methimazole and Graves-Ophthalmopathy

Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).. Guidelines, pertinent original articles, systemic reviews, and meta-analyses.. Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.. A clear trend towards serological diagnosis and medical treatment of GD has emerged.

Topics: Antithyroid Agents; Biomarkers; Diagnosis, Differential; Disease Management; Female; Graves Disease; Graves Ophthalmopathy; Humans; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Methimazole; Pregnancy; Pregnancy Complications; Receptors, Thyrotropin; Thyroid Gland; Thyroidectomy; Ultrasonography

Graves' disease is the most common cause of hyperthyroidism. Both antithyroid medications and radioiodine are commonly used treatments but their frequency of use varies between regions and countries. Despite the commonness of the diagnosis, any possible differences between the two treatments with respect to long-term outcomes remain unknown.. To assess the effects of radioiodine therapy versus antithyroid medications for Graves' disease.. We performed a systematic literature search in the Cochrane Library, MEDLINE and EMBASE and the trials registers ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was September 2015 for all databases.. Randomised controlled trials (RCTs) comparing the effects of radioiodine therapy versus antithyroid medications for Graves' disease with at least two years follow-up.. Two authors independently screened titles and abstracts for relevance. One author carried out screening for inclusion, data extraction and 'Risk of bias' assessment and a second author checked this. We presented data not suitable for meta-analysis as descriptive data. We analysed the overall quality of evidence utilising the GRADE instrument.. We included two RCTs involving 425 adult participants with Graves' disease in this review. Altogether 204 participants were randomised to radioiodine therapy and 221 to methimazole therapy. A single dose of radioiodine was administered. The duration of methimazole medication was 18 months. The period of follow-up was at least two years, depending on the outcome measured. For most outcome measures risk of bias was low; for the outcomes health-related quality of life as well as development and worsening of Graves' ophthalmopathy risks of performance bias and detection bias were high in at least one of the two RCTs.Health-related quality of life appeared to be similar in the radioiodine and methimazole treatment groups, however no quantitative data were reported (425 participants; 2 trials; low quality evidence). The development and worsening of Graves' ophthalmopathy was observed in 76 of 202 radioiodine-treated participants (38%) and in 40 of 215 methimazole-treated participants (19%): risk ratio (RR) 1.94 (95% confidence interval (CI) 1.40 to 2.70); 417 participants; 2 trials; low quality evidence. A total of 35% to 56% of radioiodine-treated participants and 42% of participants treated with methimazole were smokers, which is associated with the risk of worsening or development of Graves' ophthalmopathy. Euthyroidism was not achieved by any participant being treated with radioiodine compared with 64/68 (94%) of participants after methimazole treatment (112 participants; 1 trial). In this trial thyroxine therapy was not introduced early in both treatment arms to avoid hypothyroidism. Recurrence of hyperthyroidism (relapse) in favour of radioiodine treatment showed a RR of 0.20 (95% CI 0.01 to 2.66); P value = 0.22; 417 participants; 2 trials; very low quality evidence. Heterogeneity was high (I² = 91%) and the RRs were 0.61 or 0.06 with non-overlapping CIs. Adverse events other than development of worsening of Graves' ophthalmopathy for radioiodine therapy were hypothyroidism (39 of 41 participants (95%) compared with 0% of participants receiving methimazole, however thyroxine treatment to avoid hypothyroidism was not introduced early in the radioiodine group - 104 participants; 1 trial; very low quality evidence) and drug-related adverse events for methimazole treatment (23 of 215 participants (11%) reported adverse effects likely related to methimazole therapy - 215 participants; 2 trials; very low quality evidence). The outcome measures all-cause mortal. The only antithyroid drug investigated in the two included trials was methimazole, which might limit the applicability of our findings with regard to other compounds such as propylthiouracil. Results from two RCTs suggest that radioiodine treatment is associated with an increased risk of Graves' ophthalmopathy. Our findings suggest some benefit from radioiodine treatment for recurrence of hyperthyroidism (relapse) but there is uncertainty about the magnitude of the effect size.

Topics: Antithyroid Agents; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Methimazole; Randomized Controlled Trials as Topic; Recurrence

Interferon(IFN)γ-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of IFN-γ, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients with GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO.

Topics: Adrenal Cortex Hormones; Chemokine CXCL10; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Methimazole; Thyroidectomy

Topics: Adult; Antithyroid Agents; Combined Modality Therapy; Decompression, Surgical; Diagnosis, Differential; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Methimazole; Practice Patterns, Physicians'; Thyroid Function Tests; Vision Disorders

The objective of this study was to investigate quality of life (QoL) in patients with Graves' disease treated with radioiodine or antithyroid drugs.. The design of the study consists of an open, prospective, randomized multicenter trial between radioiodine and medical treatment. A total of 308 patients were included in the study group: 145 patients in the medical group and 163 patients in the radioiodine group. QoL was measured with a 36-item Short Form Health Status Survey questionnaire (SF-36) at six time points during the 48-month study period.. Patient who developed or got worse of thyroid-associated ophthalmopathy (TAO) at any time point during the 4-year study period (TAO group) had lower QoL when no respect was paid to the mode of treatment. TAO occurred in 75 patients who had radioiodine treatment at some time point during the study period as compared with TAO in 40 medically treated patients (P<0.0009). Comparisons between the group of patients who have had TAO versus the group without TAO, in relation to treatments and time, showed significantly decreased QoL scores for the TAO groups at several time points during the study. In patients without TAO, there were no differences in QoL related to mode of treatment.. The QoL in patients with Graves' ophthalmopathy was similar in radioiodine and medically treated patients, but patients who developed or had worsening of TAO had decreased QoL independent of mode of treatment. Furthermore, patients with TAO recovered physically within 1 year but it took twice as long for them to recover mentally.

Topics: Adult; Aged; Antithyroid Agents; Female; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Quality of Life; Treatment Outcome

To compare the therapeutic effect and side effect of the treatments on hyperthyroid exophthalmos with the combination of acupuncture and medication and with medication only.. Fifty-two cases were randomly divided into an acupuncture and medication group (27 cases) and a medication group (25 cases). Acupuncture in combination of oral taking of Thiamazole and Euthyrox were adopted for the acupuncture and medication group. And acupoints such as Jingming (BL 1), Chengqi (ST 1) and Sizhukong (TE 23) etc. were selected. Western medication for oral taking was applied as the only treatment for the medication group. Objective eye syndrome marks, side effects and accidents were compared between two groups before and after treatment.. The improvement of the objective marks of eye syndrome in the acupuncture and medication group was better than that in the medication group (P < 0.01). There were 4 cases with hypoleucocytosis, 3 cases with rash and 3 cases with aggravated symptom of exophthalmos in the medication group during the treatment, while no case with side effects was observed in the acupuncture and medication group. However, 8 cases were found with hemorrhage and 8 with hematoma in the acupuncture and medication group.. Treatment with the combination of acupuncture and medication may not only enhance the therapeutic effect, but also reduce the side effects.

Topics: Acupuncture Points; Acupuncture Therapy; Adult; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Exophthalmos; Female; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Thyroxine; Treatment Outcome; Young Adult

Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of benefit in GD.. The objective of this prospective, controlled, nonrandomized study was to investigate the effect of RTX in GD.. We studied 20 outpatients referred to a university clinic with newly diagnosed (four with relapse) untreated GD. Ten received RTX (+RTX), whereas 10 did not (-RTX).. The patients received methimazole (MMI) for a median of 102 d (+RTX) and 110 d (-RTX) before the study. Patients in the +RTX group received 375 mg RTX/m(2) iv on d 1, 8, 15, and 22, and all patients were withdrawn from methimazole (MMI) at d 22.. We measured time to relapse of hyperthyroidism and changes in autoantibody levels.. Four patients in the +RTX group remained in remission with a median follow-up of 705 d (range, 435-904 d), whereas all the patients in the -RTX group had relapsed by d 393 (P < 0.05). All of the patients in remission had initial TRAb levels below 5 IU/liter (normal, <0.7 IU/liter). However, none of the five patients in the -RTX group with correspondingly low TRAb levels were in remission (P < 0.01). RTX treatment did not affect autoantibody levels to a greater extent than did MMI monotherapy. Two patients received glucocorticoids for joint pain after RTX therapy.. RTX treatment may induce sustained remission in patients with GD with low TRAb levels. However, RTX did not affect autoantibody levels and seems ineffective in patients with high TRAb levels. At present, high cost, low efficacy, and potential side effects do not support use in uncomplicated GD.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antithyroid Agents; Autoantibodies; B-Lymphocytes; Female; Graves Disease; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Iodide Peroxidase; Lymphocyte Depletion; Male; Methimazole; Middle Aged; Pilot Projects; Prospective Studies; Receptors, Thyrotropin; Recurrence; Rituximab; Thyroid Hormones

The aim of this study was to compare long-term outcomes in terms of new onset or worsening of Graves orbitopathy (GO) in patients with Graves disease treated with different therapeutic modalities for hyperthyroidism.. A total of 1163 patients with Graves disease were enrolled in this study; 263 patients were treated with radioiodine and 808 patients received methimazole (MMI) therapy for a median of 18 months, of whom 178 patients continued MMI for a total of 96 months (long-term methimazole [LT-MMI]). The thyroid hormonal status and GO were evaluated regularly for a median of 159 months since enrollment.. The rates of relapse, euthyroidism, and hypothyroidism at the end of follow-up were as follows: radioiodine treatment group: 16%, 22%, and 62%, respectively; short-term MMI group: 59%, 36%, and 5%, respectively; and LT-MMI group: 18%, 80%, and 2%, respectively. During the first 18 months of therapy, worsening of GO (11.5% vs 5.7%) and de novo development of GO (12.5% vs 9.8%) were significantly more frequent after radioiodine treatment (P <.004). Overall worsening and de novo development of GO from >18 to 234 months occurred in 26 (9.9%) patients in the radioiodine group and 8 (4.5%) patients in the LT-MMI group (P <.037). No case of worsening or new onset of GO was observed in patients treated with LT-MMI from >60 to 234 months of follow-up.. Progression and development of GO were associated more with radioiodine treatment than with MMI treatment; GO may appear de novo or worsen years after radioiodine treatment but not after LT-MMI therapy.

Topics: Antithyroid Agents; Follow-Up Studies; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Methimazole; Neoplasm Recurrence, Local; Thyroid Neoplasms

A 28-year-old Japanese woman positive for TSH receptor antibody and anti-nuclear antibody complained of difficulty seeing nearby objects, severe throbbing retro-orbital pain, diplopia, blepharoptosis and upward gaze palsy when she became hypothyroid during treatment with 30 mg methylmercaptoimidazole for Graves' hyperthyroidism. Brain magnetic resonance imaging revealed slightly swollen bilateral inferior rectus muscles, suggesting the external ophthalmoplegia due to the muscle pathology commonly encountered in Graves' disease. The retro-orbital pain was associated with marked accommodation failure and the pupillary abnormalities. The left and/or right eye showed intermittent, asymmetric and fluctuating mydriasis, being unresponsive to ordinary light but slowly responsive to strong sunlight and slowly responsive in a dark room. During the 5-year period, mydriasis was observed 9 times on both sides, 11 times only on the right side and 4 times only on the left side. Internal ophthalmoplegia with tonic pupils and accommodation failure affecting both the pupillary sphincter muscle and ciliary muscle due to damage to the parasympathetic outflow to these muscles was suggested. Autoimmune mechanism and/or the mechanism underlying channelopathy affecting the ciliary ganglion or short ciliary nerves might be responsible for this fluctuating complication. This very rare panophthalmopathy affecting both external and internal muscles occurred when the patient was suffering from iatrogenic hypothyroidism during the 30 mg methylmercaptimidazole treatment for Graves' disease.

Topics: Adult; Female; Graves Disease; Graves Ophthalmopathy; Humans; Magnetic Resonance Imaging; Methimazole; Ophthalmoplegia

Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome.. A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of. We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.

Topics: Adult; Alemtuzumab; Antineoplastic Agents, Immunological; Antithyroid Agents; Female; Graves Disease; Graves Ophthalmopathy; Humans; Methimazole; Methionine; Multiple Sclerosis; Organoselenium Compounds

Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.

Topics: Adult; Aged; Case-Control Studies; Chitinase-3-Like Protein 1; Cytokines; Exosomes; Eye Proteins; Female; Fibroblasts; Graves Ophthalmopathy; Humans; Male; Matrix Metalloproteinase 9; Methimazole; Middle Aged; Tears; Vascular Cell Adhesion Molecule-1; Vitamin D-Binding Protein

Serum thyroglobulin levels are often elevated in Graves' disease (GD) and in most cases decrease during treatment. Its relation to Graves' orbitopathy (GO) has not been clarified. Previously, a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb).. We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO n = 12, non-GO n = 10) completed the drug regimen.. At diagnosis, Tg levels in GO patients (n = 11) were higher (84, 30-555 µg/L, median, range) than in non-GO patients (n = 19) (38, 3.5-287 µg/L), p = 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (n = 17), yielded p = 0.001 vs. non-GO (n = 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (n = 12) vs. non-GO (n = 10), p = 0.004, whereas TRAb levels did not differ.. The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.

Topics: Adult; Aged; Antithyroid Agents; Biomarkers; Female; Graves Disease; Graves Ophthalmopathy; Humans; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Orbit; Prognosis; Thyroglobulin; Thyroid Hormones; Thyroxine; Tobacco Smoking

As thyroid-stimulating immunoglobulins (TSI) are a sign of Graves' disease (GD), measuring TSI titers is becoming increasingly important for GD diagnosis. This study evaluated the diagnostic accuracy of a new fully automated TSI immunoassay (Immulite™ TSI assay) in GD patients and compared it to the third generation thyroid-stimulating hormone receptor antibody (TRAb) electrochemiluminescence assay (Elecsys Anti-TSHR assay). Additionally, clinical characteristics associated with responsiveness to methimazole in patients with newly diagnosed GD were preliminarily explored.. This study involved 324 subjects, comprising patients with untreated GD (GD-UT), Graves' ophthalmopathy (GO) patients, GD patients who had been treated for > 12 months (GD-T), autoimmune thyroiditis (AIT) patients, and healthy subjects (HS). The Immulite™ TSI and Elecsys Anti-TSHR assay were performed on all samples. According to their responsiveness to methimazole, the GD-UT patients were divided into rapid and slow responder groups, and their clinical characteristics were compared.. A receiver operating characteristic (ROC) curve analysis of GD-UT patients showed that the optimal TSI cut-off value was 0.57 IU/L. Logistic regression revealed that age and initial FT4 and TSI levels in the middle-dose methimazole group were related to a rapid response, while the initial FT4 level, but not TSI, in the high-dose group was also associated with a rapid response.. The clinical diagnostic performance of the Immulite™ TSI assay for diagnosing GD was comparable to that of the Elecsys Anti-TSHR assay. The initial FT4 and TSI levels can be used as predictors of the responsiveness to methimazole in patients with newly diagnosed GD.

Topics: Adult; Aged; Case-Control Studies; Female; Graves Disease; Graves Ophthalmopathy; Humans; Immunoassay; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Thyroid Function Tests; Treatment Outcome; Young Adult

To assess the predictive value of some clinical and biochemical parameters, and of the +49 A/G polymorphism of the CTLA-4 gene, for long-term remission following the withdrawal of antithyroid drugs before starting antithyroid drug therapy.. Observational, prospective and longitudinal study.. Seventy-two patients (11 of whom were men) with newly diagnosed Graves' hyperthyroidism who had been attended consecutively at a University Clinic in a population with sufficient iodine intake were included in the study.. patients under the age of 18, pregnant women and non-Caucasian patients. All subjects were treated following a well-defined protocol. Long-term remission was calculated at 12 and 36 months following withdrawal of the antithyroid drug.. Thirty-six of the 72 study subjects experienced a remission of at least 12 months following withdrawal of methimazole, with no differences according to their age or sex. A comparison made between the remission rates seen in both groups yielded significant differences regarding the presence of Graves' orbitopathy, the duration of the treatment with methimazole and the absence of the CTLA-4 G/G genotype. In the univariate and multivariate analyses performed, only lower frequencies of Graves' orbitopathy and an absence of the CTLA-4 G/G genotype were considered independent predictors of long-term remission.. The absence of Graves' orbitopathy and of the CTLA-4 G/G genotype are independent predictors of long-term remission following a first course of antithyroid drugs.

Topics: Adult; Antithyroid Agents; Biomarkers; CTLA-4 Antigen; Female; Genetic Predisposition to Disease; Genotype; Graves Disease; Graves Ophthalmopathy; Humans; Hyperthyroidism; Longitudinal Studies; Male; Methimazole; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Remission Induction; Time Factors; Treatment Outcome; Withholding Treatment

Serum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance.. To differentiate between thyroidal GD only and Graves orbitopathy (GD + GO).. Controlled, follow-up study.. Academic tertiary referral center for GD + GO.. Sixty patients with GD, GD + GO, and controls.. Serial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab.. Differentiation among GD phenotypes.. All undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9 in four of six assays. In contrast, all undiluted samples of hyperthyroid-untreated GD + GO patients remained positive up to dilution 1:81, P < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of stimulating TSH-R-Ab positivity in the bioassay for GD + GO patients was 75%, 35%, 5%, and 0%, respectively (all P < 0.001). The five ELISA and/or automated assays confirmed this marked difference of anti-TSH-R-Ab detection between GD-only and GD + GO. In comparison, the baseline-undiluted samples of GD vs GD + GO showed an overlap in the ranges of TSH-R-Ab levels. Subsequent to 12-month methimazole treatment, samples from euthyroid GD + GO patients were still TSH-R-Ab positive at the high dilution of 1:243. In contrast, all GD samples were negative already at dilution 1:3. A GD patient with TSH-R-Ab positivity at dilution 1:729 developed de novo GO.. TSH-R-Ab titers, as determined by dilution analysis, significantly differentiate between GD and GD + GO.

Topics: Adult; Aged; Antithyroid Agents; Autoantibodies; Diagnosis, Differential; Female; Follow-Up Studies; Graves Disease; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Prognosis; Receptors, Thyrotropin; Young Adult

Exotropia is rarely reported in thyroid eye disease (TED). We report the case of an 18-year-old patient with TED who developed exotropia and hypotropia as an initial presentation of TED.

Topics: Adolescent; Adrenergic beta-Antagonists; Antithyroid Agents; Diplopia; Exotropia; Graves Ophthalmopathy; Humans; Male; Methimazole; Treatment Outcome

Topics: Adolescent; Antithyroid Agents; Blepharoptosis; Cholinesterase Inhibitors; Drug Therapy, Combination; Exophthalmos; Graves Ophthalmopathy; Humans; Male; Methimazole; Myasthenia Gravis; Pyridostigmine Bromide; Thyrotropin; Thyroxine; Tomography, X-Ray Computed; Triiodothyronine

Treatment choices are limited, when deciding how to manage thyrotoxicosis and moderate to severe Graves ophthalmopathy (GO) with suspected optic nerve damage in patients with elevated liver transaminase levels. The situation become even more complicated, if methimazole induced hepatotoxicity is suspected and intravenous methylprednisolone is co-administrated.. A 74-year-old woman presented with spontaneous retro-bulbar pain, eyelid swelling and inconstant diplopia.. Thyrotoxicosis and severe GO with suspected optic nerve damage and drug induced liver injury (DILI).. Intravenous methylprednisolone pulse therapy was administered to treat GO and methimazole was continued for thyrotoxicosis. Dose of methimazole was reduced after exclusion of concurrent infection and active liver disease.. The GO symptoms (eyelid swelling, sight loss, proptosis, retro-bulbar pain, diplopia) markedly decreased after the treatment course. Liver transaminases spontaneously returned to normal ranges and remained normal during the next 12 months until the Graves' disease until the treatment was completed.. 1. The interaction of methimazole and methylprednisolone may result in DILI. 2. In a patient without concomitant liver diseases MP can be continued if the methimazole dose is reduced if no other treatment options are available.

Topics: Administration, Intravenous; Aged; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Liver Function Tests; Medication Therapy Management; Methimazole; Methylprednisolone; Optic Nerve Diseases; Pulse Therapy, Drug; Symptom Assessment; Thyrotoxicosis; Treatment Outcome

Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC.. We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time.. GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders.. Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments.. ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy

Topics: Administration, Intravenous; Adult; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Prognosis; Pulse Therapy, Drug; Retrospective Studies; Time Factors; Treatment Outcome

Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD.. Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12-24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5-7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up.. The mean follow-up was 80.8 ± 35.3 months for the RAI group, and 71.3 ± 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)--it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02-12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47-48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70-223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5-298], p < 0.05). Kaplan-Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up.. The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment.

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Graves Ophthalmopathy; Hormone Replacement Therapy; Humans; Iodine Radioisotopes; Maintenance Chemotherapy; Male; Methimazole; Middle Aged; Recurrence; Retrospective Studies; Thyroxine; Treatment Outcome

Localized myxoedema is a rare dermopathy in patients with Graves' disease. The pretibial area is the most commonly affected region but herein we present a case of myxoedema of the big toe.. A 44-year-old male with Graves' disease ongoing for seven years presented bilateral ophthalmopathy and myxoedema of the big toes. The myxoedema was treated successfully with intralesional steroids.. The physiopathology of myxoedema involves fibroblast activation and glycosaminoglycan production. This activation could result from stimulation of TSH receptors at their surface by TSH receptor antibodies (TRAK) or from an inflammatory process. The pretibial topography may be related to the high frequency in this area of microtrauma, with modulation of the cytokine microenvironment.. The atypical localization seems to correlate with a Koebner phenomenon. Treatment of Graves' disease is generally insufficient to resolve the cutaneous problems. Topical corticosteroid therapy generally results in rapid improvement of recent lesions.

Topics: Adult; Biopsy; Carbimazole; Decompression, Surgical; Fibroblasts; Foot Dermatoses; Glycosaminoglycans; Graves Disease; Graves Ophthalmopathy; Hormone Replacement Therapy; Humans; Immunoglobulins, Thyroid-Stimulating; Immunosuppressive Agents; Injections, Intralesional; Male; Methimazole; Myxedema; Receptors, Thyrotropin; Thyroidectomy; Thyroxine; Toes; Triamcinolone

A 42-year-old female with body weight loss, finger tremors and ocular discomfort was diagnosed with Graves' disease complicated with ophthalmopathy. Thiamazole therapy rapidly improved her hyperthyroidism. However, she was admitted to our hospital because her eye symptoms acutely deteriorated over a period of two weeks. She had ocular immotility, exposure keratitis, conjunctival edema, severe proptosis and visual impairment with a high titer of serum thyroid-stimulating antibody (TSAb). Methylprednisolone pulse therapy at a dose of 500 mg/day improved her eye symptoms. Although the mechanism of the progression of Graves' ophthalmopathy has not yet been elucidated, special attention should be paid to the occurrence of ophthalmopathy even after the initiation of thiamazole therapy.

Topics: Adult; Antithyroid Agents; Disease Progression; Female; Graves Ophthalmopathy; Humans; Methimazole; Time Factors

Topics: Aged, 80 and over; Antithyroid Agents; Autoantibodies; Autoimmune Diseases; Diabetes Mellitus, Type 2; Female; Graves Disease; Graves Ophthalmopathy; Humans; Hypoglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Insulin, Regular, Human; Methimazole; Prednisone; Recombinant Proteins; Treatment Outcome

Cytokines are involved in the pathogenesis of Graves' disease (GD), but ambiguous serum cytokine results have been described.. We studied the changes in serum interleukin (IL)-1β, soluble IL-2 receptor (sIL-2R), IL-5, IL-6 and tumor necrosis factor (TNF)-α concentrations in 29 untreated GD patients before and after restoration of euthyroidism with methimazole (MMI) treatment compared to 25 control subjects. Eleven out of 29 GD patients had active Graves' ophthalmopathy (GO).. Compared to controls, untreated GD patients had significantly higher median levels of serum IL-1β (18.7 vs. 34.0 pg/ml), sIL-2R (292.5 vs. 1,585.0 pg/ml), IL-5 (1.0 vs. 9.0 pg/ml), IL-6 (3.0 vs. 5.0 pg/ml) and TNF-α (8.1 vs. 16.0 pg/ml). In euthyroidism following MMI treatment, concentrations of IL-1β (25.0 pg/ml), sIL-2R (362.0 pg/ml), IL-5 (3.0 pg/ml), IL-6 (3.0 pg/ml) and TNF-α (5.0 pg/ml) declined significantly and were similar to controls. The greatest reductions were noted in sIL-2R (76.9%), TNF-α (68.8%) and IL-5 (66.6%) levels. Serum sIL-2R, IL-5 and TNF-α levels in active GO patients were significantly elevated, but no significant differences were observed in GD patients without GO. Using a multiple linear regression analysis, serum IL-1β was significantly associated with free thyroxine, sIL-2R with triiodothyronine and serum thyrotropin receptor antibody (TRAb) and TNF-α with TRAb.. These results support the notion that serum cytokines could be used as a marker of GD activity, and the decrease in cytokine levels might be related to the achievement of euthyroidism and the immunomodulatory effects of MMI treatment.

Topics: Adolescent; Adult; Antithyroid Agents; Cytokines; Female; Graves Disease; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Thyroid Function Tests; Young Adult

Patients with severe Graves' orbitopathy often have hyperthyroidism that is difficult to treat and a high proportion of patients experience relapse of hyperthyroidism after a course of antithyroid drug (ATD) therapy of fixed duration. The aim of the study was to evaluate the feasibility of prolonged low-dose ATD therapy for attaining stable euthyroidism in patients with severe Graves' orbitopathy and hyperthyroidism.. We performed retrospective analyses of data collected during observation of a cohort of patients (n = 108) treated for severe Graves' orbitopathy and for hyperthyroidism using partial block with low-dose thionamide + replacement with levothyroxine (L-T4) for >2 years. The study was performed at a university hospital referral center for patients with severe Graves' orbitopathy.. The median duration of thionamide therapy was 80 months (25-75 percentiles: 55-115 months); 101 patients received methimazole (median: 5 mg/day) without side effects during prolonged therapy, and 7 propylthiouracil (median: 200 mg/day); median L-T4 dose was 0.1 mg/day. Ninety percent of patients remained euthyroid throughout the period of therapy, and 65% of them had thyroid stimulating hormone (TSH) receptor antibodies in serum within the assay reference interval at the last observation. Only four (3.7%) developed episodes of hyperthyroidism during stable therapy, and 94% had serum TSH within 0.1-4.0 mU/L at the last observation. One patient developed reversible cutaneous vasculitis after 6 years of propylthiouracil therapy.. Prolonged partial block plus replacement therapy with low-dose ATD + L-T4 keeps the majority of patients with severe Graves' orbitopathy and hyperthyroidism stable and euthyroid.

Topics: Adult; Antithyroid Agents; Biomarkers; Denmark; Drug Administration Schedule; Feasibility Studies; Female; Graves Disease; Graves Ophthalmopathy; Hormone Replacement Therapy; Hospitals, University; Humans; Immunoglobulins, Thyroid-Stimulating; Male; Methimazole; Middle Aged; Propylthiouracil; Recurrence; Retrospective Studies; Severity of Illness Index; Thyroxine; Time Factors; Treatment Outcome

Immunoglobulins stimulating the TSH receptor (TSI) influence thyroid function and likely mediate extrathyroidal manifestations of Graves' disease (GD).. The aim of this study was to assess the clinical relevance of TSI in GD patients with or without Graves' orbitopathy (GO), to correlate the TSI levels with activity/severity of GO, and to compare the sensitivity/specificity of a novel TSI bioassay with TSH receptor (TSH-R) binding methods (TRAb).. TSI were tested in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness to TSI of the novel chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R) was compared with the wild-type (wt) TSH-R.. All hyperthyroid GD/GO patients were TSI-positive. TSI were detected in 150 of 155 (97%, Mc4) and 148 of 155 (95%, wt) GO patients, in six of 45 (13%, Mc4) and 20 of 45 (44%, wt) mostly treated GD subjects, and in 0 of 40 (Mc4) and one of 40 (wt) controls. Serum TSI titers were 3- and 8-fold higher in GO vs. GD and control, respectively. All patients with diplopia and optic neuropathy and smokers were TSI-positive. TSI strongly correlated with GO activity (r = 0.87 and r = 0.7; both P < 0.001) and severity (r = 0.87 and r = 0.72; both P < 0.001) in the Mc4 and wt bioassays, respectively. Clinical sensitivity (97 vs. 77%; P < 0.001) and specificity (89 vs. 43%; P < 0.001) of the Mc4/TSI were greater than TRAb in GO. All 11 of 200 (5.5%) TSI-positive/TRAb-negative patients had GO, whereas all seven of 200 (3.5%) TSI-negative/TRAb-positive subjects had GD only.. The novel Mc4/TSI is a functional indicator of GO activity and severity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antithyroid Agents; Female; Graves Disease; Graves Ophthalmopathy; Humans; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Iodine Radioisotopes; Male; Methimazole; Middle Aged; Rats; Receptors, Thyrotropin; Reference Values; Severity of Illness Index; Thyroidectomy; Young Adult

Topics: Adult; Antithyroid Agents; Combined Modality Therapy; Decompression, Surgical; Diagnosis, Differential; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Methimazole; Thyroid Function Tests; Vision Disorders

Th1 and Th2-like cytokines are involved in the pathogenesis of Graves' disease. The shift in balance in IL-12/IL-5 cytokines was applied in judging the immunological events in 74 patients with Graves' disease (50 had ophthalmopathy) during methimazole therapy and in 15 controls. The serum levels of IL-12 and IL-5 were measured with enzyme-linked immunosorbent assay in all Graves' patients. Twelve cases for IL-5 and 20 cases for IL-12 were positive. In Graves' patients only those without ophthalmopathy had higher levels of IL-12 when compared to controls (192.66 +/- 29.19 vs. 85.09 +/- 8.95 pg/ml, P < 0.04). After 2 months of methimazole therapy in Graves' patients without ophthalmopathy an increase in the ratio of IL-12 to IL-5 was also observed as compared to those with eye symptoms (91.78 +/- 34.14 vs. 20.72 +/- 6.36, P < 0.015). Age-related difference in the serum level of IL-5 could be demonstrated between Graves' patients without and those with ophthalmopathy aged < or = 35 years (4.89 +/- 0.57 vs. 50.14 +/- 20.2 pg/ml, P < 0.002). No association was found among the serum levels of IL-5 or IL-12, thyroid hormones and TSH receptor antibodies. The results demonstrated a difference in the balance shift of IL-12/IL-5 between Graves' patients with and without ophthalmopathy. The increased ratio of IL-12 to IL-5 after methimazole therapy could be explained by the elevation of serum IL-12 due to methimazole therapy and the age-related decrease of serum IL-5.

Topics: Adolescent; Adult; Age Factors; Aged; Female; Graves Disease; Graves Ophthalmopathy; Humans; Interleukin-12; Interleukin-5; Male; Methimazole; Middle Aged; Th1 Cells; Th2 Cells; Thyroid Hormones

A 59-year-old woman with a history of nodular goiter developed thyrotoxic symptoms while on levothyroxine therapy. Her thyrotoxicosis persisted after levothyroxine withdrawal, so she was given methimazole and, once euthyroid, underwent near-total thyroidectomy. Histological examination revealed a nodular variant of Graves' disease. Proptosis, eyelid swelling and diplopia appeared 2 months after surgery. These symptoms worsened, and the patient was initially given four intravenous pulses of glucocorticoids, which resulted in a transient amelioration of her eye symptoms. After glucocorticoid withdrawal, however, the patient's eye motility worsened and there was a reduction of visual acuity in the left eye. She was then referred to our hospital for further advice and treatment.. Complete thyroid and ophthalmological evaluation, computerized visual field analysis, CT scan of the orbits, routine blood tests, search for occult fecal blood, blood tests for hepatitis B and C virus markers, measurements of serum non-organ-specific autoantibodies and serum anti-TSH-receptor antibodies, and liver ultrasonography.. Nodular Graves' disease with severe, active Graves' orbitopathy complicated by optic neuropathy.. Intravenous glucocorticoid therapy for 3 consecutive days, followed by once-weekly pulses of intravenous glucocorticoids over a 10-week period, and then by oral prednisone treatment on alternate days for 2 months. During the first 2 weeks of intravenous glucocorticoid therapy the patient received orbital irradiation. Therapy resulted in optimized visual acuity and a moderate improvement of soft-tissue inflammatory signs and symptoms, whereas proptosis and eye motility improved only slightly. The patient is now scheduled for orbital decompression and rehabilitative surgery.

Topics: Antithyroid Agents; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Methimazole; Middle Aged; Orbital Diseases; Radiotherapy; Thyroxine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antithyroid Agents; B-Lymphocytes; Graves Disease; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Lymphocyte Depletion; Methimazole; Rituximab

Topics: Conjunctival Diseases; Female; Graves Ophthalmopathy; Humans; Methimazole; Middle Aged

Recent studies concerning the association between extraocular muscle (EOM) enlargement in thyroid-associated ophthalmopathy (TAO) and immunological and clinical activity have not been conclusive, probably due to a lack of uniform imaging methods (ultrasonography, computer tomography [CT] or magnetic resonance imaging [MRI]) and difficulties in the determination of EOM volume. The aim of the present study was to examine the significance of EOM enlargement as established by MRI-based volume determination, with reference to proptosis and the presence of autoantibodies, clinical activity and the duration of active disease.. We determined EOM volume using MRI in 15 patients concomitantly with the determination of TSH, thyroid hormones, thyrotropin receptor antibodies (TRab) thyroid peroxidase antibodies (TPOab) and clinical activity score (CAS) at entry. We also established the duration until cessation of clinically active TAO.. All 15 patients had bilateral EOM enlargement, but swelling of orbital fatty tissue was absent. Significant correlations between thickness of musculi rectales and proptosis, values of TRab, CAS, and duration of activity were observed.. Our results support the hypothesis of a role of thyrotropin receptor antibodies in the pathogenesis of TAO and suggest that only EOM enlargement is responsible for proptosis in TAO.

Topics: Adult; Antithyroid Agents; Autoantibodies; Exophthalmos; Female; Graves Ophthalmopathy; Humans; Hypertrophy; Iodide Peroxidase; Magnetic Resonance Imaging; Methimazole; Oculomotor Muscles; Receptors, Thyrotropin; Thyroid Hormones; Thyrotropin

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antithyroid Agents; Autoantibodies; B-Lymphocytes; Female; Glucocorticoids; Graves Disease; Graves Ophthalmopathy; Humans; Immunoglobulins, Thyroid-Stimulating; Methimazole; Middle Aged; Recurrence; Remission Induction; Rituximab; Thyroid Diseases

The treatment of Graves' disease (GD) with antithyroid drugs (ATD) leads to remission of the disease in approximately half of patients treated for at least six months, and the overall relapse rate is high, ranging from 60% to 80%. The presence of prognostic features for achieving a remission after medical treatment is a matter of discussion in the literature. The aim of this study is to evaluate the effect of different ATD regimens available in Brazil (propylthiouracil--PTU and methimazole--MMI) on remission and relapse rates of GD, as well as to determine possible predictors of remission and relapse of the disease and the side effects profile. We reviewed the records from all patients submitted to medical treatment of GD (and with no report of prior treatment of the disease) for at least six months and followed for at least 12 months after the drug withdrawal at Hospital Universitário Clementino Fraga Filho (HUCFF), between October 1978 and August 2003. We identified 127 patients, with the age ranging from 18 to 88 years (mean 39.3 +/- 12.8). Remission was observed in 58 patients (45.7%) and relapse occurred in 31 (53.4%), at a mean period of 14.5 +/- 16.1 months. We verified that the duration of symptoms before the beginning of medical treatment, age and gender did not influence the rate of remission and the relapse risk, whereas the presence of large goiter size (> 40 grams), Graves' ophthalmopathy and use of high daily doses of ATD (> or = 600 mg of propylthiouracil/60 mg of methimazole MMI) were associated with a decreased remission rate. Moreover, patients who presented a TSH measurement < 0.4 microIU/mL between 4 to 5 weeks after the drug withdrawal showed an increased relapse cumulative probability. In conclusion, our results confirms that lasting remission rate of GD treated with ATD is relatively low. We concluded that the combination of goiter size > 40 g, ophthalmopathy, and use of daily doses of PTU > or = 600 mg or MMI > or = 60 mg was vigorously related to lack of remission of GD. Furthermore, TSH measurement between 4 to 5 weeks after the drug withdrawal seems to be a useful tool to determine the remission chance and the relapse risk of the disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antithyroid Agents; Cohort Studies; Female; Follow-Up Studies; Graves Disease; Graves Ophthalmopathy; Humans; Male; Methimazole; Middle Aged; Multivariate Analysis; Propylthiouracil; Recurrence; Remission Induction; Thyrotropin; Time Factors; Treatment Outcome