Risk Factors for the Relapse of Graves’ Disease Treated With Antithyroid Drugs: A Systematic Review and Meta-analysis

Abstract

Purpose

Antithyroid drugs (ATDs) are the first-line treatment for Graves’ disease (GD). A common problem with ATD treatment is the high relapse rate after drug withdrawal. The goal of this study was to analyze the influencing factors for the relapse of GD patients treated with ATD by using a systematic review and meta-analysis, provide some predictive indexes for the susceptibility of GD recurrence, and then further explore some useful methods to decrease the GD relapse rate after ATD treatment.

Methods

Articles published in PubMed, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, Wan Fang, and Chinese Biomedical Literature databases before January 2019 were collected. Patients newly diagnosed with GD, who were aged >16 years, were treated with ATD. Follow-up was then conducted for at least 12 months after ATD withdrawal. Only prospective or retrospective studies were eligible. The primary end point was the recurrence of GD during follow-up. All the data from the trials were analyzed via meta-analysis and meta-regression. p values < 0.05 were considered statistically significant, and statistical heterogeneity was assessed by using I² statistics.

Findings

A total of 20 studies and 3242 patients were involved in this meta-analysis, with 1681 patients relapsed (incidence rate, 51.9%) during the follow-up time. Analysis of risk factors suggested that younger age (weighted raw mean difference [RMD], −3.51; 95% CI, −5.74 to −1.29), larger thyroid volume (RMD, 4.38; 95% CI, 1.68 to 7.08), bigger goiter size (1.94% risk; 95% CI, 0.43 to 3.46), higher free triiodothyronine level (RMD, 5.09; 95% CI, 4.42 to 5.77), and higher free thyroxine level (RMD, 4.21; 95% CI, 0.54 to 7.89) were associated with the higher relapse rate of GD. The block-replace ATD regimen (a fixed high dose of an ATD with levothyroxine supplementation to maintain euthyroidism) (risk ratio, 0.64; 95% CI, 0.52 to 0.78) exhibits a lower relapse rate than the titration regimen (an ATD used alone and dose adjusted according to thyroid function tests).

Implications

This analysis revealed that certain risk factors were associated with GD relapses such as younger age, larger goiter size or thyroid volume, and the higher free triiodothyronine or free thyroxine level in the diagnosing phase of GD. For patients with these clinical characteristics, early definitive treatment with radioactive iodine or surgery should be offered to those who are unlikely to achieve remission with ATDs only. In addition, more prospective cohort studies with different ATD regimens would help to determine the optimum ATD treatment for patients with GD. PROSPERO identifier: CRD 42019146825.

Introduction

Graves' disease (GD) is the most common cause of hyperthyroidism. Current therapeutic options for GD include antithyroid drugs (ATDs), radioactive iodine (RAI), and thyroidectomy.¹ Compared with RAI and surgery, ATD treatment has many advantages, including normalizing thyroid function in a relatively short period, causing little severe hypothyroidism, and improving immune disorder while avoiding radiation exposure and decreasing the possibility of the progression of severe orbitopathy.^2,3 ATD treatment may cause side effects such as rash, impaired liver function, and leukocytopenia, but these effects are usually mild and curable.⁴ Thus, ATD treatment is generally well accepted by patients and clinicians. However, the high recurrence rate after ATD withdrawal is a challenging aspect of ATD treatment. The recurrence of GD will cause frequent hospital follow-ups and blood tests, which will increase patients’ medical expenses and impair their quality of life.

A better understanding of the risk factors for relapse of GD patients with ATD treatment is therefore very important. Risk factor assessment may help clinicians distinguish high-risk patients from others who can be cured by ATD treatment alone. A more definitive treatment approach (RAI or surgery) should be offered to high-risk patients at their initial diagnosis stage or the first recurrence after one course of ATD treatment.

Many risk factors are reportedly associated with a high GD recurrence rate, including age, sex, smoking status, pressure, goiter size, thyroid hypervascularization, disease severity, presence of Graves’ orbitopathy (GO), thyrotropin receptor antibody (TRAb) level, family history, and genetic predisposition.5, 6, 7, 8, 9, 10 However, the association between these factors and the GD recurrence rate after ATD withdrawal remains controversial between different studies.11, 12, 13, 14, 15, 16 Meanwhile, researchers have focused on the relation between different antithyroid regimens, including the block-replace regimen (a fixed high dose of an ATD with levothyroxine supplementation to maintain euthyroidism) and the titration regimen (an ATD used alone and dose adjusted according to thyroid function test results), or the duration of ATD therapy and the GD relapse rate.17, 18, 19 However, no previous systematic review assessed both classical risk factors and different treatment strategies (including ATD regimen and ATD therapy duration) together on the influence of GD recurrence. Thus, the present study analyzed all these influencing factors together, with the expectation of determining more valuable predicted factors and more suitable treatment strategies for clinical practice. The goal is to decrease the relapse rate of GD after ATD withdrawal and provide patients with more valuable suggestions after the first treatment (ATD, surgery, or RAI).