Background Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals. Objectives To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism. Search strategy We searched the Cochrane Central Register of Controlled Trials (Central), MEDLINE, EMBASE, BIOSIS, CINAHL, HEALTHSTAR, Current Controlled Trials and reference lists. We contacted investigators and hand searched conference abstracts. Most recent search: July 2004. Selection criteria Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism were used. Data collection and analysis Trial allocation to included, excluded and awaiting assessment categories was made by consensus. Two reviewers independently extracted data and assessed trial quality. Pooling of data for primary outcomes, and select exploratory analyses were undertaken. Main results Twenty-three randomised trials involving 3115 participants were included. Overall the quality of trials as reported was poor; specifically in terms of allocation concealment, assessor blinding and loss to follow-up. Four trials examined the effect of duration of therapy on relapse rates of Graves' hyperthyroidism. In one trial using the Titration regimen, longer duration therapy (18 months) had significantly fewer relapses (37% versus 58%) than six month therapy (Odds ratio (OR) 0.42, 95% confidence interval (CI) 0.18 to 0.96). In one quasi-randomised trial using the Block-Replace regimen, there was no significant difference between the six and 12 month (relapses rates 41% versus 35%) arms of the study. Extending the duration of therapy to over 18 months was not associated with improved relapse rates (Peto OR 0.75, 95% CI 0.39 to 1.43). Twelve trials examined the effect of Block-Replace versus Titration regimen. The relapse rates were similar in both groups at 51% in the Block-Replace group and 54% in the Titration group (Peto OR 0.86, 95% CI 0.68 to 1.08). Participants reporting rashes (10% versus 5%) and withdrawing due to side effects (16% versus 9%) were significantly higher in the Block-Replace group compared to the Titration group respectively. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups were not significant (Odds ratio 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up with relapse rates being 31% (88/282) with thyroxine and 29% (82/284) with placebo (Peto OR 1.15, 95% CI 0.79 to 1.67). Authors' conclusions The evidence (based on four studies) suggests that the optimal duration of antithyroid drug therapy for the Titration regimen is 12 to 18 months. The six month Block-Replace regimen was found to be as effective as the 12 month treatment in one quasi-randomised study. The Titration (low dose) regimen had fewer adverse effects than the Block-Replace (high dose) regimen and was no less effective in trials (based on 12 trials) of equal duration. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. The incidence of hypothyroidism was not reported and there were no deaths reported in the study populations.

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Antithyroid drug regimen for treating Graves' hyperthyroidism

Graves’ disease (GD) is the most common cause of hyperthyroidism worldwide. Current therapeutic options for GD include antithyroid drugs (ATD), radioactive iodine, and thyroidectomy. ATD treatment is generally well accepted by patients and clinicians due to some advantages including normalizing thyroid function in a short time, hardly causing hypothyroidism, and ameliorating immune disorder while avoiding radiation exposure and invasive procedures. However, the relatively high recurrence rate is a major concern for ATD treatment, which is associated with multiple influencing factors like clinical characteristics, treatment strategies, and genetic and environmental factors. Of these influencing factors, some are modifiable but some are nonmodifiable. The recurrence risk can be reduced by adjusting the modifiable factors as much as possible. The titration regimen for 12–18 months is the optimal strategy of ATD. Levothyroxine administration after successful ATD treatment was not recommended. The addition of immunosuppressive drugs might be helpful to decrease the recurrence rate of GD patients after ATD withdrawal, whereas further studies are needed to address the safety and efficacy. This paper reviewed the current knowledge of ATD treatment and mainly focused on influencing factors for recurrence in GD patients with ATD treatment.

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Antithyroid Drug Therapy for Graves' Disease and Implications for Recurrence.

iii Preface v Acknowledgements vii Table of contents ix Lists of tables & figures xv Glossary/Abbreviations xxi

Whakangungu Rākau: Incidence, Severity & Treatment Outcomes of Thyrotoxicosis Among Māori

Antibodies to TSH receptors (TRAb) have great pathogenetic importance in the development and maintenance of hyperthyroidism in Graves' disease (GD). Measurement of their serum level could be of diagnostic and prognostic importance in autoimmune hyperthyroidism and in monitoring the efficiency of thyrosuppressive drug (TSD) treatment in GD. The aim of our study was to assess the sensitivity (SN), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) of the TRAb assay in confirming the diagnosis and to define its prognostic value for remission duration in GD patients at the end of TSD treatment with thionamide derivatives, propylthiouracil or methimazole. We studied 99 patients, 65 female, 34 male, 18-76 years old; 52 GD patients and 47 as control group. We have studied frequency of relapses and remission duration in GD patients by a 2nd generation serum TRAb commercial kit. Our results showed that, the SN, SP, PPV and NPV of the TRAb test were 100%, 97%, 98% and 100%, respectively. Remission duration after TSD treatment was longer and relapses were fewer in GD patients with lower levels of TRAb before (P<0.01) and at the end of TSD treatment (P<0.05). In conclusion, our results suggest that serum TRAb is very sensitive and specific for confirming the diagnosis of GD. TRAb levels at the beginning of TSD treatment, above 5 IU/L gives 18% greater chance, and above 15 IU/L, 36% greater chance for remission, shorter than 6 months.

TSH receptor antibodies for confirming the diagnosis and prediction of remission duration, in newly diagnosed Graves' disease patients

Carbimazole is a drug that is widely used for hyperthyroid disorders, such as Graves' disease. Agranulocytosis is a rare idiosyncratic adverse reaction to the drug which is potentially fatal. This report describes a patient with a history of successfully treated pyoderma gangrenosum, who developed agranulocytosis 3 weeks after commencement of carbimazole for Graves' disease. It may give credence to the theory that implicates antineutrophil cytoplasmic antibodies in the pathogenesis of agranulocytosis induced by antithyroid drugs.

Carbimazole-induced agranulocytosis: does antineutrophil cytoplasmic antibody have a role?

Treatment of Graves disease (GD) with antithyroid drugs (ATD) leads to remission of the disease in approximately half of patients treated for at least 6 months and the overall relapse rate is high. A few small prospective trials have considered methimazole (MMI) somewhat more effective and safer in lower doses than propylthiouracil (PTU), but the choice between the drugs has been a matter of personal preference. The aim of this clinical trial is to evaluate the effect of different ATD regimens on remission rates of GD and on the side effect profiles. The study included 55 previously untreated patients with GD who were randomized in 2 groups: 40 to 60 mg methimazole daily was prescribed to 30 patients and 200 to 300 mg propylthiouracil every 12 hours was prescribed to 25. The patients were treated for 12 months and followed for 12 to 38 months after drug withdrawal. Fifteen patients of 21 in the PTU group (71.4%) and 10 of 25 in the MMI group (40.0%) reached 1-year remission of GD (P 0.04), but there was no statistical difference between the drug regimes after adjusting for antithyroid- stimulating hormone receptor antibody (TRAb) levels. Among the 25 patients who reached 1-year remission, relapse occurred in one case at 18 months after drug withdrawal. All patients presented good compliance and only 2 patients developed minor side effects. During the treatment, both drug groups showed a significant fall in serum TRAb and thyroid peroxidase autoantibody titers, and the TRAb levels observed in the MMI group were consistently higher. There- fore, in our study, there were no significant differences between PTU and MMI groups in relation to remission rate, side effect profiles, and compliance rates. Furthermore, individuals with higher baseline antibody titers presented a lower probability of long term remission of GD.

http://www.e-sanitas.edu.co/Diplomados/endocrino/modulo_5/Bibliografia/hipertiroidismo.pdf

Antithyroid Drugs for the Treatment of Graves Disease A Randomized Clinical Trial

Objective: Treatment of Graves' disease (GD) with antithyroid drugs (ATD) leads to remission of the disease in approximately half of patients treated for at least 6 months. The overall relapse rate is high. Prognostic features that predict a remission after medical treatment are still a matter of controversy in the literature. The aim of this study is to evaluate the uuse of clinical and laboratory data for predicting a remission of GD after 12 months of treatment with ATD. Methods: The study included 46 previously untreated patients who were treated for 12 months and followed for at least 12 months after drug withdrawal. Results: Remission was observed in 25 patients and there was only 1 relapse. Greater duration of symptoms before the beginning of medical treatment, large goiter and high baseline levels of serum free T4, total T3, TRAb, and TPOAb were associated with a decreased remission rate. Individuals who presented a thyroid-stimulating hormone measurement Conclusion: Our results confirm that the rate of lasting remissions of GD treated with ATD is relatively low. Initial goiter size, duration of symptoms and baseline T3, free T4, TRAb, and TPOAb can select a subgroup of patients with GD who will most likely benefit from antithyroid drug treatment as a first choice.

Use of Clinical and Laboratory Data for Prediction of Gravesʼ Disease 1-Year Remission After 12 Months of Treatment With Antithyroid Drugs

To evaluate the incidence, behavior, clinical outcome and identify possible predictive factors of the association between thyroid cancer (TC) and Graves disease (GD), we reviewed the records from all patients submitted to thyroidectomy for treatment of GD between 01/79 and 11/02 from 2 university hospitals. Histology of the excised specimens identified TC in 7 of the 341 patients (2.1%). In the group with TC, age varied from 19 to 50 years (median: 29) and in those without TC, from 13 to 79 years (median: 34), which were not significantly different. There were 293 women (87.7%) and 41 men (12.3%) in the non-TC group and 5 women (71.5%) and 2 men (28.5%) in the TC group. By histology, all 7 cases of TC were papillary thyroid carcinoma (PTC): one with a multicentric PTC without extra-thyroidal involvement, two with the follicular variant of PTC (with 8 and 25mm diameter) but no capsular involvement, one with classic PTC (with 15mm diameter), and the remaining 3 with microcarcinomas (<10mm). Patients were followed from 6 to 16 years and none had local recurrence or distant metastasis. Our data showed an incidence of TC in patients submitted to surgery for GD concordant with those previously reported. Tumors were not more aggressive than usual, probably because of the high frequency of occult microcarcinomas.

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Maria Claudia Peixoto

Papers

Antithyroid Drugs for the Treatment of Graves Disease A Randomized Clinical Trial

Use of Clinical and Laboratory Data for Prediction of Gravesʼ Disease 1-Year Remission After 12 Months of Treatment With Antithyroid Drugs

Avaliação da incidência e do comportamento do câncer de tireóide em pacientes com doença de graves submetidos a tireoidectomia

artigo original Avaliação da Incidência e do Comportamento do Câncer de Tireóide em Pacientes Com Doença de Graves Submetidos a Tireoidectomia