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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Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs), with thyroid irAEs being the most common endocrine-related irAEs. The incidence of overt thyroid irAEs was in the range of 8.9–22.2% in real-world settings, typically triggered by antibodies against PD-1 and PD-L1 and rarely by anti-CTLA-4 antibodies alone. The representative clinical course involves biphasic changes in thyroid function: transient thyrotoxicosis and subsequent persistent hypothyroidism. The identified risk factors for thyroid irAEs include the presence of thyroid autoantibodies, thyroid uptake on 18F-FDG-PET, prior use of tyrosine kinase inhibitors (TKIs), high BMI and high thyroid-stimulating hormone levels. There is evidence that overt thyroid irAEs are associated with good prognosis, at least in non-small cell lung cancer. Although the clinical features have been well clarified, the management strategies require further refinement. Routine monitoring of thyroid function every 4–6 weeks during ICI therapy is recommended for early detection of thyroid irAEs. While thyrotoxicosis generally requires observation only, hypothyroidism should be promptly treated with levothyroxine replacement. Continuation of ICI therapy is typically feasible in patients with thyroid irAEs, provided their overall health remains stable. However, these strategies were largely based on clinical experience with monotherapy. As combination ICI therapies have been developed as first-line treatments, antitumor agents may modify the clinical features of thyroid irAEs. For example, cytotoxic agents can delay the onset of thyroid irAEs, while TKIs are often linked to early-onset hypothyroidism, independent of ICI use. Given the increasing diversity and complexity of cancer immunotherapy, it is essential to vigilantly screen for thyroid irAEs.
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Background
Thyroid eye disease (TED) is the most prevalent extrathyroidal manifestation of Graves’ disease (GD). Emerging evidence suggests a relationship between elevated total and low-density lipoprotein (LDL) cholesterol levels and TED. This study aimed to investigate this correlation in the Brazilian population by analyzing data from two tertiary care centers.
Methods
Data were collected from GD patients treated with methimazole between 1999 and 2021, excluding those receiving other treatments. Laboratory results and information on smoking habits, statin use and medications affecting lipid profiles during the euthyroid state were analyzed.
Results
Smoking and elevated LDL cholesterol levels were significantly associated with TED activity and severity. Logistic regression revealed correlations between higher LDL cholesterol, total cholesterol and increased clinical activity score (P < 0.01, OR: 1.012, 95% CI: 1.003–1.021; P < 0.01, OR: 1.010, 95% CI: 1.002–1.018). These were also associated with more severe disease forms as defined by EUGOGO (P < 0.01, OR: 1.015, 95% CI: 1.006–1.024; P < 0.005, OR: 1.011, 95% CI: 1.004–1.019). Multiple regression confirmed that TED activity was significantly correlated with LDL cholesterol (P < 0.01) and smoking status (P < 0.01). Disease severity was associated with reduced HDL cholesterol (P < 0.05, OR: 0.973, 95% CI: 0.948–0.999), elevated LDL cholesterol (P < 0.005, OR: 1.013, 95% CI: 1.004–1.023) and active smoking (P < 0.05, OR: 2.881, 95% CI: 1.190–6.971).
Conclusion
Elevated LDL cholesterol may serve as a potential indicator of TED. Further research is needed to determine whether lipid-lowering interventions could reduce TED risk or improve its management.
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Objectives
The pathogenesis of Graves’ orbitopathy (GO) remains to be fully elucidated. Here, we reviewed the role of genetics and epigenetics.
Design
We conducted a PubMed search with the following keywords: GO, thyroid eye disease; or Graves’ ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome, and methylome analyses were performed were chosen.
Results
The different prevalence of GO in the two sexes, as well as racial differences, suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and patient-derived orbital fibroblasts suggests a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated.
Conclusions
Although no pathogenic gene variants have been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.
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Background
To explore whether IgG4 is involved in the pathogenesis of IgG4 HT.
Methods
Serum TgAb IgG4 and TPOAb IgG4 were measured in IgG4 HT and non-IgG4 HT. C1q, mannose-binding lectin (MBL), Bb, C3d, C4d, and membrane attack complex (MAC) in thyroid tissues from IgG4 HT, non-IgG4 HT, and controls were examined by immunohistochemistry. We assessed IgG4 and MAC deposition in mouse thyroid by immunohistochemistry after injecting purified IgG4 into mice. The glycosylation patterns of TgAb IgG4 from IgG4 HT were identified by MALDI-TOF-MS. The ability of IgG4 to bind to MBL before and after deglycosylation was assessed by ELISA. MBL and MAC fluorescence were detected in thyrocytes after the addition of IgG4 or deglycosylated IgG4.
Results
Serum TgAb IgG4 and TPOAb IgG4 levels were significantly higher in the IgG4 HT group. MBL, Bb, C3d, C4d, and MAC levels were significantly higher in the thyroid tissues of IgG4 HT than in non-IgG4 HT (all P < 0.001). IgG4 colocalized with MBL by immunofluorescence. In mice, follicular cell structure disruption was observed after the injection of IgG4 from IgG4 HT, as well as the colocalization of IgG4 with MAC. High levels of TgAb IgG4 glycosylation patterns, including monogalactose glycan (G1F), galactose-deficient glycan (G0F), and high-mannose glycan (M5), were detected in IgG4 HT. After deglycosylation, IgG4 reduced its ability to bind to MBL, and there was low MBL and MAC activation in thyrocytes.
Conclusion
High levels of IgG4 glycosylation patterns, including G1F, G0F, and M5, may activate the complement lectin pathway, thereby participating in the pathogenesis of IgG4 HT.
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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.
Endocrinology Unit, Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Ophthalmology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Department of Specialistic Surgical Sciences, Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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National Institute of Molecular Genetics (INGM) “Romeo and Enrica Invernizzi”, 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.
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Department of Ophthalmology, 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.
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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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Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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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.
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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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.
