Hyperthyroid Graves Research Articles

Long-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ Disease

Clinical ThyroidologyVol. 35, No. 02 HyperthyroidismFree AccessLong-Term, Low-Dose Methimazole Therapy Is Effective in Protecting against Relapses in Graves’ DiseaseGiuseppe BarbesinoGiuseppe BarbesinoThyroid Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.Search for more papers by this authorPublished Online:8 Feb 2023https://doi.org/10.1089/ct.2023;35.54-56AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Review of: Lertwattanarak R, Kunavisarut T, Sriussadaporn S 2022 Benefits of Long-term continuation of low-dose methimazole therapy in the prevention of recurrent hyperthyroidism in Graves' hyperthyroid patients: A randomized prospective controlled study. Int J Endocrinol 2022:1705740. PMID: 36267362.SUMMARYBackgroundThe management of Graves’ disease (GD) hyperthyroidism has been evolving over the past two decades. The traditional standard of care suggested treatment with methimazole for 12 to18 months followed by radioactive iodine (RAI) treatment or surgery (1) in patients not achieving remission, where remission is defined as the ability to maintain euthyroidism after discontinuation of methimazole. This recommendation is supported by the recognition that longer courses of antithyroid drugs do not increase the rate of lasting remissions after discontinuation (2). This strategy has become less attractive owing to increasing evidence that RAI can cause or worsen thyroid eye disease (3) on the one hand and on the other to concerns about quality of life with hypothyroidism, even when thyroid hormone is optimally replaced (4). This study (5) was conducted to understand whether long-term therapy with low-dose methimazole could protect GD patients from relapses of hyperthyroidism.MethodsThis was a randomized controlled study in adult GD patients who had been euthyroid while taking methimazole for at least 6 months prior to randomization. The patients were randomly assigned to either continue methimazole at low doses (2.5–5 mg daily) or discontinue methimazole. The subjects’ thyroid function was then monitored every 6 months for 36 months. Standard diagnostic criteria for GD were adopted for inclusion. Patients who had already experienced a relapse were excluded. The primary outcome measured was the cumulative incidence of relapsing hyperthyroidism in the two groups.ResultsNinety-two patients were randomly assigned to the discontinuation group and 92 to the low-dose treatment group. Except for minor differences, the two groups were very similar for most epidemiologic parameters (86% female vs. 84% and mean [±SD] age, 39.9±10.9 vs. 42.2±14.9 years), indicating a reliable randomization process. The average duration of methimazole therapy prior to randomization was 37 months in the discontinuation group and 32 months in the low-dose group (not statistically different). In the discontinuation group, the number of relapses increased progressively and uniformly during the study time, reaching 41.2% at 36 months. In the low-dose group, the rate of relapse was 11%, and it was reached 18 months after randomization, with no additional relapses after that time. There were no recorded side effects during the study period.ConclusionsIn patients with GD, long-term treatment with 2.5 to 5 mg of methimazole daily is safe and effective in preventing the relapse of hyperthyroidism. This strategy is a valid alternative to RAI therapy and thyroidectomy in patients who want neither and yet worry about relapses of hyperthyroidism.COMMENTARYGraves’ disease, like many other autoimmune diseases, is often characterized by flares and remissions (6). Patients taking methimazole are typically treated for 12 to 18 months, after which a discontinuation trial is performed, in the hope of a lasting remission. Measuring serum TSH receptor antibodies (TRAbs) before antithyroid drug discontinuation helps to identify patients who are at high risk for early relapses in the 3 to 6 months after discontinuation (7). However, 20 to 30% of patients negative for TRAbs will still relapse months to years after the discontinuation (8,9). This observation, and mounting diffidence towards RAI therapy and surgery, has led to increased interest for long-term methimazole treatment. The data so far available have been mostly retrospective, or have addressed only select patient groups (for example, patients who already have experienced a relapse) (10). Like other endocrinologists, I have been advising some of my patients with GD who appear to be “currently” in remission, to continue methimazole indefinitely at very low doses, typically 2.5 mg daily. This article provides good-quality evidence to support such a practice, which I will continue to apply, especially to older patients and patients who had experienced particularly intense symptoms from the hyperthyroidism at the time of its first presentation.Disclosures: The author has no relevant conflicts of interest to declare.

Lithium as an alternative option in thionamide-resistant Graves’ disease

Conventional treatments for Graves’ disease include thionamides, radioactive iodine therapy (RAI), and thyroidectomy. Occasionally, patients may develop resistance to thionamides and may require additional treatment. We present the case of an adolescent girl with thionamide-resistant Graves’ disease who was successfully treated with lithium and subsequent RAI after stabilizing her thyroid hormone levels. Following RAI, the patient developed hypothyroidism, and thyroxine replacement therapy was initiated. This case highlights the potential of lithium as a safe and effective alternative for controlling hyperthyroidism in Graves’ disease and its role in preparing patients for more definitive treatment.

Worsening of pretibial myxedema following radioiodine treatment for hyperthyroid Graves’ disease

The development of pretibial myxedema following RAI treatment has been occasionally reported from the probable influences of thyrotropin receptor antibodies (TRAbs) similar to the RAI-associated GO. Herein, we report an interesting case of the fluctuating clinical course of pretibial myxedema following treatments of hyperthyroid Graves’ disease for over 3 years.

Ethylenediaminetetraacetic Acid-induced Pseudothrombocytopenia in Association with Graves Hyperthyroidism

Ethylenediaminetetraacetic Acid-induced Pseudothrombocytopenia in Association with Graves Hyperthyroidism

Use of thyroid stimulating hormone receptor antibodies test in an outpatient endocrinology clinic fordifferential diagnosis ofhyperthyroidism

Objective. Antibodies (Abs) to the thyroid stimulating hormone receptor (TSHR) play an important role in the pathogenesis of autoimmune thyroid disease (AITD). We define the complex terminology that has arisen to describe TSHR-Abs, and discuss significant advances that have been made in the development of clinically useful TSHR-Abs assays. Methods. Literature review and discussion. Results. TSHR-Abs may mimic or block the action of TSH or be functionally neutral. Stimulating TSHR-Abs are specific biomarkers for Graves’ disease and responsible for many of its clinical manifestations. TSHR-Abs may also be found in patients with Hashimoto thyroiditis in whom they may contribute to the hypothyroidism. Measurement of TSHR-Abs in general, and functional Abs in particular is recommended for the rapid diagnosis of Graves’ disease, differential diagnosis and management of patients with AITD, especially during pregnancy, and in AITD patients with extrathyroidal manifestations such as orbitopathy. Measurement of TSHR-Abs can be done with either immunoassays that detect specific binding of Abs to the TSHR or cell-based bioassays, which also provide information on their functional activity and potency. Application of molecular cloning techniques has led to significant advances in methodology that have enabled the development of clinically useful bioassays. When ordering TSHR-Abs, clinicians should be aware of the different tests available and how to interpret results based on which assay is performed. The availability of an international standard and continued improvement in bioassays will help promote their routine performance by clinical laboratories and provide the most clinically useful TSHR-Abs results. Conclusion. Measurement of TSHR-Abs in general, and functional (especially stimulating) Abs in particular is recommended for the rapid diagnosis, differential diagnosis, and management of patients with Graves hyperthyroidism, related thyroid eye disease, during pregnancy, as well as in Hashimoto thyroiditis patients with extrathyroidal manifestations and/or thyroid-binding inhibiting immunoglobulin positivity.

The Use of Thionamides in Graves' Disease Treatment: A Literature Review

Graves disease is an autoimmune disorder affecting the thyroid gland with a wide range of clinical manifestations. One of the most notable signs of Graves disease is hyperthyroidism. In general, there are three options in treating Graves hyperthyroidism: pharmacological therapy, thyroidectomy, and radioactive iodine therapy. Thionamides, which consist of methimazole, carbimazole, and propylthiouracil, are considered to be the most prominent pharmacological therapy of Graves disease. Among these drugs, propylthiouracil is the least favored because of its adverse effects.

HYPOTHYROID GRAVES DISEASE – REPORT OF CASE WITH REVIEW OF LITERATURE

Background: TAO is seen in about 80% of patients with Graves' disease; it may also occur in patients with thyroid cancers or autoimmune hypothyroid due to Hashimoto's thyroiditis in about 10% of TAO, while individuals with no thyroid disease were found to have orbital lesions in 10 percent of total cases. A 46-year- Case presentation: old male patient who is a known case of hypertension and hypothyroidism attended to medical OPD of SVS Hospital with foreign body sensation in both eyes, bulging of eyeballs and excessive watering in both eyes. He was on 40 mg of telmisartan and 50 micrograms of thyroxine daily for about 6 months. Pulse was 56 per minute and a blood pressure of 146/96 mmHg. The patient was treated with methyl prednisolone initially weekly intravenous doses followed by oral medication along with increased levothyroxine to 150 micrograms, selenium and statins. He was symptomatically better after 6 weeks of therapy. Summary and conclusion: Hypothyroid grave disease is very rare that too in a male patient. Treatment does not differ from Hyperthyroid Graves' disease except the supplementation of levothyroxine instead of anti-thyroid measures. The literature has been reviewed.

ODP531 Worsening of pretibial myxedema following repeated doses of radioiodine treatment in a patient with hyperthyroid Graves’ disease

Abstract Introduction The development of new-onset pretibial myxedema following radioiodine (RAI) treatment has been occasionally reported from the probable influences of thyrotropin receptor antibodies (TRAbs) similar to the RAI-associated Graves’ ophthalmopathy (GO). However, the worsening of pre-existing pretibial myxedema after RAI treatment has never been reported. Herein, we report an interesting case of fluctuating clinical course of pretibial myxedema following treatments of hyperthyroid Graves’ disease for over 3 years. Case Report A 49-year-old Thai woman with underlying hyperthyroid Graves’ disease with GO and pretibial myxedema for 1 year came to our hospital for relapsed hyperthyroidism and active, moderate-to-severe GO in 2019. A plague form of pretibial myxedema with indurated hyperpigmented lesion was found on both legs. Intravenous pulse methylprednisolone (IVMP) was given to control her active GO. Both GO and pretibial myxedema significantly improved after IVMP treatments. Then, RAI (30 mCi) was administered at 1 month later as a definitive treatment. Low dose of oral prednisolone (20 mg/ day) was also given before and after RAI treatment. Transient hypothyroidism developed at 4 months post-RAI and the estimated weights of the thyroid decreased from 60 grams to 30 grams. However, hyperthyroidism relapsed again within 6 months post-RAI treatment. At that time, her pretibial myxedema flared up slightly but her GO was still inactive. Eventually, a second dose of RAI (20 mCi) was given at 11 months apart from the first RAI administration. Low dose of oral prednisolone was also given. She developed post-radiation thyroiditis at 4 months after RAI with worsening of pretibial myxedema and mild exacerbation of GO. Topical corticosteroid ointment was given for pretibial myxedema and only local supportive measures was applied to treat GO. Finally, permanent hypothyroidism was achieved at 6 months after the second course of RAI. Currently, her pretibial myxedema is stable without further flareup. Conclusion Our case highlights the potential of RAI treatment to precipitate both GO and pretibial myxedema in patients with pre-existing skin lesions. Low dose prednisolone prophylaxis might not ensure preventative effect in exacerbation. Whether the risk of worsening of pretibial myxedema is higher in patients with persistent hyperthyroidism requiring a second dose of RAI is a question that warrants further studies. Presentation: No date and time listed

PSAT271 The Impact of Maternal Autoimmune thyroid disease on neonatal thyroid conditions in Urban City Population

Abstract Background There is a wide spectrum of maternal autoimmune thyroid disorders (AITD) in pregnancy ranging from Graves’ hyperthyroidism (GD) to Hashimoto thyroiditis (HT), both of which share similar immunological properties. A variety of maternal thyroid autoantibodies can cross transplacentally which may potentially cause varying degrees of neonatal thyroid dysfunction. Objective To study the neonatal outcomes of thyroid function in mothers with AITD in urban setting. Methods Mothers with AITD and newborns were included for retrospective analysis over 12 months. AITD encompassed all mothers diagnosed prior/during pregnancy with either HT or GD. Results Maternal Data: A total of 147 mothers were included (HT 87%, GD 13.6%). Among mothers with HT, thyroid auto-Abs were tested in 51/127 (40%) mothers, of which 32/47(68%) were positive for TPO, 11/21(2%) positive for ATA, 2/6(33%) positive for TSI, 1/2 (50%) positive for TRAb. L-Thyroxine was administered to 90% HT mothers. Among mothers with GD, thyroid auto-Abs were tested in 17/20 (85%) mothers, of which 7/17(41%) were positive for TSI, 6/10(60%) positive for TRAb, 7/14(50%) were positive for TPO, 3/5 positive for ATA. Methimazole (MMI) was administered to 25% GD mothers. Neonatal outcome: A total of 150 neonates (115 FT, 35 PT) were born to AITD mothers. Newborn screen was abnormal in 2 infants. 7 neonates (4.6%) were tested for thyroid auto-Abs, of which 1/2 was positive for TPO, 1/2 positive for ATA, 3/3 negative for TSI, 5/5 negative for TRAb. Serum TFTs were performed in 62/150 neonates; majority 57/62(92%) were normal, 3 had mild compensated hyperthyrotropinemia (mean TSH 17.1 mIU/L, FT4 1.93 ng/dl) and were followed elsewhere. 2 neonates developed congenital hypothyroidism requiring L-Thyroxine. Infant 1: TSH 4.56mIU/L, FT4 1.1 ng/dl, TPO and ATA positive on DOL7 and had ectopic thyroid, infant born to TPO positive HT mother on Synthroid. Infant 2: TSH 149.5mIU/L, FT4 0.8 ng/dl, TSI negative on DOL7 and had hyperemic thyroid, born to TSI, TPO and TRAb positive GD mother on MMI. Overall, only 3.3% of neonates had evidence of thyroid function abnormality which may have either been transient or permanent. Conclusion Although rare, mothers with AITD might potentially impair neonatal thyroid function. This may be due to various thyroid auto-Abs or anti- thyroid medication that cross transplacentally. Maternal history of AITD should therefore raise suspicion to screen neonates and thus warrants continued vigilance. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Benefits of Long-Term Continuation of Low-Dose Methimazole Therapy in the Prevention of Recurrent Hyperthyroidism in Graves' Hyperthyroid Patients: A Randomized Prospective Controlled Study.

Background The long-term continuation of the low-dose antithyroid drug (ATD) beyond the standard duration of ATD therapy of 12–18 months to prevent recurrent hyperthyroidism (RH) is recommended with low quality of evidence. Objectives To examine whether long-term continuation of low-dose ATD beyond the recommended duration of treatment would provide a benefit in the prevention of RH in patients with Graves' hyperthyroidism (GH) who achieved euthyroid status with a standard course of ATD therapy. Methods A 36-month prospective randomized controlled study was conducted in 184 patients who had first diagnosed GH and were treated with a standard regimen of ATD therapy using methimazole (MMI) until achieving euthyroidism that was stably maintained for at least 6 months with a low-dose of (2.5–5 mg/day) MMI. All patients had neither a history of adverse effects from MMI, recurrent GH, severe and active ophthalmopathy nor conditions known to affect thyroid function before randomization. The patients were randomized into 2 groups: one group (92 cases) was assigned to discontinue (DISCONT-MMI) and the other (92 cases) was assigned to continue low-dose MMI (CONT-MMI) that was taken at the time of enrollment. The patients in both groups were followed up at 3, 6, 12, 18, 24, 30, and 36 months. The rate of RH was compared between both groups, and the adverse effects and risk factors of RH were also studied. Results At the end of the 36-month study, 83 cases in CONT-MMI and 90 cases in DISCONT-MMI were eligible for analysis. The cumulative rates of RH in CONT-MMI were significantly lower than those in DISCONT-MMI at every follow-up time point (1.2% vs. 11.2%, 6.8% vs. 18.4%, 11.0% vs. 27.2%, 11.0% vs. 35.0%, and 11.0% vs. 41.2% at 6, 12, 18, 24, and 36 months, respectively; p < 0.01). Cox proportional hazard multivariate analysis showed that there were 2 factors independently associated with the risk of RH, including continuation of low-dose MMI therapy, which decreased the risk of RH by 3.8 times (HR = 0.26, p = 0.007, 95% CI = 0.10–0.70) and age onset of hyperthyroidism before 40 years, which increased the risk of RH by 2.9 times (HR = 2.9, p = 0.015, 95% CI = 1.23–6.88). Neither minor nor major adverse effects of low-dose MMI therapy were observed during the study period. Conclusions In Graves' hyperthyroid patients with no or nonsevere ophthalmopathy who have completed a standard course of methimazole therapy without an adverse effect and have achieved an euthyroid status that is stably maintained with low-dose methimazole, a long-term continuation of the low-dose methimazole of 2.5–5 mg daily is effective and safe in the prevention of recurrent hyperthyroidism or maintenance of euthyroid status as long as the low-dose methimazole is continued. (TCTR20170705002).

The Mediation Role of Thyrotropin Receptor Antibody in the Relationship Between Age and Severity of Hyperthyroidism in Graves' Disease.

Background: The severity of hyperthyroidism in Graves' disease (GD) has been reported to be worse in younger patients and to gradually improve with advancing age, accompanied by declining thyrotropin (TSH) receptor antibody (TRAb) values. This study was conducted to explore the extent to which the declining TRAb production may contribute to a decrease in severe hyperthyroidism with advancing age in patients with GD. Methods: This study was a cross-sectional analysis of retrospectively reviewed data. The medical records of patients newly diagnosed with GD at Ito Hospital, between January 2005 and June 2019, were examined. Patients were divided into age-stratified groups for evaluation. Multivariable logistic regression was performed to estimate the odds ratio (OR) of severe hyperthyroidism by increasing age. Mediation analyses were also conducted to quantify the association between age and declining severity of hyperthyroidism mediated through decreased TRAb productivity. Results: A total of 21,018 patients with newly diagnosed GD (3848 male and 17,170 female) were included. A correlation was observed between TRAb value and thyroid hormone values in each age-stratified group, which became weaker with an increase in age. Patients aged <40 years had a higher risk of severe hyperthyroidism (free thyroxine [fT4] level >7.0 ng/dL [n = 5616], OR [confidence interval, CI] = 1.80 [1.68-1.92]; free triiodothyronine [fT3] level >25 pg/mL [n = 4501], OR [CI] = 2.06 [1.92-2.23]) than those aged ≧40 years. In examining the relationship between age and severe hyperthyroidism, the proportion mediated through TRAb productivity was 8.5% and 8.4% using fT4 and fT3 as an outcome index, respectively. Conclusions: Declining TRAb value mediated only 8.5% of the negative association between age and severity of hyperthyroidism. The presence of other underlying mechanisms, such as the decline in the reactivity of thyrocytes to TSH stimulation, requires further investigation.

Advances in the differential diagnosis of transient hyperthyroidism in pregnancy and Graves' disease.

The occurrence of thyrotoxicosis during pregnancy is mainly attributed to gestational transient thyrotoxicosis (GTT) and Graves' disease (GD). It is important to distinguish between GTT and Graves' disease because the two diseases are treated very differently. However, a gold standard for the differential diagnosis of the two diseases is currently lacking, and the most common method of differentiation is based on past medical history and clinical presentation combined with thyroid-related antibodies. A literature search of the electronic databases PubMed, Embase, Medline, Google Scholar, Cochrane Library, China Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Full Text Database and China Biomedical CD-ROM was performed. The search period ranged from journal inception until 2022. We used the following search terms in "All fields": {["thyroid" (common field) OR "thyroid" (subject line)] OR "hyperthyroidism" (common field)} AND {["pregnancy" (title) OR "pregnancy" (title)] AND "one over" (common field)} OR {["pregnancy" (common field) OR "pregnancy" (common field) OR "pregnancy" (subject line)] AND "Graves'" (common field)}. In recent years, some clinical studies at home and abroad have proposed other meaningful differential indicators, such as thyroid stimulating hormone, chorionic gonadotropin, thyroid hormone levels and thyroid ultrasound. The differential diagnostic significance of each of these indicators is summarised here with the goal of providing a better reference for the differential diagnosis of hyperthyroidism during pregnancy in clinical practice.

High levels of thyroid hormones promote recurrence of Graves' disease via overexpression of B-cell-activating factor.

BackgroundElevated thyroid hormone (TH) levels have been suggested to be associated with the pathological progression of Graves' disease (GD). However, direct evidence from clinical studies remains unclear.MethodsPeripheral blood samples were collected from patients with or without the recurrence of Graves' hyperthyroidism (GH) and healthy donors. Thyroid tissue samples were obtained from patients with benign thyroid nodules. To assess the differentiation of autoreactive B cells, the expression of B‐cell‐activating factor (BAFF) and the proportion of CD11c+/–IgG+/− subsets of B cells stimulated by high levels of triiodothyronine (T3) in vivo and in vitro were examined by ELISA, flow cytometry, western blotting, and qRT‐PCR.ResultsSerum BAFF levels in patients with GD were significantly and positively correlated with FT3, FT4, and TRAb levels. Furthermore, the ratio of abnormally differentiated CD11c+ autoreactive B cells positively correlated with BAFF and TRAb. High levels of triiodothyronine (T3) induced BAFF overexpression in thyroid follicular cells and mononuclear cells of the normal thyroid in vitro, thereby promoting the differentiation of CD11c+IgG+ autoreactive secretory B cells (ASCs). However, the precise knockdown of BAFF expression significantly inhibited the abnormal differentiation of ASCs.ConclusionThe pathological progression of GD was prolonged and exacerbated by autoimmune positive feedback modulation caused by high TH levels. BAFF could be considered a potential target for localized thyroid immunosuppressive treatment of Graves' hyperthyroidism recurrence.

Hyperthyroidism in graves' disease and subacute thyroiditis and association with cardiovascular events

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Duration of antithyroid drug treatment may predict weight gain after radioactive iodine therapy in patients with Graves’ disease

BackgroundWeight gain post-radioiodine (RAI) treatment is observed in patients with hyperthyroid Graves’ disease. Previous studies, mostly in Caucasian patients, demonstrated excessive weight gain averaging 5–7 kg from initial presentation. AimThe aim of this study was to determine the extent and risk factors of weight gain in Thai patients with RAI-treated Graves’ disease. MethodsThis was a 5-year retrospective study of patients with hyperthyroid Graves’ disease who received RAI treatment during 2016–2020. The proportion and associated risk factors of weight gain ≥5% in patients who was followed for at least 3 months when compared with weight at RAI administration were analyzed. ResultsThere were 347 patients with Graves’ disease (females 81.0%, mean age 38.8 ± 12.1 years, BMI 23.3 ± 4.0 kg/m2) who were treated with RAI. Almost all RAI-treated patients (91.9%) eventually developed hypothyroidism. During the median follow-up period of 25 months, 73.1% of them had weight gain. The mean weight change was +2.5 ± 4.9 kgs when compared with weight at the time RAI administration and +3.4 ± 6.5 kgs when compared with recalled body weight before the onset of hyperthyroidism. The proportion of patient in the obesity class I (BMI 25.0–29.9 kg/m2) increased from 23.6% to 28.0% and obesity class II (BMI ≥30.0 kg/m2) increased from 5.2% to 8.9%. Duration of antithyroid drug treatment less than 6 months after the diagnosis of hyperthyroidism was the only factor associated with weight gain ≥5%. ConclusionsWeight gain post-RAI treatment was common, and a significant proportion of patients went on to develop obesity. Early intervention with weight management support should be employed in patients with less than 6 months of antithyroid drug treatment before RAI.

Urticarial vasculitis in a young woman with Graves hyperthyroidism.

A 29-year-old woman presented to the emergency department with dyspnea and palpitations, as well as a pruritic and painful rash that had developed over the previous 5 days. Her temperature was 38.6°C, heart rate was 174 beats/min and respiratory rate was 24 breaths/min. We observed a diffusely

Long-term methimazole therapy in Graves' hyperthyroidism and adverse reactions: a Danish multicenter study.

PurposeIn this prospective multicenter study with patients newly diagnosed with Graves’ hyperthyroidism (GH), we studied the timing and characteristics of adverse drug reactions in patients treated with anti-thyroid drugs (ATD) for up to 48 months.MethodsPatients with GH were treated with ATD until remission and hereafter with a low-dose regime to keep the patients in remission. The patients were followed with blood samples and recording of adverse events approximately every second month for the first 2 years and every third month for the following 2 years.ResultsWe included 208 patients and the patients were treated for a median of 22 (range: 0.5–49) months. Ten percent of the patients experienced adverse drug reactions and 75% of the cases occurred during the first 6 months. After 24 months, the methimazole dose was lowered to 5 mg/day, and after this time point, no further adverse drug reactions were recorded. Skin reactions were the most prominent reaction, comprising 68% of the registered reactions, and no hepatic and bonemarrow affection was recorded.ConclusionWith this study, we report the frequency, timing of occurrence, and characteristics of adverse drug reactions when treating GH with the ATD drug methimazole for up to 48 months. Long-term low-dose methimazole treatment can be a cost-effective and straightforward treatment option if adverse drug reactions such as severe hepatic and bone marrow affection are kept in mind.

Iodide-sensitive Graves' hyperthyroidism and the strategy for resistant or escaped patients during potassium iodide treatment.

The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves' hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT4 levels became low or normal in 422 patients (83.7%, KI-sensitive group) without serious side effects. Among these patients, serum TSH levels became high (n = 92, hypothyroid) or normal (n = 78) in 170 patients (33.7%) (KI-sensitive with a recovered TSH response, Group A), but remained suppressed in 252 patients (50.0%) (KI-sensitive with TSH suppression, Group B). Serum fT4 levels decreased but remained high in 82 patients (16.3%) (KI-resistant, Group C). Older patients, or those with small goiter and mild GD were more KI-sensitive with a recovered TSH response than others. Escape from KI effect occurred in 0%, 36% and 82% in Group A, B and C, respectively. Patients in Group B and C were successfully treated with additional low-dosage MMI or RI. After 2-23 years' treatment (n = 429), remission (including possible remission) and spontaneous hypothyroidism were significantly more frequent in Group A (74.3% and 11.1%, respectively,) than in Groups B (46.3% and 2.8%, respectively) or C (53.6% and 1.5%, respectively) (p < 0.0001). In conclusion, a high KI sensitivity with a recovered TSH response was observed in about a third of the patients in GD associated with a better prognosis. Additional MMI or RI therapy was effective in escaped or KI-resistant patients with suppressed TSH level.

Mechanisms in Graves Eye Disease: Apoptosis as the End Point of Insulin-Like Growth Factor 1 Receptor Inhibition.

Background: Graves' eye disease, also called Graves' orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retro-orbital inflammation and tissue expansion, involving both fibroblasts and adipocytes, resulting in periorbital edema, worsening proptosis, and muscle dysfunction with diplopia and may ultimately threaten sight. Accumulating evidence has indicated that autoantibodies to the thyrotropin receptor (TSHR), which induce the hyperthyroidism of Graves' disease, also help mediate the pathogenesis of the eye disease in susceptible individuals through TSHR expression on retro-orbital cells. Since it has long been known that the effects of insulin-like growth factor 1 (IGF-1) and thyrotropin are additive, recent clinical trials with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab; IGF-1R-B-monoclonal antibody [mAb]) have demonstrated its ability to induce significant reductions in proptosis, diplopia, and clinical activity scores in patients with GO. However, the molecular mechanisms by which such an antibody achieves this result is unclear. Methods: We have used Li-Cor In-Cell Western, Western blot, and immunohistochemistry to define levels of different proteins in mouse and human fibroblast cells. Proteomic array was also used to define pathway signaling molecules. Using CCK-8 and BrdU cell proliferation ELISA, we have analyzed proliferative response of these cells to different antibodies. Results: We now show that a stimulating TSHR antibody was able to induce phosphorylation of the IGF-1R and initiate both TSHR and IGF-1R signaling in mouse and human fibroblasts. IGF-1R-B-mAb (1H7) inhibited all major IGF-1R signaling cascades and also reduced TSHR signaling. This resulted in the antibody-induced suppression of autophagy as shown by inhibition of multiple autophagy-related proteins (Beclin1, LC3a, LC3b, p62, and ULK1) and the induction of cell death by apoptosis as evidenced by activation of cleaved caspase 3, FADD, and caspase 8. Furthermore, this IGF-1R-blocking mAb suppressed serum-induced perkin and pink mitophagic proteins. Conclusions: Our observations clearly indicated that stimulating TSHR antibodies were able to enhance IGF-1R activity and contribute to retro-orbital cellular proliferation and inflammation. In contrast, an IGF-1R-B-mAb was capable of suppressing IGF-1R signaling leading to retro-orbital fibroblast/adipocyte death through the cell-extrinsic pathway of apoptosis. This is likely the major mechanism involved in proptosis reduction in patients with Graves' eye disease treated by IGF-1R inhibition.

Graves' Autoantibodies Exhibit Different Stimulating Activities in Cultures of Thyrocytes and Orbital Fibroblasts Not Reflected by Clinical Assays.

Background: The pathogenesis of Graves' hyperthyroidism (GH) and associated Graves' orbitopathy (GO) appears to involve stimulatory autoantibodies (thyrotropin receptor [TSHR]-stimulating antibodies [TSAbs]) that bind to and activate TSHRs on thyrocytes and orbital fibroblasts. In general, measurement of circulating TSHR antibodies by clinical assays correlates with the status of GH and GO. However, most clinical measurements of TSHR antibodies use competitive binding assays that do not distinguish between TSAbs and antibodies that bind to but do not activate TSHRs. Moreover, clinical assays for TSAbs measure stimulation of only one signaling pathway, the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, in engineered cells that are not thyrocytes or orbital fibroblasts. We determined whether measuring TSAbs by a cAMP-PKA readout in engineered cells accurately reveals the efficacies of stimulation by these antibodies on thyrocytes and orbital fibroblasts. Methods: We measured TSAb stimulation of normal human thyrocytes and orbital fibroblasts from patients with GO in primary cultures in vitro. In thyrocytes, we measured secretion of thyroglobulin (TG) and in orbital fibroblasts secretion of hyaluronan (hyaluronic acid [HA]). We also measured stimulation of cAMP production in engineered TSHR-expressing cells in an assay similar to clinical assays. Furthermore, we determined whether there were differences in stimulation of thyrocytes and orbital fibroblasts by TSAbs from patients with GH alone versus from patients with GO understanding that patients with GO have accompanying GH. Results: We found a positive correlation between TSAb stimulation of cAMP production in engineered cells and TG secretion by thyrocytes as well as HA secretion by orbital fibroblasts. However, TSAbs from GH patients stimulated thyrocytes more effectively than TSAbs from GO patients, whereas TSAbs from GO patients were more effective in activating orbital fibroblasts than TSAbs from GH patients. Conclusions: Clinical assays of stimulation by TSAbs measuring activation of the cAMP-PKA pathway do correlate with stimulation of thyrocytes and orbital fibroblasts; however, they do not distinguish between TSAbs from GH and GO patients. In vitro, TSAbs exhibit selectivity in activating TSHRs since TSAbs from GO patients were more effective in stimulating orbital fibroblasts and TSAbs from GH patients were more effective in stimulating thyrocytes.