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CURRENTOPINION Relapse following antithyroid drug therapy forGraves hyperthyroidism

Peter Laurberga,b

, Anne Krejbjerga,b

, and Stine Linding Andersena,b

Purpose of review

In most patients with hyperthyroidism caused by Graves disease, antithyroid drug (ATD) therapy isfollowed by a gradual amelioration of the autoimmune abnormality, but about half of the patients willexperience relapse of hyperthyroidism when the ATDs are withdrawn after a standard 1 to 2 years oftherapy. This is a major drawback of ATD therapy, and a major concern to patients. We review currentknowledge 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 riskof relapse after ATD withdrawal may vary from around 10 to 90%. Risk factors for relapse should be takeninto 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 andpatients with active Graves orbitopathy, and in patients with previous relapse who prefer such therapyrather than surgery or radioiodine.

Keywords

antithyroid drug therapy, Graves disease, hyperthyroidism, hyperthyroidism relapse, thyrotropin-receptorantibodies

INTRODUCTION

In most patients with hyperthyroidism caused byGraves disease, antithyroid drug (ATD) therapy isfollowed by a gradual amelioration of the auto-immune abnormality, which is also observed aftersurgical thyroidectomy, but not after radioiodinetherapy [1] (Fig. 1). Autoimmune remission is notinfluenced by the type of drug used to restoreeuthyroidism or by the dose of drug. Consideringthis, we find it likely that remission is not caused by

the drugs themselves but is part of the naturalhistory of Graves disease in a euthyroid patient.Thus, focus should be on achieving and maintainingeuthyroidism [2].

However, a small group of hyperthyroid patientsdo not remit during ATD therapy, and if the ATD iswithdrawn, hyperthyroidism will immediatelyreappear. Moreover, some patients enter partialremission and remain euthyroid for a period of timeafter ATD withdrawal, but hyperthyroidism oftenrelapses. Finally, even a subgroup of the patientswho, based on available measures, are in full

remission at the time of drug withdrawal mayexperience reoccurrence of hyperthyroidism.

Relapse of hyperthyroidism is a prominent draw-back of ATD therapy. In a retrospective study, satis-faction with therapy in Swedish patients who hadbeen randomized to treatment with ATD, surgery orradioiodine, was in general high [3]. However, thefraction of patients who had experienced a relapse ofhyperthyroidism after withdrawal of medicationexpressed concerns about this [3], and thus, it is

important to discuss the possibility of later relapseof 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

aDepartment of Endocrinology, Aalborg University Hospital and bDepart-

Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

Correspondence to Peter Laurberg, Department of Endocrinology, Aal-

borg University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark. Tel:

+45 97 66 36 82; fax: +45 99 32 68 57; e-mail: [email protected]

Curr Opin Endocrinol Diabetes Obes 2014, 21:415421

DOI:10.1097/MED.0000000000000088

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REVIEW
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number of patient and disease characteristics, aswell as environmental factors and mode of ATDtherapy, may influence the risk of relapse. Factorsthat may be associated with the risk of relapse ofhyperthyroidism after withdrawal of antithyroiddrug 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 identifi-able when Graves hyperthyroidism is diagnosed,whereas other predictors have to be evaluatedduring therapy when ATD withdrawal is considered.Finally, exposure to certain factors in later life mayalter the risk of relapse (see the above list). Riskfactors for relapse should be taken into accountwhen choosing between therapeutic modalities in

a patient with newly diagnosed disease, and alsowhen discussing duration of ATD therapy.

Because relapse of hyperthyroidism is a majorclinical concern, the number of published studieson possible predictors is large. Unfortunately, stud-ies on relapse prediction are nearly all clinic-basedand very heterogeneous. These studies are therefore

difficult to compile, and even heterogeneity withinsome of the studies may have altered the findings somuch that all associations became negative. Forexample, the majority of studies find at least someassociation between risk of relapse and measures ofdisease activity either at diagnosis or when ATDis withdrawn, whereas some large investigator-initiated European multicenter studies reportedassociations to be mostly negative or useless[4,5].

We describe some of the predictors of relapsethat 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 likelypresent regarding the risk of relapse following ATDtherapy. In general, factors suggesting more severe

KEY POINTS

Risk of relapse of hyperthyroidism after ATD withdrawalvaries between approximately 10 and 90% insubgroups of patients with Graves disease.

Risk can be estimated from clinical and biochemicalevaluation 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 ofrelapse such as young children, patients with activeorbitopathy, and patients with previous relapse whoprefer such therapy rather than radioiodine or surgery.

TSH-receptor measurement is a valuable but not perfectindicator of risk of relapse, especially when ATD hasbeen given for at least 12 months.

0

10

20

30

40

50

60

70

0 1 2 3 4 5

Years

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

Radioiodine

Surgery

Medication

FIGURE 1. Thyrotropin-receptor antibodies in serum inpatients with Graves disease after various types of therapyfor hyperthyroidism. Patients were randomized to receiveeither antithyroid drug for 18 months, radioiodine therapy,or near total thyroidectomy. Thyrotropin-receptor antibodiesvalues were not different after surgery and antithyroid drug,but significantly higher after radioiodine therapy at all timesafter inclusion. Horizontal dotted line indicates upperreference for thyrotropin-receptor antibodies method (10%).Reproduced with permission from[1].

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416 www.co-endocrinology.com Volume 21 Number 5 October 2014



immune system abnormalities leading to disease(for example, disease developing at a very youngage) and signs of more severe disease (for example, alarge goiter) indicate that lasting remission follow-ing 1 to 2-years of ATD therapy is less likely.

Family history

Graves disease shows familial clustering, which isprobably caused by a heritable variation in immune

regulation, as shown by some association with var-ious genes. It might be anticipated that a familyhistory of Graves disease, and possibly autoimmunehypothyroidism might influence the risk of relapseafter ATD withdrawal[6]. However, clinically usefulevidence for such association is limited[7].

Age

Graves disease is rare in children and shows agradual increase in incidence starting from earlypuberty until the age of 30 years. After this, the

incidence remains quite stable [8]. The patientswho develop disease at a very young age tend tohave more severe immune abnormalities with ahigh frequency of relapse if ATD therapy is givenfor a fixed period of 1 to 2 years[9]. Thus, a recentFrench observational prospective multicenter studyreported the positive impact of more prolonged ATD

therapy in children [10]. Reports on the influence ofage in adults are more diverse [7,11], but someinvestigators found a higher relapse rate in youngadults than in old adults[12,13].

Sex

Graves disease is four to five times more common inwomen than in men [8], and some studies haveshown a higher risk of relapse after ATD withdrawalin men than in women [13,14

&

]. However, this hasnot been a universal finding[7,11].

Thyroid size

About half of patients with newly diagnosed Graveshyperthyroidism have a large thyroid gland [15

&

],and a palpable goiter at the time of diagnosis wasamong the first factors shown to have a major valuein the prediction of relapse after ATD therapy offixed duration (Fig. 2)[11]. The positive associationbetween thyroid size and relapse was observed asearly as in 1951 [16], and similar results have sub-sequently been reported from many studies [6,7,12,17]. When planning ATD therapy, it is impor-

tant to determine that the cause of the hyper-thyroidism is Graves disease, as nearly all patientswith toxic multinodular goiter have a rapid relapseof hyperthyroidism after ATD withdrawal (Fig. 2).

Graves orbitopathy and thyroid function

There is a positive correlation between the presenceand severity of the major clinical manifesta-tions of Graves disease, and the concentration ofTSH-receptor antibodies (TRAb) at the time ofdiagnosis [15

&

]. Some degree of clinical orbitopathy

is present in 20 to 30% of patients at t he time ofdiagnosis of Graves hyperthyroidism [15

&

,18&&

],and some studies have found this to correlate posi-tively with the risk of relapse [14

&

]. Similarly, insome series, the degree of biochemical hyperthyr-oidism has been a marker of prognosis, whereasthis was not an independent predictor in otherstudies [11,18

&&

]. A small proportion of patientswith mild hyperthyroidism may enter remissionwhen treated with beta-blockers alone [19] and,in general, patients with very mild disease at onsethave a good prognosis[7].

GD, no goitre

Time after ATD withdrawal (months)

Multinodular toxic goitre

GD, small goitre

GD, medium or large goitre

Fractionofpatientsstillinrem

ission(%)

100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

100

0

FIGURE 2. Goitre size and type, and the fraction (%)staying euthyroid after withdrawal of antithyroid drug.Antithyroid drug had been given for hyperthyroidism for2 years. Type diagnosis of hyperthyroidism (Graves diseasevs. multinodular toxic goiter) was based on thyroidscintigraphy at the time of diagnosis, and goiter size at thetime of diagnosis was estimated from clinical evaluation.Reproduced with permission from[11]. GD, Graves

disease.

Relapse after antithyroid drug therapyLaurberg et al.

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Thyrotropin-receptor antibodies

Assays forTRAb are nowof goodquality andclinicallyuseful, although not perfect. The relatively simplereceptor assays that do not distinguish between stim-ulating and blocking antibodies (if the patient ishyperthyroid, antibodies are predominantly stimu-lating) are positive in at least 95% of patients with

newly diagnosed Graves hyperthyroidism[2022].Patients who are TRAb negative tend tohave a milderdisease and a better prognosis [23

&&

].

RISK EVALUATION BEFORE WITHDRAWAL

OF ANTITHYROID DRUG THERAPY

Typically, ATD therapy is planned for a fixedduration of 1 to 2 years [24], with some differencesin approach between countries. However, more pro-longed low-dose ATD therapy based on individualevaluation of patients has been used in Japan [25]. Avariety of factors may assist in the risk evaluationwhen ATD withdrawal is discussed with a patient.

Duration of therapy

When ATD therapy was introduced approximately70 years ago, the pathogenesis of Graves disease wasunknown. Thus, the knowledge that hyperthyroid-ism might relapse even after cure had beenachieved with ATD came with experience. A limitednumber of studies have compared relapse rates afterdifferent durations of ATD therapy [26]. Relapserates were higher after 6 rather than after 18 months

of therapy, but no further advantage has been foundwhen duration of therapy was expanded beyondthis[24]. Thus, current recommendation is to treatfor 1218 months, and then consider ATD with-drawal[24].

Smoking

Several studies have observed that smokers have ahigher relapse rate than nonsmokers after ATD with-drawal [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 greatimpact on autoimmune thyroid disease. It may bespeculated that patients who develop Graves dis-ease during a temporary worsening of thyroid auto-immunity may have a low risk of relapse, once thistemporary increase in risk is over. An example maybe the temporary worsening of autoimmunity andthe increased risk of developing Graves diseaseduring the first postpartum year[31,32]. A tempor-ary increase in risk of autoimmune thyroid diseasehas also been observed in people who quit smoking

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

develop Graves disease and start ATD therapy afterquitting smoking may have a low risk of relapsewhen ATDs are withdrawn some years later. Thiswould fit the results of the Swedish study [18

&&

]. Thefindings in Sweden should be confirmed in futurestudies, but they may be clinically important,because patients who have developed Graves dis-ease after quitting smoking may be told that theirrisk of relapse after ATD withdrawal will be low ifthey remain a nonsmoker.

Iodine intakeIodine is a key substrate for thyroid hormone syn-thesis and the effects of ATDs are to interfere withthyroid peroxidase-catalyzed iodine utilization forthyroid hormone synthesis. In general, Graveshyperthyroidism is easier to treat with ATD wheniodine intake is low [5], and it has been proposedthat a shift from a low to a high intake of iodine inthe population may be followed by a higher relapserate and, thus, a less favorable outcome after ATDtherapy[33]. In a population with adequate iodineintake, such as Sweden, relapse rates are not high,

Fractionofpatientsstillinremission(%)

Time after ATD withdrawal (years)

Previous smokers

Current smokers

Nonsmokers

Log-rank P= 0.003

100

80

60

40

20

0

0 2 4 6 8 10 12

FIGURE 3.

Smoking history and fraction staying euthyroidafter withdrawal of antithyroid drug. Antithyroid drug hadbeen given for Graves hyperthyroidism for more than 6months (median around 18 months). Current smoking wasmore common among patients than in the general Swedishpopulation but did not associate with the risk of relapse inthis study. Previous smoking with quitting at least 6 monthsbefore Graves disease was diagnosed was protectiveagainst relapse (P0.003). Reproduced with permissionfrom [18&&].

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reported positive results from the use of ATDtherapy during the postpartum period to maintainhigh-risk patients euthyroid[49].

Immune modulating therapies

A number of immune modulating drugs mayincrease the risk of Graves disease [50

&

]. Thus,patients in remission after a previous course ofATD therapy are at high risk of experiencing arelapse of hyperthyroidism during such therapy,and regular testing of thyroid function is advisableduring therapy with these drugs.

CONCLUSION

The risk of relapse of hyperthyroidism after with-drawal of ATD therapy of Graves hyperthyroidism ishighly variable between patients, and this chal-lenges the use of a standard 1 to 2-year period of

ATD administration [15&

]. This is especially so insubgroups 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 variableapproach to patients. More prolonged low-dose ATDmay be feasible in some patients[24], but ATD doseshould be kept low to reduce the risk of side-effects[24], and methimazole and not propylthiouracilshould be used [24]. Women of childbearing ageshould be instructed about special precautions toprevent ATD associated birth defects if they shouldbecome pregnant [51

&

,52&

].

Acknowledgements

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED

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50.

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&

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Very early withdrawal of ATD in pregnancy is likely to substantially reduce risk ofbirth defects.

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