ETJ autoimmune thyroid diseases collection

 

Autoimmune thyroid diseases are the commonest autoimmune conditions of mankind and make up a large proportion of the caseload for endocrinologists. This topic collection brings together articles focusing on biological mechanisms, diagnosis and clinical management of thyroid diseases of autoimmune origin, including thyroid-associated orbitopathy which will be of broad interest to both clinicians and non-clinical scientists alike.

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Thyroid autoimmunity

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Jingyue Chen Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Chenyan Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Weiping Teng Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Zhongyan Shan Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Jun Jin Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yining Wei Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Jing Sun Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Yushu Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Huifang Zhou Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

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Objective

The management of thyroid eye disease (TED) has undergone significant changes for decades. The study sought to investigate current clinical practice on the management of TED in China.

Methods

An online questionnaire survey was conducted from April to May 2023. The questionnaire involved diagnostic criteria for TED, multidisciplinary treatment (MDT) collaboration, and treatment preference for mild, moderate, and severe TED.

Results

A total of 289 questionnaires were collected, with 165 from endocrinologists and 124 from ophthalmologists. Only 36.7% of participants claimed there was an MDT clinical pattern for TED in their institutions. The coverage of biological agents was around 10% or lower. These were distinctly lower than in Western countries. About 62.6% of participants believed the incidence of TED has increased in recent years. Imaging techniques were used widely to assist in the diagnosis of TED. However, there was still controversy regarding the definition of proptosis in the Chinese population. Most doctors managed risk factors and provided orbital supportive treatments of artificial tears and glasses. For mild active TED, endocrinologists (39.4%) were inclined to recommend therapy for hyperthyroidism alone, while ophthalmologists (43.6%) preferred orbital corticosteroid injections. Currently, the most widely used treatment for moderate to severe active TED was high-dose intravenous corticosteroid (94.8%), while orbital radiotherapy combined with immunosuppressive agents was the most recognized second-line therapy (43.6%).

Conclusion

The study documented the consistency and differences between current clinical practices in the management of TED in China and the recently updated guidelines. There was a remarkable difference between ophthalmology and endocrinology departments, warranting management optimization.

Open access
Ilaria Muller Department of Clinical Sciences and Community Health, University of Milan, Italy
Endocrinology Unit, Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Sara Maioli Department of Clinical Sciences and Community Health, University of Milan, Italy

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Mirco Armenti Department of Clinical Sciences and Community Health, University of Milan, Italy

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Laura Porcaro Department of Clinical Sciences and Community Health, University of Milan, Italy

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Nicola Currò Endocrinology Unit, Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Ophthalmology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Elisabetta Iofrida Department of Specialistic Surgical Sciences, Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Lorenzo Pignataro Department of Clinical Sciences and Community Health, University of Milan, Italy
Department of Specialistic Surgical Sciences, Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Jacopo Manso Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy

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Caterina Mian Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy

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Jens Geginat Department of Clinical Sciences and Community Health, University of Milan, Italy
National Institute of Molecular Genetics (INGM) “Romeo and Enrica Invernizzi”, Milan, Italy

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Mario Salvi Endocrinology Unit, Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Introduction

Secondary thyroid autoimmunity, especially Graves’ disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment.

Case presentation

A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy.

Conclusion

RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.

Open access
Leonidas Duntas Evgenideion Hospital, Unit of Endocrinology, Diabetes and Metabolism, National and Kapodeistrian University of Athens, Greece

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Haitao Zhang Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Hao Hu Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Yueyue Wang Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Xinjie Duan Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Lu Chen Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Jiang Zhou Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Wen Chen Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Weizhong Zhang Department of Ophthalmology, The Friendship Hospital of Ili Kazakh Autonomous Prefecture Ili & Jiangsu Joint Institute of Health, Ili, China
Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Xiaoquan Xu Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Huanhuan Chen Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

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Purpose

The aim was to determine the combined value of serological lipid metabolism and an orbital MRI quantitative parameter in predicting the effectiveness of glucocorticoid (GC) therapy in patients with thyroid eye disease (TED).

Methods

This study retrospectively enrolled 46 patients with active and moderate-to-severe TED (GC-effective group, n = 29; GC-ineffective group, n = 17). Serological lipid metabolism, the orbital MRI-based minimum signal intensity ratio of extraocular muscles (EOM-SIRmin), as well as other clinical parameters before GC therapy were collected and compared between the two groups. Multivariate logistic regression and receiver operating characteristic curve analysis were adopted to identify independent predictable variables and assess their predictive performances.

Results

Compared to the GC-ineffective group, the GC-effective group showed lower serum total cholesterol levels (P = 0.006), lower serum low-density lipoprotein cholesterol levels (P = 0.019), higher EOM-SIRmin values (P = 0.005), and shorter disease durations (P = 0.017). Serum total cholesterol and EOM-SIRmin were found to be independent predictors of GC-effective TED through multivariate analysis (odds ratios = 0.253 and 2.036 per 0.1 units, respectively) (both P < 0.05). The integration of serum total cholesterol ≤4.8 mmol/L and EOM-SIRmin ≥ 1.12 had a better predictive efficacy (area under the curve, 0.834) than EOM-SIRmin alone, with a sensitivity of 75.9% and a specificity of 82.4% (P = 0.031).

Conclusion

Serological lipid metabolism, combined with an orbital MRI-derived parameter, was a useful marker for predicting the effectiveness of GCs in patients with active and moderate-to-severe TED.

Open access
Hsu-Hua Tseng Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

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Yen-Bo Lin Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan

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Kuan-Yu Lin Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliu City, Taiwan

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Chia-Hung Lin Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan

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Hung-Yuan Li Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

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Chia-Hsuin Chang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

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Yi-Ching Tung Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

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Pei-Lung Chen Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan

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Chih-Yuan Wang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

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Wei-Shiung Yang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

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Shyang-Rong Shih Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
Center of Anti-Aging and Health Consultation, National Taiwan University Hospital, Taipei, Taiwan

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Purpose

Autoimmune polyendocrine syndrome (APS) is a rare immune-endocrinopathy characterized by the failure of at least two endocrine organs. Clinical characteristics have mainly been described in the Western population. This study comprehensively analyzed the demographic and clinical manifestations of APS II and APS III in Taiwan.

Methods

Patients aged ≥20 years with a diagnosis of APS II or APS III in ten hospitals between 2001 and 2021 were enrolled. The clinical and serological characteristics of the patients were retrospectively reviewed.

Results

Among the 187 enrolled patients (45 men and 142 women); only seven (3.7%) had APS II, while the others had APS III. Fifty-five patients developed hyperthyroidism and 44 patients developed hypothyroidism. Men were diagnosed with APS at a younger age than women (16.8 vs 27.8 years old, P = 0.007). Most patients were initially diagnosed with type 1 diabetes mellitus. There was a positive correlation between age at diagnosis and the likelihood of developing thyroid dysfunction. For every year older patients were diagnosed with APS III, the risk of developing hyperthyroidism increased by 3.6% (P = 0.002), and the risk of developing hypothyroidism increased by 3.7% (P = 0.035). Positive anti-parietal cell antibodies (APCA) were associated with a higher risk of anemia in patients with APS III (P < 0.001).

Conclusion

This study provides the most comprehensive analysis of APS II and APS III in Asia. The percentage of patients with APS II was significantly lower than in the Western population. A second autoimmune endocrinopathy may develop several years after the first one. APCA examination is valuable when evaluating anemia in patients with APS.

Open access
Jinrong Fu Department of Endocrinology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Zihao Fan Department of Geriatrics, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Liang He Department of Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China

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Qian Liu Department of Endocrinology and Metabolism, Jilin Cancer Hospital, Changchun, Jilin, China

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He Liu Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Yushu Li Department of Endocrinology and Metabolism, Institute of Endocrinology, NHC Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China

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Haixia Guan Department of Endocrinology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

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Objective

A vicious cycle between circadian disruption and escalating immune responses has been described in diverse inflammatory disease. The current study aimed to explore the role of circadian clock disruption in autoimmune thyroiditis (AIT).

Methods

Thirty AIT patients and 30 controls were enrolled and biopsied for thyroid tissues. Alterations of core clock genes expression in AIT thyroid tissues, and its association with serum and tissue inflammatory biomarkers were assessed. For animal studies, C57BL/6J mice administered with porcine thyroglobulin or PBS (as control) combined with adjuvants were sacrificed at four time points to investigate the circadian characteristic of experimental autoimmune thyroiditis (EAT). Light shift (LS) conditions were used to explore the influence of external circadian disturbance on EAT.

Results

The expression of clock genes BMAL1 and PER2 was significantly reduced in thyroid tissues from AIT patients and was negatively correlated to levels of thyroid peroxidase antibodies. In mouse models, diurnal fluctuations of proinflammatory cytokines were demonstrated, and further exposing mice to LS led to overproduction of TNF-α, IFN-γ, and anti-thyroglobulin antibodies. Circadian analysis revealed significant oscillations of Bmal1, Clock, Per2, Cry1, Ror, and Rev-erb, which was broadly disturbed in EAT, LS, and EAT + LS groups.

Conclusions

This study demonstrates that expression pattern of clock genes was disrupted in AIT thyroid, and chronic circadian disruption may aggravate the inflammatory responses in AIT. Whether maintaining a regular circadian rhythm can alleviate autoimmune thyroid diseases warrants further research.

Open access
Jacopo Manso Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy
Department of Women’s and Children’s Health, Pediatric Endocrinology Unit, Padua University Hospital, Padua, Italy

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Simona Censi Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Cristina Clausi Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Ilaria Piva Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Yi Hang Zhu Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Alberto Mondin Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Maria Chiara Pedron Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Susi Barollo Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Loris Bertazza Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Giulia Midena Department of Molecular Medicine, University of Padua, Padua, Italy

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Raffaele Parrozzani Department of Ophthalmology, University of Padua, Padua, Italy

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Caterina Mian Department of Medicine (DIMED), Endocrinology Unit, University of Padua, Padua, Italy

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Objective

Thyroid eye disease (TED) is an immune-mediated disorder of the eye. Intravenous glucocorticoid (GC) is the first-line treatment for patients with active moderate-to-severe TED. However, the response rate is between 50% and 80%. There are still no simple and reliable markers of responsiveness to GC therapy. We aimed to explore the possible role of miR-146a and miR-21 as predictors of responsiveness to GC treatment in TED.

Methods

We carried out a prospective longitudinal study on 30 consecutive adult patients with active moderate-to-severe TED and eligible for GC therapy. All patients received the standard GC treatment with methylprednisolone i.v. In cases of progressive worsening of Gorman Score for diplopia or with duction restriction <30° in at least two consecutive controls, patients also underwent orbital radiotherapy. Response to GC treatment was defined as a decrease of two or more points in the clinical activity score (CAS) or CAS <4/10 at 24 weeks. Circulating miRNAs were extracted from patients’ serum and quantified by real-time PCR.

Results

Twenty-three (77%) patients responded to GC. Thyroid surgery, higher CAS, greater proptosis and higher pre-treatment circulating levels of miR-146a emerged as predictive factors of responsiveness to GC. A ROC analysis revealed that miR-146a could predict responsiveness to GC with a positive predictive value of 100%.

Conclusion

This is the first study investigating the role of pre-treatment circulating miR-21 and miR-146a to predict responsiveness to GC in TED. miR-146a emerged as a simple, objective, new marker of GC sensitivity that could be used to avoid ineffective administration of GC therapy to TED patients.

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Petros Perros Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

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Laszlo Hegedüs Department of Endocrinology Odense University Hospital, Odense, Denmark

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Progress in the management of thyroid eye disease (TED) has been slow for many decades. The recent introduction of teprotumumab (TEP) in the therapeutic arena for TED has had a major impact in view of its efficacy, particularly with respect to its ability to reduce proptosis. However, the high cost of TEP, limited availability to patients outside the USA, and the lack of data on cost-effectiveness are significant barriers to improving the care of patients with TED globally. Recent guidance from authoritative professional organisations deliver different perspectives on the role of TEP in the routine management of patients with TED, underscoring the complexities of interpreting the evidence. The advance that TEP undoubtedly represents in managing TED effectively has highlighted inequities faced by patients and uncertainties about appropriate metrics of efficacy. Professional organisations have an important role addressing these problems. Future studies need to focus on optimising the measurement of outcomes and on assessing cost-effectiveness.

Open access
Liliana Ribeiro Santos Internal Medicine Department, Hospital of Santa Maria, Lisbon, Portugal
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

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Inês Vasconcelos Bessa Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal

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Adriana Gaspar da Rocha Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal
Public Health Unit, ACES Baixo Mondego, Coimbra, Portugal

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Celestino Neves Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Department of Endocrinology, Hospital University Centre of São João, Porto, Portugal

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Cláudia Freitas Department of Endocrinology, Hospital University Centre of Porto, Porto, Portugal

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Paula Soares Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
Health Investigation and Innovation Institute (i3S), University of Porto, Porto, Portugal
Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal

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Objective

Previous trials show that selenium could be a very useful tool in the control and treatment of autoimmune thyroid diseases. In this cross-sectional study, through a survey, we aim to evaluate Portuguese endocrinologists' perception and pattern of prescription of selenium supplements in these diseases and verify its agreement with current guidelines.

Methods

The endocrinologists registered in the Portuguese Medical Association were sent an email with a web-based questionnaire, regarding their knowledge and use of selenium supplements in thyroid autoimmune pathology.

Results

A total of 105 physicians (33% of the total) submitted the survey. The selenium serum concentration in the general population was unknown to 80% of respondents. Over a third of respondents have never prescribed selenium for autoimmune thyroid disease. However, 89% are not afraid of recommending it, and 61% indicate Graves’ orbitopathy as the pathology they would supplement. In Hashimoto’s thyroiditis, 36% of respondents use selenium occasionally or frequently, and this percentage rises to 60% in Graves’ disease.

Conclusions

Although recommendations only encompass mild Graves’ orbitopathy, selenium is prescribed across the spectrum of autoimmune thyroid diseases, probably due to recent studies that consistently show improvement of biochemical hallmarks in these patients. Further investigation is required on the impact of selenium supplements on primarily clinical outcomes and to identify disorders and/or patients who will benefit the most. Also, there is still insufficient knowledge of this field in the medical community, and evidence-based practice should continue to be promoted by endocrinology societies.

Open access
Henry B Burch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Endocrinology Division, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA

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Petros Perros Department of Endocrinology, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

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Tomasz Bednarczuk Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland

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David S Cooper Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Peter J Dolman Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

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Angela M Leung Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UCLA David Geffen School of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA

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Ilse Mombaerts Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium

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Mario Salvi Department of Clinical and Community Services, Graves’ Orbitopathy Center, Endocrinology, Fondazione IRCCS Cà Granda, Milan, Italy

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Marius N Stan Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, Minnesota, USA

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Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this Consensus Statement.

Open access