| BackgroundHyperthyroidism is defined as an syndrome of thyrotoxisosis due to producing an excess of thyroid hormone by thyroid gland itself. Its causes include Graves’ disease(GD), toxicmultinodulargoiter, Plummer disease, but GD is the most common, whose prevalence in cohort is 80～85%.GD is usually defined as an Organ-specific autoimmune disease. It is characterized by high metabolic syndrome, goiter and proptosis etc in clinic, but the mechanism remains unclear. It is generally considered to be caused by various stress factors such as mental simulation and infecion on the base of genetic defects. Factors such as female and hereditary can increase the risk of disease.Currently, the major treatment for Graves’ disease include Antithyroid drug treatment (ATD), Radioiodine ablation (RAI) and surgery. In the United States, RAI is used more frequently used in clinical because of its fewer side effects and safety, however ATD is considered as the first choice of therapy in China, Japan and most countries in Europe.The mechanism of ATDs is to inhibit the organising of iodine and iodination of tyrosinein in thyroid, which is important in the synthesis of T4 and T3. Furthermore, ATD has the ability to inhibit immune system by reducing the level of serum thyrotrophin receptor antibody(TRAb). Despite the lacks, such as long course, high relapse rate and the remission rate is just about 40～50%, most newly diagnosed patients with hyperthyroidism prefer ATD, because its advantages of economic, non-invasive and difficult to cause permanent hypothyroidism.Methimazole (MMI), and propylthiouracil (PTU) are the main clinically used for antithyroid-drug therapy in our country. PTU has a function to prevent T4 changing into T3 in peripheral tissues, therefore is often used in rescuing of thyroid crisis. Fever, rash, neutropenia and liver injury are the main adverse effect of MMI and PTU.But there is a higher incidence of hepatotoxicity, severe exfoliative dermatitis, and vasculitis especially antineutrophil cytoplasmic antibody (ANCA) positive vasculitis in the use of PTU. So MMI is recommended the first line treatment for hyperthyroidism.The common course of ATD therapy is 12 to 18 weeks, so as to control the symptoms of Graves’ disease and to achieve long-term remission of purpose. Studies have shown that long course can reduce the level of thyroid-associated antibodies, which should make 40-60% of patients in remission, and better than short course. Other factors to effect remission and relapse of GD include serum TRAb and thyroiglobulin antibody(TGAb), age, thyroid volume, proptosis and smoking. Patients with small thyroid volume and mild initial symptoms may easily mitigated, while the others with bulky thyroid, younger, smoking or have high serum TRAb levels easier suffer from relapse. But now there is definite yet reliable indicators used to predict prognosis and recurrence rate of Graves’ disease.Since the 1940s, ATDs are widely used in clinical, for decades many experts worked on finding a method of optimizing therapeutic intent to increase the remission rate of ATD treatment while reduce the recurrence rate of side effects. In 1967 Howard found that during or after the treatment of ATD, to add levo-thyroixine(L-T4) can remote the remission of GD. In 1983 Romaldini seems to confirm the occurrence of ATD combined with L-T4 can prevent drug-induced hypothyroidism. In 1991 Hashizume verify this, the results showed that the patients in group of ATD addition of L-T4, the relapse rate of is 20 times lower than that with ATD group.The possible mechanism is that ATD and L-T4 can affect the thyroid immune response by inhibiting the plasma cells from producing thyrotropin receptor antibody, or reduce the thyroid cell surface antigen expression by other mechanisms. In addition, he put forward that exogenous L-T4 can put to rest the thyroid status by suppression of TSH levels, reduce TSH stimulating to the thyroid gland, so as the recurrence rate. However, some scholars put forward that block-replace regimen refers to the option of maintaining the high dose of ATD, which would cause a higher frequency of side effects but fail to reduce the relapse rate of hyperthyroidism. There were several studies had shown no difference in remission and relapse rates or TSH receptor antibody concentrations between ATD alone and combination therapy. In addition, many endocrinologists in the treatment of GD are often based on their own experience of drug use. The dose, treatment and whether the addition of L-T4 and other issues are very randomized. The treatment results do not provide accurate and reliable treatment experience. Thus, we have conducted a multicenter randomized controlled clinical trial to compare MMI alone to the combination of methimazole plus L-T4 for 12 months, in respect of remission and repalpse rates after 2-year follow up, while analysis the predictors of relapse.ObjectsTo investigate the effect of ATD whether in combination with Levo-thyroxine on remission and relapse rates of Graves’ disease, and to analysis to determine relapse indicators.Methods1 Study population The study is a multicenter randomized controlled clinical trial, and divided into two parts according to the different stages of this study.1.1 This study enrolled patients with newly diagnosed, previously untreated Graves’ disease in nine research centers in JiangSu province from July 2011 to February 2013, a total 684 patients to be selected.1.2 This study include patients had completed the 12-months regular medication regimen as of February 2013, a total 518 cases included in the study2 Study method2.1 All treated initially with 20mg of MMI twice a day for an average of 4 to 6 weeks, and were randomly assigned to group A (MMI alone group) and group B (MMI in combination with L-T4 group), when hyperthyroidism was controlled. The dosage of MMI in both groups was dropped to 20mg qd, while 100 μg of L-T4 per day was added in group B. At the end of week 16, adjusted the dosage of MMI in group B to 10 mg qd but the dosage of L-T4 remained unchanged. Patients in group B began to take MMI 5 mg qd and L-T4 50μg qd from the 48th week, and both drugs were discontinued until the 52th week. In group A, patients were treated with titration, which adjusted the dosage of MMI according to biochemical index such as serum free triiodothyronine (FT3), free thyroxine (FT4), triiodothyronine (T3), thyroxine (T4) and thyrotrophin (TSH), and achieved withalwal until the 52th week. The clinical and bichemicao assessments including vital signs, routine blood test, liver and kidney functions, levels of thyroid hormone, TSH-receptor antibodies (TRAb) and thyroid echography, were recorded before treatment groups. Thyroid function tests, routine blood test, liver and kidney functions were retested once every 4 weeks, meanwhile it was necessary to record the rates of drug-induced thyroid hypothyroidism and side effects of ATD in two groups. We compared the outcomes between two groups, the change of thyroid function, serum level of TRAb and the thyroid volume before and after treatment were concluded. The total course of regimen was 12 months.2.2 Retested thyroid functions every 8 weeks regularly after withdrawal, continue follow-up for 24 months, observed the relapse rate, analysed indicators and factors of disease recurrence.Results1. Medical therapy of Graves’ disease:effect on remission of mathimazole in combination with levo--thyroxine684 patients were enrolled from July 2011 to February 2013 in 9 hospital centers in JiangSu province, while 166 patients (61 patients in group A and 105 patients in group B) were excluded because of out of follow-up within 12 months regular medication regimen.A total of 518 patients were included in this analysis.After 12 months treatment with MMI alone or MMI in combination with L-T4, all patients were returned to euthyroidism. The changing trend of thyroid functions in two groups before and after treatment as follows:group A:FT3 (23.9±10.6; 4.2±1.8) pmol/L,FT4 (54.3±18.6; 15.2±3.2) pmol/L, T3 (11.2±4.1; 1.8±0.4) nmol/L, T4 (253.5±70.9;107.1±25.0)nmol/L,TSH(1.1±1.3)mIU/L; group B:FT3(22.8±11.9; 5.1±1.4) pmol/L, FT4 (56.5±22.9; 15.9±5.1) pmol/L, T3 (13.0±7.3; 1.4±0.7) nmol/L; T4 (267.5±69.2; 101.4±22.1) nmol/L, TSH (0.6±1.3) mIU/L. The serum thyroid hormone level decreased more rapidly in group B compared with group A, but there were no significantly differences between two groups before drug discontinuance. Atter 3 months of drug therapy, the rates of drug-induced thyroid hypofunction was lower in group B than group A.After 12 months of ATD treatment, the serum concentration of TRAb in group A was higher than that in group B:5.7±1.9 vs.2.5±2.3mIU/L (t=0.401, P=0.02). And by the time of drug discontinuation, the mean thyroid volume of group A was greater than that of group B:24.1±3.1 vs.22.0±3.9ml (t=1.443, P=0.03).The difference has statistically significant.2. Study of Two-year follow-up after treatment24 months after withdrawal of drug therapy, the overall estimated relapse rate of hyperthyroidism was 47%. The relapse rate in group B (45%) was lower than group A (49%), but the difference had no significance (P=0.3).Positive TRAb at the end of ATD treatment and regular cigarette smoking were identified that might be useful in predicting relapse risks after ATD withdrawl, TRAb were significantly associated with a greatly increased relapse risk. Compared with the overall 47% relapse risk, non-smoking patients with a negative TRAb had a lower (19%) replase risk; smoking patients with negative TRAb had a 52% replase risk; non-smoking patients with TRAb had a high (82%) replase risk; the replase risk was 97% in those patients who both smoked and maintained a positive TRAb at the end of ATD treatment.Conclusion1. There was no significant difference of the remission rate and recovery time of thyroid function between ATD monotherapy group and combination group. The recovery time of TSH was later than thyroid function for 1 month in ATD monotherapy group, and the TSH in combination was always in a suppressed status.2. Combination therapy had an advantage in lowering levels of TRAb and reducing thyroid volume than ATD monotherapy.3. Combination therapy can reduce the incidence of drug-induced hypothyroidism, and there was no significant difference in the incidence of side effects with the ATD monotherapy.4. The combination group and ATD monotherapy group had no significant difference in relapse rate within 24 months after treatment.5. Patients with serum TRAb positive and regular smoker when the withdrawal had a high relapse rates, which were probably considered as predictors of relapse. However the patient’s sex, age and size of thyroid volume was no significant correlation with relapse rate. |
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