or hypothyroidism (Hypo) due to supraphysiological concentrations of iodine in the contrast solution. The prevalence of ICM-induced TD varies from 1 to 15%. ICM-induced Hyper is predominantly found in regions with iodine deficiency and in patients with underlying nodular goiter or latent Graves’ disease. Patients at risk for ICM-induced Hypo include those with autoimmune thyroiditis, living in areas with sufficient iodine supply. Most cas…

Arrhythmia profile in acromegaly.

In a controlled study, the cardiac involvement and arrhythmia profile of 32 patients with acromegaly were correlated with endocrine parameters (somatomedine C, growth hormone), clinical score and duration of the disease. Data were compared with those of 50 controls free of cardiac disease. Stress ECG, 24 h Holter monitoring and echocardiography were performed. Supraventricular premature complexes occurred no more often in acromegalics than in controls. Both prevalence and severity of ventricular arrhythmia, however, were significantly higher in patients compared to controls (P less than 0.01). 15/32 (48%) acromegalic patients had complex ventricular arrhythmias (Lown III-IV) as compared wit…

Ciamexone in endocrine orbitopathy. A randomized double-blind, placebo-controlled study.

Abstract The influence of ciamexone on the activity and course of endocrine orbitopathy was investigated. Fifty-one patients with active orbitopathy classes II-VI were allocated randomly to two groups: over a period of six months, 26 patients received 300 mg/day ciamexone and 25 patients received placebo tablets. In both groups, prednisolone was administered in addition in the first four weeks. Ophthalmological investigations and clinical tests as well as orbit sonography were carried out before as well as one, three and six months after the beginning of therapy. Before and after treatment, computer tomography of the orbit was performed. Symptoms and signs did not show any significant impro…

Reply to Drs. Kiaei and Molinaro Regarding the Publication “Comparison of a Bridge Immunoassay with Two Bioassays for Thyrotropin Receptor Antibody Detection and Differentiation”

Dear Editor,Drs. Kiaei and Molinaro 1 put forth two criticisms of the manuscript published by us 2. They state that the experimental design of this study is flawed and that the authors falsely claim that negative Thyretain™ TSI Reporter BioAssay results for two Graves’ diseases patients undergoing drug treatments means the absence of stimulating antibodies. To substantiate this claim Drs. Kiaei and Molinaro point out that the manufacturer of the Thyretain TSI Reporter BioAssay clearly states in the package insert that “[t]he effects of various drug therapies on the performance of this Kit have not been established” 1. Second, the package insert explicitly states that “[a] negative result do…

Urinary glycosaminoglycans in Graves' ophthalmopathy.

An increased accumulation of glycosaminoglycans (GAG) in retrobulbar tissues has been reported in patients with thyroid eye disease. We examined the quantitative urinary GAG excretion in 101 patients with Graves' ophthalmopathy of different classes, 36 patients with Graves' hyperthyroidism without ophthalmopathy, 14 patients with toxic nodular goitre and 103 control subjects. Glycosaminoglycans were isolated from 24-h urine collections by precipitation with cetylpyridinium chloride and ethanol followed by photometrical quantification of hexuronic acids after reaction with carbazole. In comparison with the control group (15.8, 10.4, 21.6 mg/24 h; median, 25th, 75th percentile) a significant …

Concurrent autoimmune diseases in patients with autoimmune hepatitis.

Although the pathomechanisms of autoimmune diseases in various organs remain unresolved, an accumulation of autoimmune diseases in individual patients has been observed. An overlap of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis has been well documented. However, the overlap of autoimmune diseases other than PBC or PSC has not yet been investigated in a large cohort.The goal of our analysis was to investigate the incidence of concurrent autoimmune diseases in patients with AIH.We analyzed our cohort of 278 patients with AIH for concurrent autoimmune diseases.A total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Be…

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and DQ8 (DQA1*0301-DQB1*0302), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as the cytotoxic T-lym…

Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study

Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Methods: Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Results: Ten subjects received all 10 doses of ATX-GD-59,…

Kardiopulmonale Parameter bei Hyperthyreose

Background Hyperthyroid patients often suffer from impaired exercise capacity with dyspnoea. Two well established, non-invasive methods were used to evaluate the influence of hyperthyroidism on cardiopulmonary function. Patients and methods In 42 patients with hyperthyroidism we performed spirometry and cardiopulmonary exercise testing before and after 7 days of propranolol therapy as well as in euthyroidism. Results In hyperthyroidism reduced vital capacity and 1-second capacity were observed (95.5 +/- 2.4% vs 102.6 +/- 1.5%; p = 0.0087; 89.4 +/- 2.3% vs 95.2 +/- 2.2%; p = 0.0179). No changes showed during beta-blockade. At the anaerobic threshold reduced tidal volume and enhanced respirat…

Aktuelle interdisziplinäre Diagnostik und Therapie der endokrinen Orbitopathie*

Retrobulbäre Bestrahlung bei endokriner Orbitopathie - Erfahrungen im Langzeitverlauf

Background Significance of retrobulbar irradiation in patients suffering form Graves' ophthalmopathy, though established since almost one century, is subject of scientific debate. The present study investigated the effect of retrobulbar irradiation using a standardized protocol focussing on long term results. Patients and methods Between 1981 and 1997, 104 patients treated by retrobulbar irradiation (10 to 20 Gray) due to Graves' disease. Twenty-nine of these underwent irradiation as sole treatment (mean follow-up 57 months), while in the remaining 75, it was combined with a systemic steroid treatment (mean follow-up 40 months). Patients were evaluated regarding proptosis, intraocular press…

Management of Graves‘Thyroidal And Extrathyroidal Disease – An Update

Abstract Context Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO). Evidence acquisition Guidelines, pertinent original articles, systemic reviews, and meta-analyses. Evidence synthesis Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistent…

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340…

Thyroid Stimulating Hormone Receptor Antibodies in Thyroid Eye Disease-Methodology and Clinical Applications.

Background Thyroid stimulating hormone receptor antibodies (TSHR-Ab) cause autoimmune hyperthyroidism and are prevalent in patients with related thyroid eye disease (TED). Purpose To provide a historical perspective on TSHR-Ab and to present evidence-based recommendations for clinical contemporary use. Methods The authors review the recent literature pertaining to TSHR-Ab in patients with TED and describe the various immunoassays currently used for detecting TSHR-Ab and their clinical applications. Results We provide a historical summary and description of the various methods used to detect TSHR-Ab, foremost, the functional TSHR-Ab. Increasing experimental and clinical data demonstrate the …

Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials

Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia.We analysed integrated outcomes and follow-up data from two randomised, double-masked, placebo-controlled, multicentre, trials done at a total of 28 academic referral tertiary specialised centres offering joint thyroid eye clinics, or orbital clinics or practices, or both, in Europe and the…

Effect of a Biofeedback Intervention on Heart Rate Variability in Individuals With Panic Disorder: A Randomized Controlled Trial

OBJECTIVE Some individuals with panic disorder (PD) display reduced heart rate variability, which may result in an increased risk of cardiovascular mortality. Heart rate variability-biofeedback (HRV-BF) training has been shown to improve the modulation of the autonomic activity. Therefore, this randomized controlled trial was conducted to investigate the effect of a four-week HRV-BF intervention in individuals with PD. Heart rate variability-biofeedback (HRV-BF) training improved the modulation of the autonomic activity. Therefore, with this randomized controlled trial we aimed to investigate the effect of a four-week HRV-BF intervention in people with PD. METHODS Thirty-six women and sixte…

Ciclosporin and thyroid-stimulating immunoglobulins in endocrine orbitopathy.

The study investigated whether ciclosporin (C) affected the thyroid-stimulating immunoglobulins (TSI) in serum of patients with endocrine orbitopathy (EO). The effect of C was compared with that of prednisone (P). Fifteen patients with EO classes III-V received C (n = 7) or P (n = 8). In addition to the immunosuppressants, five patients with Graves' disease in each group received methimazole (MMI). The stimulation of the cAMP levels in the medium of thyrocyte cultures was determined as a parameter of TSI. The TSI levels were markedly lowered in both groups during and after therapy. C group: before therapy 6.2 pmol/ml +/- 1.63 (100%, mean +/- SEM), during treatment 4.6 pmol/ml +/- 2.28 (74%)…

Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127- and CD4 + IL17+/CD4 + CD25 + CD127 - FoxP3+ T cells in children with autoimmune thyroid diseases (.).

Until now, altered balance of Th1 and Th2 immune cells has been postulated to play an important role in the pathogenesis of autoimmune thyroid diseases (AITD). However, recent studies on thyroid diseases have suggested a new role for Th17 cells that have been classified as a new lineage, distinct from Th1, Th2 and Treg cells. Despite wide interest, the role of Th17 cells in the pathogenesis of inflammatory and autoimmune diseases is still debated. The aim of the study was to estimate the proportions of Th17/Treg T cells in peripheral blood from patients with Graves' disease (GD; n = 29, mean age 15.4 ± 5.1 years), Hashimoto's thyroiditis (HT; n = 39, mean age 15.2 ± 4.1 years) and in health…

Glycosaminoglycans in Thyroid-Associated Ophthalmopathy

Glycosaminoglycan (GAG) accumulation in the retrobulbar space of patients with thyroid-associated ophthalmopathy (TAO) has been documented in a number of immunohistochemical studies. In order to gain further insight into possible immunopathogenic mechanisms, the influence of humoral immunity on retrobulbar fibroblasts (RF) as GAG producing cells as well as on GAGs themselves was investigated. The effect of lymphocytes on hyaluronic acid (HA) synthesis of RF as well as in turn the influence of RF on lymphocytes were evaluated. In search of methods which would facilitate management of patients with TAO and allow assessment of disease activity, GAGs were determined in both urine and plasma. Im…

Selektive Blutentnahme aus dem Sinus petrosus inferior: Vergleich von CRF- und TRH-Stimulation

In 10 patients with hypophyseal Cushing microadenomas, selective bilateral sampling from the inferior petrosal sinuses was performed and the effect of stimulation by iv TRH and CRF was compared. On the side of the microadenoma. ACTH concentration rose from 650 +/- 242 pg/ml to 2712 +/- 843 pg/ml following injection of CRF and 2025 +/- 242 pg/ml after TRH. Contralateral values were 165 +/- 79 pg/ml, 490 +/- 200 pg/ml and 165 +/- 72 pg/ml respectively. Prolactin concentration on the side of the adenoma was 98 +/- 49 ng/ml before stimulation, 236 +/- 62 ng/ml after CRF and 747 +/- 168 ng/ml after TRH. Contralateral concentration was 22 +/- 10 ng/ml, 64 +/- 19 ng/ml respectively. Sampling local…

Early onset of polyglandular failure is associated with HLA-DRB1*03.

ObjectivesPolyglandular failure or autoimmunity (PGA) involves at least two endocrine diseases. Several genes may play a role in its etiology. This study analyzed 1) whether HLA-DRB1, HLA-DQB1, and MHC class I chain-related gene A (MICA) polymorphisms are associated in PGA and 2) whether PGA patients display stronger associations with these immune genes than patients with monoglandular autoimmunity (MGA).DesignAssociation study.MethodsHLA-DRB1, HLA-DQB1, and MICA alleles were analyzed in 73 patients with PGA, 283 with MGA, and 206 healthy controls. The HLA-DRB1 and HLA-DQB1 polymorphisms were determined with PCR-amplified DNA being hybridized with PCR-sequence-specific oligonucleotide probe…

United States and European Multicenter Prospective Study for the Analytical Performance and Clinical Validation of a Novel Sensitive Fully Automated Immunoassay for Calcitonin.

Abstract BACKGROUND The objective of this study is the validation and proof of clinical relevance of a novel electrochemiluminescence immunoassay (ECLIA) for the determination of serum calcitonin (CT) in patients with medullary thyroid carcinoma (MTC) and in different diseases of the thyroid and of calcium homeostasis. METHODS This was a multicenter prospective study on basal serum CT concentrations performed in 9 US and European referral institutions. In addition, stimulated CT concentrations were measured in 50 healthy volunteers after intravenous calcium administration (2.5 mg/kg bodyweight). RESULTS In total, 1929 patients and healthy controls were included. Limits of blank, detection, …

Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment

PURPOSE To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. DESIGN The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. PARTICIPANTS Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC. METHODS OPTIC nonresponders or …

Comparison of a Novel Homogeneous Cyclic Amp Assay and a Luciferase Assay for Measuring Stimulating Thyrotropin-Receptor Autoantibodies.

Objective: Stimulating thyrotropin-receptor antibodies (TSAb) cause Graves’ disease (GD). We tested a novel homogeneous fluorescent 3′,5′ cyclic adenine monophosphate (cAMP) assay for the detection of TSAb in a bioassay. Methods: Chinese hamster ovary (CHO) cell lines expressing either a chimeric (MC4) or wild-type (WT) TSH-R were incubated with the adenyl cyclase activator forskolin, a human TSAb monoclonal antibody (M22), and with sera from GD patients. Intracellular cAMP levels were measured using a Bridge-It® cAMP assay, and the results were compared with a luciferase-based bioassay. Results: Both cell lines were stimulated with forskolin concentrations (0.006–200 µM) in a dose-dependen…

Teprotumumab for Thyroid-Associated Ophthalmopathy

Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to r…

A cyclic peptide significantly improves thyroid function, thyrotropin-receptor antibodies and orbital mucine /collagen content in a long-term Graves’ disease mouse model

BALB/c mice which received long-term immunizations of adenovirus (Ad) expressing thyrotropin receptor A-subunits (TSHR) developed stable Graves' disease (GD). TSHR-derived cyclic peptide 19 (P19) was identified as effective therapy in this model.In Ad-TSHR mice, we investigated shorter disease intervals up to 4 months for histological alterations of the orbits, fine tuning of anti-TSHR antibodies (Ab) and free thyroxine (fT4) hormone levels by using novel detection methods in an independent laboratory. Therapy (0.3 mg/kg P19 or vehicle) was given intravenously after the fourth Ad-TSHR immunization (week 11) and continued until week 19.Thyrotropin binding inhibitory immunoglobulins (TBII, br…

Petit-mal-Status bei Hyperthyreose

A 68-year-old woman who, for the first time, had a generalized tonic-clonic seizure and persisting confusional state was found to have nodular enlargement of the thyroid and a tachycardic arrhythmia. Electroencephalography (EEG) demonstrated a continuous irregular polyspike wave pattern. Total T4 concentration was elevated to 23 micrograms/dl. Consecutive Administration of 250 mg phenytoin, 4 mg clonazepam and 7.5 mg midazolam changed neither the clinical nor the EEG findings. But after general intensive care measures and high-dose thyrostatic treatment (40 mg thiamazole intravenously every four hours) the clinical and neurological status became normal. Serial EEGs over the subsequent weeks…

HLA Class II Differentiates Between Thyroid and Polyglandular Autoimmunity.

The HLA class II genes are susceptibility genes for autoimmune endocrine diseases; however, scarce data are available pertaining to the determinants of genetic susceptibility to polyglandular autoimmunity (PGA). A total of 300 consecutive and unselected patients with either PGA or monoglandular autoimmune thyroid disease (AITD) and 100 healthy control subjects were genotyped for the HLA class II DRB1, -DQA1, and -DQB1 alleles. Compared to patients with AITD and controls, the HLA-DRB1*03 (pc =0.001), *04 (pc<0.001), -DQA1*03 (pc<0.001), and -DQB1*02 (pc =0.001) alleles were increased in patients with PGA. When dividing patients with Hashimoto's thyroiditis (HT) into those with PGA (PGA-HT) v…

Long-term observation of endocrine ophthalmopathy and retrospective appraisal of therapeutic measures.

The course of endocrine ophthalmopathy was investigated on the basis of clinical and biochemical parameters and in relation to different therapeutic strategies. A retrospective appraisal was made of 297 patients (44 +/- 14 yr, 249 women) with inclusion of anamnestic and clinical data as well as the results of computer tomography. At the beginning of therapy, 253 patients were hyperthyroid, 36 were euthyroid and eight were hypothyroid. The HLA typing carried out in 89 patients showed the phenotypes B8 and DR3 in 32% and 42% of the cases, respectively. Raised microsomal antibodies were present in 56% of the patients and there were raised thyroglobulin antibodies in 19%. Sixty-three % of the p…

Future Research in Graves' Orbitopathy: From Priority Setting to Trial Design Through Patient and Public Involvement

Graves' orbitopathy (GO) is a disfiguring autoimmune condition, which can sometimes cause blindness (1). The disease has profound effects on quality of life (2), psychological health (3), and socioeconomic status (4). Progress in understanding and treating this disease has been slow. However, recent advances include delineation of plausible immunological mechanisms (5), development of an animal model (6), and publication of randomized studies defining the role and limitations of intravenous steroids (7), rituximab (8,9), and selenium (10). Yet, some of this knowledge remains to be translated into improvement in clinical care. Access of patients to specialist treatments is patchy and seems t…

Is there a methimazole dose effect on remission rate in Graves' disease? Results from a long-term prospective study

OBJECTIVE The optimal antithyroid drug regimen for Graves' disease remains a matter of controversy. The European Multicentre Trial Group has investigated the effects of methimazole drug dose on the long-term outcome of Graves' disease. DESIGN Extended follow-up of patients from a prospective multicentre trial, designed to study methimazole dose effects on the outcome of Graves' disease. We have reported previously that the relapse rates did not differ after a medication-free observation period of 12 months; the relapse rates were 37 and 38%, respectively. In this paper, we describe the outcome in these patients after a mean observation period of 4.3 ± 1.3 years and have looked for potential…

Declaratión de consenso del Grupo europeo sobre la orbitopatía de Graves (EUGOGO) sobre el tratamiento de la orbitopatía de Graves' (OG)

Arrestin-β-1 Physically Scaffolds TSH and IGF1 Receptors to Enable Crosstalk

Endogenously expressed TSH receptors (TSHRs) on orbital fibroblasts of patients with Graves ophthalmopathy (GO) use crosstalk with IGF1 receptors (IGF1R) to synergistically stimulate secretion of hyaluronan (HA), a major component of GO pathology. We previously showed crosstalk occurred upstream of mitogen-activated protein kinase (ERK) phosphorylation. Because other G protein-coupled receptors engage arrestin-β-1 (ARRB1) and ERK, we tested whether ARRB1 was a necessary component of TSHR/IGF1R crosstalk. HA secretion was stimulated by the TSHR-stimulating monoclonal antibodies M22 and KSAb1, or immunoglobulins from patients with GO (GO-Igs). Treatment with M22, as previously shown, resulted…

Type 1 diabetes and polyglandular autoimmune syndrome: A review

Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial cluster…

Kardiale Beteiligung bei Funktionsstörungen der Schilddrüse

Fetal/Neonatal Thyrotoxicosis in a Newborn From a Hypothyroid Woman With Hashimoto Thyroiditis.

Context: Fetal/neonatal thyrotoxicosis is a rare but potentially life-threatening condition. It is most commonly observed in poorly controlled Graves’ disease during pregnancy. Case Description: Here we describe the first reported case of thyrotoxicosis in a fetus/newborn from a woman with Hashimoto’s thyroiditis and levothyroxine-treated hypothyroidism. Transplacental passage of stimulating TSH-receptor antibodies, measured by a cell-based bioassay, was the underlying mechanism of fetal/neonatal thyrotoxicosis even though the mother had no history of hyperthyroidism. Conclusion: Diagnosis and management of fetal hyperthyroidism can be challenging. TSH receptor antibody testing should be co…

Graves Disease With Thyroid-Stimulating Hormone Receptor–Blocking Autoantibodies During Pregnancy

Heart in Hyperthyroidism

Hyperthyroidism is a common endocrine disorder that produces important clinical consequences on the cardiovascular system. In overt hyperthyroidism the increase in left ventricular performance is predominantly sustained by an increased preload with enhanced left ventricular diastolic function and reduced systemic vascular resistance. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Untreated overt and subclinical hypothyroidism can lead to an increased risk of coronary heart disease (CHD), heart failure (HF), and cardiovascular mortality.

A CRF-Producing and -Secreting Tumor of the Lung

Corticotropin-releasing factor (CRF) has recently been isolated from ovine hypothalamus, characterized chemically, and synthesized. Upton and Amatruda (1971) first suggested that CRF-like activity occurred in neoplastic tissues, and Hashimoto et al. (1980) subsequently detected CRF-like activity in an extract of an ACTHproducing nephroblastoma. Recently, Carey et al. (1984) and Asa et al. (1984) used immunocytochemical techniques to demonstrate CRF in postmortem tumor material obtained from patients with a carcinoma of the prostate and an intrasellar gangliocytoma.

Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic b cells, and skeletal muscle) to explain the mechanism linking…

Teprotumumab reduces extraocular muscle and orbital fat volume in thyroid eye disease

PurposeThyroid eye disease (TED) is a progressive, debilitating and potentially vision-threatening autoimmune disease. Teprotumumab, a novel human monoclonal antibody, has been shown to reverse the clinical manifestations of TED. Patients receiving teprotumumab have been shown in two multicenter, randomized placebo-controlled trials to have decreased proptosis, diplopia and inflammation after 24 weeks of treatment. This study aims to analyse volumetric and inflammatory changes on orbital imaging prior to and after teprotumumab treatment from one of these trials.DesignRetrospective review.SubjectsSix patients enrolled in the phase III teprotumumab clinical trial (OPTIC, NCT03298867) with act…

Proteomics of Orbital Tissue in Thyroid-Associated Orbitopathy.

A potentially altered protein expression profile in orbital tissue from patients with thyroid-associated orbitopathy (TAO) is suspected.To detect for the first time changes in proteomic patterns of orbital connective tissue in TAO and compare these with control tissue using mass spectrometry.Proteomics cross-sectional, comparative study.Two academic endocrine institutions.A total of 64 orbital and peripheral adipose tissue samples were collected from 39 patients with TAO and 25 control subjects.Samples were analyzed and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technology.Mean intensity values of all identified peptides per protein.Thirty-…

TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis.

AbstractContext:The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role.Objective:We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies.Design/Setting/Participants:Immunoglobulins were purified from the…

Selective bilateral blood sampling from the inferior petrosal sinus in Cushing's disease: effects of corticotropin-releasing factor and thyrotropin-releasing hormone on pituitary secretion.

We sought to enhance the sensitivity of selective bilateral blood sampling to determine adrenocorticotropin (ACTH) and prolactin levels in the inferior petrosal sinus (IPS) by administering two stimulatory agents--corticotropin-releasing factor (CRF) and thyrotropin-releasing hormone (TRH). We then determined the ACTH and prolactin levels in the IPS of 10 patients with Cushing's disease. After peripheral administration of both CRF and TRH, ACTH levels were significantly higher on the tumor side in all patients. The prolactin level was significantly higher on the tumor side when CRF or TRH was used to stimulate pituitary secretion. Postsurgical immunohistochemistry studies revealed productio…

Proteomics of tear fluid in thyroid-associated orbitopathy.

Proteomics and mass spectrometry are useful tools for peptide screening in body fluids. In thyroid-associated orbitopathy (TAO), evidence for lacrimal gland involvement with altered composition of tears has been reported. Our objective was to detect and evaluate potential changes in the proteomic patterns of tear fluid in TAO.Tear fluid was collected from 45 patients with TAO and 15 healthy controls. Tear proteins were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, and peptides were identified using matrix-assisted laser desorption/ionization time-of-flight technology.Peptides with molecular weights 3808 Dalton (Da, p=0.004), 3734 Da (p=0.034),…

Stimulatory TSH-Receptor Antibodies and Oxidative Stress in Graves Disease

CONTEXT: We hypothesized that TSH-receptor (TSHR) stimulating antibodies (TSAbs) are involved in oxidative stress mechanisms in patients with Graves disease (GD). METHODS: Nicotinamide adenine dinucleotide phosphate oxidase, isoform 2 (NOX2); oxidative parameters; and oxidative burst were measured in serum, urine, and whole blood from patients with GD and control subjects. Superoxide production was investigated in human embryonic kidney (HEK)-293 cells stably overexpressing the TSHR. Lipid peroxidation was determined by immunodot-blot analysis for protein-bound 4-hydroxy-2-nonenal (4-HNE) in human primary thyrocytes and HEK-293–TSHR cells. RESULTS: Serum NOX2 levels were markedly higher in …

Genetics of Polyglandular Failure

The rare autoimmune polyglandular failure syndromes (APS) comprise a juvenile (APS1) and an adult type (APS2 and 3). APS1 is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene impair self-tolerance and result in defect proteins causing autoimmune destruction of target organs. Genetic testing identifies patients with APS1. For APS2/3 disease susceptibility genes are the human leucocyte antigen on chromosome 6, the cytotoxic T lymphocyte antigen (chromosome 2), the protein tyrosine phosphatase nonreceptor type 22 (chromosome 1), the forkhead box P3 (X chromosome), and the interleukin-2 rec…

TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types

We previously showed that thyrotropin (TSH)/insulinlike growth factor (IGF)-1 receptor cross-talk appears to be involved in Graves’ orbitopathy (GO) pathogenesis and upregulation of thyroid-specific genes in human thyrocytes. In orbital fibroblasts from GO patients, coadministration of TSH and IGF-1 induces synergistic increases in hyaluronan secretion. In human thyrocytes, TSH plus IGF-1 synergistically increased expression of the sodium-iodide symporter that appeared to involve ERK1/2 activation. However, the details of ERK1/2 activation were not known, nor was whether ERK1/2 was involved in this synergism in other cell types. Using primary cultures of GO fibroblasts (GOFs) and human thyr…

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time.METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000.RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, includi…

Autoimmune endocrine ophthalmopathy and retrobulbar antigens.

Endocrine Ophthalmopathy (EO) is based on autoimmune processes that lead to lymphocyte infiltration of the retrobulbar space. In this study, antigenic character of retrobulbar adipose, connective and muscle tissue as well as of cultured fibroblasts and myoblasts were examined. Samples were obtained from EO patients (n = 13, 8 fem., age 26-82 years, median 47 years) undergoing orbital decompression surgery. Retrobulbar and abdominal tissue from 7 controls (4 fem., 48 - 74 y) was investigated, too. Tissues were homogenized and the proteins were separated by SDS-PAGE according to molecular weight. In order to recover the separated proteins in soluble form, an electroelution technique was emplo…

Heart in Hypothyroidism

The transition from the fetal to the adult phenotype heart depends on the increase in thyroid hormone (TH) in perinatal period (Liu and Gerdes, J Mol Cell Cardiol 22:1339–1348, 1990; Gerdes and Iervasi, Circulation 122:385–393, 2010). Moreover, T3 action is essential for preserving both cardiac morphology and performance in adult life because thyroid hormone controls the inotropic and lusitropic properties of the myocardium, cardiac growth, myocardial contractility, and vascular function (Liu and Gerdes, J Mol Cell Cardiol 22:1339–1348, 1990; Gerdes and Iervasi, Circulation 122:385–393, 2010; Fazio et al., Recent Prog Horm Res 59:31–50, 2002; Kahaly and Dillmann, Endocr Rev 26:704–728, 2005…

Clinical relevance of thyroid-stimulating autoantibodies in pediatric graves' disease-a multicenter study.

Context and Objective: The incidence of TSH receptor (TSHR) stimulating autoantibodies (TSAbs) in pediatric Graves' disease (GD) is controversial. This large, multicenter study evaluated the clinical relevance of TSAbs in children with GD both with Graves' orbitopathy (GO) and without orbital disease. Design: We conducted a cross-sectional retrospective study. Setting: Sera were collected in seven American and European academic referral centers and evaluated in a central laboratory. Patients and Samples: A total of 422 serum samples from 157 children with GD, 101 control individuals with other thyroid and nonthyroid autoimmune diseases, and 50 healthy children were studied. Main Outcome Me…

Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease

Summary The prevalence and clinical relevance of thyroid stimulating hormone (TSH) receptor (TSHR) blocking antibodies (TBAb) in patients with autoimmune thyroid disease (AITD) was investigated. Serum TBAb were measured with a reporter gene bioassay using Chinese hamster ovary cells. Blocking activity was defined as percentage inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off 40% inhibition). All samples were measured for TSHR stimulatory antibody (TSAb) and TSHR binding inhibiting immunoglobulins (TBII). A total of 1079 unselected, consecutive patients with AITD and 302 healthy controls were included. All unselected controls were negative for TBAb and…

Double-Blind, Placebo-Controlled, Randomized Trial of Selenium in Graves Hyperthyroidism.

Abstract Context Supplemental selenium (Se) may affect the clinical course of Graves disease (GD). Objective Evaluate efficacy of add-on Se on medical treatment in GD. Design Double-blind, placebo-controlled, randomized supplementation trial. Setting Academic endocrine outpatient clinic. Patients Seventy untreated hyperthyroid patients with GD. Intervention Additionally to methimazole (MMI), patients received for 24 weeks either sodium selenite 300 µg/d po or placebo. MMI was discontinued at 24 weeks in euthyroid patients. Main Outcome Measures Response rate (week 24), recurrence rate (week 36), and safety. Results A response was registered in 25 of 31 patients (80%) and in 27 of 33 (82%) a…

Update endokrine Orbitopathie

PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity

Context Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce. Objective Evaluate potential associations of eight SNPs with APSs. Setting Academic referral endocrine clinic. Patients A total of 543 patients with APS and monoglandular autoimmunity and controls. Intervention The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte‒associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor α rs1800630 (-863); and inte…

Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves' Orbitopathy.

Clinical Relevance of Thyroid-Stimulating Immunoglobulins in Graves' Ophthalmopathy

Purpose Thyroid-stimulating immunoglobulins (TSIs) likely mediate Graves' ophthalmopathy (GO). The clinical relevance of these functional autoantibodies was assessed in GO. Design Cross-sectional trial. Participants A total of 108 untreated patients with GO. Methods Thyroid-stimulating immunoglobulins, assessed with a novel bioassay, bind to the thyrotropin receptor (TSHR) and transmit signals for cyclic adenosine monophosphate (cAMP)-dependent activation of luciferase gene expression. The cAMP/cAMP response element-binding protein/cAMP-regulatory element complex induces luciferase that is quantified after cell lysis. The TSI levels were correlated with activity and severity of GO and compa…

Autoimmune polyglandular diseases.

Autoimmune polyglandular diseases (APD) are defined as the presence of two autoimmune -induced endocrine failures. With respect to the significant morbidity and potential mortality of APD, the diagnostic objective is to detect APD at an early stage, with the advantage of less frequent complications, effective therapy and better prognosis. This requires that patients at risk be regularly screened for subclinical endocrinopathies prior to clinical manifestation. Regarding the time interval between manifestation of first and further endocrinopathies, regular and long-term follow-up is warranted. Quality of life and psychosocial status are poor in APD patients and involved relatives. Familial c…

Humoral immunity and retrobulbar fibroblasts in endocrine ophthalmopathy

The exact role of retrobulbar fibroblasts in the immunopathogenesis of endocrine ophthalmopathy still remains to be elucidated. To evaluate the in vitro influence of humoral immunity on retrobulbar fibroblasts, the effects of immunoglobulin G as well as of the sera of 50 euthyroid patients with endocrine ophthalmopathy and 30 controls on both porcine and human (patients' and controls') retrobulbar fibroblasts were measured by means of several assays: a colorimetric test involving a heterocyclic chemical, a tetrazolium bromide, was applied to quantify the activity of mitochondrial dehydrogenases; the incorporation of 3H-thymidine was determined as a sensitive parameter for cell proliferation…

Impaired Cardiopulmonary Exercise Capacity in Patients With Hyperthyroidism

Hyperthyroidism (H) has been implicated as a primary cause of decreased exercise tolerance. To our knowledge, analysis of respiratory gas exchange, an efficient noninvasive method in evaluating cardiopulmonary capacity, has not been performed in patients with H.Using cardiopulmonary exercise testing, 12 consecutive women with Graves' H were examined and controlled in euthyroidism (E). Eighteen women with E, in whom cardiac catheterization had ruled out heart disease, served as control subjects (C).The ventilatory anaerobic threshold was determined by means of the V-slope method. Ergometry was performed with patients in a semisupine position using a continuous ramp protocol of 20 W/min. Echo…

Comparison of a Bridge Immunoassay with Two Bioassays for Thyrotropin Receptor Antibody Detection and Differentiation

AbstractA rapid and fully automated chemiluminescent immunoassay for the detection of thyrotropin receptor autoantibodies (TSHR-Ab) based on a bridge technology was compared with two bioassays that measure either stimulating (TSAb) or blocking (TBAb) antibodies for the detection and differentiation of TSHR-Ab. A total of 229 patients with various thyroid disorders [151 with Graves’ disease (GD), 35 with Hashimoto’s thyroiditis (HT), 32 with nodular goiter, and 11 with thyroid cancer] were included. The bridge immunoassay was performed according to the manufacturer’s instructions (cut-off&gt;0.55 IU/l). TSAb and TBAb were measured with reporter bioassays. Blocking activity was defined as per…

HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III.

Background: Genetics of the adult autoimmune polyglandular syndrome (APS) is poorly understood. Aim: The aim of this study was to gain further insight into the genetics of the adult APS types. Site: The study was conducted at a university referral center. Methods: The human leukocyte antigen (HLA) class II alleles, haplotypes, and genotypes were determined in a large cohort of patients with APS, autoimmune thyroid disease (AITD), and type 1 diabetes and in healthy controls by the consistent application of high-resolution typing at a four-digit level. Results: Comparison of the allele and haplotype frequencies significantly discriminated patients with APS vs AITD and controls. The HLA class…

Therapeutic Use of Levothyroxine: A Historical Perspective

Analytical Performance and Validation of a Bioassay for Thyroid-Blocking Antibodies

A cell-based bioassay for the measurement of thyroid blocking autoantibodies (TBAb) has been recently reported. The analytical performance and validation of this bioassay is assessed and described.Chinese hamster ovary cells expressing a chimeric thyrotropin receptor were treated with bovine (b) TSH and different concentrations of an immunoglobulin G (IgG) monoclonal human TBAb (K1-70). TBAb was measured as a function of luciferase activity relative to bTSH alone and expressed as percent inhibition. Results obtained in the chimeric cell line were compared with those of a wild-type cell line. Analytical performance studies were subsequently performed with the chimeric cell line only.Immunode…

Functional TSH receptor antibodies in children with autoimmune thyroid diseases

The diagnostic value of the level of TSH receptor antibodies (TSHR-Ab) in the population of children with autoimmune thyroid diseases (AITDs) is still unknown. The aim of this cross-sectional study was to investigate the prevalence of TSHR-Ab in a paediatric cohort with AITD and healthy controls.A total of 240 serum samples were obtained from 205 patients with AITD, type 1 diabetes (T1D), juvenile arthritis (JA), and healthy controls (C). TSHR stimulating (TSI) and -blocking (TBI) immunoglobulins were measured in cell-based bioassays using CHO cells expressing a chimeric TSHR and a c-AMP response-element-dependent luciferase. TSI was reported as percentage of specimen-to-reference ratio (cu…

Steroids Are Effective for Preventing Post-RAI Graves’ Orbitopathy In Those with Graves’ Disease of &lt;5 Years’ Duration

Response to comment by Smith on the 2021 EUGOGO guidelines

Standardization of a bioassay for thyrotropin receptor stimulating autoantibodies.

Cell-based bioassays for functional thyroid stimulating autoantibodies (TSAb) are sensitive diagnostic tools. However, there is no bioassay available that is standardized with international reference material. We aimed to promote the standardization of the test results among laboratories that perform TSAb bioassays and calibrate TSAb levels against the second international standard (IS) 08/204 from the National Institute for Biological Standards and Control (NIBSC).Serum TSAb activity was measured with a FDA-cleared bioassay that utilizes CHO cells expressing a chimeric thyrotropin receptor (TSHR) and a c-AMP response-element-dependent luciferase. The IS was applied for calibration. TSAb re…

Graves' Autoantibodies Exhibit Different Stimulating Activities in Cultures of Thyrocytes and Orbital Fibroblasts Not Reflected by Clinical Assays

Background: The pathogenesis of Graves' hyperthyroidism (GH) and associated Graves' orbitopathy (GO) appears to involve stimulatory autoantibodies (thyrotropin receptor [TSHR]-stimulating antibodies [TSAbs]) that bind to and activate TSHRs on thyrocytes and orbital fibroblasts. In general, measurement of circulating TSHR antibodies by clinical assays correlates with the status of GH and GO. However, most clinical measurements of TSHR antibodies use competitive binding assays that do not distinguish between TSAbs and antibodies that bind to but do not activate TSHRs. Moreover, clinical assays for TSAbs measure stimulation of only one signaling pathway, the cyclic adenosine monophosphate (cAM…

Immunotherapies for thyroid eye disease

Thyroid eye disease is a complex autoimmune disorder which causes substantial morbidity. It can result in orbital disfigurement, double vision, and visual loss. Consequently, it has a substantial negative effect on quality of life, mental health, and socioeconomic status. Most signs and symptoms of thyroid eye disease (TED) can be explained by the expansion of the orbital contents. Steroids are the mainstay of treatment in TED. However, recurrence may occur once steroids are withdrawn. Furthermore, in most cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required to reduce disfigurement, double vision, and to preserve vision. Therefore, novel, causal, and…

Teprotumumab for the treatment of active thyroid eye disease

Abstract Background Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration–approved medical therapy is available...

Somatostatin-Rezeptor-Szintigraphie bei endokriner Orbitopathie

Somatostatin receptor scintigraphy with 111In-labeled octreotide proves to be a very sensitive diagnostic tool for evaluation of inflammative activity in endocrine ophthalmopathy (EO). The results of somatostatin receptor scintigraphy (SRS) in 40 patients with EO show a high orbital accumulation of 111In-octreotide in clinically active EO (4 h-median/orbit-brain-ratio: 12.6; controls 4 h-median: 5.8) Patients with clinically inactive EO (4 h-median: 7.1) show a similar orbital accumulation of radioactivity compared to controls. 5 patients with active orbital myositis also revealed an even higher orbital accumulation of radioactivity (4 h-median: 42.3). The diagnostic value of SRS lies in it…

Is there a relationship between the degree of preoperative motility impairment or the muscle thickness and the outcome of strabismus surgery in patients with graves' orbitopathy after decompression surgery?

There is considerable controversy regarding the performance of strabismus surgery in patients with Graves' orbitopathy (GO). The spectrum of recommendations extends from variable dose-effect correlations for these procedures (Esser, 1994; Mourits et al., 1990; Nguyen et al., 2002) to individualized approaches such as passive intraoperative motility testing and postoperative adjustment of sutures (Lueder et al., 1992; Nguyen et al., 2002), and to local anesthesia for intraoperative assessment of active motility (Kalpadakis et al., 2004). Furthermore, prior decompression surgery is known to contribute to an unpredictable outcome (Eckstein and Esser, 2003; Esser, 1994). We retrospectively anal…

A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism—A Proof-of-Concept Trial

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalima…

Inhibition of TSH/IGF-1 Receptor Crosstalk by Teprotumumab as a Treatment Modality of Thyroid Eye Disease

Abstract Context We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza). Objective To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibrobla…

Individuell dosiertes Levothyroxin mit 150 µg Jodid versus 100 µg Levothyroxin kombiniert mit 100 µg Jodid: Eine randomisierte Doppelblindstudie

BASIC PROBLEM AND OBJECTIVE Intrathyroid deficiency and the influence of thyroid stimulating hormone (TSH) are the main pathogenetic factors in the development of endemic euthyroid goitre. Goitre reduction is achieved with either administration of levothyroxine, which diminishes hypophyseal TSG production, or of iodide. Aim of this study was to compare the efficacy of treatment with a dose-fixed combination of levothyroxine plus iodide with that of an individualized dosage of levothyroxine plus iodide. PATIENTS AND METHODS After randomization 49 patients with euthyroid goitre (24 women, 25 men, aged 20-43 years) were treated for 12 weeks in a double-blind trial. Patients in group A received…

Celiac disease and endocrine autoimmunity.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affect…

Metabolic and psychosocial effects of minimal invasive gastric banding for morbid obesity

Obesity is considered a primary risk factor for cardiovascular disease and related mortality. The current study aimed to investigate the efficacy of minimal invasive gastric banding (GB) surgery for reducing caloric intake in morbid obesity, and to analyze the effects of weight loss on body composition and metabolic and psychosocial outcomes. Twenty-six adult severely obese patients (mean body mass index [BMI], 48.1 kg/m(2); range, 42 to 56) underwent adjustable silicone laparoscopic GB. Nine additional obese patients who declined surgery were treated with metformin (2 g daily) and served as a small additional group (BMI, 50.5 kg/m(2); range, 41 to 68). Presurgery and 17 +/- 2.2 months post…

Glucocorticoids in Graves’ orbitopathy: mechanisms of action and clinical application

Background:Graves’ orbitopathy (GO) is the most frequent extrathyroidal manifestation of the autoimmune Graves’ disease. GO significantly impacts quality of life and has a psycho-social morbidity. Inflammation and swelling of the orbital tissue often leads to proptosis, diplopia, and decrease of visual acuity. Due to the inflammatory background of the disease, glucocorticoids (GC) have been used as a first-line treatment for decades.Methods:PubMed and MeSH database were searched for original articles, clinical trials, reviews, and meta-analyses published between 1 January 2000 and 31 March 2020 and pertaining to both the mechanism of action and immunological effects of GC as well as to the …

Insulin-dependent diabetes mellitus and glycosaminoglycans.

The influence of diabetic nephropathy on urinary glycosaminoglycan distribution was assessed in 96 patients with insulin-dependent diabetes mellitus (IDDM, 49 female, age: 16 - 64 yrs, median 35; duration of IDDM: 0 - 43 yrs, median 13 yrs) in comparison to 103 healthy controls (57 female, 17 - 82 yrs, median 40 yrs). Glycosaminoglycan concentration of 24 h urine samples was determined by means of precipitation with cethylpyridinium chloride and potassium acetate in ethanol followed by a colorimetric test with carbazole. A marked difference (p = 0.0008) in urinary glycosaminoglycan excretion between patients (19.0, 12.4, 35.6 mg/24 h, median, 25th, 75th percentile) and controls (15.8, 10.4,…

Consensus statement of the European Group on Graves' Orbitopathy (EUGOGO) on management of Graves' Orbitopathy

Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Das polyglanduläre Autoimmunsyndrom Typ II: Epidemiologie und Manifestationsformen

Background and objective Polyglandular autoimmune syndrome (PAS), is characterized by the coexistence of several autoimmune diseases, affecting predominantly the endocrine glands. The juvenile form (PAS type I) is distinguished from the adult type II in which autoimmune thyroiditis, adrenal cortical insufficiency and diabetes mellitus type I predominate. The connections between epidemiological, clinical and immunological aspects were analysed and described in this study of patients with PAS type II. Patients and methods Among a total patient population of over 15,000 seen in our endocrinological university policlinic from 1992 through 1996, the clinical data of all 151 patients with PAS typ…

New imaging procedures in thyroid-associated ophthalmopathy

Lymphocytic and other mononuclear cell infiltrations of the retrobulbar space are observed in thyroid-associated ophthalmopathy (TAO). The identification of somatostatin receptors on lymphocytes has provided a rationale for receptor-imaging with the radiolabeled somatostatin analog Octreotide in TAO. Furthermore, previous investigations have shown that quantitative magnetic resonance imaging (MRI) allows non-invasive detection of acute inflammatory changes in extraocular muscles. Therefore, in patients with TAO and controls, scans of the orbits were obtained at 4h and 24h after i.v. injection of the radionuclide and orbital MRI was performed. Compared to controls, patients with TAO showed a…

Quality of Life and Occupational Disability in Endocrine Orbitopathy

SUMMARY Background: In endocrine orbitopathy (EO), disfiguring proptosis and diplopia impair patients' quality of life both at home and at work. Methods: From late 2006 to the beginning of 2008, 250 outpatients in an interdisciplinary thyroid and eye clinic filled out a questionnaire about their quality of life, occupational disability, and use of psychotherapy. 400 physicians who referred their EO patients to the clinic also participated in a survey on these issues. Results: 45% of the patients complained of restrictions in their daily activities, and 38% reported impaired selfperception. 36% were on sick leave because of EO. 28% were disabled, 5% had retired early, and 3% had lost their j…

Bioassays for TSH Receptor Antibodies: Quo Vadis?

Autoantibodies (Ab) to the TSH receptor (TSHR) are responsible for many of the clinical manifestations of Graves' disease (GD) and are specific biomarkers of this autoimmune thyroid disorder (AITD) [1,2,3]. These Ab can be measured either via competitive-binding immunoassays or with bioassays [4]. Antibody-binding assays only report the presence or absence of TSHR-Ab and their concentrations, but do not indicate their functional activity. Bioassays, in contrast, indicate whether TSHR-Ab have stimulatory or blocking activity [5]. Historically, bioassays for TSHR-Ab were research tools used to study the pathophysiology of GD. Recently, however, there are increasing data that demonstrate the c…

Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity

Abstract Context The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed. Objective To investigate CgA utility as a marker of endocrine autoimmunity. Methods CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology. Results Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy…

Prospective Trial of Functional Thyrotropin Receptor Antibodies in Graves Disease

Abstract Context Scarce data exist regarding the relevance of stimulatory (TSAb) and blocking (TBAb) thyrotropin receptor antibodies in the management of Graves disease (GD). Objective To evaluate the clinical utility and predictive value of TSAb/TBAb. Design Prospective 2-year trial. Setting Academic tertiary referral center. Patients One hundred consecutive, untreated, hyperthyroid GD patients. Methods TSAb was reported as percentage of specimen-to-reference ratio (SRR) (cutoff SRR &amp;lt; 140%). Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine thyrotropin (TSH, thyroid stimulating hormone) alone (cutoff &amp;gt; 40% inhibitio…

Analytical performance and clinical utility of a bioassay for thyroid-stimulating immunoglobulins.

Abstract The analytical performance and the clinical utility of a thyrotropin receptor (TSHR)–stimulating immunoglobulin (TSI) bioassay were compared with those of a TSHR-binding inhibitory immunoglobulin (TBII) assay. Limits of detection (LoD) and quantitation (LoQ), assay cutoff, and the half-maximal effective concentration (EC50) were measured. Dilution analysis was performed in sera of hyperthyroid patients with Graves disease (GD) during antithyroid treatment (ATD). Titer was defined as the first dilution step at which measurement of TSI or TBII fell below the assay cutoff. The LoD, LoQ, cutoff, and EC50 of the bioassay were 251-, 298-, 814-, and 827-fold lower than for the TBII assay.…

Predictive Factors for Changes in Quality of Life after Steroid Treatment for Active Moderate-to-Severe Graves' Orbitopathy: A Prospective Trial.

&lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; To investigate the predictive factors for changes in the quality of life (GO-QoL) of patients with Graves’ orbitopathy (GO) prior to and after specific treatment. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A prospective follow-up study was conducted at an academic tertiary referral orbital center with a joint thyroid-eye clinic on 100 consecutive patients with GO. Before and after the standard 12-week course of weekly intravenous methylprednisolone (cumulative dose 4.5 g), the GO-QoL questionnaire provided by the European Group on Graves’ Orbitopathy (EUGOGO) was completed. Endocrine and ophthalmic assessments were performed at each visi…

Prevalence of myxomatous mitral valve prolapse in patients with lymphocytic thyroiditis

Abstract In conclusion, given the cardiac (mitral regurgitation, endocarditis, thromboembolic complications, arrhythmic sudden death) and neurologic (cerebral embolic event) complications of the pathologic forms of MVP, 6,8 physicians should look carefully for myxomatous involvement of the mitral valve and prolapse in patients with autoimmune thyroid diseases. Patients should be monitored and prophylactic antibiotic treatment recommended when appropriate.

Homozygous Resistance to Thyroid Hormone β: Can Combined Antithyroid Drug and Triiodothyroacetic Acid Treatment Prevent Cardiac Failure?

Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteri…

OR18-01 Effect of Teprotumumab on Proptosis Reduction Across Various Demographic Sub-Groups

Abstract Introduction: Teprotumumab, an insulin-like growth factor 1 receptor inhibitory monoclonal antibody, was recently shown to significantly reduce proptosis in patients with active, moderate-to-severe thyroid eye disease (TED) in phase 2 and phase 3 clinical trials.1,2 Prior analyses have demonstrated a combined trial proptosis response (≥2 mm reduction) rate of 77.4% in the teprotumumab group and 14.9% in the placebo group after 24 weeks of therapy (p &amp;lt; 0.001).3 The current analysis was performed to investigate whether or not patient demographic characteristics influence the teprotumumab proptosis response. Methods: Data from two 24-week randomized, double-masked, placebo-cont…

Radiotherapy for Graves’ ophthalmopathy

The interest in the treatment of benign diseases with radiation therapy has grown particularly in the Western part of the world. In 1996, a questionnaire was sent to 1348 institutes worldwide listed in the directory of the Society for Therapeutic Radiology and Oncology asking whether the respondents considered a list of 28 most common benign disorders as being a good indication for orbital radiotherapy.1 Questions concerned the frequency of such treatments and the treatment schedules used. The prevention of keloid formation was the most widely accepted indication, followed by Graves’ ophthalmopathy. Thus, radiotherapy for this orbital disorder is generally accepted and applied worldwide.

Randomisierte, doppelblinde Crossover-Studie zur Bioverfügbarkeit von Levothyroxin

Fragestellung: Synthetische Schilddrusenhormonpraparate mit der Wirkstoffgruppe Levotyroxin-Natrium (LT4) gelten als Mittel der Wahl be der Substitutionstherapie jeder Form der Hypothyreose sowie bei der Mitbehandlung des euthyreoten Kropfes. Fallbeschreibungen aus der Literatur zufolge fuhrte wahrend der Therapie mit LT4-Praparaten ein Praparatwechsel zur Stoffwechselentgleisung. Zwei gangige LT4-Praparate, L-Thyroxin Henning®100 und Eferox®100, wurden deshalb in dieser Studie an euthyreoten Probanden auf Unterschiede in ihrer Bioverfugbarkeit analysiert. Probanden und Methodik: In einer randomisierten Doppelblindstudie nahmen 60 freiwillige euthyreote Probanden 2 Wochen lang taglich 1 Tbl…

Arrhythmieprofil und Herzfrequenz bei Hyperthyreose

Arrhythmia profiles and heart rates, obtained by 24-hour ECG monitoring, were analysed in 48 patients with hyperthyroidism before (T3 level: 331 +/- 108 ng/100 ml, heart rate: 95 +/- 13/min), during (T3 level: 202 +/- 98 ng/100 ml, heart rate: 85 +/- 11/min) and after (T3 level: 149 +/- 41 ng/100 ml, heart rate: 79 +/- 9/min) antithyroid treatment. 50 persons in whom organic heart disease has been excluded by invasive and noninvasive tests served as controls. Only 6% of patients had repetitive ventricular arrhythmias (Lown group IV) before treatment (controls: 4%; P greater than 0.05). Supraventricular extrasystoles were common both before and after treatment (P less than 0.001), especially…

Autoantibodies against the calcium-sensing receptor and cytokines in autoimmune polyglandular syndromes types 2, 3 and 4

OBJECTIVE: The frequency of autoimmunity against the parathyroid glands in patients with polyglandular autoimmunity that is not due to autoimmune polyendocrine syndrome type 1 (APS1) is unclear. To investigate this, the current study aimed to determine the prevalence of autoantibodies against parathyroid autoantigens the calcium-sensing receptor (CaSR) and NACHT leucine-rich-repeat protein 5 (NALP5) in a large group of patients with non-APS1 polyendocrine autoimmunity. Possible occult APS1 was investigated by cytokine autoantibody measurement and AIRE gene analysis. DESIGN, SUBJECTS, AND MEASUREMENTS: Subjects were 178 patients with APS2, 3 or 4, and 80 healthy blood donors. Autoantibodies …

Retrobulbar adipocytes and humoral immunity in Graves' ophthalmopathy

As CT and MR-imaging revealed an enlargement of retrobulbar fat tissue in patients with Graves' ophthalmopathy, the role of the retrobulbar adipocytes in the pathogenesis of this disorder remains to be elucidated. To evaluate the in vitro influence of humoral immunity on retrobulbar adipose tissue, the effects of IgG and sera from 56 euthyroid ophthalmopathy patients and 53 controls on both porcine and human (patients' and controls') retrobulbar adipocytes were measured by means of several assays: An enzyme-linked immunosorbent assay was employed to reveal specific binding of antibodies to the adipocytes. Metabolic activity was determined by means of a colorimetric dimethyl thiazolium-diphe…

Genetics of Polyglandular Failure

Publisher Summary This chapter discusses the genetic aspects of polyglandular failure syndromes (APS).The polyglandular failure syndromes comprise of a wide spectrum of autoimmune disorders and encompass a rare juvenile type (APS1) and more frequent adult types (APS2 and APS3). The juvenile type APS1 is also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy because it consists of three main disorders, namely chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism and autoimmune Addison's disease. APS2 is defined as the association between Addison's disease and either autoimmune thyroid disease or type 1 diabetes mellitus and APS3 is characterized by the presen…

New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95-105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox ) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed a…

Type I Diabetes is the Main Cost Driver in Autoimmune Polyendocrinopathy

Abstract Context Autoimmune polyendocrinopathy (AP), a chronic complex orphan disease, encompasses at least two autoimmune-induced endocrine diseases. Objective To estimate for the first time total, indirect and direct costs for patients with AP, as well as cost drivers. Design Cross-sectional cost of illness study. Setting Academic tertiary referral center for AP. Patients 146 consecutive, unselected AP patients. Intervention Interviews pertaining to patients’ socioeconomic situation covered a recall period of 12 months. Both the human capital (HCA) and the friction cost approaches (FCAs) were applied as estimation methods. Main outcome measures Direct and indirect annual costs, and sick l…

Celiac disease and endocrine autoimmunity - the genetic link.

Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley and rye. The prevalence of celiac disease is increased in patients with monoglandular and/or polyglandular autoimmunity and their relatives. Between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5 to 7% of patients with autoimmune thyroid disease and/or type 1 diabetes are IgA anti-tissue transglutaminase antibody positive. The close relationship between celiac disease and endocrine autoimmunity is largely explained by sharing a common genetic back…

Performance and Specificity of 6 Immunoassays for TSH Receptor Antibodies: A Multicenter Study

Background: The measurement of TSH receptor (TSHR) antibodies is warranted for diagnosis of Graves’ disease (GD). Objective: The performance, detection sensitivity, and specificity of 6 TSHR immunoassays were compared. Methods: Two bioassays and 4 binding assays (Kronus, Immulite, Kryptor, Dynex) were compared in a dilution study performed in patients with autoimmune thyroid disease. Both bioassays were compared to 2 binding assays using stimulatory (M22) and blocking (K1–70) monoclonal antibody (MAb) mixtures. Results: Thirty samples from stimulatory (TSAb)-positive/blocking (TBAb)-negative patients with GD were diluted serially and measured in all assays. Samples were positive until dilut…

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

BackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.MethodsWe extracted genomic DNA from th…

High Titers of Thyrotropin Receptor Antibodies Are Associated With Orbitopathy in Patients With Graves Disease.

AbstractContextSerum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance.ObjectiveTo differentiate between thyroidal GD only and Graves orbitopathy (GD + GO).DesignControlled, follow-up study.SettingAcademic tertiary referral center for GD + GO.SubjectsSixty patients with GD, GD + GO, and controls.InterventionSerial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab.Main Outcome MeasureDifferentiation among GD phenotypes.ResultsAll undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9…

Prevalence, Phenotype, and Psychosocial Well-Being in Euthyroid/Hypothyroid Thyroid-Associated Orbitopathy.

At the onset of thyroid-associated orbitopathy (TAO), most patients are hyperthyroid, while scarce data are available on euthyroid/hypothyroid TAO. The aim of this study was to assess the prevalence, phenotype, and psychosocial burden of patients with initially euthyroid/hypothyroid TAO.The medical records of 461 consecutive and unselected patients with TAO followed at a specialized joint thyroid-eye clinic were analyzed within this retrospective cross-sectional study. Main outcome measures were the prevalence of initially eu- or hypothyroid TAO as well as ophthalmic signs and symptoms, disease-specific quality of life (QoL), work impairment, and rate of psychotherapy in initially eu-/hypot…

Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors

Background: Graves' ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like growth factor 1 receptors (IGF-1Rs), stimulating insulin-like growth factor receptor antibodies (IGFRAbs), remains controversial. This study attempted to determine whether there are stimulating IGFRAbs in patients with GO. Methods: Immunoglobulins (Igs) were purified from normal volunteers (NV-Igs) and patients with GO (GO-Igs). The effects of TSH, IGF-1, NV-Igs, and GO-Igs on pAKT and pERK1/2, members of pathways used by IGF-1R and TSHR, were compared in orbital fibroblasts from GO patients (GOFs) a…

Relationship of eye muscle antibodies with HLA phenotypes and thyroid-stimulating immunoglobulins in endocrine orbitopathy.

The relationship between endocrine orbitopathy and Graves' hyperthyroidism is still not clairified. The purpose of this study was to elucidate the incidence of eye muscle antibodies and the relationship with HLA phenotypes and thyroid antibodies in 65 patients with endocrine orbitopathy classes 1–5. Both bovine and abdominal muscles were used as antigens in ELISA systems in which IgG and IgM antibodies were assayed. Before starting the immunosuppressant therapy, 46/65 patients (71%) showed a positive result for eye muscle antibodies. Those patients with an active disease had such antibodies more frequently. Where the ophthalmopathy was of recent onset IgM antibodies were found, whereas pati…

A 2013 European survey of clinical practice patterns in the management of Graves' disease

SummaryObjective Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 American survey. Design Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey. Results A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the …

Thyroid Stimulating Antibodies Are Highly Prevalent in Hashimoto's Thyroiditis and Associated Orbitopathy

Thyroid-associated orbitopathy (TAO) rarely occurs in patients with Hashimoto's thyroiditis (HT).There is evidence that TSH receptor stimulating antibodies (TSAb) play a role in the pathogenesis of TAO. In this report, the prevalence of TSAb in HT patients with and without TAO was studied.This is a longitudinal observational study.The study took place in an academic joint thyroid-eye clinic.A total of 1055 subjects were included.TSAb was measured with a Food and Drug Administration-cleared bioassay that uses Chinese hamster ovary cells expressing a chimeric TSH receptor and a cAMP response element-dependent luciferase. Results of TSAb activity were reported as percentage of specimen-to-refe…

Left ventricular function analyzed by Doppler and echocardiographic methods in short-term hypothyroidism

Abstract In conclusion, a significant reversible decrease in contractility and an impaired diastolic relaxation was demonstrated in patients with short-term hypothyroidism. This must be considered in patients with preexisting heart disease.

Immunohistochemical Staining of Retrobulbar Adipose Tissue in Graves' Ophthalmopathy

An increase of retrobulbar adipose tissue has been shown by imaging techniques in patients with Graves' ophthalmopathy (GO). Immunohistochemical staining was applied to investigate the involvement of different retrobulbar (especially adipose) tissue components in the autoimmune process of the disease. Cryostat sections from retrobulbar tissues of 15 GO patients and 11 controls were analyzed with a battery of monoclonal antibodies against CD2, CD4, CD8, CD11a, CD19/22, CD25, CD54, CD57, CD68, C3b, HLA-A, B, C, and HLA-DR. In contrast to controls, the retrobulbar adipose tissue showed an increase of HLA-DR expression, an activation of intercellular adhesion molecule I (ICAM-1, CD54), as well …

Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity

Summary Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid–eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) …

Graves’ disease

Autoimmune polyglanduläre Syndrome

The autoimmune polyglandular syndrome (APS) is defined as the manifestation of at least two endocrine autoimmune diseases. In order to take the wide spectrum of components and the variations of the disease fully into account, APS is usually divided up into the rare juvenile type (APS I) and the more common adult type (APS II-IV). APS I is caused by a monogenetic mutation whereas APS II-IV has a multifactorial genesis with combination related subgroups. Early diagnosis, individual adjustment of therapy and screening of high risk patients in particular are regarded as clinically relevant. In addition to the patient's history, the diagnosis of APS encompasses serologic measurement of organ-spe…

Sex Alters the MHC Class I HLA-A Association With Polyglandular Autoimmunity.

Abstract Context The major histocompatibility complex (MHC) strongly contributes to the development of polyglandular autoimmunity (PGA). Objective To evaluate the impact of sex on human leukocyte antigen (HLA) association with PGA for the first time. Design Cross-sectional immunogenetic study. Setting Academic tertiary referral Orphan Disease Center for PGA (ORPHA 282196) and immunogenetics laboratory. Subjects Patients (158) with coexistent type 1 diabetes and autoimmune thyroid disease (adult type 3 PGA, ORPHA 227982) and 479 unrelated healthy controls. Interventions All 637 white subjects were typed for HLA-A, -B, -DRB1, -DQA1, and -DQB1 alleles at a two-field level. Main Outcome Measure…

Cellular Immunity and Retrobulbar Fibroblasts in Graves' Ophthalmopathy

In Graves' ophthalmopathy (GO), retrobulbar connective tissue is infiltrated by T cells whose role in the pathogenesis of the disease was investigated in the present work. The aims included firstly to characterize subsets of blood lymphocytes and of sessile lymphocytes cloned from a retroorbital tissue specimen. Second, in counterstimulation assays, the ability of patients' T cells to influence cultivated retrobulbar fibroblasts and in turn the enhancement of lymphocyte proliferation by retrobulbar fibroblasts was investigated. Blood lymphocytes of 16 GO patients and 12 controls isolated by density gradient centrifugation and retrobulbar fibroblasts obtained from orbital decompression were …

Role of Octreoscan and Correlation with MR Imaging in Graves' Ophthalmopathy

Since the identification of somatostatin receptors on lymphocytes, orbital infiltration with mononuclear cells in Graves' ophthalmopathy has provided a rationale for receptor imaging with the radiolabeled somatostatin analog Octreotide. In 40 patients with Graves' ophthalmopathy and 10 controls, 110 MBq indium-Octreotide were administered i.v., and scans were performed at 4 and 24 h after injection. An uptake ratio between the orbits and the brain was determined. In 20 ophthalmophathy patients, magnetic resonance imaging (MRI) of the orbits was performed and the T2 relaxation time was measured within the rectus muscles. Compared to controls (4 h Octreotide uptake: median 6.0 counts/pixel/MB…

Improvement of asymmetric thyroid eye disease with teprotumumab

PurposeTeprotumumab, a specific blocking antibody to the insulin like growth factor 1 receptor, significantly reduced proptosis in patients with thyroid eye disease (TED) in recent clinical trials. Given its specificity, we expect it to demonstrate greater efficacy on the worse affected orbit, in patients with asymmetric TED. Herein, we investigate the differential impact of teprotumumab on the orbits of such patients.MethodsIn this pooled analysis of patients who were enrolled in the recent phase 2 (NCT01868997) and phase 3 (NCT03298867) trials, all patients with asymmetric TED (difference in exophthalmometry of ≥3 mm) were screened for eligibility. The primary outcomes of the trials, prop…