Graves' disease (GD) is an autoimmune thyroid disorder caused by antibodies stimulating the thyrotropin (TSH) receptor on thyroid follicular cells [1]. One standard treatment for GD includes antithyroid drugs (ATD) usage for 12 to 18 months course [2]. This offers the possibility of disease remission without post-interventional hypothyroidism. However, risk for relapse is high and patients may experience side effects [2].

ATD may also have immunomodulating effects associated with normalization of TSH receptor antibody (TRAb) levels over time, which is potentially important in mediating remissions after therapy [3]. In addition, thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb) changes during ATD treatment also had been reported [4]. The remission rate varies among ethnicities and geographic areas [5]. In patients with normalized TRAb, relapse rates are 20% to 30% over 3 to 5 years of follow-up [1]. Overall, the risk of relapse after a 1 to 2 year course of ATD therapy is around 50% [6,7].

Some previously identified predictors of relapse are younger age, larger goiters, smoking, male sex, severe hyperthyroidism, higher concentration of antibodies, and presence of Graves' ophthalmopathy [2,7,8,9]. The usefulness of TRAb measurement at the time of ATD withdrawal for predicting a later relapse of hyperthyroidism has been studied intensively [10,11,12,13]. However, the effect of TPOAb or TgAb on the course of GD after ATD withdrawal remains unclear.

The aim of this study was to investigate the effect of autoimmune antibodies on risk of GD relapse in patients who underwent ATD treatment.

The risk of GD relapse after withdrawal of ATD therapy is highly variable among patients [6]. In patients with high risk of disease recurrence, definitive ablative therapy is recommended. Identification of patients who require definitive therapy at an early stage may be beneficial [15]. Numerous previous studies reported factors that may be associated with risk of hyperthyroidism relapse. These studies mostly focused on the usefulness of TRAb or thyroid stimulating antibody (TSAb) for predicting relapse [10,11]. However, the role of TPOAb or TgAb in GD relapse is not well known. This study shows that TPOAb and TgAb do not change uniformly during treatment with ATD. In TPOAb positive patients at diagnosis, increased TPOAb or TgAb titers during treatment might be related to shorter relapse free survival, independent of thyroid function or TRAb change.

The main clinical manifestations of autoimmune thyroid diseases are GD and Hashimoto's thyroiditis [15]. Although the presence of TPOAb or TgAb is a hallmark of Hashimoto's thyroiditis, both antibodies are also present in many patients with GD [16]. In some previous studies, GD patients with high TPOAb titers had a high relapse rate [16,17,18]. These studies suggest that in GD, TPOAb may represent a secondary immune process rather than a sign of antibody-dependent cell-mediated cytotoxicity [16]. The immunosuppressive action of ATD was previously reported [3,19]. One study reported that during ATD treatment, TPOAb values significantly decreased, as observed with TSAb, but they increased once again after drug withdrawal [4]. Increasing TPOAb titers during ATD therapy, even with decreasing TRAb, could represent greater disease severity and higher likelihood of relapse. Another study reported that patients with well-controlled hyperthyroidism had a greater decrease in TPOAb level than patients who were still hyperthyroid during ATD treatment [20,21]. Marcocci et al. [20] also showed that increased TPOAb titer after withdraw of ATD is associated with increased risk of relapse. This may indicate that TSAb increases TPOAb titers by mediating an increase in microsomal antigen [17,21]. However, some other studies showed opposite results [14,22,23]. Those reports showed decreased recurrence or even progression to hypothyroidism after ATD therapy in patients with high TPOAb or TbAb titers. GD may evolve gradually into chronic thyroiditis, leading to hypothyroidism. Another study showed significantly shorter T3 normalization time in the group with higher TPOAb [24]. The discrepancy between studies on the role of TPOAb and TgAb for predicting relapse might be due to several reasons. First, the duration and treatment protocols of ATD therapy differed. Second, the initial autoantibody status was not considered in previous studies.

Relapse of hyperthyroidism is a prominent drawback of ATD therapy [6]. Patients may suffer from repeated recurrence. It is important to identify factors that may be associated with relapse after withdrawal of ATD therapy. Previous studies did not focus on TPOAb or TgAb status or changes regarding disease relapse. In Korea, repeated measurement of TPOAb or TgAb during GD treatment is not recommended because it is not cost-effective. The current study showed new insights into the role of TPOAb or TgAb on GD relapse. These factors might help to guide early ablative treatment for those with very high relapse risk. Our study had an inherent limitation because of its retrospective design. There was no uniform protocol for the titration and duration of ATD treatment. There was a relatively small number of study subjects. Lastly, we did not consider other clinical factors such as smoking status, goiter size, and presence of thyroid-associated ophthalmopathy that might affect disease recurrence.

In summary, we conclude that increase of TPOAb or TgAb titer during ATD therapy, in patients with positive TPOAb at diagnosis, might have a higher likelihood of disease relapse.