BACKGROUND: Supplemental methotrexate (MTX) may affect the clinical course of Graves\' disease (GD).
OBJECTIVE: Evaluate efficacy of add-on MTX on medical treatment in GD.
METHODS: Prospective, open-label, randomized supplementation controlled trial.
METHODS: Academic endocrine outpatient clinic.
METHODS: One hundred and fifty-three untreated hyperthyroid patients with GD.
METHODS: Patients received MTX 10 mg/d with methimazole (MMI) or MMI only. MTX and MMI were discontinued at months 12-18 in euthyroid patients.
METHODS: Discontinuation rate at months 18 in each group.
RESULTS: In the MTX with MMI group, the discontinuation rate was higher than the MMI group at months 15-18 (50.0 vs. 33.3%, P=0.043, 95% CI 1.020 to 3.922; and 55.6 vs 38.9%, P=0.045, 95%CI 1.011 to 3.815, respectively). The decrease in TRAb levels in the MTX with MMI group was significant from baseline to months 6 compared to the MMI alone group [MTX+MMI 67.22% (43.12-80.32), MMI 54.85% (33.18-73.76), P= 0.039) and became more significant from months 9 [MTX+MMI 77.79% (62.27-88.18), MMI 69.55% (50.50-83.22), P= 0.035] to months 18 (P < 0.01 in 15-18 months). A statistically significant difference between the levels of TRAb in the MTX with MMI group and the MMI group at 9-18 months. There were no significant differences in the levels of FT3, FT4 and TSH between two groups. No serious drug-related adverse events were observed in both groups(P=0.771).
CONCLUSIONS: Supplemental MTX with MMI resulted in higher discontinuation rate and improvement in decreased TRAb levels to homeostatic levels faster than methimazole treatment alone at months 12-18.

UNASSIGNED: Classification of thyroid eye disease (TED) is largely based on guidelines developed in Europe and North America. Few studies have investigated the presentation and treatment of TED in Black populations. The objective is to examine the manifestations of TED in secondary and tertiary care center-based populations with a significant proportion of Black patients.
UNASSIGNED: Retrospective chart review identifying patients with a reported race/ethnicity and a presenting clinical diagnosis of TED at Kings County Hospital and SUNY Downstate Medical Center and affiliated clinics from January 1, 2010 through July 31, 2021. Main outcome measures include age of disease onset, sex, smoking status, insurance status, postal code of residence, clinical exam features, number of follow-up visits, length of follow-up, and treatments received.
UNASSIGNED: Of the 80 patients analyzed, 49 were Black (61.2%) and 31 were White (38.8%). Between Black and White patients, there were differences in the mean age of presentation (48.1 [range 21-76] vs 56.8 [range 28-87] years, P=0.03), insurance status (51.0% vs 77.4% private insurance, P=0.02), and mean follow up length among those with multiple visits (21.6 [range 2-88] vs 9.7 [range 1-48] months, P=0.02). The distribution of EUGOGO scores were not significantly different between Black and White patients. On initial presentation, fewer Black patients had chemosis (OR 0.21, 95% CI, 0.08 to 0.57, P=0.002), and caruncular swelling (OR 0.19, 95% CI, 0.06 to 0.59, P=0.002) compared to White patients. During the overall disease course, fewer Black patients had subjective diplopia (OR 0.20, 95% CI, 0.07 to 0.56, P=0.002), chemosis (OR 0.24, 95% CI, 0.09 to 0.63, P=0.004), and caruncular swelling (OR 0.18, 95% CI, 0.07 to 0.51, P=0.001) compared to White patients. Black patients received oral steroids (42.9% vs 67.7%, P=0.03), intravenous steroids (18.4% vs 16.1%, P=0.8), orbital decompression surgery (16.7% vs 6.5%, P=0.19), and teprotumumab (22.9% vs 22.6%, P=0.99) at similar rates.
UNASSIGNED: Black patients presented with fewer external exam findings suggestive of active TED compared to White patients, but the rate of compressive optic neuropathy and decompression surgery were similar in the two groups. These differences may be due to disease phenotypes, which warrant further study.

Interleukin-17A (IL-17A) plays a pivotal role in the pathogenesis of Graves\' disease (GD), an autoimmune disorder affecting thyroid function, but the detailed regulatory mechanisms remain elusive. Circular RNAs (circRNAs) have emerged as key regulators of IL-17A expression and secretion in autoimmune diseases, yet their specific role in GD, especially within CD4 + T lymphocytes, are not well understood. In this study, a circRNA, circPHF16 (hsa_circ_0090364) was found to be highly expressed in the peripheral blood mononuclear cells and serum of GD patients. In vitro experiments in Jurkat T cells revealed that silencing of circPHF16 suppressed IL-17A expression and secretion, while overexpression of circPHF16 had the opposite effect. Furthermore, bioinformatics analysis demonstrated a circPHF16/miR-378a-3p/IL6ST pathway, in which circPHF16 regulates IL6ST expression, which, in turn, influences IL-17A expression and secretion by interacting with miR-378a-3p. In vivo studies in a mouse model of GD showed similar trends in molecular expression levels, consistent with competitive endogenous RNA interactions. Together the results of the study identify circPHF16 as a potential target in the development of new strategies for GD diagnosis and treatment, and thus, offer a theoretical foundation for clinical therapeutic approaches in GD.

Autoimmune thyroid diseases (AITDs), mainly including Graves\' disease (GD) and Hashimoto\'s thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane\'s Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.

BACKGROUND: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue.
METHODS: The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses.
RESULTS: Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age.
CONCLUSIONS: In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age.
UNASSIGNED: HINTERGRUND: Die endokrine Orbitopathie (EO) ist eine Autoimmunerkrankung, meist mit einer Schilddrüsenerkrankung assoziiert, die zu Entzündungen, Adipogenese und Fibrose führt. Die Schwere der EO kann zwischen Individuen stark variieren, was es schwierig macht, den natürlichen Verlauf der Erkrankung genau vorherzusagen. Dies ist jedoch wichtig, um die Behandlung individuell anpassen zu können. Ziel dieser Studie war es, die klinischen Merkmale, den Verlauf, die Behandlung und die Prognose von EO-Patienten unter 50 Jahren mit älteren Patienten zu vergleichen. Für dieses Sonderheft wurden dabei die Ergebnisse der Arbeit mit Schwerpunkt auf die Motilität reproduziert.
UNASSIGNED: Analysiert wurden die Krankenakten einer zufällig ausgewählten Stichprobe von 1000 Patienten aus unserer EO-Datenbank in Essen (GODE), die 4260 Patienten umfasst. Die Patienten wurden in 2 Gruppen unterteilt: Gruppe 1 (≤ 50 Jahre) und Gruppe 2 (> 50 Jahre). Nur Patienten mit vollständigen Datensätzen wurden in die weitere statistische Analyse einbezogen.
UNASSIGNED: Jüngere Patienten (n = 484) waren signifikant häufiger mit milder EO (53 % vs. 33 %, p < 0,0001) vorstellig, während ältere Patienten (n = 448) häufiger an moderaten bis schweren Formen litten (44 % vs. 64 %, p < 0,0001). Ältere Patienten zeigten schwerwiegendere Strabismus‑, Motilitäts- und klinische Aktivitätsscores (5,9 vs. 2,3 PD/310° vs. 330°, beide p < 0,0001, CAS: 2,1 vs. 1,7, p = 0,001). Proptosis und das Auftreten einer Optikuskompression zeigten keinen signifikanten Unterschied zwischen den Gruppen (jeweils 3 %). Die multiple logistische Regression ergab, dass der Bedarf an einer zweiten Augenmuskeloperation am stärksten mit einer vorherigen Dekompression assoziiert war (OR = 0,12, 95 % CI: 0,1–0,2, p < 0,0001), gefolgt von orbitaler Bestrahlung und Alter.
CONCLUSIONS: Zusammenfassend präsentieren sich jüngere EO-Patienten mit milderen klinischen Merkmalen wie einer geringeren Rate an restriktiven Motilitätsstörungen und weniger ausgeprägten Entzündungszeichen. Ältere Patienten benötigen daher häufiger Steroide, Bestrahlung sowie Lid- und Augenmuskeloperationen. Das Risiko für eine Optikuskompression und die Notwendigkeit einer zweiten Augenmuskeloperation sind jedoch nicht bzw. nur geringfügig mit dem Alter assoziiert.

UNASSIGNED: This meta-analysis examines peak systolic velocities (PSVs) in thyroid arteries as potential biomarkers for thyroid disorders, which includes treated and untreated Graves\' disease(GD) and destructive thyrotoxicosis(DT).
UNASSIGNED: A search across databases including PubMed, Google Scholar, Embase, and Web of Science identified studies assessing peak systolic flow velocity in the inferior thyroid artery (ITA-PSV) and superior thyroid artery (STA-PSV) diagnostic efficacy in GD and DT.And the search was restricted to publications in the English language.The analysis compared STA-PSV and ITA-PSV across patient groups, evaluating intra-group variances and synthesizing sensitivity and specificity data.
UNASSIGNED: The analysis covered 18 studies with 1276 GD, 564 DT patients, and 544 controls. The difference of STA-PSV between GD group, DT group and normal group and the difference of ITA-PSV were analyzed in subgroups, and there was no statistical significance between subgroups when comparing any two groups. Normal subjects displayed intra-group ITA-PSV and STA-PSV differences with established cut-off values of 20.33 cm/s (95% CI, 17.48-23.18) for ITA-PSV and 25.61 cm/s (95% CI, 20.37-30.85) for STA-PSV. However, no significant intra-group differences were observed in the STA-PSV and ITA-PSV cut-off values among groups with GD or DT. The combined cut-off values for these patient groups and normal subjects were 68.63 cm/s (95% CI, 59.12-78.13), 32.08 cm/s (95% CI, 25.90-38.27), and 23.18 cm/s (95% CI, 20.09-26.28), respectively. The diagnostic odds ratio(DOR) for these values was 35.86 (95% CI, 18.21-70.60), and the area under the summary receiver operating characteristic (SROC) curve was 0.91, with a sensitivity estimate of 0.842 (95% CI, 0.772-0.866).
UNASSIGNED: PSVs in thyroid arteries are useful diagnostic tools in distinguishing DT from GD. A PSV above 68.63 cm/s significantly improves GD diagnosis with up to 91% efficacy. No notable differences were found between superior and inferior thyroid arteries in these conditions.

Orbital radiotherapy for Graves\' ophthalmopathy is an example of non-oncological radiotherapy. First introduced in the 1930s, this treatment has become widely used since the 1980s with several studies showing proof of both effectiveness and safety: a decrease of soft tissue involvement in 70 to 80% of patients and an improvement of ocular mobility in 30 to 80% of patients. Nowadays, it\'s one of the second line treatment options recognized by the European Group on Graves\' orbitopathy in the management of a moderate to severe and active disease after failure of glucocorticoids. In that setting, orbital radiotherapy should be combined with glucocorticoids. To our knowledge, there are no practical recommendations on how orbital radiotherapy should be planned and conducted for Graves\' ophthalmopathy. Optimal dose is not defined however the most frequent regimen consists of 20Gy in ten fractions of 2Gy, though other options may yield better results. Lastly, the use of modern technique of radiotherapy such as intensity-modulated radiation therapy may allow a better sparing of organs at risk compared to three-dimensional radiotherapy using lateral opposing fields.

BACKGROUND: The association between psoriasis and hyperthyroidism/hypothyroidism remains inconclusive, with conflicting findings in prior studies.
OBJECTIVE: This study employs Mendelian randomization methods to assess the potential relationship.
METHODS: Given the inability to accurately observe the link between psoriasis and thyroid dysfunction, we prioritized utilizing known genetic variants to investigate the potential impacts of the disease.We analyzed data from genome-wide association studies (GWASs), FinnGen, and UK Biobank to extract information on psoriasis, hyperthyroidism, and hypothyroidism. Three MR approaches (MR Egger, weighted median, and inverse variance weighted) were used to scrutinize the causal link.
RESULTS: Our analysis revealed no correlation between psoriasis and hyperthyroidism/hypothyroidism. However,  vulgar psoriasis and guttate psoriasis were associated with hypothyroidism/myxedema (IVW odds ratio (OR) = 1.00, 95% confidence interval (CI) = 1.00-1.00, P = 2.53E-03), and Graves\' disease (IVW OR = 0.86, 95% CI = 0.72-1.01, P = 4.75E-02).In a subsequent analysis, we observed that hypothyroidism with mucinous edema showed no correlation with Graves\' disease in the opposite(P = 9.33E-01).
CONCLUSIONS: This MR analysis suggests no association between psoriasis and thyroid dysfunction, but highlights associations of vulgar/guttate psoriasis with hypothyroidism/myxedema and Graves\' disease. In clinical practice, diagnosing guttate psoriasis requires vigilance for associated risks from hypothyroidism and Graves\' disease. For patients with both vulgar psoriasis and hypothyroidism, careful monitoring for mucinous edema is crucial, as it may signal a hypothyroid crisis.

OBJECTIVE: This meta-analysis aims to analyze the relationship between serum vitamin D (VD) levels and Graves\' disease (GD).
METHODS: We conducted a search for publications on VD and GD in the English language. Our search encompassed databases such as PubMed, Embase, Web of Science, and the Cochrane Library, covering publications available through August 2023. A meta-analysis was performed using Cochrane RevMan 5.4 software. The standardized mean difference (SMD) and 95% confidence interval (CI) were used for outcome calculation. We used R software to test for publication bias.
RESULTS: Twelve studies were selected, comprising 937 (22.4%) cases with GD and 3254 (77.6%) controls. The overall meta-analysis revealed that patients with GD are significantly more likely to have low VD levels (SMD = - 0.66; 95% CI: -1.05, - 0.27; p = 0.001) than those in the control group. Egger\'s test results indicated no publication bias (p = 0.0791). These studies exhibited a high degree of heterogeneity (chi-square = 205.86, p < 0.00001; I2 = 95%). Subgroup analysis was conducted based on assay method, geographic location, and mean age of the case group to explore the heterogeneity sources. Assay methods and geographic locations were identified as potential heterogeneity sources. Based on the mean age, there were no statistically significant differences found in the subgroup analysis of the included studies.
CONCLUSIONS: There is promising evidence that low serum VD levels may increase the risk of GD. Further rigorous and long-term trials are needed to explore the role of VD in the onset and treatment of GD.

Objectives: Graves\' disease (GD) is the most common cause of hyperthyroidism. Antithyroid drugs (ATDs) are the first-line treatment, but when discontinued, >50% of patients experience relapses. Conventional definitive treatment options include surgery and radioiodine therapy (RAI), each with its own disadvantages. Radiofrequency ablation (RFA) achieved promising short-term remission rates in a previous pilot study. The current study reports our experience of using RFA to treat relapsed GD in the largest cohort of patients with a longer follow-up period. Methods: This single-arm prospective study recruited consecutive patients aged ≥18 with persistent/relapsed GD requiring ATD from two tertiary endocrine surgery centers. Those with compressive goiter, suspected thyroid malignancy, moderate-to-severe Graves\' ophthalmopathy, preference for surgery/RAI, or pregnancy were excluded. Eligible patients received ultrasound-guided RFA to the entire bulk of the thyroid gland. ATDs were discontinued afterward, and thyroid function tests were monitored bimonthly. The primary outcome was the disease remission rate at 24 months follow-up after single-session RFA, defined as being biochemically euthyroid or hypothyroid without ATD. Secondary outcomes were complication rates. Results: Of the 100 patients considered, 30 (30.0%) patients were eligible and received RFA. Most were female patients (93.3%). The median total thyroid volume was 23 mL (15.9-34.5). All completed 24 months follow-up. After single-session RFA, disease remission rates were 60.0% at 12 months and 56.7% at 24 months. Among the 13 patients with relapse after RFA, 9 (69%) required a lower ATD dose than before RFA; 2 received surgery without complications. Total thyroid volume was the only significant factor associated with relapse after RFA (odds ratio 1.054, confidence interval 1.012-1.099, p = 0.012). At 24 months, RFA led to disease remission in 100% of the 9 patients with a total thyroid volume <20 mL and 35% of patients with a total thyroid volume ≥20 mL (p = 0.007). There was no vocal cord palsy, skin burn, hematoma, or thyroid storm after RFA. Conclusions: In a highly selected group of patients with relapsed GD and predominantly small thyroid glands, single-session RFA may achieve disease remission. Smaller total thyroid volume may be a favorable factor associated with disease remission after RFA. The results of this study need to be confirmed with a long-term clinical trial. Clinical Trial Registration: This study is registered at www.clinicaltrial.gov with identifier NCT06418919.