Endocrine

DOI 10.1007/s12020-013-9895-0

ORIGINAL ARTICLE

Predictors of long-term remission in patients with Graves’

disease: a single center experience
Panagiotis Anagnostis • Fotini Adamidou • Stergios A. Polyzos •

Simoni Katergari • Eleni Karathanasi • Chrisanthi Zouli •

Athanasios Panagiotou • Marina Kita

Received: 9 November 2012 / Accepted: 30 January 2013

Ó Springer Science+Business Media New York 2013

Abstract Antithyroid drugs (ATDs) remain the first-line duration of ATDs therapy for more than 24 months inde-
therapy in patients with Graves’ disease (GD), despite a high pendently predicted predict long-term remission in GD.
relapse rate. The purpose of this study was to identify the
predictors of remission in patients with GD treated with Keywords Graves’ disease
Antithyroid drugs

ATDs—retrospective study at an endocrine referral service Orbitopathy
Predictors of remission
in Northern Greece. Two-hundred and eleven patients met
the study’s criteria. Females (p = 0.049), non-smokers
(p = 0.017), patients without ophthalmopathy (p = 0.033), Introduction
and those developing pharmaceutical hypothyroidism
(p = 0.018) experienced longer duration of remission. Graves’ disease (GD) is the most common etiology of
Duration of remission was positively associated with therapy hyperthyroidism, caused by circulating IgG antibodies that
duration (rs = 0.151, p = 0.030), maximum TSH levels activate G-protein-coupled TSH receptor (TRABs) [1, 2].
during (rs = 0.241, p = 0.001), at the end (rs = 0.280, GD affects about 0.5 % of the general population and is
p \ 0.001) and 3 months after therapy (rs = 0.341, p = more common in ages 40–60 years with a male-to-female
0.003). There was a negative association with free T4 (FT4) ratio of 1:10. Ophthalmopathy is present in 30–50 % of
(rs = -0.426, p \ 0.001) and free triiodothyronine (FT3) patients with GD [1].
(rs = -0.467, p = 0.038) levels at 6 months after ATDs Antithyroid drugs (ATDs) remain the cornerstone of
discontinuation. In multiple-regression analysis, only dura- treatment in GD, but recurrence rates after discontinuation
tion of the first ATDs course for more than 24 months are high. Indeed, the percentage of patients with permanent
independently predicted duration of remission. Female remission (defined as normal TSH levels after ATDs dis-
gender, non-smoking, the absence of orbitopathy, treatment continuation) is 30–50 % in adults [3–6] and 30 % in
duration, pharmaceutical hypothyroidism, higher TSH levels children [7, 8]. ATDs include carbimazole, methimazole
during, at the end and 3 months after ATDs discontinuation, (the active metabolite of carbimazole) and propylthioura-
and lower FT4 and FT3 levels 6 months after therapy were cil, which inhibit the synthesis of thyroid hormones. Pro-
associated with longer duration of remission. However, only pylthiouracil additionally inhibits peripheral conversion of
thyroxine to triiodothyronine. A course of 12–18 months
with ATDs is generally recommended for patients with
P. Anagnostis (&)
F. Adamidou
S. Katergari
GD [5, 6].
E. Karathanasi
C. Zouli
A. Panagiotou
M. Kita
Several studies in adults aimed to identify potential
Department of Endocrinology, Hippokration Hospital of
Thessaloniki, 10 Sarantaporou Street, 54 640 Thessaloniki, predictors of remission after treatment with ATDs, either at
Greece the beginning or during therapy. In general, younger age
e-mail: [email protected] (\40 years), smoking, male gender, thyroid gland size,
severity of hyperthyroidism at initial diagnosis, the pres-
S. A. Polyzos
Second Medical Clinic, Medical School, Aristotle University ence of ophthalmopathy and high titers of TRABs at the
of Thessaloniki, Thessaloniki, Greece beginning and at the end of therapy are associated with

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higher relapse rate [1, 9–12]. In a large prospective study, a one relapses, only the first course of ATDs therapy with
TRABs titer C46.5 UI/L could identify patients without was accounted for in the analysis.
remission (52 % sensitivity, 78 % specificity). A lesser
magnitude of decrease (\52.3 %) or an increase in TRABs Thyroid function assessments
at 6 months during and after therapy withdrawal could also
identify patients who had never achieved permanent Serum FT4, FT3, and TSH levels were determined by
remission (55 % sensitivity, 79 % specificity) [11]. radioimmunoassay (RIA) for the period 1990–1999, while
Another study showed a significant association between for the period 2000–2011 an immunochemiluminescent
serum TRABs levels at the end of ATDs treatment and non-competitive assay (ICMA) (Immnulite 2500 DPC,
disease relapse. In particular, TRABs levels [3.85 UI/L USA) was used and their normal ranges were 0.8–1.9 ng/
after withdrawal of methimazole had a positive predictive mL, 1.8–4.2 pg/mL, and 0.4–4 mIU/mL, respectively. The
value of 96.7 % [12]. Recently, it was published that total coefficient of variation (CV) for TSH assay was 3 %,
vitamin D seems to play a role in the pathogenesis of GD for FT4 it was 5–6 % and for FT3 the CV was 9 % at low
since low vitamin D levels are associated with lower rates level and 4 % at high level. Thyroid autoimmunity was
of remission [13] and vitamin D receptor polymorphisms, defined as serum TgAb and TPOAb levels[60 IU/L. TgAb
such as BsmI and TaqI, are associated with higher risk of and TPOAb were measured by RIA from 1990–1999 and
autoimmune thyroid disease, such as GD [14]. Conflicting Micro-Enzyme Immunoassay (ELISA, Varelisa, EliA,
data exist with respect to other factors, such as duration of Sweden Diagnostics, GmbH, Freiburg, Germany) from
therapy, ATDs type and dosage, as well as co-administra- 2000–2011. The total CV for thyroid autoantibodies was
tion of L-thyroxine [1]. \10 %.
The primary endpoint of this study was to identify
variables associated with duration of GD remission after Statistical analysis
treatment with ATDs.
The continuous variables are described as mean val-
ues ± standard error of the mean (SE) and the categorical
Subjects and methodology variables as numbers and/or percentages. The Kolmogorov–
Smirnov test was used to test the normality of distribution of
Patients’ data continuous variables; parametric or non-parametric tests
were subsequently chosen accordingly. The independent
This was a retrospective observational study conducted at the T test or Mann–Whitney test was used for the comparison of
department of Endocrinology in Hippokration General continuous variables between 2 independent groups. The
Hospital (Thessaloniki, Greece), a tertiary referral centre for analysis of variance (ANOVA) or Kruskal–Wallis test was
endocrinology and diabetes. Data from patients enrolled used for the comparison of continuous variables among more
between 1990 and 2011 were extracted from the depart- than 2 independent groups. In the cases of statistical signif-
ment’s electronic database. Inclusion criteria were (a) diag- icance, post hoc analysis was performed by the Bonferroni’s
nosis of GD based on physical examination, laboratory tests, adjustment. For comparisons between categorical variables,
and radionuclide imaging, and (b) at least 6 months of fol- Chi-square or Fischer exact test was used. For bivariable
lowup after ATDs treatment discontinuation. correlations, Spearman (rs) correlation was used. Multiple
For each patient, the following parameters were linear regression analysis was performed by the ‘‘enter’’
retrieved from the database: age, gender, smoking history, method. Dependent variable in this analysis was the duration
the presence of ophthalmopathy, assessment of nodular of remission (in months). The level of statistical significance
disease, number of relapses, maximum dose of ATDs, (p) was set at\0.05 for all the tests. Statistical analysis was
therapy duration, time to achieve euthyroidism, and the performed by the Statistical Package for the Social Sciences
development of pharmaceutical hypothyroidism. Thyroid (SPSS) for Windows (version 17.0). (SPSS Inc., Illinois,
auto-antibody status [anti-thyroglobulin (TgAb) and anti- USA).
thyroperoxidase antibodies (TPOAb)], TSH, free thyroxine
(FT4), and triiodothyronine (FT3) levels were evaluated at
the beginning and at the end of the first course with ATDs, Results
at 3–6-month intervals for 2 years after ATDs withdrawal
and TSH only levels yearly thereafter. Two-hundred and eleven patients (44 males, 167 females)
The duration of remission was defined as the period fulfilled the study’s criteria. The age of patients at the time
between ATDs withdrawal and the time of normal thyroid of diagnosis was 47.2 ± 0.9 years (range 14–81). Of those
function tests at end of followup. In the case of more than with available data, 65 % were smokers, ophthalmopathy

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was present in 36 %, while TPOAb, TgAb, or both, were (45.8 ± 4.9 vs. 33.0 ± 5.8 months, p = 0.033), and those
positive in 65, 60, and 49 %, respectively. without pharmaceutical hypothyroidism (46.9 ± 7.4 vs.
The patients’ ATDs treatment characteristics are pre- 34.8 ± 4.6 months, p = 0.018), respectively. Sixty-five per-
sented in Table 1. One-hundred and thirty-five patients cent of patients received ATDs for [24 months and longer
(64 %) were treated only with ATD, 82 (61 %) of whom duration of remission was observed in them (47.5 ± 5.0 vs.
remained on remission after drug withdrawal for 56.7 ± 29.7 ± 5.8 months, p = 0.021).
5.0 months of followup (range 6–240). From the remainder, Furthermore, duration of remission was positively associ-
34 (16.1 %) were treated with ATDs plus radioiodine (RAI), ated with duration of ATDs treatment (rs = 0.151, p =
39 (18.5 %) with ATDs, and surgery and 3 (1.4 %) were 0.030), maximum TSH value during treatment (rs = 0.241,
treated with ATDs, RAI, and surgery. The duration of the p = 0.001), TSH value at the end (rs = 0.280, p \ 0.001) and
first course of ATDs was 38.6 ± 1.83 months (range 4–168) at the third month (rs = 0.341, p = 0.003) after ATDs dis-
and the time to achieve euthyroidism was 14.8 ± 1.3 months continuation, and negatively associated with FT4 levels
(range 1–114). Most patients (63 %) achieved euthyroidism (rs = -0.426, p \ 0.001) and FT3 (rs = -0.467, p = 0.038)
within 12 of treatment. Of the 135 patients, 14 (6.6 %) at sixth month after ATDs discontinuation.
received concomitant therapy with L-thyroxine (block-and- Patients’ age at diagnosis, co-administration of L-thy-
replace treatment). Three patients (1.4 %) were subjected to roxine, the type, and the maximum dose of ATDs were not
both RAI and surgery. associated with duration of remission.
Fifty-two (24.6 %) patients developed pharmaceutical In multiple regression analysis, duration of first course
hypothyroidism during the first course of ATDs treatment of ATDs treatment for [24 months was the only inde-
(TSH levels 11.3 ± 1.5 mIU/mL; range 4.2–57.7). Thirty- pendent predictor of duration of remission (Table 1). In
seven (71.1 %) of them had TSH: 4–10 mIU/L, 7 (13.5 %) addition, patients who received longer duration of treat-
had TSH: 10–20 mIU/L and 8 (15.4 %) had TSH [ 20 ment with ATDs experienced longer duration of remission.
mIU/L. The time to development of hypothyroidism was
13.7 ± 2.0 months (range 1–60) and mean duration of
hypothyroidism was 4.4 ± 0.7 months (range 1–28). The Discussion
mean dose of carbimazole or methimazole at the time of
diagnosis of hypothyroidism was 13.9 ± 1.2 mg (range The current study is one of the largest in the literature and
5–30) and 14.0 ± 1.6 mg (range 5–20), respectively. the first one in Greece regarding the prognostic factors of
Ten patients (4.7 %) reported adverse events related to long-term remission in patients with GD treated with
ATDs use, mainly from carbimazole, and, in particular, 6 ATDs. The main findings relate to the significance of
(2.8 %) allergic reactions, 2 (0.9 %) gastrointestinal dis- therapy duration with ATDs as an independent predictor of
turbances (abdominal pain, transaminase elevation), and 2 long-term remission and the favorable effect of hypothy-
(0.9 %) leukopenia (neutropenia). No adverse event was roidism development during therapy with ATDs on dura-
observed after PTU treatment. tion of remission.
Longer duration of remission was observed in females, non- Conflicting data exist regarding the effect of the duration
smokers, patients without ophthalmopathy, and those who of therapy with ATDs on GD relapse. Older studies com-
developed pharmaceutical hypothyroidism during ATDs pared the effect of 12 or 18 months of ATDs treatment
treatment in comparison to males (44.1 ± 4.9 vs. 30.6 ± (with or without co-administration of L-thyroxine) to
4.6 months, p = 0.049), smokers (45.8 ± 6.4 vs. 25.5 ± 6-months therapy with contradictory results [15, 16].
5.4 months, p = 0.017), patients with ophthalmopathy Similarly, studies comparing longer durations of therapy,

Table 1 Multiple linear regression analysis for the prediction of the duration of remission in patients with Graves’ disease
Variable Beta coefficient p value 95 % CI

Gender 7.97 0.502 -15.5–31.4

Smoking -13.04 0.210 -33.6–7.5
Ophthalmopathy -14.01 0.175 -34.4–6.4
Hypothyroidism during therapy 16.23 0.115 -4.0–36.5
Duration of first therapy [24 months 33.25 0.002 12.7–53.8
Dependent variable was the duration of remission of Grave’s disease (in months)
Independent variables were dichotomous or transformed to dichotomous as follows: gender (male = 0; female = 1), smoking (No = 0;
Yes = 1), orbitopathy (No = 0; Yes = 1), duration of first therapy (B24 months; [24 months)

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i.e., 12 versus 24 months [17] or 18 versus 42 months [18], has been also confirmed by others [24, 26–28]. Conflicting
did not find any difference in the relapse rates after therapy data exist with respect to the effect of age at GD diagnosis
discontinuation. A recent meta-analysis did not find any on therapy outcomes. It has been supported that patients
difference between long- or short-term regimens regarding aged [40 years at presentation are more likely to experi-
relapse of hyperthyroidism [Relative Risk = 0.88, 95 % ence longer duration of remission after therapy with ATDs
confidence interval: 0.67–1.16] [5]. Two retrospective [9, 29, 30] although other authors did not confirm an
studies of 60 [19] and 106 [20] patients showed a negative association with age [24, 26].
association between the treatment duration and relapse Moreover, female sex, non-smoking status, and the
rates [19], comparing 19 months of therapy to less than absence of orbitopathy had a favorable effect on duration
6 months [19]. The present study is readdressing this issue of remission in the present study, but could not indepen-
and indicates that, apart from a positive correlation of dently predict it. With respect to gender, most [1, 9, 31],
therapy duration of [24 months with duration of remis- but not all [26] studies support the observation that GD in
sion, longer duration of ATDs treatment predicts longer males presents lower remission rates than in females. The
remission independently from other factors, such as gender, unfavourable effect of smoking on the achievement of
smoking, ophthalmopathy, and the development of hypo- remission has also been previously documented [23, 31];
thyroidism during therapy. smoking has been reported to have an additive detrimental
Regarding the development of hypothyroidism during effect in the presence of TRABs positivity [20]. Conflicting
ATDs, it is considered to be the result of more aggressive data exist with regard to the effect of ophthalmopathy on
therapy in cases of mild hyperthyroidism or a failure to the duration of remission [24, 27].
adjust ATDs dosage [21]. In our series, patients developing Finally, the present study indicates that higher TSH
hypothyroidism during therapy experienced longer dura- levels at the end and at 3 months after therapy termination
tion of remission than those who remained hyperthyroid or are associated with longer duration of remission, while
achieved euthyroidism. This finding is further enhanced by there was a negative association of duration of remission
the positive correlation between maximum TSH value and with FT4 and FT3 levels at 6 months after ATDs with-
duration of remission. Another recent retrospective study, drawal. Assessment of thyroid function for a long period of
also showed a positive correlation between ATDs-induced time (57 months, range 0–240) allowed us to make safe
hypothyroidism and long-term remission in patients with conclusions regarding its association with duration of
GD [22]. In that study, the duration of hypothyroidism and remission. Data from small retrospective studies [32] and
mean daily methimazole dose was similar to our study, from a large prospective multicenter trial [10] have shown
whereas mean time to detection of hypothyroidism was that TSH suppression at the end of therapy is followed by
shorter (7.3 ± 5.5 vs. 13.7 ± 13.8 months) and TSH levels higher relapse rates. It has also been shown that TSH \0.3
were higher (10.5–40 mIU/L). In the same study, all the 40 mIU/L 4 weeks after the end of therapy has a positive
patients included had TSH [10 mIU/L, whereas in our predictive value of 70 % and a negative predictive value of
study only 28.9 % of patients who developed hypothy- 62 % for disease relapse [33] Another study showed that
roidism had a TSH [10 mIU/L. Despite these differences, TSH levels [1.2 mIU/L on the first month after therapy
the final conclusion was compatible with ours. Thus, the discontinuation had a positive predictive value of 100 %
development of hypothyroidism during ATDs treatment for disease remission [34]. In contrast, an older study
seems to be a favorable prognostic indicator. showed that TSH levels had little prognostic value in
Regarding co-administration of L-T4 (block-and-replace comparison with thyroglobulin levels and the titer of thy-
regimen), we did not find any significant differences between rotropin-binding inhibiting immunoglobulins (TBII) [35].
this regimen and simply titrating ATDs dose according to Although high levels of FT4 and FT3 before therapy
thyroid function tests although only a minority of our with ATDs have been regarded as significant predictors of
patients received block and replace regimen. This has been relapse in several studies [31, 32, 36], there are no avail-
confirmed by several studies in the literature [23, 24], as well able data regarding an association of their levels with
as by a recent meta-analysis [5] although some authors have disease remission after therapy discontinuation. A negative
shown that co-administration of L-T4 may decrease both association of FT4 and FT3 levels at 6 months after ATDs’
TRABs levels and the possibility of relapse [25]. An older withdrawal with the duration of remission is reported for
study showed that block-and-replace regimen may in fact the first time in the present study.
delay relapse detection rather than reduce the possibility of Limitations of the present study include its retrospective
relapse itself and is more frequently related to adverse events nature and the absence of data regarding TRABs (due to
in comparison with ATDs-only treatment titration. [26]. unavailability of this assay from our hospital laboratory)
As far as the dose or type of ATDs is concerned, we did and thyroid volume (due to absence of full sonographic
not find any association with duration of remission, which data regarding thyroid gland size).

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In conclusion, treatment with ATDs for more than Serum thyrotropin receptor antibodies concentrations in patients
24 months is an independent predictor of long-term with Graves’ disease before, at the end of methimazole treatment,
and after drug withdrawal: evidence that the activity of thyrot-
remission in patients with GD. The development of hypo- ropin receptor antibody and/or thyroid response modify during
thyroidism during therapy, female gender, and the absence the observation period. Thyroid 16, 295–302 (2006)
of smoking or ophthalmopathy are favorable indicators of 13. T. Yasuda, Y. Okamoto, N. Hamada, K. Miyashita, M. Takahara,
long-term remission. Higher TSH levels during, at the end, F. Sakamoto, T. Miyatsuka, T. Kitamura, N. Katakami, D. Kawa-
mori, M. Otsuki, T.A. Matsuoka, H. Kaneto, I. Shimomura,
and at 3 months, as well as lower levels of FT4 and FT3 at Serum vitamin D levels are decreased in patients without
6 months after ATDs discontinuation, are also associated remission of Graves’ disease. Endocrine 43(1), 230–232 (2012)
with longer duration of remission. 14. M. Feng, H. Li, S.F. Chen, W.F. Li, F.B. Zhang, Polymorphisms
in the vitamin D receptor gene and risk of autoimmune thyroid
Conflict of interest The authors have no conflict of interest to diseases: a meta-analysis. Endocrine, (2012). doi:10.1007/
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15. H. Allannic, R. Fauchet, J. Orgiazzi, A.M. Madec, B. Genetet,
Y. Lorcy, A.M. Le Guerrier, C. Delambre, V. Derennes, Anti-
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