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Original Studies |
Division of Endocrinology and Metabolism, Department of Medicine, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada B3H 2Y9
Address all correspondence and requests for reprints to: Roger S. Rittmaster, M.D., Room 2035D, Victoria Building, QEII Health Sciences Centre, 1278 Tower Road, Halifax, Nova Scotia, Canada B3H 2Y9.
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Abstract |
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1.0) or group B (TSH < 1.0), based on the mean TSH
achieved during methimazole treatment. One hundred forty-nine patients
have been followed for at least 6 months after stopping methimazole
(mean 27 months). Fifty-eight percent of patients have relapsed. There
were no significant differences in relapse rates after stopping
methimazole. Among those patients who did relapse, however, there was a
significant difference in the months to relapse after stopping
methimazole between groups B and 1 (group 1: 3.3 ± 0.7, group A:
5.6 ± 0.8, group B: 7.4 ± 1.7; P = 0.01
for the comparison between groups B and 1). We conclude that the
addition of T4 to methimazole does not improve long-term
remission rates in Graves’ disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One hundred ninety-nine patients with active, previously
untreated Graves’ disease entered the study. Fifty patients have
dropped out, mostly because of inability to comply with study
requirements (n = 28), drug reactions (n = 16), and pregnancy
(n = 5). One hundred forty-nine patients have been followed at
least 6 months after the discontinuation of methimazole and are the
basis for this report. Mean age was 38 yr (range 10–72). The racial
composition of the group was Caucasian (n = 144), Native American
(n = 3), Asian (n = 1), and African-American (n = 1).
The diagnosis of Graves’ disease was based on the symptoms of
hyperthyroidism, a thyroid examination consistent with Graves’
disease, biochemical evidence of hyperthyroidism, and an increased
thyroidal uptake of radioiodine or a rapid and diffuse uptake of
technetium. The size of the thyroid was estimated by palpation.
Cigarette use (average number per day) was recorded. All subjects
provided written consent, using a protocol approved by the Queen
Elizabeth II Health Sciences Centre Research Ethics Committee. The
baseline clinical features and laboratory data of these patients are
shown in Table 1
. There were no
significant differences among the groups, with respect to age, thyroid
gland size, severity of hyperthyroidism, or history of cigarette
smoking.
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All patients were treated initially with 10 mg methimazole (Tapazole, Eli Lilly Canada, Scarborough, Ontario), three times daily, until the serum total T3 concentrations entered the normal range (0.9–2.8 nmol/L). The length of time necessary to achieve this was 7.9 ± 6.2 weeks (mean ± SD). Patients having an allergic reaction to methimazole were switched to propylthiouracil (n = 16) and continued in the study unless the allergic reaction was felt to be too severe to warrant the risk of a similar reaction with propylthiouracil.
Patients then were randomly assigned to 1 of 3 groups. Group 1 patients
(n = 51) were maintained on methimazole alone for a total of 18
months, the dosage being adjusted such that the patients’ serum TSH
concentration remained in the normal range (0.3–5.4 mIU/L). Patients
in groups 2 (n = 50) and 3 (n = 48) were given a fixed dose
of 15 mg methimazole, twice daily, for a total of 18 months. Group 2
patients were treated also with sufficient T4 (Synthroid,
Knoll Pharmaceuticals, Etobicoke, Ontario) to maintain the TSH in the
mid- to high-normal range (2.0–5.4 mIU/L). Group 3 patients received
sufficient T4 to maintain the serum TSH less than or equal
to 0.6 mIU/L. Because patients in groups 2 and 3 did not always achieve
their target TSH levels, for analysis of endpoints, such patients were
reassigned to group A (TSH 1) and group B (TSH < 1),
based on the mean TSH achieved during the study (see Statistical
Analysis for further details).
After 18 months, methimazole was stopped in all patients, and T4 was continued in groups 2 and 3. In the absence of methimazole, serum TSH was suppressed into the low-normal range or below normal in all patients in groups 2 and 3. Therefore, no attempt was made to differentiate between these two groups after methimazole was stopped. If TSH was suppressed to undetectable levels, the dose of T4 was decreased until either the TSH became detectable or the T4 was discontinued. Relapse of Graves’ disease was defined as a TSH below normal when the patient was off all thyroid medications. Patients were followed after relapse to ensure that the suppressed TSH was not caused by a delayed recovery of the hypothalamic-pituitary-thyroid axis. Because it was necessary for patients in groups 2 and 3 to have their T4 medication discontinued before they could be defined as having relapsed, there was a delay in defining relapse, of about 2 months, compared with group 1.
Laboratory evaluation
Patients were assessed, and serum was obtained, at 3–4 week intervals during the first 6 months of treatment, and then every 2 months, until month 18. Serum TSH, free T4, and total T3 were measured at each assessment. TSH receptor antibodies were measured at baseline and after 6 and 18 months of treatment. Serum thyroglobulin was measured at baseline and after 18 months. Urinary iodine excretion was measured in a 24-h urine collection in 58 patients after they were euthyroid. Once methimazole was stopped, thyroid function tests were repeated, after 2 or 3 weeks, to identify patients who never achieved remission. For patients in remission, thyroid function tests were then followed every 1–2 months for the next 2 yr and then every 6–12 months thereafter.
Serum TSH (Delfia, Wallac, Turku, Finland), free T4 (Amerlex, Kodak Diagnostics, Amersham, UK), and total T3 (Quanticoat, Kallestad Diagnostics, Chaska, MN) were measured using kits, as previously validated (13). The mean sensitivity of the TSH assay was 0.02 mIU/L. Serum thyroglobulin was measured using an immunoradiometric assay from E.R.I.A. Diagnostics Pasteur (Marnes La Coquette, France). The normal range was 2.3–76 pmol/L. Urine iodine was measured in the laboratory of Dr. Lewis Braverman (Worcester, MA). TSH receptor antibodies were measured both by the ability of patients’ sera to stimulate cAMP production by FRTL-5 cells (thyroid-stimulating Ig, TSI) and by the ability of patients’ sera to inhibit binding of radiolabeled TSH to solubilized porcine thyroid membranes (thyroid-binding inhibiting Ig, TBII; RSR Limited, Cardiff, Wales). TSI was measured in the first 84 patients to complete the first 18 months of the study, and TBII was measured in all patients. The validation and results of TSH receptor antibody measurements for the first 70 patients in this study were previously published (14).
Statistical analysis
Data were collected and stored in a database created using the Filemaker Program (Claris Corp.; Santa Clara, CA) on a Macintosh computer (Cupertino, CA). Results were expressed as the mean ± SEM, unless otherwise noted. ANOVA was used for the comparison of means among the three treatment groups, and Fisher’s protected least-square derivative test was used for post hoc pair-wise comparisons. The paired Students t test was used to compare changes from baseline within the groups. P values of less than 0.05 were considered significant.
All three groups were initially analyzed based on the assigned treatment group. Because some patients in groups 2 and 3 did not achieve the target TSH concentration, results in these patients also were analyzed based on the mean serum TSH concentration achieved between months 6 and 18 of the study. On this basis, the patients in groups 2 and 3 were divided into two new groups: group A (TSH = 1.0–7.8 mIU/L, n = 68) and group B (TSH = 0–0.99 mIU/L, n = 29). Of patients originally assigned to group 2 (TSH: 2.0–5.4), 47 were reassigned to group A, and 3 to group B. Of patients originally assigned to group 3 (TSH < 0.6), 22 were reassigned to group A, and 26 to group B. There was no difference in any results (other than serum thyroid hormone levels) based on this reanalysis of the data. We have chosen to report the results of this reanalysis because such results are a better test of the hypothesis that near-total suppression of thyroid function correlates best with the likelihood of long-term remission of Graves’ disease.
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Results |
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There were no significant differences between the groups at
baseline, with respect to age, gender, size of the thyroid gland at
baseline, history of cigarette smoking, or thyroid hormone levels
(Table 1
). Mean urine iodine excretion (µg/24 h) was 214 ± 140
(mean ± SD; range 45–768). Five of the 58 patients
(9%) in whom it was measured had urinary iodine excretion less than
100 µg/24 h, and 9 patients (16%) had urinary iodine excretion
greater than 300 µg/24 h, suggesting moderate iodine intake in
the majority of patients.
Thyroid hormone, thyroglobulin, and TSH receptor antibody concentrations
The mean time required for total T3 to enter the
normal range was 7.9 ± 6.2 weeks (mean ± SD).
Medication doses and serum concentrations of thyroid hormones and
thyroglobulin after 18 months of therapy are shown in Table 2. Free T4 levels were higher
in groups A and B than in group 1 (P < 0.001) and were
higher in group B than in group A (P = 0.036). There
was no significant difference in total T3 levels in any of
the groups.
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). Thyroglobulin levels were
unchanged over the 18 months of the study in all groups combined
(173 ± 23 baseline vs. 195 ± 26 at 18 months).
There were also no significant differences in thyroglobulin levels
between baseline and 18 months in any group, although thyroglobulin
levels decreased by a mean of 28 ± 22 pmol/L in group B
(P = 0.22).
Changes in TSH receptor antibody concentrations (TBII) are shown in
Fig. 1. There were no significant
differences in the antibody concentrations among groups 1, A, and B,
both using the TSI and TBII techniques.
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After a mean follow-up of 27 months (range 6–47), 58% of the
patients have relapsed (59% in groups 1 and B, and 58% in group A).
The cumulative percent of patients that relapsed in groups 1, A, and B
are shown in Fig. 2 as a function of
duration of follow-up after stopping methimazole. Three months after
stopping methimazole, more patients in group 1 had relapsed (35%) than
in groups A and B combined (21%; P = 0.07), and
similar reductions persisted in group B during the first 9 months of
the study. This difference could be explained partly by the delay in
diagnosing relapse in groups A and B (because of the need to
discontinue T4 treatment), and at no point did this
difference reach statistical significance. Among those patients who did
relapse, however, there was a significant difference in the mean months
to relapse (3.3 ± 0.7 in group 1, 5.6 ± 0.8 in group A, and
7.4 ± 1.8 in group B, P = 0.01 for the difference
between groups 1 and B).
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Drug reactions were common but usually were not severe enough to require discontinuation from the study. Forty-one patients developed a rash and/or itching, 31 patients complained of joint or muscle discomfort (it was difficult to differentiate whether this symptom was caused by medication or Graves’ disease), 45 patients noted a metallic taste (which persisted throughout the study), 9 patients had gastrointestinal complaints thought to be related to the medication, 2 developed jaw pain, 1 developed agranulocytosis, and 2 developed drug-induced hepatitis (1 was severe, and the other was increasing liver enzymes only). Of the 16 patients who dropped out because of drug reactions, 12 were because of severe rashes, 1 was from gastrointestinal intolerance, 2 were because of hepatitis, and 1 was because of agranulocytosis. Sixteen patients were switched to propylthiouracil, 13 because of rashes; the rash recurred in only two of these patients.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results differ from two initial studies that suggested that the combination of antithyroid drug and T4 decreases TSH receptor antibodies and improves remission rates, compared with antithyroid drugs alone. Romaldini et al. (6) randomized 113 patients to receive either combination therapy with high doses of antithyroid drugs (propylthiouracil or methimazole) plus T3 or antithyroid drugs alone. Remission occurred in 75% of patients receiving combination therapy and 42% of patients receiving antithyroid drugs alone. TSH receptor antibodies (TSI) were negative at the end of treatment in 71% of patients receiving combination therapy and in 29% of patients on monotherapy. Hashizume et al. (7) treated 109 Japanese patients with 30 mg methimazole daily for 6 months and then randomized patients to receive 10 mg methimazole plus either 100 µg T4 or placebo daily. Remission occurred in 98% of patients on combination therapy and 63% of patients receiving methimazole alone. TSH receptor antibodies (TBII) decreased to a greater degree in patients receiving combination therapy. In both of these studies, the serum TSH level was not carefully controlled, and many patients receiving an antithyroid drug alone had serum TSH concentrations above normal. It is tempting to speculate that this endogenous thyroid stimulation led to greater expression of thyroid antigens and lower remission rates. In our study, serum TSH levels were carefully controlled to avoid hypothyroidism. However, a nonrandomized study from Taiwan also found a greater decrease in TBII in patients receiving combination therapy, compared with T4 alone, and TSH levels were low-normal or suppressed in both groups (8).
In spite of the initial research suggesting that the combination of methimazole plus T4 might be more effective than methimazole alone, our study contributes to a mounting body of evidence that neither higher doses of methimazole nor suppression of endogenous TSH contributes to enhanced remission rates in Graves’ disease. Reinwein et al. (15) found no difference in remission rates or TSH receptor antibody levels among 309 European patients randomized to receive either low- (10 mg daily) or high- (40 mg daily) dose methimazole, both doses given in combination with T4 for 12 months. Wilson et al. (4) reported higher remission rates in patients from Scotland receiving 60 mg carbimazole daily (64%), compared with 20 mg daily (43%), with both groups receiving supplemental T3. However, the difference in both remission rates and TSH receptor antibodies (TBII) between the two groups was not statistically significant. In a study of 17 patients undergoing subtotal thyroidectomy for relapsing Graves’ disease, there was no correlation between the intrathyroidal concentration of methimazole and the intensity of the lymphocytic infiltrate (16). In patients with persistently elevated TBII levels after 1 yr of methimazole therapy alone, Tamai et al. (10) found no difference in TBII concentrations in 35 patients given 10 mg methimazole daily for a second year, compared with 70 patients given a combination of 10 mg methimazole and 100 µg T4, whose TSH was either normal or suppressed. Finally, McIver et al. followed 53 patients from Scotland, given either carbimazole alone for 18 months with the dose adjusted to maintain TSH in the normal range or a combination of 40 mg carbimazole daily plus sufficient T4 to suppress TSH to an undetectable level. After 18 months, carbimazole was stopped and the T4 dose was unchanged. With all patients followed for at least 3 months after carbimazole was stopped, 8 patients in each group had relapsed (12).
In our patients who have been followed for at least 2 yr after stopping methimazole, the relapse rate was 58%. This is above average for relapse rates in the literature, especially for studies in which patients were treated with antithyroid drugs for at least 18 months (17, 18). Some studies have suggested that high iodine intake may increase the likelihood of developing or relapsing from Graves’ disease (19, 20, 21, 22). Although there was large variation in the 24-h urinary iodine excretion, the mean levels suggest a moderately high dietary iodine intake in Nova Scotia.
In summary, we have found no difference in remission rates in Graves’ disease patients treated for 18 months with either methimazole alone or a combination of methimazole and T4. Combination therapy did result in a modest delay in the time to relapse after stopping methimazole, but this required suppression of TSH to less than 1 mIU/L, and the relapse rate after 2 yr of follow-up was no different among the groups. The choice between these two methods of medical therapy should be dictated by individual preference, rather than an anticipated improvement in clinical outcome.
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Footnotes |
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Received August 25, 1997.
Revised November 5, 1997.
Accepted November 11, 1997.
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References |
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