Introduction

Graves’ disease (GD) is the most common cause of hyperthyroidism in iodine-replete regions, usually affecting women aged 40 to 60 years old [1]. It is an autoimmune disorder characterized by the presence of thyroid-stimulating hormone receptor antibodies (TRAb) that stimulate follicular thyroid cells to synthesize and secrete thyroxine (T4) and triiodothyronine (T3) [2]. Consequently, the thyroid gland increases its volume and vascularity. The main extra-thyroidal manifestation is Graves’ orbitopathy (GO), which affects 20% of patients with Graves’ hyperthyroidism (GH) [3]. GD is easily recognized by the triad: thyrotoxicosis, diffuse goiter, and ophthalmopathy [4].

Management of GD implies drug treatment using anti-thyroid drugs (ATDs) in different regimens, radioactive iodine (RAI), or thyroidectomy (Tx) [5]. The first-line treatment in Europe is anti-thyroid medication, while in the United States RAI is preferred [6]. The course of GO is not influenced by thionamides or surgery, but it is worsened by RAI treatment [7]. RAI and total thyroidectomy (TTx) have a low risk for hyperthyroidism recurrence, but patients require lifelong treatment with levothyroxine (LT4) [8]. Using ATDs, the risk of GD recurrence is ~50% [9].

The main ATDs used are carbimazole (CBZ), with its active metabolite methimazole (MMI) and propylthiouracil (PTU). They control hyperthyroidism by inhibiting thyroid hormone synthesis and by their immunosuppressive effect. In addition, PTU inhibits the peripheral conversion of T4 to T3 [10]. The most common adverse reactions are skin rash, arthralgia, and transient mild leukopenia, which develop in 1% to 5% of patients. Very rarely (< 0.1% of cases) agranulocytosis may occur with MMI or CBZ therapy and liver failure during PTU therapy [11]. The optimal duration of ATDs administration is considered to be 12–18 months [12].

ATDs can be administrated in a titration (T) regimen or using a block-and-replace regimen, as first described by Hashizume [13]. No difference was observed between the risk of GD relapse between the 2 treatment regimens or in the duration of therapy [12]. However, no systematic review has described the control of thyroid function during block and replace therapy (BRT) versus T of ATDs and how these therapies would influence the onset of GO.

We want to assess the control of GH during ATDs therapy. We compared ATDs used in a block-and-replace regimen versus a T regimen to evaluate the incidence of overt hypothyroidism during therapies, the number of euthyroid patients during 18 months of treatment, and the number of thyroid function tests (TFT) during therapies. Secondary outcomes are assessment of GO development, body weight changes, and lipid profile evolution in the BRT group versus the T group.

Material and methods

Criteria for considering studies for this review

Types of studies

Prospective and retrospective cohort studies that met the inclusion criteria were included in this systematic review and meta-analysis. The minimum duration of therapy should be 18 months, and thyroid function should be assessed during this period.

Types of participants

Patients with a first episode of GD following medical treatment were included. Diagnosis of GD was made on documentation of thyrotoxicosis [suppressed thyroid-stimulating hormone (TSH), increased free T4 (fT4) and/or free T3 (fT3)], positive TRAb, enlarged goiter, with increased vascularity or diffuse increased radioiodine uptake on thyroid scans. Patients aged < 18 years, pregnant women, or patients with a positive history of RAI or TTx were excluded.

Types of interventions

The intervention consists of using medical therapy with ATDs in patients with GD. We compared the number of patients with overt hypothyroidism during BRT versus T regimen. After 18 months of therapy, we compared the number of patients with stable thyroid function in each group. We defined stable thyroid function as: euthyroidism (TSH and fT4 in reference range), subclinical hypothyroidism (TSH > 4.5 mIU/L, fT4 in reference range), and subclinical hyperthyroidism (TSH < 0.4 mIU/L, fT4 in reference range). The ATDs used were CBZ, MMI, or PTU. BRT consisted of the addition of LT4 to a high dose of thionamide. In addition, we compared the number of GD patients who developed GO during BRT versus T and the number of TFT performed.

Types of outcome measures

Primary outcomes

Primary outcomes included:

Secondary outcomes

Secondary outcomes included:

Search methods for identification of studies

Electronic searches

The following sources were used to identify cohort studies:

The terms used to identify potential articles were: “block replace”, “thyroid”, and “Graves”. The search was restricted to articles written in English with full text available.

Searching other resources

The reference lists of retrieved papers were searched for additional cohort studies.

Data collection and analysis

Selection of studies

Two authors independently searched the literature and evaluated each record by the title and abstract of the article. Articles containing patients diagnosed with GD on ATD treatment for a period of 18 months were read in full text. Any queries regarding the criteria for inclusion of certain articles in the meta-analysis were discussed between the authors.

Data extraction and management

The extraction of data related to the first author, name of the journal, year of publication, title, and abstract of the article was done automatically in Reference Manager. Two authors independently extracted the data on sample size, age and sex of patients, accuracy of GD diagnosis, type of intervention, duration of treatment, and outcomes (number of euthyroid patients at the end of therapy, incidence of hypothyroidism during therapy, presence of GO among the patients, and number of TFT during therapy). Statistical analysis was done in Review Manager 5.4.

Assessment of risk of bias in the included studies

Two authors independently assessed the risk of bias in the studies using the Newcastle-Ottawa scale (NOS). For each answer marked with asterisk one point is added. The maximum score for each section is as follows: 4 points for Selection, 2 points for Comparability, and 3 points for Outcomes. A score higher than 7 points indicates a high quality of the study. Any disagreements were discussed between the authors.

Measures of treatment effect

We expressed dichotomous data as Mantel-Haenszel (M-H) odds ratio (OR) with 95% confidence intervals (CI) using a random-effects model. We expressed continuous variables as mean difference or adjusted mean difference.

Dealing with missing data

To have complete data we chose the original studies of each author and avoided duplicate publications. We checked the guidelines for appropriate medical management of GD (doses of drugs used, addition to LT4). We calculated the proportion of patients lost to follow-up. We estimated the number of patients with stable thyroid function during therapy using values at different treatment endpoints.

Assessment of heterogeneity

Heterogeneity was assessed by visual inspection of the forest plot and I2 calculation. An I2 value greater than 75% indicates high heterogeneity, while a value less than 25% indicates low heterogeneity. For this meta-analysis a random-effects model was used.

Assessment of reporting biases

Each publication was assessed for risk of bias. In addition, forest plots were inspected for their asymmetry.

Data synthesis

We used a random-effects model to statistically process data from heterogeneous studies. For each outcome the data were combined using dichotomous variables, expressed as OR, with 95% CI.

Quality of the evidence

Two authors independently assessed the quality of evidence on main outcomes according to Grading of Recommendation, Assessment, Development, and Evaluations (GRADE) [14]. Factors such as study design or the risk of bias of each study were taken into account.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was not performed.

Sensitivity analysis

We only included published articles written in English that met the inclusion criteria and that we assessed for risk of bias. For each outcome we statistically processed using both fixed-effect and random effect-models and expressed the results in risk ratio (RR), OR, and risk difference.

Results

Description of studies

The publication dates of the articles included in the meta-analysis are from 2014 to the present day. One study included patients from a single center [15], and the other study is a multicenter study, including 10 centers from Europe [16]. Both articles included observational cohort studies.

Results of the search

Two databases were searched, including a total of 115 studies: PubMed (MEDLINE) — 62 studies and Cochrane Library (CENTRAL) — 53 studies. An additional search was done using reference lists of retrieved articles. Three more studies were subsequently added. Duplicate papers and those without full-text available or not written in English were excluded. Also, articles that were not in accordance with the terms: “block replace”, “thyroid”, or “Graves” were excluded. Twenty-seven articles were sought for retrieval, and 17 of them were screened for eligibility (Fig. 1). Twelve articles [17–28], one conference paper [29], and 2 clinical trials were excluded.

Figure 1. PRISMA chart

Included studies

Only 2 articles were included in this meta-analysis and used for data abstraction (Tab. 1). Each study had 2 subgroups of patients: those who underwent BRT and those who underwent a T regimen of ATDs.

Overview of study population

The two studies included 794 GD patients who completed 18 months of treatment, but only 716 patients were included in the statistical analysis. We excluded 78 patients treated using both BRT and T [15]. In total, 289 (40.36%) GD patients were on BRT and 427 (59.64%) GD patients were on T. Approximately 8.75% (33/377) of patients were lost at follow-up [16].

Study design and settings

The 2 cohort studies included were performed between 1997 and 2015. One was conducted in a retrospective design [15], while the other had a prospective design [16]. Consecutive hospitalized patients who followed ATD therapy for GD were included. Each main group was divided into 2 subgroups according to the ATD regimen used.

Participants

Patients included in both studies had a mean age of 40 years. Female patients were more prevalent in both studies: 82.52% (307/372) [15] and 82.55% (284/344) [16]. The number of current smokers was 29.36 % (101/344) in the first study and 21.5% (80/372) in the second one. Only one study [16] reported a higher prevalence of non-Caucasian patients in the block-and-replace subgroup.

Diagnosis

In both studies, the diagnosis of GD was based on the association of hyperthyroidism (suppressed TSH, increased fT4 and/or fT3), diffuse goiter (ultrasound/scintigraphy), and positive TRAb. The presence of extra-thyroidal manifestations of GD (e.g., GO, dermopathy) at baseline as a diagnostic criterion was included in only one study [15].

Intervention

All patients included in the 2 studies were at their first episode of GD and were treated with ATDs ± LT4. Duration of treatment was 18 months regardless of the regimen used. One study [15] reported the use of CBZ and PTU as ATDs. None of the studies described the drug doses used or the method of administration. We assumed that the doses of drugs used were in line with current guidelines. Five centers used both ATDs regimens to treat GD patients and 6 centers used only the T regimen.

Outcomes

Both studies aimed to determine the maintenance of stable thyroid function during drug therapy and express the frequency of euthyroidism and overt hypothyroidism over 18 months of treatment. One study provided information on the number of thyroid function tests [15], and the other on the number of patients who developed GO during therapy [16].

Excluded studies

The main reasons for exclusion of studies initially considered as eligible were as follows: block-and-replace therapy consisting of the addition of T3 to ATDs [27,28], absence of a control group [22], assessment of risk of relapse of GD (short duration of therapy or no assessment of thyroid function during therapy) [18, 19, 24, 26, 30], inclusion of patients with RAI and/or TTx [20, 21, 23], and hyperthyroidism of other causes or other primary outcomes [17, 29] (Tab. 2).

Risk of bias in the included studies

The risk of bias was assessed using the Newcastle-Ottawa scale (NOS). Both studies scored 7/9 points, indicating high study quality (Tab. 3).

Allocation

The allocation of GD patients to a particular type of ATDs regimen was not mentioned in any of the studies.

Blinding

This criterion was not applied for the type of studies included in the meta-analysis.

Incomplete outcome data

The percentage of patients lost to follow-up during therapy was low (8.75%) and was not taken into consideration in the statistical analysis. In one study, the percentage of euthyroid patients or patients with abnormal thyroid function during therapy was expressed at different endpoints of treatment. We used these values to calculate an average number of patients with normal or abnormal thyroid function tests.

Selective reporting

The 2 studies had a low risk of bias and reported data on thyroid function testing over 18 months of medical treatment of GD. However, outcomes such as development of GO during therapy were not reported in one study [15]. Weight gain during therapy was not reported in the other study [16]. None of the studies reported data on lipid profile changes during medical therapy of GD.

Other potential sources of bias

Other potential sources of bias could be estimating the number of patients with stable thyroid function by including subclinical hypothyroidism and/or hyperthyroidism. Also, the number of patients with stable thyroid function during therapy in one study was obtained by calculating an average of the number of patients at different treatment endpoints.

Effects of intervention

The main results of this meta-analysis are the proportion of patients with overt hypothyroidism and euthyroidism during 18 months of treatment with ATDs using a block-and-replace regimen versus a T regimen.

Baseline characteristics

No differences were observed between studies in terms of mean age of groups, proportion of female gender, current smokers, or duration of therapy. At baseline in both studies, the mean TSH was less than 0.03 mIU/L and fT4 was 1.5 times the upper normal limit (UNL). Only one of the studies [16] included patients without GO at baseline.

Primary outcomes

Incidence of overt hypothyroidism

No statistically significant differences were observed between the ATD regimens used in terms of incidence of overt hypothyroidism during 18 months of treatment (M-H OR: 1.54, 95% CI: 0.75–3.16, p-value = 0.24) (Fig. 2A). Only 8.3% (24/289) of patients treated with a block-and-replace regimen had clinical hypothyroidism, compared to 3.98% (17/427) of patients on the titration (T) regimen.

Figure 2. A. Forest plot of comparison 1: Number of patients with overt hypothyroidism during 18 months of block-and-replace therapy (BRT) versus titration (T). Main outcome: 1. Incidence of overt hypothyroidism during 18 months of medical treatment of Graves’ disease (GD). B. Forest plot of comparison 2: Prevalence of euthyroid patients over 18 months of BRT versus T. Main outcome: 2. Prevalence of euthyroid patients over 18 months of anti-thyroid drugs (ATDs) treatment for GD. C. Forest plot of comparison 3: Incidence of GO development during medical treatment. Secondary outcome: 1. Incidence of GO development during ATDs treatment for GD. D. Forest plot of comparison 4: Incidence of GO development during medical treatment. Secondary outcome: 1. Incidence of GO development during ATDs treatment for GD. BRT — block-and-replace therapy; CI — confidence interval; M-H — Mantel-Haenszel odds ratio

Prevalence of euthyroidism

GD patients who followed a block-and-replace therapy were less likely to achieve control of thyroid function than patients on a titration regimen (M-H OR: 0.55, 95% CI: 0.34–0.88, p = 0.01) (Fig. 2B). In this statistical analysis, all patients who achieved euthyroidism, or subclinical hypo- or hyperthyroidism were considered to have obtained control of overt hyperthyroidism due to GD.

Number of TFT during medical therapy

The number of TFT was assessed in one study during medical treatment of GD. Patients on BRT performed on average 3.2 ± 1.2 thyroid function tests per year, while patients on the T regimen required 3.4 ± 1.5 tests per year (adjusted mean difference –0.4, 95% CI: –0.7; –01, p = 0.008) [15].

Secondary outcomes

Incidence of GO development during ATD treatment

We assumed that both studies included at baseline GD patients without GO. No statistically significant difference in terms of incidence of GO development during BRT versus T regimen was observed (M-H OR: 1.18, 95% CI: 0.20–7.06, p = 0.86) (Fig. 2C).

If only the study that specified no GO at baseline is included in the analysis, then the incidence of GO during BRT was lower than in the T regimen (9.1% versus 17.8%), with no statistically significant difference between the 2 regimens (M-H OR: 0.47, 95% CI: 0.19–1.14, p = 0.10) (Fig. 2D).

Changes in weight during medical treatment

Only one study assessed weight gain during BRT versus T regimen, which was greater in the former group, but not significantly. The adjusted mean difference between the groups was 1.6 kg (95% CI: –0.3–3.5, p = 0.09) [15].

Lipid profile changes during GD therapy

No data regarding the evolution of lipid profile during medical treatment of GD were included in the studies.

Subgroup analyses

Subgroup analysis was not performed.

Sensitivity analyses

Sensitivity analysis was performed only for one outcome (development of GO) by excluding articles not mentioning the absence of GO at baseline.

Assessment of reporting bias

Both studies were assessed as low risk of bias in terms of primary outcomes.

Discussion

Summary of outcomes and quality of evidence

Two observational cohort studies were included in this meta-analysis. Participants were following either a BRT or T regimen to treat GD hyperthyroidism. No differences in the incidence of overt hypothyroidism were observed between the 2 regimens. None of the studies mentioned the doses of drug used. In a systematic review by Abraham et al. CBZ was used in dose ranges between 30 and 60 mg per day and only in one study up to 100 mg per day [10]. Current guidelines recommend CBZ 40 mg/day, MMI 30 mg/day, or PTU 50–150 mg 3 times daily as the starting dose [6, 31].

There was a lower probability of achieving stable thyroid function using BRT compared to the T regimen. This result has low GRADE quality evidence, and further research is needed. One reason is that the number of patients considered to have stable thyroid function was estimated and included patients with euthyroidism and subclinical hypo- or hyperthyroidism. The second reason is that in the retrospective cohort study there were more patients at baseline with complicated GD in the BRT group than in the T-regimen group. This is consistent with studies in the literature, where BRT can be considered for patients with fluctuating thyroid disease [32]. Lewandowski et al. described an atypical onset of GD with myocardial infarction in a 31-year-old woman. She achieved control of hyperthyroidism using BRT [33]. It may also be suitable for patients with difficult access to healthcare due to the reduced number of thyroid function tests during therapy [15, 31].

GO development during BRT compared to T regimen was evaluated in a single study. The incidence of GO was lower in the group treated with BRT than in the T group, but the difference was not statistically significant [15]. No other studies were found to assess the occurrence of GO during different ATD regimens. The other study did not report on the proportion of patients with GO at baseline. However, more patients with extra-thyroidal manifestations were treated with BRT. In the BRT group, 15.5% of patients had GO and 2.8% of patients had dermopathy, compared to 6.3% and 1.4% in the T group [16]. The combined results of these studies have a very low quality of evidence. Further research is needed to assess whether BRT could be a protective factor in GO development.

We found no studies comparing the effects of different ATDs regimens used in GD on metabolism.

Summary of main results

BRT and T regimens have the same effectiveness in avoiding overt hypothyroidism during treatment.

BRT could offer a stable thyroid function with fewer thyroid function tests during therapy than the T regimen.

BRT could be more suitable for complicated GD than the T regimen.

This meta-analysis is assessed overall as having a low to very low quality of evidence.

Potential bias in the review process

One of the limitations of this study relates to the small number of articles included. Unpublished data were not included. Articles written in languages other than English were also not included.

Agreements and disagreements with other studies or reviews

To our knowledge there are no other publications comparing the incidence of overt hypothyroidism and GO development in GD patients using different ATD regimens.

Conclusion

Although initially controversial, block-and-replace therapy is now more and more accepted as being indicated for selective categories of patients diagnosed with Graves’ disease.

Conflict of interest

Authors declare no conflict of interest.

Acknowledgements

Publication of this paper was supported by the University of Medicine and Pharmacy Carol Davila through the institutional program Publish not Perish.

Author contribution

A.M.S. and C.B. independently searched the literature and evaluated each article. A.M.S. performed the statistical analysis and wrote the article. C.B. supervised the writing of the article. Both authors reviewed and approved the final draft.

Funding

This work was co-financed by the European Social Fund through the Operational Program, project number POCU/993/6/13/154722.

Disclosures

None declared.

Data availability

Original data generated and analyzed during this study are available from the corresponding author on reasonable request.