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Colin M. Dayan Cardiff University School of Medicine, Heath Park, Cardiff, UK

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Vijay Panicker Department of Endocrinology, Sir Charles Gairdner Hospital, Nedlands, W.A., Australia

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Background: A relationship between hypothyroidism and depression has been assumed for many years; however, the true nature of this association has been difficult to define with many conflicting studies. In recent years, our knowledge in this area has increased significantly with large cohort studies and genetically driven studies being published. Objectives: We reviewed the literature on thyroid function and depression to determine if this relationship has been clarified. Methods: We performed a search on the Pubmed database using the terms ‘thyroid' and ‘mental health', ‘depression' and ‘well-being'. Results: Large epidemiological studies generally suggest no association between thyroid function and depression in subjects without thyroid disease. Subjects on thyroxine have poorer psychological well-being than subjects with no thyroid disease even if biochemically euthyroid, they also show an association between thyroid function and well-being. Whilst there is some early evidence that genetic factors can influence well-being on thyroxine and response to combination therapy, there is also evidence to suggest that much morbidity on thyroxine may be due to initial misdiagnosis and mis-attribution of symptoms. Conclusion: Despite the large number of studies, the relationship between thyroid function and depression remains poorly defined. Clarification of the proportion of subjects on thyroxine incorrectly may assist the large (perhaps genetically driven) studies needed to move forward in this area, as it is expected that they cloud the results.

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Tim I.M. Korevaar Department of Internal Medicine and the Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands

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Peter N. Taylor Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK

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Colin M. Dayan Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK

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Robin Patrick Peeters Department of Internal Medicine and the Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands

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Ilaria Muller Thyroid Research Group, Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom

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Carla Moran Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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Beatriz Lecumberri Department of Endocrinology and Nutrition, La Paz University Hospital, IdiPAZ, Autonomous University of Madrid, Madrid, Spain

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Brigitte Decallonne Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium

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Neil Robertson Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom

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Joanne Jones Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

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Colin M. Dayan Thyroid Research Group, Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom

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Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1–3); (2) monitoring during/after IRT (recommendations 4–7); (3) management of TD post-IRT (recommendations 8–17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.

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Ilaria Muller Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Lucy S. Kilburn Institute of Cancer Research – Clinical Trials & Statistics Unit (ICR-CTSU), London, United Kingdom

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Peter N. Taylor Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Peter J. Barrett-Lee Academic Breast Department, Velindre Cancer Centre, Cardiff, United Kingdom

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Judith M. Bliss Institute of Cancer Research – Clinical Trials & Statistics Unit (ICR-CTSU), London, United Kingdom

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Paul Ellis Guy’s Hospital and King’s College, London, United Kingdom

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Marian E. Ludgate Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Colin M. Dayan Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Background: Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome. Objectives: We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). Methods: TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1–3a, pN0–1, M0), with stored plasma (n = 1,974), taken 15.5 (median; IQR 7.0–24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive ≥6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to-recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months. Results: No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78–1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79–1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82–1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments. Conclusions: No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date.

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Jacqueline Jonklaas Division of Endocrinology, Georgetown University, Washington, District of Columbia, USA

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Antonio C. Bianco Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, Illinois, USA

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Anne R. Cappola Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Francesco S. Celi Division of Endocrinology, Diabetes and Metabolism, Virginia Commonwealth University, Richmond, Virginia, USA

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center, Amsterdam, The Netherlands

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Heike Heuer Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Elizabeth A. McAninch Division of Endocrinology, Rush University, Chicago, Illinois, USA

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Lars C. Moeller Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Anna M. Sawka Division of Endocrinology, University Health Network and University of Toronto, Toronto, Ontario, Canada

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Torquil Watt Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

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Colin M. Dayan Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

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