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JAMA Oct 2023Overt hyperthyroidism, defined as suppressed thyrotropin (previously thyroid-stimulating hormone) and high concentration of triiodothyronine (T3) and/or free thyroxine... (Review)
Review
IMPORTANCE
Overt hyperthyroidism, defined as suppressed thyrotropin (previously thyroid-stimulating hormone) and high concentration of triiodothyronine (T3) and/or free thyroxine (FT4), affects approximately 0.2% to 1.4% of people worldwide. Subclinical hyperthyroidism, defined as low concentrations of thyrotropin and normal concentrations of T3 and FT4, affects approximately 0.7% to 1.4% of people worldwide. Untreated hyperthyroidism can cause cardiac arrhythmias, heart failure, osteoporosis, and adverse pregnancy outcomes. It may lead to unintentional weight loss and is associated with increased mortality.
OBSERVATIONS
The most common cause of hyperthyroidism is Graves disease, with a global prevalence of 2% in women and 0.5% in men. Other causes of hyperthyroidism and thyrotoxicosis include toxic nodules and the thyrotoxic phase of thyroiditis. Common symptoms of thyrotoxicosis include anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, and heat intolerance. Patients with Graves disease may have a diffusely enlarged thyroid gland, stare, or exophthalmos on examination. Patients with toxic nodules (ie, in which thyroid nodules develop autonomous function) may have symptoms from local compression of structures in the neck by the thyroid gland, such as dysphagia, orthopnea, or voice changes. Etiology can typically be established based on clinical presentation, thyroid function tests, and thyrotropin-receptor antibody status. Thyroid scintigraphy is recommended if thyroid nodules are present or the etiology is unclear. Thyrotoxicosis from thyroiditis may be observed if symptomatic or treated with supportive care. Treatment options for overt hyperthyroidism from autonomous thyroid nodules or Graves disease include antithyroid drugs, radioactive iodine ablation, and surgery. Treatment for subclinical hyperthyroidism is recommended for patients at highest risk of osteoporosis and cardiovascular disease, such as those older than 65 years or with persistent serum thyrotropin level less than 0.1 mIU/L.
CONCLUSIONS AND RELEVANCE
Hyperthyroidism affects 2.5% of adults worldwide and is associated with osteoporosis, heart disease, and increased mortality. First-line treatments are antithyroid drugs, thyroid surgery, and radioactive iodine treatment. Treatment choices should be individualized and patient centered.
Topics: Adult; Female; Humans; Male; Pregnancy; Antithyroid Agents; Graves Disease; Hyperthyroidism; Iodine; Iodine Radioisotopes; Osteoporosis; Thyroid Neoplasms; Thyroid Nodule; Thyroiditis; Thyrotoxicosis; Thyrotropin; Thyroxine; Weight Loss
PubMed: 37847271
DOI: 10.1001/jama.2023.19052 -
Acta Medica Indonesiana Apr 2018Graves' disease is an autoimmune disorder which affect thyroid gland. Graves' disease is the most common cause of hyperthyroidism and thyrotoxicosis. Understanding of... (Review)
Review
Graves' disease is an autoimmune disorder which affect thyroid gland. Graves' disease is the most common cause of hyperthyroidism and thyrotoxicosis. Understanding of disease pathophysiology, diagnostic and treatment strategies, and prevention of disease relapse are important for all clinicians especially internal medicine specialist to give optimal and comprehensive management for Graves' disease patients. This article highlights clinical points to treat Grave's disease patients from reviews and latest guidelines from American Thyroid Association (ATA), European Thyroid Association (ETA), and Japan Thyroid Association/ Japan Endocrine Society.
Topics: Graves Disease; Humans; Practice Guidelines as Topic; Recurrence; Societies, Medical
PubMed: 29950539
DOI: No ID Found -
Endocrinology and Metabolism Clinics of... Jun 2022The management of hyperthyroidism and extrathyroidal manifestations of Graves disease remains complex. Considerations that include patient preference, age, comorbidity,... (Review)
Review
The management of hyperthyroidism and extrathyroidal manifestations of Graves disease remains complex. Considerations that include patient preference, age, comorbidity, pregnancy, tobacco smoking, and social determinants of health must all be weaved into a cohesive management plan. A multidisciplinary team is required to manage all aspects of Graves disease, particularly thyroid eye disease, for which new therapeutic options are now available.
Topics: Antithyroid Agents; Female; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Pregnancy; Thyroidectomy
PubMed: 35662442
DOI: 10.1016/j.ecl.2021.12.004 -
The New England Journal of Medicine May 2017Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.
METHODS
We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed.
RESULTS
In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.
CONCLUSIONS
In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Diabetes Complications; Double-Blind Method; Exophthalmos; Female; Graves Ophthalmopathy; Humans; Hyperglycemia; Immunologic Factors; Intention to Treat Analysis; Logistic Models; Male; Middle Aged; Quality of Life; Receptor, IGF Type 1
PubMed: 28467880
DOI: 10.1056/NEJMoa1614949 -
Indian Journal of Ophthalmology Jul 2023Infections of orbit and periorbita are frequent, leading to significant morbidity. Orbital cellulitis is more common in children and young adults. At any age, infection... (Review)
Review
Infections of orbit and periorbita are frequent, leading to significant morbidity. Orbital cellulitis is more common in children and young adults. At any age, infection from the neighboring ethmoid sinuses is a likely cause and is thought to result from anatomical characteristics like thin medial wall, lack of lymphatics, orbital foramina, and septic thrombophlebitis of the valveless veins between the two. Other causes are trauma, orbital foreign bodies, preexisting dental infections, dental procedures, maxillofacial surgeries, Open Reduction and Internal Fixation (ORIF), and retinal buckling procedures. The septum is a natural barrier to the passage of microorganisms. Orbital infections are caused by Gram-positive, Gram-negative organisms and anaerobes in adults and in children, usually by Staphylococcus aureus or Streptococcus species. Individuals older than 15 years of age are more likely to harbor polymicrobial infections. Signs include diffuse lid edema with or without erythema, chemosis, proptosis, and ophthalmoplegia. It is an ocular emergency requiring admission, intravenous antibiotics, and sometimes surgical intervention. Computed tomography (CT) and magnetic resonance imaging (MRI) are the main modalities to identify the extent, route of spread from adjacent structures, and poor response to intravenous antibiotics and to confirm the presence of complications. If orbital cellulitis is secondary to sinus infection, drainage of pus and establishment of ventilation to the sinus are imperative. Loss of vision can occur due to orbital abscess, cavernous sinus thrombosis, optic neuritis, central retinal artery occlusion, and exposure keratopathy, and possible systemic sequelae include meningitis, intracranial abscess, osteomyelitis, and death. The article was written by authors after a thorough literature search in the PubMed-indexed journals.
Topics: Child; Young Adult; Humans; Orbital Cellulitis; Abscess; Orbit; Exophthalmos; Anti-Bacterial Agents
PubMed: 37417106
DOI: 10.4103/IJO.IJO_3283_22 -
Nature Reviews. Endocrinology Feb 2020Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative... (Review)
Review
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.
Topics: Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Disease Management; Drug Therapy, Combination; Glucocorticoids; Graves Ophthalmopathy; Humans
PubMed: 31889140
DOI: 10.1038/s41574-019-0305-4 -
Clinical & Experimental Optometry Jan 2017Thyroid eye disease is a multifactorial autoimmune disease with a spectrum of signs and symptoms. Oftentimes, the diagnosis of thyroid eye disease is straightforward,... (Review)
Review
Thyroid eye disease is a multifactorial autoimmune disease with a spectrum of signs and symptoms. Oftentimes, the diagnosis of thyroid eye disease is straightforward, based upon history and physical examination. The purpose of this review is to assist the eye-care practitioner in staging the severity of thyroid eye disease (mild, moderate-to-severe and sight-threatening) and correlating available treatment modalities. Eye-care practitioners play an important role in the multidisciplinary team by assessing functional vision while also managing ocular health.
Topics: Graves Ophthalmopathy; Humans; Quality of Life
PubMed: 27701774
DOI: 10.1111/cxo.12472 -
Ophthalmology Apr 2022To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare.
DESIGN
The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial.
PARTICIPANTS
Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC.
METHODS
OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks.
MAIN OUTCOME MEASURES
Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life.
RESULTS
Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment.
CONCLUSIONS
Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.
Topics: Antibodies, Monoclonal, Humanized; Diplopia; Exophthalmos; Graves Ophthalmopathy; Humans
PubMed: 34688699
DOI: 10.1016/j.ophtha.2021.10.017 -
Frontiers in Immunology 2023Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective... (Review)
Review
Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. β-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.
Topics: Humans; Graves Ophthalmopathy; Receptors, Thyrotropin; Signal Transduction; Receptors, G-Protein-Coupled; Phenotype
PubMed: 36742308
DOI: 10.3389/fimmu.2023.1062045 -
Frontiers in Cellular and Infection... 2021Graves' disease (GD) is a clinical syndrome with an enlarged and overactive thyroid gland, an accelerated heart rate, Graves' orbitopathy (GO), and pretibial myxedema... (Review)
Review
Graves' disease (GD) is a clinical syndrome with an enlarged and overactive thyroid gland, an accelerated heart rate, Graves' orbitopathy (GO), and pretibial myxedema (PTM). GO is the most common extrathyroidal complication of GD. GD/GO has a significant negative impact on the quality of life. GD is the most common systemic autoimmune disorder, mediated by autoantibodies to the thyroid-stimulating hormone receptor (TSHR). It is generally accepted that GD/GO results from complex interactions between genetic and environmental factors that lead to the loss of immune tolerance to thyroid antigens. However, the exact mechanism is still elusive. Systematic investigations into GD/GO animal models and clinical patients have provided important new insight into these disorders during the past 4 years. These studies suggested that gut microbiota may play an essential role in the pathogenesis of GD/GO. Antibiotic vancomycin can reduce disease severity, but fecal material transfer (FMT) from GD/GO patients exaggerates the disease in GD/GO mouse models. There are significant differences in microbiota composition between GD/GO patients and healthy controls. , , and often increase in GD patients. The commonly used therapeutic agents for GD/GO can also affect the gut microbiota. Antigenic mimicry and the imbalance of T helper 17 cells (Th17)/regulatory T cells (Tregs) are the primary mechanisms proposed for dysbiosis in GD/GO. Interventions including antibiotics, probiotics, and diet modification that modulate the gut microbiota have been actively investigated in preclinical models and, to some extent, in clinical settings, such as probiotics () and selenium supplements. Future studies will reveal molecular pathways linking gut and thyroid functions and how they impact orbital autoimmunity. Microbiota-targeting therapeutics will likely be an essential strategy in managing GD/GO in the coming years.
Topics: Animals; Gastrointestinal Microbiome; Graves Disease; Graves Ophthalmopathy; Humans; Mice; Quality of Life; Receptors, Thyrotropin
PubMed: 35004341
DOI: 10.3389/fcimb.2021.739707