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BACKGROUND AND OBJECTIVE: The recurrence risk ratio (λ) expresses the risk ratio of index patients' first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature. METHODS: Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings). RESULTS: As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11-21 and 16, 12-19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17-30.69)/17.57 (11.80-24.36) and 13.48 (8.42-20.52)/10.68 (6.76-16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated. CONCLUSION: These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD.
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Doenças Autoimunes , Doenças do Sistema Endócrino , Doença de Hashimoto , Doenças da Glândula Tireoide , Tireoidite Autoimune , Criança , Humanos , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/genética , Tireoidite Autoimune/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/genética , Predisposição Genética para DoençaRESUMO
Background: Thyroid eye disease (TED) involves several pathogenic pathways and a battery of infiltrating mononuclear cells, cytokines, and chemokines in the orbit. Revealing the main molecules, which play a major role in the pathogenesis of TED, will help developing novel treatment strategies. Methods: In a multicenter, single-blind, case-control study, 60 tissue samples were collected during orbital decompression (44 TED patients) or non-TED related oculoplastic (16 controls) surgeries. Formalin-fixation and paraffin embedding preserved orbital tissue. Tissue sections were immunostained with 18 antibodies by the micro-polymer labeling technique. Immunostaining slides were scanned by Panoramic Desk and blindly evaluated by a user-independent viewer software. Results: Marked lymphocyte infiltration was observed in orbital tissue specimens of patients with clinically active TED (n = 22) and to a much lesser extent in inactive cases (n = 22), while it was absent in controls. Increased vascularity was noted in all samples, with orbital congestion in specimens of clinically active TED. Tissue fibrosis was present in TED samples but not in controls. Immunohistochemistry of orbital tissue clearly differentiated between TED and controls, as well as between active and inactive TED. In contrast to controls and with the exception of cluster of differentiation 20 (CD20), 17 out of 18 antibodies were highly expressed in orbital connective tissue of TED patients. Especially, thyrotropin receptor (TSH-R), insulin-like growth factor 1 receptor (IGF-1R), CD40, cluster of differentiation 40 ligand (CD40L), CD3, CD68, interleukin-17A (IL-17A), IL-23A, IL-1ß, IL-4, regulated on activation, normal T cell expressed and secreted (RANTES), macrophage chemoattractant protein 1 (MCP-1), IL-16, and B cell activating factor (BAFF) were overexpressed in clinically active TED (all p < 0.001). Also, the expression of CD40L, IL-17A, IL-23A, IL-6, IL-1ß, RANTES, and BAFF was very high (TED/control ratio >3), moderate (ratio >2), and low in active (p < 0.001), inactive TED and controls, respectively. The expression of TSH-R, IGF-1R, CD40, CD40L, CD3, CD68, CD20, IL-17A, IL-23A, RANTES, MCP-1, and BAFF positively and significantly correlated with both serum TSH-R stimulatory antibody concentrations and clinical activity scores while it negatively correlated with TED duration. Orbital irradiation decreased TSH-R (p < 0.001) and IGF-1R expression (p = 0.012); in contrast, neither smoking, age, nor gender did impact immunohistochemical staining. Conclusions: Adaptive and cell-mediated immunity, overexpression of TSH-R/IGF-1R and CD40/CD40L are the relevant pathomechanisms in TED. Targeting these key players in the active phase of the disease offers specific and novel treatment approaches.
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Oftalmopatia de Graves , Humanos , Oftalmopatia de Graves/metabolismo , Interleucina-17 , Ligante de CD40 , Estudos de Casos e Controles , Método Simples-Cego , Receptores da Tireotropina , TireotropinaRESUMO
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 treatment of GO by GC. The publications were evaluated according to their setting and study design. RESULTS: GC act through genomic (trans-activation and trans-repression) and rapid non-genomic mechanisms. GC in general, and the intravenous (IV) administration of GC in particular, markedly decrease the activity and number of the most potent antigen-presenting dendritic cells. According to the internationally acknowledged European Thyroid Association Guidelines for the management of GO, weekly IVGC application over 12 weeks is recommended as first-line treatment for patients with active and severe GO. The daily and cumulative dose should be tailored according to clinical severity, for example, 4.5 g of IV methylprednisolone for the inflammatory component versus 7.5 g in the presence of diplopia and severe proptosis. Fast and significant improvements in orbital symptoms and signs are noted in 65-70% of patients. Long-term experience over decades, and worldwide availability at low cost, underline the clinical and therapeutic relevance of GC. Adverse events are rarely severe, dose-dependent, and usually reversible, hence easy to handle by medical investigators. Oral GC application on a daily basis is characterized by high bioavailability but reduced efficacy and increased toxicity. CONCLUSION: IVGC still represents the standard of care in active/severe GO. Innovative biologicals, like monoclonal antibodies targeting the thyrotropin/Insulin-like growth factor-1 receptors or pro-inflammatory cytokines (e.g., Interleukin-6) should be compared with standard GC treatment with respect to short- and long-term efficacy, safety, costs, and global availability.