Predicting the Likelihood of Remission in Children With Graves Disease: A Prospective, Multicenter Study Nicole S. Glaser, Dennis M.

Styne and for the Organization of Pediatric Endocrinologists of Northern California Collaborative Graves Disease Study Group Pediatrics 2008;121;e481-e488; originally published online Feb 11, 2008; DOI: 10.1542/peds.2007-1535

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/121/3/e481

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Predicting the Likelihood of Remission in Children With Graves Disease: A Prospective, Multicenter Study
Nicole S. Glaser, MD, Dennis M. Styne, MD, for the Organization of Pediatric Endocrinologists of Northern California Collaborative Graves Disease Study Group Department of Pediatrics, University of California Davis, School of Medicine, Sacramento, California
The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. The optimal treatment for Graves disease in children is controversial. An-

tithyroid medications are often used initially, but many children eventually require alternative therapies. We evaluated predictors of remission after 2 years of antithyroid medication use.
METHODS. We prospectively studied children who had Graves disease and were treated

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1535 doi:10.1542/peds.2007-1535

Key Words hyperthyroidism, Graves disease, propylthiouracil Abbreviations T4 thyroxine T3triiodothyronine SDSSD score TSIthyroid-stimulating immunoglobulin TBIIthyroid-binding inhibitory immunoglobulin TPOantithyroid peroxidase antibody ANAantinuclear antibody
Accepted for publication Jul 21, 2007 Address correspondence to Nicole S. Glaser, MD, Department of Pediatrics, University of California, Davis, School of Medicine, 2516 Stockton Blvd, Sacramento, CA 95817. E-mail: nsglaser@ucdavis.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2008 by the American Academy of Pediatrics

with antithyroid medications. We compared children who achieved remission after 2 years with those who had persistent disease to determine which variables were associated with remission; multiple logistic regression and binary recursive partitioning analyses were used to evaluate interactions among predictive variables.
RESULTS. Of 51 children who completed the study, 15 (29%) achieved remission.

Children who achieved remission had lower thyroid hormone concentrations at presentation than those with persistent disease (free thyroxine: 6.17 3.10 vs 9.86 7.54 ng/dL; total triiodothyronine: 431 175 vs 561 225 ng/dL). Children who achieved remission were also more likely to be euthyroid within 3 months of initiating propylthiouracil (82% vs 29%). Binary recursive partitioning analysis identied rapid achievement of euthyroid status after initiation of propylthiouracil, lower initial triiodothyronine, and older age as signicant predictors of remission.
CONCLUSIONS. Thyroid hormone concentrations at diagnosis, age, and initial response to

propylthiouracil can be used to stratify patients according to the likelihood of remission after 2 years of antithyroid medication use. These data provide a useful guide for clinical decision-making regarding Graves disease in children.

HE OPTIMAL APPROACH to treatment of Graves disease in children has long been a subject of controversy. Available therapies, including antithyroid medications, radioactive iodine therapy, and thyroidectomy, all entail risks.17 Antithyroid medications are often favored as the initial treatment approach for children,8,9 in hopes of avoiding permanent hypothyroidism, which occurs frequently after either radioactive iodine therapy or surgery. Achieving remission with medical therapy, however, usually requires many years of treatment,10,11 and the risk for adverse reactions from antithyroid medications is relatively high (11%22%).1,2,12 Many children who are initially treated with antithyroid medication eventually receive other treatments, most often radioablation.10,1316 In some cases, alternative therapies are necessary because of adverse reactions to antithyroid medication, but many patients discontinue antithyroid mediations because of difculties maintaining long-term compliance.10,1315 Previous studies suggested that, of children who were treated with antithyroid medication, 25% achieved remission with every 2 years of treatment.11,14 Probabilities of remission with long-term antithyroid therapy, however, are based on data from small numbers of patients and differ from adult data, which suggested that remission is unlikely with continued use of antithyroid medication beyond 18 months.17,18 Because only a minority of children who are treated with antithyroid medications eventually achieve remission with medical therapy alone, information regarding whether individual patients are likely to achieve remission within

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a relatively brief period using antithyroid medication would be useful in guiding therapy. We undertook this study to determine whether clinical characteristics or biochemical measures could be used to determine the likelihood of remission after 2 years on antithyroid medication. METHODS Patient Population Patients were eligible for participation in the study if they were younger than 18 years, had a diagnosis of hyperthyroidism as a result of Graves disease (elevated free thyroxine [T4] and/or triiodothyronine [T3] concentrations with subnormal thyrotropin concentration and evidence of thyroid autoimmunity not thought to be consistent with Hashitoxicosis [see Discussion]), and chose to be treated with antithyroid medication. Patients were excluded from the study if they had a history of previous episodes of autoimmune thyroid disease or had already initiated treatment with antithyroid medication at the time of initial consultation. Patients were also excluded from the study if hyperthyroidism was found to be caused by a thyroid adenoma or when hyperthyroidism was attributed to the hyperthyroid phase of Hashimotos thyroiditis (low uptake of radioactive iodine on thyroid scan at diagnosis and/or absence of thyrotropin receptor antibodies with remission occurring within 6 months of diagnosis). Study Protocol The study was approved by the institutional review board of each participating institution. After obtaining written informed consent from the patients parent or legal guardian, as well as assent for children who were older than 7 years, we recorded data regarding clinical features at presentation, including age, gender, ethnicity, family history of thyroid disease, height, weight, blood pressure, heart rate, goiter size, and presence or absence of exophthalmos (abnormal anterior protrusion of the eye determined by clinical judgment of the attending endocrinologist). We calculated the BMI and standardized the BMI for age and gender by calculating a BMI SD score (SDS): BMI SDS (patients BMI mean BMI for age and gender)/SD for BMI. We assessed goiter size using 2 methods: (1) measurement of the longest length (diagonal) of right and left lobes and (2) physicians estimation of the percentage enlargement. Endocrinologists who participated in the study received standardized instructions on measurement of thyroid lobe length before the initiation of the study. Goiter size was classied according to the lobe length measurements (mean of right and left lobes) and estimated percentage enlargement as none, small, moderate, or large on the basis of standards described previously (Appendix).14 At the time of presentation, serum thyroid hormone concentrations and thyroid antibody levels were measured at a single central laboratory (Quest Diagnostics, San Juan Capistrano, CA). We measured serum free T4, total T3, and thyrotropin concentrations, as well as thye482 GLASER, STYNE

roid-stimulating immunoglobulins (TSIs), thyroid-binding inhibitory immunoglobulins (TBIIs), antithyroid peroxidase antibodies (TPOs), and antinuclear antibodies (ANAs) using the following methods: free T4, direct equilibrium dialysis radioimmunoassay; total T3, immunochemiluminometric assay; ultrasensitive thyrotropin, immunochemiluminometric assay; TSIs, in vitro bioassay using Chinese hamster ovary cell line containing human thyrotropin receptor and cyclic adenosine monophosphate generating system linked to a luciferase reporter; TBIIs, radiobinding assay (Kronus, Boise, ID); TPOs, immunochemiluminometric assay; and ANAs, enzyme immunoassay. Reference values were as follows: free T4, 0.8 to 2.2 ng/dL; total T3, 1 to 9 years: 127 to 221 ng/dL, 10 to 13 years: 123 to 211 ng/dL, 14 to 18 years: 97 to 186 ng/dL; thyrotropin, 0.7 to 6.4 mU/L; TSIs 125% basal activity; TBIIs 10% inhibition; TPOs 2.0 IU/mL; ANA negative. In addition, a complete blood count and serum liver enzymes were measured at the time of enrollment in the laboratory of each participating institution. After the initial laboratory evaluation, children began treatment with propylthiouracil at a dosage of 5 to 7 mg/kg per day in 3 divided doses, up to a maximum of 450 mg/day. When the serum free T4 concentration declined to within the reference range, levothyroxine was added to the regimen according to the following age-based initial dosages: 1 to 5 years, 4 g/kg per day; 6 to 12 years, 3 g/kg per day; 12 years, 2 g/kg per day, up to a maximum dosage of 150 g/day. The dosage of levothyroxine was adjusted to maintain the serum free T4 and thyrotropin concentrations within the reference range. The medical regimen described was chosen for the study protocol because this regimen was used by the majority of participating endocrinologists from the Organization of Pediatric Endocrinologists of Northern California at the time of initiation of the study. By using the most frequently used regimen, we hoped to parallel actual clinical practice as closely as possible. Enrolled patients were seen monthly for the initial 3 months and quarterly thereafter during a 2-year period. At each visit, we measured goiter size as described previously and sent blood samples to the central laboratory for measurement of serum free T4, total T3, and thyrotropin concentrations. A complete blood count and measurement of serum liver enzymes were repeated at the 1- and 3-month visits with subsequent additional measurements made at the discretion of the treating physician. Children who developed adverse reactions to propylthiouracil (rash, arthralgias/arthritis, elevated liver enzymes, neutropenia) were switched to methimazole and continued to be followed in the study, unless the treating physician believed that the adverse reaction was of sufcient severity to warrant avoidance of all antithyroid medications. The dosage and frequency of administration of methimazole for these patients was chosen at the discretion of the attending physician. After 2 years of therapy, both propylthiouracil and levothyroxine were discontinued and serum free T4, total T3, and thyrotropin concentrations were measured at 2 weeks, 1 month, 3 months, 6 months, and 12

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months after discontinuation of medications. Children who continued to be euthyroid 12 months after the discontinuation of medications were considered to have achieved remission. Sample-size determinations for the study were based on the observed differences between groups and SD values for free T4 and total T3 concentrations from our previous retrospective study.14 We assumed an acceptable probability of type 1 error to be .05 and an acceptable probability of type 2 error to be .20. Children who achieved remission after 2 years of treatment with antithyroid medications in this study were compared with those who had persistent disease at 2 years. For univariate comparisons, we used Students t test for continuous variables and the 2 test for categorical variables. To determine which variables were independent predictors of early remission and to assess interactions among predictive variables, we also compared the 2 groups using 2 separate multivariable methods: multiple logistic regression and binary recursive partitioning. We used these 2 different multivariable methods to help verify the selection of predictive variables. Binary recursive partitioning is a nonparametric analytic technique that is used to classify patients on the basis of the presence of predictive variables, using a tree-like structure with decision nodes.19 Recursive partitioning analysis may be preferable to multiple logistic regression when the objective is derivation of a highly sensitive clinical prediction rule.20 Recursive partitioning allows for the inclusion of patients with missing predictors by substituting surrogate variables that contain information similar to that contained in the missing variables. Interactions between variables are also considered automatically during the process of recursive partitioning. These and other attributes of recursive partitioning may make this technique superior to logistic regression in accurately identifying patients with the outcome of interest.19 For these reasons, we considered the recursive partitioning analysis to be the primary multivariable analysis. Variables that were chosen for inclusion in the multivariate analyses were those with signicant univariate associations with remission status in this study, as well as those found in previous studies to be signicant predictors of remission (age, gender, goiter size, BMI, thyroid hormone concentrations, and initial response to antithyroid medication). Total T3 was not included in the logistic regression analysis because of collinearity with free T4. Univariate comparisons and logistic regression analysis were performed by using Stata 8.0 (Stata Corp, College Station, TX). We performed binary recursive partitioning using Answer Tree 3.0 (SPSS Inc, Chicago, IL). Candidate variables that were selected for the recursive partitioning analysis were identical to those entered into the logistic regression analysis with the exception that both total T3 and free T4 were considered because recursive partitioning analysis automatically chooses a candidate variable from among those that are collinear. Cutoff values for the conversion of continuous to dichotomous variables are also chosen automatically in the recursive partition-

ing program to separate optimally the data into risk proles for the outcome of interest. RESULTS Seventy children were enrolled in the study at 7 centers during a period of 5 years (Table 1). Seven children were lost to follow-up before completion of the study. In addition, 12 children discontinued medical therapy before completion of the study, either because of adverse reactions to the medication (4 children) or because of patient preference (8 children). The remaining 51 children comprised the study population for purposes of analysis. There were no signicant differences in clinical or biochemical features between the children who dropped out of the study or were lost to follow-up and the group who completed the study. There was, however, a trend toward higher free T4 concentrations in the children who did not complete the study (Table 1). Eleven (16%) of the 70 children initially enrolled developed adverse reactions to propylthiouracil, including skin rash (1 patient), rash with arthralgias (2 patients), arthritis with purpura and hematuria (1 patient), mild elevation in liver enzymes (3 patients), marked elevation in liver enzymes (2 patients), and neutropenia (2 patients). For 4 of these children, the adverse reaction was considered to be of sufcient severity to warrant avoidance of all antithyroid medications, and these patients were treated with alternative therapies. The other 7 children who developed adverse reactions to propylthiouracil were treated with methimazole (and thyroid hormone replacement) without additional adverse effects. Of the 51 children who completed the study, 15 (29%) achieved remission after 2 years of antithyroid medication (Table 2). In univariate analyses, there were no signicant differences in age, gender, or family history of thyroid disease between children who achieved remission within 2 years and those who did not. There were no signicant differences in the frequency of exophthalmos, mean BMI, or BMI SDS between the 2 groups. Of note, however, when the population was divided into groups on the basis of ethnicity, patients who achieved remission in the white group (n 25) tended to have higher BMI SDSs (remission group BMI SDS: 0.1 0.8; persistent disease group BMI SDS: 0.7 1.1; P .17), whereas patients of other ethnicities (n 26) showed an opposite trend (remission group BMI SDS: 0.4 1.9; persistent disease group BMI SDS: 0.1 1.1; P .66). We did not detect signicant differences in the initial goiter size between the 2 groups, either when compared using thyroid lobe length measures or when compared using the physicians estimation of percentage enlargement compared with normal size (Table 2). A decrease in goiter size during treatment was more frequent among the children who achieved remission, but this difference did not achieve statistical signicance. In contrast to the clinical measures, thyroid hormone concentrations were signicantly associated with remission status in univariate analyses. Both serum free T4 and serum total T3 concentrations were signicantly lower at the
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TABLE 1 Clinical and Biochemical Characteristics of the Study Population

Characteristic Age, mean (SD), y Gender, % female Family history of autoimmune thyroid disease, % Goiter size (length of thyroid lobes), %a None Small Moderate Large Goiter size (estimated enlargement), %a None Small (150) Moderate (150250) Large (250) Exophthalmos BMI, mean (SD) BMI SDS, mean (SD) Initial free T4, mean (SD) ng/dL pmol/L Initial total T3, mean (SD) ng/dL pmol/L TSIs Positive, % TSI % of basal activity, mean (SD)c TBIIs Positive, % TBII % inhibition, mean (SD)c TPOs Positive, % TPO, mean (SD), IU/mLc Positive ANAs, %
a Goiter bP

Patients Who Completed Study (n 51) 12.0 (3.7) 74 57

Dropped out or Lost to Follow-up (n 19) 12.5 (4.3) 78 40

20 28 26 26 10 24 34 31 55 18.5 (5.0) 0.37 (1.20) 8.9 (6.8) 137 (104) 523 (218) 8033 (3348) 51 244 (90) 98 54 (35) 87 535 (582) 30

47 20 13 20 7 53 20 20 61 20.3 (8.0) 0.15 (1.16) 16.0 (23.7)b 246 (364) 565 (335) 8678 (5146) 59 245 (94) 100 58 (23) 93 569 (506) 31

size classied according to Glaser and Styne14 (see Appendix). .06 for comparison with the study group. All other comparisons were nonsignicant (P .20). c For patients with detectable levels of specied antibody.

time of presentation in the remission group. In addition, children in the remission group were much more likely to achieve euthyroid status within the rst 3 months of treatment with propylthiouracil. Eighty-two percent of children in the remission group were euthyroid within the rst 3 months of treatment, compared with only 29% of children in the nonremission group. The mean dosage of propylthiouracil in the remission group (6.0 3.9 mg/kg) was not signicantly different from that of the nonremission group (5.5 2.1 mg/kg; P .62). At the time of presentation, 98% of patients had positive tests for TBIIs, but only 51% had positive tests for TSIs (Table 1). TPO antibodies were also detected frequently (87%). Thirty percent of children had positive tests for ANAs before treatment with propylthiouracil. There were no signicant differences in the frequency of positive thyroid antibody tests between the remission group and the nonremission group (Table 2). The measured levels of thyroid antibodies likewise were not different between the 2 groups. In the multivariable logistic regression analysis, only the initial response to propylthiouracil treatment maine484 GLASER, STYNE

tained a signicant association with remission after adjustment for the other variables (Table 3). There was a trend toward a signicant association with remission for age, with older age associated with greater likelihood of remission (P .06). In the binary recursive partitioning analysis, the initial response to propylthiouracil was also the most important predictive variable (Fig 1). Age and the initial total T3 concentration were also signicantly associated with remission in this analysis, with older age and lower total T3 indicating a higher likelihood of remission. When stratied according to these variables, children who were euthyroid within 3 months of initiating treatment with propylthiouracil and who were older (14.6 years of age) had the highest likelihood of achieving remission (83%). Those who were not euthyroid within 3 months of initiating treatment and who had high initial T3 concentrations (383 ng/dL) had the lowest likelihood of achieving remission (5%). DISCUSSION Choosing the ideal treatment approach for children with hyperthyroidism is often problematic, and clinicians and

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TABLE 2 Univariate Clinical and Biochemical Comparison of Children Who Achieved Remission With Those Who Did Not Achieve Remission
Parameter Age, mean (SD), y Gender, % female Family history of autoimmune thyroid disease, % Goiter size (length of thyroid lobes), %a None Small Moderate Large Goiter size (estimated enlargement), %a None Small (150) Moderate (150250) Large (250) Exophthalmos BMI, mean (SD) BMI SDS, mean (SD) Initial free T4, mean (SD) ng/dL pmol/L Initial total T3, mean (SD) ng/dL pmol/L Euthyroid after 3 mo PTU, % Decrease in goiter size during treatment, % TSIs Positive, % TSI % of basal activity, mean (SD)b TBIIs Positive, % TBII % inhibition, mean (SD)b TPOs Positive, % TPO, mean (SD), IU/mLb Positive ANAs, % Remission After 2 y (n 15) 12.8 (3.6) 80 64 No Remission (n 36) 11.8 (3.5) 72 53 Difference (95% CI) 1.0 (3.2 , 1.1) 8 (33 , 17) 11 (40 , 20) P .32 .56 .48

21 21 29 29 0 29 42 29 53 20.1 (7.5) 0.25 (1.34) 6.17 (3.10) 94.8 (47.6) 431 (175) 6620 (2688) 82 75

19 31 25 25 13 23 32 32 56 18.0 (3.5) 0.34 (1.12) 9.86 (7.54) 151.4 (115.8)

.94

.74

3 (28 , 33) 2.1 (5.2 , 1.1) 0.10 (0.85 , 0.67) 3.7 (6.8 , 0.6) 130 (254 , 6)

.87 .19 .79 .02

.04

561 (225) 8617 (3456) 29 54

53 (81 , 25) 21 (52 , 10) 7 (25 , 39) 19 (72 , 109) 3 (9 , 3) 2 (27 , 22) 7 (16 , 31) 263 (214 , 740) 22 (56 , 11)

.003 .21

46 230 (106) 100 55 (54) 83 334 (494) 45

53 249 (87) 97 53 (26) 91 597 (601) 23

.67 .67 .55 .83 .47 .27 .17

PTU indicates propylthiouracil. a Goiter size classied according to Glaser and Styne14 (see Appendix). b For patients with detectable levels of specied antibody.

patients must weigh the risks and benets of each treatment option. Although antithyroid medications are often favored as the initial approach, recent debate has focused on whether radioactive iodine or surgery should be used with greater frequency.21,22 Relatively few data have previously been available to guide these clinical decisions, and no previous studies evaluated this issue

TABLE 3 Factors Associated With Remission: Multivariable Logistic Regression Analysis

Variable Age Gender BMI SDS Goiter size Initial T3 Euthyroid by 3 mo on PTU
OR indicates odds ratio; CI, condence interval.

OR (95% CI) 1.33 (0.99 to 1.79) 4.30 (0.29 to 62.90) 0.89 (0.42 to 1.89) 0.96 (0.24 to 3.94) 0.99 (0.98 to 1.00) 22.30 (2.06 to 242.30)

P .06 .29 .76 .96 .20 .01

prospectively. In this prospective study, we demonstrate that lower thyroid hormone concentrations at the time of diagnosis, older age, and more rapid achievement of euthyroid status after start of antithyroid medications predicted remission after 2 years of therapy. These predictive variables can be used to stratify patients according to the likelihood of achieving remission. Previous studies suggest that 25% of children achieve remission with every 2 years of treatment with antithyroid medications.10,11,14 In theory, therefore, most medically treated patients should eventually achieve remission, provided that medications are continued for sufcient periods. Probabilities of remission with longterm antithyroid medication use, however, are largely statistical predictions, based on data from relatively few patients, and may therefore be less accurate than shortterm data.11 In addition, data from adult studies contrast with the more limited data from pediatric studies and suggest that prolonged treatment with antithyroid medPEDIATRICS Volume 121, Number 3, March 2008 e485

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Early remission: 15 patients (29%) Persistent disease: 36 patients (71%)

Euthyroid within 3 mo on PTU

No
Early remission: 3 patients (12%) Persistent disease: 22 patients (88%)

Yes
Early remission: 12 patients (46%) Persistent disease: 14 patients (54%)

Initial total T3 < 383 ng/dL

(5883 pmol/L)

Initial total T3 > 383 ng/dL

(5883 pmol/L)

Age < 14.6 y

Age > 14.6 y

Early remission: 2 patients (33%) Persistent disease: 4 patients (67%)

Early remission: 1 patient (5%) Persistent disease: 18 patients (95%)

Early remission: 7 patients (35%) Persistent disease: 13 patients (65%)

Early remission: 5 patients (83%) Persistent disease: 1 patient (17%)

FIGURE 1 Results of the recursive partitioning analysis of variables that were predictive of early remission. Each branch provides the number (and percentage) of patients with remission or persistent disease after 2 years of medical treatment, given the specied combination of predictive variables. PTU indicates propylthiouracil.

ications beyond 18 months is not associated with higher remission rates.17,18 Regardless of whether long-term treatment with antithyroid medications can improve remission rates, descriptive data indicate that many patients eventually receive alternative therapies. In previous retrospective studies, 25% to 66% of patients who initially were treated with antithyroid medications discontinued medications before achieving remission and were eventually treated with either radioactive iodine or, less commonly, surgery.10,11,1316,23 Over time, progressively fewer patients continued medical therapy, with 14% to 18% per year opting for alternative treatment.14 Although some patients discontinue medications because of adverse reactions, these patients generally account for a minority of the total.10,1316 Poor compliance and personal preference seem to be more frequent reasons for these changes in treatment modality.11 Previous retrospective studies evaluated factors that were associated with time to achieve remission in children with hyperthyroidism, but the results were variable and conicting. Older age, lower initial thyroid hormone concentrations, a more rapid response to antithyroid medications, smaller goiter size at presentation, a decrease in goiter size during treatment, and higher initial BMI all have been associated with increased likelihood of remission in some studies but not in others.13,14,2426 In a previous retrospective study by our group using multivariable analysis, smaller goiter size at presentation and higher initial BMI SDS were found to be independent predictors of early remission.14 Because this was a retrospective study, however, the methods for measuring thyroid hormone concentrations and thyroid antibody
e486 GLASER, STYNE

levels varied, and goiter size was not measured in a standardized manner. Therefore, we could not exclude the possibility that variations in these measures may have biased the results in favor or against nding an association with early remission. Because this study was done prospectively, using standardized methods, the results differ in some respects from earlier reports. In agreement with some previous studies, older age, lower initial thyroid hormone concentrations, and a more rapid initial response to antithyroid medications were important predictors of early remission. In contrast to previous retrospective studies, however, initial goiter size was similar in the remission and nonremission groups. The reason for this difference is unclear. It is possible that clinicians tend to overestimate goiter size in children who are known to have very high thyroid hormone concentrations or more pronounced symptoms of hyperthyroidism, leading to bias when medical charts are reviewed retrospectively. In addition, in this study, we did not detect an association between BMI SDS and likelihood of remission. The reason for this difference is also unclear but may reect underlying differences in the ethnic makeup of the population. Notably, when data were analyzed for white patients only, the differences in BMI SDSs between the remission group and the group with persistent disease were similar to those documented in our previous retrospective study.14 Ethnicity was not recorded in the previous retrospective study, but it is possible that the ethnic makeup of that population may have differed from that in this study, accounting for the observed variation in predictive value of BMI SDS. The multivariate analyses in this prospective study likewise differ from previous analyses using retrospec-

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tively collected data.14 In this prospective study, the initial response to antithyroid medication, initial thyroid hormone concentrations, and age were the most important predictive variables. In contrast, in our previous retrospective study, BMI SDS and goiter size were the most important predictors in the multivariate analysis. This discrepancy likely reects the use of standardized methods for measurement of goiter size and the use of a single laboratory for measurement of thyroid hormone concentrations in this study. These methods greatly limited sources of potential bias that are unavoidable in retrospective studies but might bias the results either in favor of or against nding associations between variables. A notable nding in this study is the relatively low rate of detection of thyrotropin receptor autoantibodies by TSI bioassay, despite detection of thyrotropin receptor autoantibodies by TBII assay in almost all enrolled patients. Some previous studies demonstrated a high prevalence (90%) of both TSIs and TBIIs in children with Graves disease,2729 whereas others showed a lower rate of detection of TSIs compared with TBIIs.30 In our previous retrospective study of children with Graves disease, TSIs were detected in 76% of patients, but no data were collected regarding TBII measurements.14 The reason for the observed differences among studies is unclear. Thyrotropin receptor blocking antibodies may be involved but are thought to be uncommon in patients with Graves disease and clinical hyperthyroidism.28 It is possible that the lower rate of detection of TSIs among patients in this study may reect relatively milder disease, although TSI detection rates were similar in the remission group and persistent disease group. Lower rates of detection of TSIs may also indicate lower sensitivity of the TSI assay compared with the TBII method. An additional notable nding in this study is the high frequency of detection of ANAs before treatment with antithyroid medications. Similar ndings were reported in a previous study of adults with Graves disease,31 as well as a previous pediatric study.13 The current data reinforce these ndings and suggest that detection of ANAs need not be taken as an indication of adverse reaction to antithyroid medication. This study has limitations. The study population was relatively small compared with previous retrospective studies, and we were therefore limited in our ability to detect associations of smaller magnitude. In addition, the small sample size makes it difcult to estimate precisely the likelihood of early remission given various combinations of predictive variables. These variables could be evaluated with greater precision in a larger study. In addition, several patients were lost to follow-up or dropped out of the study before study completion. In this lost population, the initial free T4 concentrations tended to be higher than those of the study group. Because initial thyroid hormone concentrations are important predictors of early remission, it is possible that the study population overrepresented patients with a greater previous probability of achieving early remission. In addition, although we attempted to exclude patients with Hashitoxicosis from the study, there is substantial over-

lap in both clinical features and laboratory measures between patients with Hashitoxicosis and those with Graves disease,32 and it is possible that rare patients with Hashitoxicosis may have been included. Inclusion of these patients seems relatively unlikely, however, because none of the study subjects developed hypothyroidism and almost all patients had evidence of thyrotropin receptor antibodies. An additional limitation of the study is that goiter size was assessed using manual measurements, rather than ultrasound, which may be more precise. Ultrasound measurements of goiter size were not included in the study protocol so that the variables assessed would be those that are routinely and readily available to clinicians. It is possible, however, that goiter size would have been a more important predictor of outcome, if measured more precisely by ultrasound. Finally, patients in the study were followed for only 1 year after discontinuation of antithyroid medications. It is possible that some patients experienced a relapse of the disease after the 1-year follow-up period; however, data from previous studies indicated that the frequency of such late relapses is very low.11 CONCLUSIONS These results indicate that children with hyperthyroidism who respond rapidly to antithyroid medication and are older (14 15 years of age) are most likely to achieve early remission. These children should likely be encouraged to continue antithyroid medications, given the good prognosis for remission and the possibility of avoiding permanent hypothyroidism. Children who continue to have elevated thyroid hormone concentrations after 3 months of treatment with antithyroid medication and who have very high initial total T3 concentrations are unlikely to achieve early remission. These factors should be taken into account in determining the treatment plan, and for patients who are less likely to achieve remission, consideration of alternative therapeutic options may be advisable. ACKNOWLEDGMENTS Members of the Organization of Pediatric Endocrinologists of Northern California Collaborative Graves Disease Study Group (listed alphabetically by name of collaborating institution) are: California Pacic Medical Center, San Francisco, CA: Irene Solomon, MD; Kaiser Permanente, Sacramento, CA: Sobha Kollipara, MD; Kaiser Permanente, Santa Clara, CA: Debra Cohen, MD, and Pratima Misra, MD; Quest Diagnostics, San Juan Capistrano, CA: Delbert Fisher, MD; Reno, Nevada: Kathryn Eckert, MD; Stanford University, Palo Alto, CA: Bruce Buckingham, MD, Laura Bachrach, MD, Darrell Wilson, MD, E. Kirk Neely, MD, Patricia Fechner, MD, Diane Suchet, MD, Laura Gandrud-Pickett, MD, Suruchi Bhatia, MD, Mark Daniels, MD, Sofa Jonasdottir, MD, Angela Badaru, MD, Kupper Wintergerst, MD, and Carolyn Chi, MD; Sutter Medical Center, Sacramento, CA: Bagher Sheikholislam, MD; University of California, Davis, School of Medicine, Sacramento, CA: Gia Oh, BA, and Maria Chuang, BA (research assistants).
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We gratefully acknowledge the generous assistance of Quest Diagnostics in conducting the assays for thyroid hormone concentrations and thyroid antibody levels. We are also grateful to Dr Nathan Kuppermann for his helpful assistance with the statistical analyses. REFERENCES
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APPENDIX Classication of Goiter Size as Described by Glaser and Styne14

Parameter 19 y None/minimal Small goiter (1.5 times normal size) Moderate goiter (1.52.5 times normal size) Large goiter (2.5 times normal size) 3 3 and 4 4 and 5 5 Longest Lobe Length, cm 1014 y 3.5 3.5 and 4.5 4.5 and 5.5 5.5 15 y 4 4 and 5 5 and 6 6

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Predicting the Likelihood of Remission in Children With Graves Disease: A Prospective, Multicenter Study Nicole S. Glaser, Dennis M. Styne and for the Organization of Pediatric Endocrinologists of Northern California Collaborative Graves Disease Study Group Pediatrics 2008;121;e481-e488; originally published online Feb 11, 2008; DOI: 10.1542/peds.2007-1535
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/121/3/e481 This article cites 30 articles, 14 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/121/3/e481#BIBL One P3R has been posted to this article: http://www.pediatrics.org/cgi/eletters/121/3/e481 This article, along with others on similar topics, appears in the following collection(s): Endocrinology http://www.pediatrics.org/cgi/collection/endocrinology Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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