REVIEW

URRENT
C
OPINION

Relapse following antithyroid drug therapy for

Graves hyperthyroidism
Peter Laurberg a,b, Anne Krejbjerg a,b, and Stine Linding Andersen a,b

Purpose of review
In most patients with hyperthyroidism caused by Graves disease, antithyroid drug (ATD) therapy is
followed by a gradual amelioration of the autoimmune abnormality, but about half of the patients will
experience relapse of hyperthyroidism when the ATDs are withdrawn after a standard 1 to 2 years of
therapy. This is a major drawback of ATD therapy, and a major concern to patients. We review current
knowledge on how to predict and possibly reduce the risk of such relapse.
Recent findings
Several patient and disease characteristics, as well as environmental factors and duration of ATD therapy,
may influence the risk of relapse after ATD withdrawal. Depending on the presence of such factors, the risk
of relapse after ATD withdrawal may vary from around 10 to 90%. Risk factors for relapse should be taken
into account when choosing between therapeutic modalities in a patient with newly diagnosed disease,
and also when discussing duration of ATD therapy.
Summary
Prolonged low-dose ATD therapy may be feasible in patients with high risk of relapse, such as children and
patients with active Graves orbitopathy, and in patients with previous relapse who prefer such therapy
rather than surgery or radioiodine.
Keywords
antithyroid drug therapy, Graves disease, hyperthyroidism, hyperthyroidism relapse, thyrotropin-receptor
antibodies

INTRODUCTION
In most patients with hyperthyroidism caused by
Graves disease, antithyroid drug (ATD) therapy is
followed by a gradual amelioration of the autoimmune abnormality, which is also observed after
surgical thyroidectomy, but not after radioiodine
therapy [1] (Fig. 1). Autoimmune remission is not
influenced by the type of drug used to restore
euthyroidism or by the dose of drug. Considering
this, we find it likely that remission is not caused by
the drugs themselves but is part of the natural
history of Graves disease in a euthyroid patient.
Thus, focus should be on achieving and maintaining
euthyroidism [2].
However, a small group of hyperthyroid patients
do not remit during ATD therapy, and if the ATD is
withdrawn, hyperthyroidism will immediately
reappear. Moreover, some patients enter partial
remission and remain euthyroid for a period of time
after ATD withdrawal, but hyperthyroidism often
relapses. Finally, even a subgroup of the patients
who, based on available measures, are in full

remission at the time of drug withdrawal may

experience reoccurrence of hyperthyroidism.
Relapse of hyperthyroidism is a prominent drawback of ATD therapy. In a retrospective study, satisfaction with therapy in Swedish patients who had
been randomized to treatment with ATD, surgery or
radioiodine, was in general high [3]. However, the
fraction of patients who had experienced a relapse of
hyperthyroidism after withdrawal of medication
expressed concerns about this [3], and thus, it is
important to discuss the possibility of later relapse
of hyperthyroidism with patients treated with ATDs.
Overall, the risk of relapse after a 1 to 2 year
course of ATD therapy is around 50%. However, a
a
Department of Endocrinology, Aalborg University Hospital and bDepartDepartment of Clinical Medicine, Aalborg University, Aalborg, Denmark

Correspondence to Peter Laurberg, Department of Endocrinology, Aalborg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark. Tel:
+45 97 66 36 82; fax: +45 99 32 68 57; e-mail: peter.laurberg@rn.dk
Curr Opin Endocrinol Diabetes Obes 2014, 21:415421
DOI:10.1097/MED.0000000000000088

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Thyroid

KEY POINTS

Risk of relapse of hyperthyroidism after ATD withdrawal
varies between approximately 10 and 90% in
subgroups of patients with Graves disease.

Risk can be estimated from clinical and biochemical
evaluation at the time of diagnosis, and from the
response to therapy.

Prolonged low-dose methimazole (or carbimazole)
therapy may be advisable in patients with a high risk of
relapse such as young children, patients with active
orbitopathy, and patients with previous relapse who
prefer such therapy rather than radioiodine or surgery.

TSH-receptor measurement is a valuable but not perfect
indicator of risk of relapse, especially when ATD has
been given for at least 12 months.

number of patient and disease characteristics, as

well as environmental factors and mode of ATD
therapy, may influence the risk of relapse. Factors
that may be associated with the risk of relapse of
hyperthyroidism after withdrawal of antithyroid
drug therapy are as follows:
(1) At time of diagnosis of hyperthyrodism
(a) Family history,
(b) Age,
(c) Sex,
(d) Thyroid size,
(e) Orbitopathy,
(f) Thyroid function,
(g) Thyrotropin (TSH)-receptor antibodies.
(2) At time of medication withdrawal
(a) Duration of therapy,
(b) Smoking,
(c) Iodine intake level,
(d) TSH-receptor antibodies,
(e) Thyroid size,
(f) Thyroid function,
(g) Orbitopathy.
(3) Later
(a) Pregnancy,
(b) Immune modulating medication,
(c) Iodine intake level.
Some of these factors are immediately identifiable when Graves hyperthyroidism is diagnosed,
whereas other predictors have to be evaluated
during therapy when ATD withdrawal is considered.
Finally, exposure to certain factors in later life may
alter the risk of relapse (see the above list). Risk
factors for relapse should be taken into account
when choosing between therapeutic modalities in
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a patient with newly diagnosed disease, and also

when discussing duration of ATD therapy.
Because relapse of hyperthyroidism is a major
clinical concern, the number of published studies
on possible predictors is large. Unfortunately, studies on relapse prediction are nearly all clinic-based
and very heterogeneous. These studies are therefore
difficult to compile, and even heterogeneity within
some of the studies may have altered the findings so
much that all associations became negative. For
example, the majority of studies find at least some
association between risk of relapse and measures of
disease activity either at diagnosis or when ATD
is withdrawn, whereas some large investigatorinitiated European multicenter studies reported
associations to be mostly negative or useless [4,5].
We describe some of the predictors of relapse
that have been identified in a number of studies,
although these findings are somewhat inconsistent.

RISK EVALUATION AT TIME OF

DIAGNOSIS OF HYPERTHYROIDISM
At the time of diagnosis, some indication is likely
present regarding the risk of relapse following ATD
therapy. In general, factors suggesting more severe

s-TRAb (% inhibition of 125-I TSH binding)

70
60
50
40
30
Radioiodine
Surgery

20
10

Medication
0
0

Years

FIGURE 1. Thyrotropin-receptor antibodies in serum in

patients with Graves disease after various types of therapy
for hyperthyroidism. Patients were randomized to receive
either antithyroid drug for 18 months, radioiodine therapy,
or near total thyroidectomy. Thyrotropin-receptor antibodies
values were not different after surgery and antithyroid drug,
but significantly higher after radioiodine therapy at all times
after inclusion. Horizontal dotted line indicates upper
reference for thyrotropin-receptor antibodies method (10%).
Reproduced with permission from [1].
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Relapse after antithyroid drug therapy Laurberg et al.

100
90

Fraction of patients still in remission (%)

GD, no goitre
80
70
GD, small goitre

60
50

incidence remains quite stable [8]. The patients

who develop disease at a very young age tend to
have more severe immune abnormalities with a
high frequency of relapse if ATD therapy is given
for a fixed period of 1 to 2 years [9]. Thus, a recent
French observational prospective multicenter study
reported the positive impact of more prolonged ATD
therapy in children [10]. Reports on the influence of
age in adults are more diverse [7,11], but some
investigators found a higher relapse rate in young
adults than in old adults [12,13].

40
GD, medium or large goitre
30
20

Sex
Graves disease is four to five times more common in
women than in men [8], and some studies have
shown a higher risk of relapse after ATD withdrawal
in men than in women [13,14 ]. However, this has
not been a universal finding [7,11].
&

Multinodular toxic goitre

10
0
0

10

20

30

40

50

60

70

80

90 100

Time after ATD withdrawal (months)

Thyroid size
About half of patients with newly diagnosed Graves
hyperthyroidism have a large thyroid gland [15 ],
and a palpable goiter at the time of diagnosis was
among the first factors shown to have a major value
in the prediction of relapse after ATD therapy of
fixed duration (Fig. 2) [11]. The positive association
between thyroid size and relapse was observed as
early as in 1951 [16], and similar results have subsequently been reported from many studies [6,7,
12,17]. When planning ATD therapy, it is important to determine that the cause of the hyperthyroidism is Graves disease, as nearly all patients
with toxic multinodular goiter have a rapid relapse
of hyperthyroidism after ATD withdrawal (Fig. 2).
&

FIGURE 2. Goitre size and type, and the fraction (%)

staying euthyroid after withdrawal of antithyroid drug.
Antithyroid drug had been given for hyperthyroidism for
2 years. Type diagnosis of hyperthyroidism (Graves disease
vs. multinodular toxic goiter) was based on thyroid
scintigraphy at the time of diagnosis, and goiter size at the
time of diagnosis was estimated from clinical evaluation.
Reproduced with permission from [11]. GD, Graves
disease.

immune system abnormalities leading to disease

(for example, disease developing at a very young
age) and signs of more severe disease (for example, a
large goiter) indicate that lasting remission following 1 to 2-years of ATD therapy is less likely.

Family history
Graves disease shows familial clustering, which is
probably caused by a heritable variation in immune
regulation, as shown by some association with various genes. It might be anticipated that a family
history of Graves disease, and possibly autoimmune
hypothyroidism might influence the risk of relapse
after ATD withdrawal [6]. However, clinically useful
evidence for such association is limited [7].

Graves orbitopathy and thyroid function

There is a positive correlation between the presence
and severity of the major clinical manifestations of Graves disease, and the concentration of
TSH-receptor antibodies (TRAb) at the time of
diagnosis [15 ]. Some degree of clinical orbitopathy
is present in 20 to 30% of patients at the time of
diagnosis of Graves hyperthyroidism [15 ,18 ],
and some studies have found this to correlate positively with the risk of relapse [14 ]. Similarly, in
some series, the degree of biochemical hyperthyroidism has been a marker of prognosis, whereas
this was not an independent predictor in other
studies [11,18 ]. A small proportion of patients
with mild hyperthyroidism may enter remission
when treated with beta-blockers alone [19] and,
in general, patients with very mild disease at onset
have a good prognosis [7].
&

&

&&

&

&&

Age
Graves disease is rare in children and shows a
gradual increase in incidence starting from early
puberty until the age of 30 years. After this, the

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Thyroid

Thyrotropin-receptor antibodies

&&

RISK EVALUATION BEFORE WITHDRAWAL

OF ANTITHYROID DRUG THERAPY
Typically, ATD therapy is planned for a fixed
duration of 1 to 2 years [24], with some differences
in approach between countries. However, more prolonged low-dose ATD therapy based on individual
evaluation of patients has been used in Japan [25]. A
variety of factors may assist in the risk evaluation
when ATD withdrawal is discussed with a patient.

Duration of therapy
When ATD therapy was introduced approximately
70 years ago, the pathogenesis of Graves disease was
unknown. Thus, the knowledge that hyperthyroidism might relapse even after cure had been
achieved with ATD came with experience. A limited
number of studies have compared relapse rates after
different durations of ATD therapy [26]. Relapse
rates were higher after 6 rather than after 18 months
of therapy, but no further advantage has been found
when duration of therapy was expanded beyond
this [24]. Thus, current recommendation is to treat
for 1218 months, and then consider ATD withdrawal [24].

Smoking
Several studies have observed that smokers have a
higher relapse rate than nonsmokers after ATD withdrawal [17,27]. A recent Swedish study [18 ]
reported a very low relapse rate in patients who
had previously quit smoking (Fig. 3). Smoking
[28,29] and quitting smoking [30] may have great
impact on autoimmune thyroid disease. It may be
speculated that patients who develop Graves disease during a temporary worsening of thyroid autoimmunity may have a low risk of relapse, once this
temporary increase in risk is over. An example may
be the temporary worsening of autoimmunity and
the increased risk of developing Graves disease
during the first postpartum year [31,32]. A temporary increase in risk of autoimmune thyroid disease
has also been observed in people who quit smoking

100

Fraction of patients still in remission (%)

Assays for TRAb are now of good quality and clinically

useful, although not perfect. The relatively simple
receptor assays that do not distinguish between stimulating and blocking antibodies (if the patient is
hyperthyroid, antibodies are predominantly stimulating) are positive in at least 95% of patients with
newly diagnosed Graves hyperthyroidism [2022].
Patients who are TRAb negative tend to have a milder
disease and a better prognosis [23 ].

80

Previous smokers

60

Current smokers

40

Nonsmokers

20

Log-rank P = 0.003

0
0

10

12

Time after ATD withdrawal (years)

FIGURE 3. Smoking history and fraction staying euthyroid

after withdrawal of antithyroid drug. Antithyroid drug had
been given for Graves hyperthyroidism for more than 6
months (median around 18 months). Current smoking was
more common among patients than in the general Swedish
population but did not associate with the risk of relapse in
this study. Previous smoking with quitting at least 6 months
before Graves disease was diagnosed was protective
against relapse (P 0.003). Reproduced with permission
from [18 ].
&&

[30]. Thus, it may be speculated that patients who

develop Graves disease and start ATD therapy after
quitting smoking may have a low risk of relapse
when ATDs are withdrawn some years later. This
would fit the results of the Swedish study [18 ]. The
findings in Sweden should be confirmed in future
studies, but they may be clinically important,
because patients who have developed Graves disease after quitting smoking may be told that their
risk of relapse after ATD withdrawal will be low if
they remain a nonsmoker.
&&

&&

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Iodine intake
Iodine is a key substrate for thyroid hormone synthesis and the effects of ATDs are to interfere with
thyroid peroxidase-catalyzed iodine utilization for
thyroid hormone synthesis. In general, Graves
hyperthyroidism is easier to treat with ATD when
iodine intake is low [5], and it has been proposed
that a shift from a low to a high intake of iodine in
the population may be followed by a higher relapse
rate and, thus, a less favorable outcome after ATD
therapy [33]. In a population with adequate iodine
intake, such as Sweden, relapse rates are not high,
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Relapse after antithyroid drug therapy Laurberg et al.

56.5% of patients were still in remission 5 years after

ATD withdrawal [18 ].
&&

Thyrotropin-receptor antibodies
The usefulness of TRAb measurement at the time
of ATD withdrawal for predicting a later relapse
of hyperthyroidism has been studied rather intensively. A meta-analysis based on old methods
concluded that TRAb measurement was not costeffective [34], but more recent studies using better
methods have demonstrated a clinically useful predictive power [23 ].
An interesting observation appeared in a Swedish prospective randomized study [1], in which ATD
therapy was given for a fixed period of 18 months.
During 3.5 years of observation after ATD withdrawal, 42% of patients had a relapse of hyperthyroidism. TRAb values were not significantly different
between those who relapsed and those who stayed
in remission at the time of diagnosis of hyperthyroidism, or after 6 months of ATD therapy. However,
after 18 months just before ATD therapy was
stopped, a clear difference was observed. Fifty percent of patients who subsequently relapsed were
TRAb positive, but only 3% of patients staying in
remission were TRAb positive. Conversely, among
patients who were TRAb positive after 18 months of
therapy, 89% relapsed, whereas only 29% of TRAb
negative patients relapsed. Thus, TRAb positivity
was a strong predictor of a high relapse rate. TRAb
negativity was no guarantee that relapse would not
occur, but chance of remission was good. Some of
the discrepancy between the studies on the usefulness of TRAb for predicting relapse might have been
due to differences in the duration of ATD therapy
before drug withdrawal.
&&

why such patients are still clinically hyperthyroid,

despite serum thyroxine becoming normal or even
low during ATD therapy. Inevitably, these patients
have a relapse of hyperthyroidism if ATDs are withdrawn, and we offer such patients total thyroidectomy preceded by high-dose iodine administration
together with the ATD [41]. In general, patients who
show clear signs of thyroid hyperactivity during
ATD therapy should not have the medication
withdrawn.

Graves orbitopathy
A subgroup of patients, mostly those more than 40
years of age [42], have severe orbitopathy that may
often develop after the patient has started drug
therapy for hyperthyroidism. In patients with active
orbitopathy, the risk of relapse of hyperthyroidism
after ATD withdrawal is very high [43]. Therefore,
some clinics have used very prolonged ATD therapy
in such patients with satisfactory results [44,45].

Other measurements of thyroid hyperactivity

Various types of test have been proposed to predict
the risk of relapse, usually some measurements of
persistent abnormal thyroid stimulation, such as
persistently suppressed serum TSH despite ATD
therapy and lack of thyroid I-123 uptake suppression by triiodothyronine administration [46].

LATE INCREASE IN THE RISK OF RELAPSE

Most relapses of hyperthyroidism after previous
ATD therapy do not appear immediately, but within
the first years after ATD withdrawal (Figs. 2 and 3).
Certain exposures may increase the risk, as outlined
below.

Thyroid function
A small fraction of patients with Graves disease
show little or no evidence of remission during
ATD therapy [1]. They have persistently high TRAb
values, may have an increase in goiter size, and show
a characteristic pattern of high serum triiodothyronine compared with serum thyroxine [3537].
In general, triiodothyronine is more elevated than
thyroxine in untreated Graves hyperthyroidism
[38] caused by high intrathyroidal type 1 deiodinase activity, and preferential synthesis of triiodothyronine in the hyperactive thyroid [39,40].
Normally, this high triiodothyronine to thyroxine
ratio disappears with remission during therapy,
but not in this syndrome of persistent thyroid drive
[41]. If serum triiodothyronine is not measured
during therapy, it may be difficult to understand

High iodine intake

Patients who are euthyroid after previous ATD
therapy may have a relapse of hyperthyroidism if
pharmacological doses of iodine are given [47], and
in general, such patients should not be exposed to
excessive iodine (for example, kelp supplements).
Some exposures (for example, radiographic iodinerich contrast agents) may be unavoidable, but
should be limited when possible.

Postpartum period
The postpartum period is characterized by a worsening of thyroid autoimmunity, and patients in remission of Graves hyperthyroidism may experience a
relapse during this period [48]. A Japanese study

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Thyroid

reported positive results from the use of ATD

therapy during the postpartum period to maintain
high-risk patients euthyroid [49].

Immune modulating therapies

A number of immune modulating drugs may
increase the risk of Graves disease [50 ]. Thus,
patients in remission after a previous course of
ATD therapy are at high risk of experiencing a
relapse of hyperthyroidism during such therapy,
and regular testing of thyroid function is advisable
during therapy with these drugs.
&

CONCLUSION
The risk of relapse of hyperthyroidism after withdrawal of ATD therapy of Graves hyperthyroidism is
highly variable between patients, and this challenges the use of a standard 1 to 2-year period of
ATD administration [15 ]. This is especially so in
subgroups with a high risk, such as children [9,10]
and patients with Graves orbitopathy [44,45]. Also,
in Japan several clinics prefer to use a more variable
approach to patients. More prolonged low-dose ATD
may be feasible in some patients [24], but ATD dose
should be kept low to reduce the risk of side-effects
[24], and methimazole and not propylthiouracil
should be used [24]. Women of childbearing age
should be instructed about special precautions to
prevent ATD associated birth defects if they should
become pregnant [51 ,52 ].
&

&

&

Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

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&
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