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The association between breast cancer and benign thyroid disorders, in particular thyroid autoimmunity, has been debated for decades. Autoantibodies to thyroid peroxidase, the hallmark of thyroid autoimmunity, have a higher prevalence among patients with breast cancer compared with the general population. Furthermore a correlation between their positivity and a better prognosis of breast cancer was found in several independent small-scale studies, even if such observation was not confirmed in a subsequent retrospective study conducted on the largest patient cohort to date. The thyroid and mammary glands present several biological similarities, therefore the hypothesis of an immune response to shared thyroid/breast antigens could in part explain the association between thyroid autoimmunity and breast cancer. The sodium iodide symporter is expressed in both glands, however it seems unlikely to be the key common antigen, considering that autoantibodies targeting it are rare. Instead thyroid peroxidase, one of the major thyroid autoantigens, is also expressed in breast tissue and therefore represents the main antigenic link between thyroid autoimmunity and breast cancer. Furthermore lactoperoxidase, an enzyme of the same family that shares structural similarities with thyroid peroxidase, is expressed in neoplastic breast cells and is responsible for the cross-reactivity with some autoantibodies to thyroid peroxidase. Novel strategies for the diagnosis and treatment of breast cancer might take advantage of the antigenic link between thyroid and breast tissues. [ABSTRACT FROM AUTHOR]

Background: Thyroid autoimmunity, especially Graves' disease or hypothyroidism with positive autoantibodies (TRAb) to the thyrotropin receptor (TSHR), occurs in 30–40% of patients with relapsing multiple sclerosis following treatment with alemtuzumab (ALTZ). ALTZ therapy therefore provides a unique opportunity to study the evolution of TRAb prior to clinical presentation. TRAb can stimulate (TSAb), block (TBAb), or not affect ("neutral") the TSHR function, causing hyperthyroidism, hypothyroidism, or euthyroidism, respectively. Methods: A longitudinal retrospective analysis was conducted of TRAb bioactivity over a period of nine years in 45 multiple sclerosis patients receiving ALTZ using available stored serum. Of these 45 patients, 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of five years (NO-TD). The presence of TRAb was evaluated at standardized time points: (i) before ALTZ, (ii) latest time available following ALTZ and before TD onset, and (iii) following ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry detecting any TSHR-binding TRAb, and luciferase bioassays detecting TSAb/TBAb bioactivity. Purified immunoglobulin G was used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb, antithyroid peroxidase autoantibodies (TPOAb), thyrotropin, free thyroxine, and free triiodothyronine were also collected. Results: Before ALTZ, combined ihTRAb (positive with flow cytometry and/or luciferase bioassay) but not automated TRAb were present in 5/16 (31.2%) TD versus 0/14 (0%) NO-TD (p = 0.017). Detectable ihTRAb preceded TD development in 9/28 (32.1%) and by a median of 1.2 years (range 28 days–7.3 years). Combination testing of ihTRAb and TPOAb at baseline predicted 20% of subsequent cases of hyperthyroidism and 83% of hypothyroidism. Conclusions: Evidence is presented that TRAb measured with custom-made assays can be detected prior to any change in thyroid function in up to a third of cases of ALTZ-related TD. Furthermore, the presence of ihTRAb prior to ALTZ treatment was strongly predictive of subsequent TD. The findings suggest that a period of affinity maturation of TRAb may precede clinical disease onset in some cases. Combined testing of TPOAb and ihTRAb may increase the ability to predict those who will develop TD following ALTZ. [ABSTRACT FROM AUTHOR]

Background: Current guidelines suggest high-dose steroids as first-line treatment for dysthyroid optic neuropathy (DON). When steroids fail, decompressive surgery is mandatory. Methods: We conducted a single-center, retrospective cohort study in a tertiary care combined Thyroid-Eye clinic in Milan, Italy. We studied 88 orbits of 56 patients that were submitted to surgical orbital decompression to treat DON from 2005 to 2020. Of these, 33 orbits (37.5%) underwent surgery as first-line treatment for DON whereas the other 55 (62.5%) were decompressed after being unresponsive to very high-dose steroids. Previous orbital surgery, concurrent neurological or ophthalmologic diseases, or incomplete follow-up were considered as exclusion criteria from this study. Surgery was considered successful if no further decompression was needed to preserve vision. Pinhole best corrected visual acuity (p-BCVA), color sensitivity, automated visual field, pupil reflexes, optic disk and fundus appearance, exophtalmometry, and ocular motility were studied before and after surgery (1 week, 1, 3, 6, and 12 months). Activity of Graves' Orbitopathy (GO) was graded using a clinical activity score (CAS). Results: Surgery was successful in 77 orbits (87.5%). The remaining 11 orbits (12.5%) needed further surgery to treat DON definitively. All parameters of visual function improved significantly at follow-up and GO inactivated (CAS <3) within 1 month. At 3 months, all 77 responding orbits had p-BCVA >0.63 whereas all of the 11 non-responding orbits had p-BCVA ≤0.63. Visual field parameters and color sensitivity were not associated with response to surgery. High-dose steroid treatment before surgery was associated with a better response rate (96% vs. 73%; p = 0.004). Balanced decompression was associated with a higher response rate compared with medial wall decompression (96% vs. 80%; p = 0.04). A significant inverse correlation was observed between final p-BCVA and the patient's age (r = −0.42; p = 0.0003). Conclusions: Surgical decompression was found to be a very effective treatment for DON. In this study, all clinical parameters improved after surgery and further intervention was rarely needed. [ABSTRACT FROM AUTHOR]

Autoimmune thyroid diseases (AITDs) are chronic autoimmune disorders that cause impaired immunoregulation, leading to specific immune responses against thyroid antigens. Graves' disease (GD) and Hashimoto's thyroiditis (HT) are the major forms of AITDs. Increasing evidence suggests a possible role of microbiota alterations in the pathogenesis and progression of AITDs. This systematic review was designed to address the following question: "Is microbiota altered in patients with AITDs?" After screening the selected studies using the inclusion and exclusion criteria, 16 studies were included in this review (in accordance with PRISMA statement guidelines). A meta-analysis revealed that patients with HT showed significantly higher values of diversity indices (except for the Simpson index) and that patients with GD showed significant tendencies toward lower values of all assessed indices compared with healthy subjects. However, the latter demonstrated a higher relative abundance of Bacteroidetes and Actinobacteria at the phylum level and thus Prevotella and Bifidobacterium at the genus level, respectively. Thyroid peroxidase antibodies showed the most significant positive and negative correlations between bacterial levels and thyroid functional parameters. In conclusion, significant alterations in the diversity and composition of the intestinal microbiota were observed in both GD and HT patients. [ABSTRACT FROM AUTHOR]

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose. Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events. Results: Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p = 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome. Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON. [ABSTRACT FROM AUTHOR]

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose. Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events. Results: Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p = 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome. Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON. [ABSTRACT FROM AUTHOR]

Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient's quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials. [ABSTRACT FROM AUTHOR]

Hyaluronan (HA), an extra-cellular matrix glycosaminoglycan, may play a role in mesenchymal stem cell differentiation to fat but results using murine models and cell lines are conflicting. Our previous data, illustrating decreased HA production during human adipogenesis, suggested an inhibitory role. We have investigated the role of HA in adipogenesis and fat accumulation using human primary subcutaneous preadipocyte/fibroblasts (PFs, n = 12) and subjects of varying body mass index (BMI). The impact of HA on peroxisome proliferator-activated receptor gamma (PPARγ) expression was analysed following siRNA knockdown or HA synthase (HAS)1 and HAS2 overexpression. PFs were cultured in complete or adipogenic medium (ADM) with/without 4-methylumbelliferone (4-MU = HA synthesis inhibitor). Adipogenesis was evaluated using oil red O (ORO), counting adipogenic foci, and measurement of a terminal differentiation marker. Modulating HA production by HAS2 knockdown or overexpression increased (16%, p < 0.04) or decreased (30%, p = 0.01) PPARγ transcripts respectively. The inhibition of HA by 4-MU significantly enhanced ADM-induced adipogenesis with 1.52 ± 0.18- (ORO), 4.09 ± 0.63- (foci) and 2.6 ± 0.21-(marker)-fold increases compared with the controls, also increased PPARγ protein expression (40%, (p < 0.04)). In human subjects, circulating HA correlated negatively with BMI and triglycerides (r = −0.396 (p = 0.002), r = −0.269 (p = 0.038), respectively), confirming an inhibitory role of HA in human adipogenesis. Thus, enhancing HA action may provide a therapeutic target in obesity. [ABSTRACT FROM AUTHOR]

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, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones (r = 0.85, p = 0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism. [ABSTRACT FROM AUTHOR]

The article presents a randomized controlled crossover trial on the effectiveness of treating inactive Graves' orbitopathy using the prostaglandin F2-alpha analogue bimatoprost to reduce proptosis. It states participants were randomized between a placebo or receiving bimatoprost for three months and then underwent a two-month washout before switching to the opposite treatment. It discusses changes in exophthalmometry readings found no apparent improvement in proptosis.

SARS-CoV-2 infections have been associated with the onset of thyroid disorders like classic subacute thyroiditis (SAT) or atypical SAT upon severe COVID disease (COV-A-SAT). Little is known about thyroid anti-viral immune responses. To define the role of T-cells in COV-A-SAT. T-cells from COV-A-SAT patients were analyzed by multi-dimensional flow cytometry, UMAP and DiffusionMap dimensionality reduction and FlowSOM clustering. T-cells from COVID-naïve healthy donors, patients with autoimmune thyroiditis (ATD) and with SAT following COVID vaccination were analyzed as controls. T-cells were analyzed four and eight months post-infection in peripheral blood and in thyroid specimen obtained by ultrasound-guided fine needle aspiration. SARS-COV2-specific T-cells were identified by cytokine production induced by SARS-COV2-derived peptides and with COVID peptide-loaded HLA multimers after HLA haplotyping. COV-A-SAT was associated with HLA-DRB1*13 and HLA-B*57. COV-A-SAT patients contained activated Th1- and cytotoxic CD4+ and CD8+ effector cells four months post-infection, which acquired a quiescent memory phenotype after eight months. Anti-SARS-CoV-2-specific T-cell responses were readily detectable in peripheral blood four months post-infection, but were reduced after eight months. CD4+ and CD8+ tissue-resident memory cells (TRM) were present in the thyroid, and circulating CXCR3+T-cells identified as their putative precursors. SARS-CoV-2-specific T-cells were enriched in the thyroid, and acquired a TRM phenotype eight months post-infection. The association of COV-A-SAT with specific HLA haplotypes suggests a genetic predisposition and a key role for T-cells. COV-A-SAT is characterized by a prolonged systemic anti-viral effector T-cell response and the late generation of COVID-specific TRM in the thyroid target tissue. [ABSTRACT FROM AUTHOR]

Background Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child's IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II. Methods/Design Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant's home. Discussion The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation. [ABSTRACT FROM AUTHOR]