DISEASE PRESENTATION AND REMISSION RATE IN GRAVES' DISEASE TREATED WITH ANTI-THYROID DRUGS: IS GENDER REALLY A FACTOR?

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1 EDOCRIE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP DISEASE PRESETATIO AD REMISSIO RATE I GRAVES' DISEASE TREATED WITH ATI-THYROID DRUGS: IS GEDER REALLY A FACTOR? Talia Diker-Cohen, MD PhD 1, 2, 3, Hadar Duskin-Bitan, MD 1, 3, Ilan Shimon, MD 1, 3, Dania Hirsch, MD 1, 3, Amit Akirov, MD 1, 3, Gloria Tsvetov, MD 1, 3, Eyal Robenshtok, MD 1, 3 From: 1 Institute of Endocrinology, Rabin Medical Center, Petah-Tikva, Israel; 2 Medicine A, Rabin Medical Center, Petah-Tikva, Israel; 3 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Running title: Role of gender in Graves disease Corresponding address: Eyal Robenshtok, MD, Institute of Endocrinology, Rabin Medical Center, Petah-Tikva, Israel. robensht@gmail.com Key words: Autoimmune thyroid diseases, Graves disease, gender, antithyroid drugs, outcome

2 Abstract Objective: Male gender is considered an adverse prognostic factor for remission of Graves' disease treatment with anti-thyroid drugs (ATD), though published data is conflicting. This often results in early consideration of radioiodine treatment and surgery for men. Our objective was to compare disease presentation and outcome in men versus women treated with ATDs. Methods: Retrospective study of 235 patients (64 men, 171 women) with Graves disease who were evaluated for features at presentation and outcome at the end of follow-up between 2010 and Results: Disease presentation was similar in men and women for age at diagnosis (41.4±14 vs. 40±15 years), duration of follow up (6.6±7 vs. 7.7±6 years), rates of co-morbid autoimmune diseases, and rate of Graves' ophthalmopathy. Smoking was more prevalent in males (31% vs. 15%, p=0.009). Free T4 and T3 levels were comparable. ATDs were first line treatment in all males and in 168 of 171 females, for a median duration of 24 and 20 months, respectively (p=0.55). Remission rates were 47% in men and 58% in women (p=0.14). Males had less adverse events (9% vs. 18%) and treatment (5% vs. 16%). Disease recurrence was comparable (14% vs. 20%, p=0.32), as was requirement for second line treatment, either radioiodine therapy or thyroidectomy. Conclusion: Graves' disease presentation is similar in men and women. Men treated with ATDs have high remission rates and similar recurrence rates compared to women, with less adverse events and less of treatment. ATDs are an attractive first line treatment for both genders.

3 Abbreviations: ATD = anti-thyroid drugs, GO = Graves' ophthalmopathy, ATA = American thyroid association, EUGOGO = European group on Graves' orbitopathy, MRI = magnetic resonance imaging.

4 Introduction Graves' disease is an autoimmune thyroid disease with an interplay between environmental factors and genetic predisposition 1 4. Gender is considered a predisposing factor, as women are affected 4 to 10 times more than men 1,2,5 8, but only a few studies evaluated the possible effects of gender on the clinical course of Graves disease. While gender has a known effect on Graves' ophthalmopathy (GO), which is more prevalent in women yet men are more likely to have severe disease 9,10, the impact of gender on hyperthyroidism and remission rate is less clear, with conflicting data in the literature Therapeutic options in Graves patients include anti-thyroid drugs (ATDs), radioiodine therapy and thyroidectomy. Since there is no consensus for an algorithmic approach to treatment of Graves disease, either can be used as first line therapy 11. When ATDs are used as first line therapy, remission is induced in up to 68% of subjects, varying considerably between geographic areas 11. Male gender is often associated with lower rates and shorter duration of remission after a course of ATD 6, a notion that has been translated to early consideration of alternative therapies in men, namely radioiodine ablation and surgery 6,11. In line with the above, recent guidelines state that there is a higher likelihood of remission after ATD in women 11, though data is conflicting. Moreover, autoimmune thyroid disease is much more common in women 5,12, so men are less likely to be represented in studies on Graves' disease, leading to uncertainty regarding the optimal therapeutic approach in men. We therefore aimed to compare disease presentation and treatment outcomes in male and female patients with Graves disease.

5 Subjects and Methods Medical records of patients with Graves' disease who were treated as outpatients at the endocrinology service of Rabin Medical Center between 2010 and 2015 were reviewed. Charts coded by Graves disease or Graves ophthalmopathy (GO) were screened. Diagnostic criteria for Graves disease included laboratory values consistent with overt hyperthyroidism confirmed by either positive anti-tsh receptor antibodies or diffuse uptake on thyroid scan. We included only a first episode of Graves' disease. Major exclusion criteria were subclinical hyperthyroidism, GO with laboratory euthyroidism, onset of disease at <18 years of age, cases with insufficient data, and noncompliance with medical treatment or clinic visits as stated in the medical record. Patients were mostly started on methimazole 20 to 40 mg daily, and treatment was then individualized at the physician s discretion. Remission was defined according to the 2016 American Thyroid Association (ATA) hyperthyroidism guidelines 11 as laboratory euthyroidism 12 months after of ATD therapy. At time of data cut point, patients who were on ongoing treatment with ATD (for longer than 18 months) were defined as no remission. Recurrence was defined as overt hyperthyroidism detected after at least 12 months of clinical and laboratory euthyroidism following ATDs in patients with previous documentation of remission. Patients were defined to have goiter as clinically assessed by physical examination during their office visits. Patients were defined to have GO in case of any of the following: 1) there were any signs of ophthalmopathy in the physical examination report per the EUGOGO criteria, 2) documentation of an imaging study (e.g. MRI of orbital muscles) supporting the diagnosis of GO, 3) they received any treatment for GO, or 4) chart was coded by Graves ophthalmopathy. Treatment of GO was defined according to use of drops, ointment, selenium, steroids or surgery. o patient required external beam radiation.

6 Menopause was defined based on the report in the medical chart, coding in the medical chart, age above 60 years or laboratory tests of gonadotropins that were consistent with a menopausal status. The study was approved by the hospital's Institutional Review Board. Informed consent was not required for this retrospective analysis. Serum TSH was measured by a two-site sandwich immunoassay using a direct chemiluminometric technology (normal range ), and free T4 and free T3 levels were measured by a competitive immunoassay (normal range pmol/l and pmol/l, respectively) using a direct chemiluminescence technique (ADVIA Centaur, Siemens Healthcare Diagnostics, Tarrytown, Y, USA). Anti-TPO antibodies were measured by a chemiluminescent sequential immunometric assay (Immulite 2000, Siemens Healthcare Diagnostics, Gwynedd, United Kingdom). TSH receptor antibodies were measures by ELISA (ETI-Max 3000, DiaSorin, Saluggia, Italy). Statistical analysis All statistical analyses were performed with the SPSS v.20.0 (IBM Corp., Armonk, Y, USA). Associations between two categorical variables were examined using χ 2 test and Fisher's exact test; associations between continuous and quantitative variables were examined using the Mann-Whitney nonparametric U-Test. A two-sided p-value of <.05 was considered statistically significant for all analyses. Results Three hundred sixteen medical records coded by Graves disease or Graves ophthalmopathy were screened (231 female subjects, 82 male subjects) (Fig. 1). A total of 80 cases were excluded for either insufficient data (n=38), diagnosis of subclinical

7 hyperthyroidism (n=7), GO with laboratory euthyroidism (n=7), onset of disease in childhood (n=10), non-compliance with medical treatment (n=12) or other causes (n=6). The final analysis included data of 235 patients (171 females, 64 males). Males consisted 27% of the study cohort. Patient characteristics at disease presentation Men and women had similar age at disease presentation, 41.4±14 years for men and 40±15 years for women, and similar duration of follow up with 6.6±7 years for men, and 7.6±6 years for women (S) (table 1). Active smoking was twice more prevalent among male subjects (31% male vs. 15% female, p=0.009). Rates of GO were similar (31% vs. 28%, p=0.62), and the rate of GO necessitating treatment was also comparable (25% vs. 21%, p=0.75). on-thyroidal autoimmune co-morbidities were present in both groups: male subjects had type 1 diabetes mellitus (n=3), celiac disease (n=3) and pernicious anemia (n=2). Female subjects presented with type 1 diabetes mellitus (n=5), celiac disease (n=1), pernicious anemia (n=8) and other diseases (1 myasthenia gravis, 1 rheumatoid arthritis,1 Bechcet disease, 1 crohn's disease, 1 systematic lupus erythematosus, 2 immune thrombocytopenic purpura cases); nonetheless, the overall rate of co-morbid autoimmune diseases did not differ between study groups (13% in men, 12% in women, p=0.98). Laboratory data showed slightly higher values of free T4 at presentation among male subjects (46.9±21.9 pmol/l vs. 40.7±17.5, p=0.06), but no significant difference in values of free T3 (16.8±6.5 vs. 15.6±6.7 pmol/l, p=0.35) or positivity of anti-tsh receptor antibodies (90% vs. 85%, p=0.61). Treatment of Graves patients

8 All male patients and 168 of 171 female patients were treated with anti-thyroid drugs as first line for a median time of 24 and 20 months, respectively (p=0.55) (table 2). Only 3 females (1.7% of female subjects) and none of the male patients received radioactive iodine as the initial treatment modality; reasons for prescribing iodine therapy in these cases were pregnancy planning (n=1), baseline neutropenia (n=1) and patient's preference (n=1). o patient underwent thyroidectomy as first line therapy. Outcome data Remission rates after the first course of ATD were comparable with 47% in men and 58% in women (p=0.14), after mean follow-up of 9 ± 21 years and 6 ± 6 years respectively. Men had lower rates of adverse effects (9% vs. 18%, p=0.09) and of ATD treatment (5% vs. 16%, p=0.02) compared to women (Table 2). Adverse events in men included rash or pruritus in 3 subjects and elevated liver enzymes in 3 subjects. Adverse events in women included the following: rash or pruritus (n=16), elevated liver enzymes (n=7), neutropenia (n=2), gastrointestinal intolerance (n=2), arthritis (n=1) or arthralgia (n=1) or thrombocytopenia (n=1). Recurrence rates were comparable in men and women (14% vs. 20%, S), as well as time to recurrence (58 ± 71 months vs. 51 ± 78 months, S), and radioiodine treatment (20% vs 23%, S) (table 2). Predictors for remission on ATD therapy Overall, 126 patients (54%) had remission (96 females, 30 males). Male subjects represented 34% of those who failed to achieve remission and 24% of those who did achieve remission with ATDs. Gender was not a predictor of remission in univariate analysis of the full study cohort (p=0.124) (Table 3). Also, neither age at diagnosis of Graves' disease, menopause, smoking, personal history of other autoimmune diseases, ophthalmopathy, blood

9 levels of thyroid hormone or anti-thyroid antibodies predicted treatment success with ATD. Duration of therapy predicted remission (p=0.003) as patients who achieved remission were treated for shorter periods of time compared to patients without remission (mean 27±42 versus 45±43 months). A second predictor for remission was report of adverse effects (p<0.001), as more adverse events predicted lower rates of remission. Discussion The optimal treatment algorithm for Graves' disease is controversial, with three optional treatments including ATDs, radioiodine or surgery. While the most common treatment of Graves' disease in the United States and Europe today is with ATDs 30, 31, the choice of treatment for each patients is tailored according to severity of disease, presence of GO, and the probability of remission with ATDs. Our study demonstrates that men and women with Graves' disease have similar disease presentation and response to ATD as first line treatment. ATD treatment did not only result in comparable remission rates and recurrences in both genders, but men experienced less adverse effects and of treatment. This is in contrast to the common notion of men having low success rates with ATD therapy 8. The 2016 ATA guidelines on diagnosis and management of hyperthyroidism state that there is a lower likelihood of remission after ATD therapy in men 11, with four studies as reference However, Pubmed search of this topic results in a list of at least 18 papers 13 30, the majority showing that male gender is not a negative predictor for remission in ATDtreated patients, with one notable exception 11 (Table 4). Most of these studies were designed to assess predictors for remission, considering gender as one among many other variables. Only two other studies thus far were specifically designed to explore the role of gender in the natural history and response to treatment in Graves' disease 13,31 ; The first, by Allahabadia et

10 al. 13, is the most cited report which lent credence for consideration of male gender as a negative predictor for response to ATD. In that study, 92 males of 536 patients with Graves hyperthyroidism had both more severe biochemical disease at presentation compared to females (statistically significant higher free T4 and free T3 levels), as well as lower remission rates after a course of ATDs (19.6% vs. 40%; p<0.01) or one dose of radioiodine (47% vs. 74%; P<0.0001). The authors concluded that as males have low remission rates to ATD they should be offered definitive treatment with radioiodine or surgery soon after presentation. However, as men had more severe disease compared to women in this study, the worse outcome of males could be attributed to the baseline disease severity rather than the gender difference in ATDs response. In contrast to this study, patients in our cohort had comparable baseline characteristics and therefore there is less concern for bias. Also, the ATA definition of remission is euthyroidism at 12 months after therapy 11, whereas as shown in Table 4, many studies have used other definitions. In the study by Allahabadia et al. remission was defined as euthyroidism six months after ATD 13, and the mean follow up of patients was only 9 months after the end of therapy. As the definition of remission in that study was much shorter than recommended in the ATA guidelines, some of the cases defined as remissions would probably be classified as treatment failures after longer follow-up. In this context, another major strength of our work is the definition of remission as euthyroidism 12 months after the end of drug therapy. The second study specifically designed to explore the role of gender in Graves disease, by Magri et al. 31, retrospectively evaluated the response to ATD in 294 patients (66 men). The response of men to ATD was less favorable compared to women due to a higher rate of relapse. It should be noticed that males had larger goiter size at presentation, a parameter that was later found to be associated with relapse in that cohort. Also, looking carefully at the data presented in the paper, a similar rate of males and females achieved biochemical normalization and were considered in remission after 18 months of

11 ATD treatment (75.7% and 79.4%, respectively); most of the recurrences occurred during the first year after of ATD (defined in the paper as early relapse, 48% males, 30.9% females, p=0.024). As discussed above, according to the ATA hyperthyroidism guidelines relapse is considered only after 1 year of euthyroidism, and again these cases, which most of them continued to definitive therapy, would probably be classified as treatment failures after longer follow-up. There was no statistically significant difference between men and women in the rate of late relapse by the definition in Magri s work (between 1 and 5 years after ATD ), which is consistent with the definition and the results in our cohort. The choice of an appropriate mode of therapy in Graves disease should take into account the rates of remission and recurrence. Several studies looked for predictors for treatment success either before the start of treatment or during therapy; the most established adverse predictors of long term remission after ATD include young age, smoking, severe biochemical disease (especially high free T4) at disease presentation, large goiter, or high TSH-receptor antibodies 4,11,13 15,28,29,32. Others have suggested multi-factorial models for predicting remission with consideration of clinical and laboratory parameters as well as genetic polymorphisms 4. Yet, most of these studies used various definitions of remission and recurrence and should be interpreted considering this limitation. In our cohort neither the clinical parameters (gender, menopausal status, autoimmune co-morbidities, smoking or presence of ophthalmopathy) nor the laboratory values (thyroid function tests, anti-thyroid antibodies) at presentation were found to be predictors for remission. It should be noted that TSH receptor antibodies were measured only at diagnosis and not before a decision to discontinue ATD as the 2016 ATA guidelines recommend, and in roughly 30% of the cohort. This is since in our country TSH receptor antibody tests are not reimbursed, and patients need to pay

12 for the test. This might explain why TSH receptor antibodies did not predict remission after ATD therapy. Also of note, there is a growing body of evidence suggesting that estrogen may play a role in the pathogenesis of autoimmunity 12,33,34. This has led us to question whether there may be differences between pre- and post-menopausal women in regards to the response to ATD treatment, yet menopause did not predict higher remission rates. evertheless, we think that the role of sex hormones should be further evaluated in this context. A statistically significant association was detected between remission and the overall ATD treatment duration, as patients who achieved remission were treated for shorter periods of time compared to patients without remission; yet, it is somewhat intuitive to assume that treatment was ended earlier in those who achieved earlier normalization of the thyroid function. onetheless, treatment duration per se in our study was longer than the recommended in the ATA guidelines. As this was a retrospective study, treatment duration was not pre-determined, and the results rather reflect the common practice in our clinic; the similarities in treatment duration in both sexes further attests to this interpretation of local practice of the treating endocrinologists and not to confounding reasons or biases that led to longer-than-expected duration of therapy. The lack of widely available TRAb testing as recommended per the ATA guidelines may be one of the reasons for prolonged ATD therapy. It should nevertheless be pointed out that the recommendation for months of treatment duration is based on one meta-analysis of old data 35 (4 trials included, latest one was published in 1999) with enrollment of less than 80 patients in each study arm, and mostly comparison of 12 or above months of therapy to less than 6 months of therapy (not months vs. longer duration). Moreover, some papers have been published since, that suggest benefit for longer duration of therapy 27, especially in children 36. It would be interesting to see in current practice whether length of treatment per the ATA guidelines is indeed implemented in other centers and if new data still attests to short duration of treatment.

13 Also, more adverse events during ATD therapy predicted lower rates of remission. This could be explained by earlier drug withdrawal upon the occurrence of an adverse event, resulting in higher rates of treatment failure. A 2011 international survey on the management of GD showed that 85.7% of endocrinologists in Europe versus only 40.5% of the endocrinologists in orth America would select ATD as the primary treatment modality for an index case of uncomplicated GD 37. Yet, the use of ATD is constantly increasing in both U.S. and Europe 37,38. In our study ATD were used as first line treatment in almost 100% of patients, resulting in a cohort with less selection bias. First line treatment with ATDs was not an inclusion criterion, but rather reflects the common practice in our institute. Our study has several limitations. First, the retrospective design has inherent bias with the potential for missing data, and reliance of the common practice of treating physicians. Second, the length of treatment with ATD was dependent on individual physicians' practices and patients' preferences, potentially extending treatment beyond time of remission. This could theoretically result in overestimation of no-remission cases due to our definition of ATD treatment duration longer than 18 months at time of data cut point as failure to remit. Third, noncompliance was considered per the physician s report in the medical files that were reviewed and not by number of prescriptions or other systematic method. Moreover, though non-compliant cases to ATD therapy were excluded, one cannot fully detect partial nonadherence to treatment. Additionally, definition of goiter was based on clinical experience and physical examination rather than imaging studies, and we did not have accurate estimation of the thyroid volume. In the same line, GO was defined if clinically assessed or based on coding, however data was not sufficient to accurately assess severity and activity in

14 most cases. Lastly, TRAb results are expressed in a qualitative manner and not in a precise levels. In summary, our results and others have not found gender to play a major role in the response to ATD therapy, either in remission or recurrence rates. Though there was a trend for more remission in female subjects in this cohort, the difference from male subjects was not statistically significant. We believe that the notable response of males to ATD treatment per se lends credence to a trial of ATD as first line therapy with no consideration of the patient s sex. We conclude that given the high rates of remission after ATD therapy among males and females with similar disease presentation, with less adverse events and less of treatment in males, ATDs are an attractive first line treatment in Graves disease for both genders.

15 Declaration of interest Authors have nothing to disclose. Funding This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Figure Legends: Figure 1. Case selection process

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19 Thyrotoxicosis of Graves s Disease. Engl J Med. 1977;297: Liu X, Shi B, Li H. Valuable predictive features of relapse of Graves disease after antithyroid drug treatment. Ann Endocrinol (Paris). 2015;76: Mohlin E, Filipsson yström H, Eliasson M. Long-term prognosis after medical treatment of Graves disease in a northern Swedish population Eur J Endocrinol. 2014;170: Anagnostis P, Adamidou F, Polyzos SA, et al. Predictors of long-term remission in patients with Graves disease: a single center experience. Endocrine. 2013;44: Daukšienė D, Daukša A, Mickuvienė. Independent pretreatment predictors of Graves disease outcome. Medicina (Kaunas). 2013;49: Ishtiaq O, Waseem S, Haque M, Islam, Jabbar A. Remission of Grave s disease after oral anti-thyroid drug treatment. J Coll Physicians Surg Pak. 2009;19: Léger J, Gelwane G, Kaguelidou F, Benmerad M, Alberti C. Positive impact of longterm antithyroid drug treatment on the outcome of children with Graves disease: national long-term cohort study. J Clin Endocrinol Metab. 2012;97: Magri F, Zerbini F, Gaiti M, et al. Gender Influences The Clinical Presentation And Long-Term Outcome Of Graves Disease. Endocr Pract. 2016;22: Carella C, Mazziotti G, Sorvillo F, et al. Serum Thyrotropin Receptor Antibodies Concentrations in Patients with Graves Disease Before, at the End of Methimazole Treatment, and After Drug Withdrawal: Evidence That the Activity of Thyrotropin Receptor Antibody and/or Thyroid Response Modify During the Observation Period. Thyroid. 2006;16:

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21 Fig 1

22 Table 1. Baseline characteristics at presentation Male (n=64) Female (n=171) p value Age, years (median, range) 41 (21-74) 38 (18-79) 0.54 Autoimmune co-morbidity (%) 13% (8/64) 12% (21/170) 0.98 Family history of AITD (%) 32% (17/53) 41% (52/127) 0.26 Current smoking (%) 31% (19/61) 15 % (23/150) Graves ophthalmopathy (%) 31% (20/64) 28% (47/168) 0.62 Goiter (%) 26% (16/62) 40% (66/163) Free T4 at diagnosis, pmol/l (mean±sd) 46.9± ± Free T3 at diagnosis, pmol/l (mean±sd) 16.8± ± Positive anti-tpo (%) 55% (26/47) 71% (92/130) Positive TSH receptor antibodies (%) 90% (18/20) 85% (53/62) 0.61 AITD, autoimmune thyroid disease, TPO, thyroid peroxidase, TSH, thyroid stimulating hormone.

23 Table 2. Treatment of patients with Graves disease Men (n=64) Women (n=171) p value ATDs as 1st line treatment (%) 100% 98% 0.29 Duration of ATDs treatment, months (mean±sd) 38 ± ± Remission on ATDs (%) 47% 58% 0.14 Adverse events on ATDs (%) 9% 18% 0.09 Discontinuation d/t adverse events (%) 5% 16% 0.02 Ongoing ATDs at data cut point (%) 25% 16% Recurrence after ATDs (%) 14% 20% 0.32 Time to recurrence, months, n±sd (median) 58 ± ± Follow up after ATDs, years, mean±sd 9 ± 21 6 ± Radioiodine treatment (%) 20% 23% 0.68 Radioiodine activity (mci) 12 ± 3 10 ± Thyroidectomy (%) 6% 6% 0.96 ATDs, anti-thyroid drugs

24 Table 3. Predictors for remission on ATDs treatment p value Age at diagnosis Gender Menopause Autoimmune co-morbidity Current smoking Graves' ophthalmopathy Free T4 at diagnosis Free T3 at diagnosis Anti-TPO antibodies Anti TSH receptor antibodies Overall treatment duration with ATD* Adverse events on ATDs** <0.001 * Patients who achieved remission were treated for shorter periods of time compared to patients without remission (mean 27±42 versus 45±43 months) ** More adverse events predicted lower rates of remission. ATDs, anti-thyroid drugs, TPO, thyroid peroxidase, TSH, thyroid stimulating hormone,

25 Table 4. Male Gender as a Predictor for Remission after ATD Treatment Study Allahabadia 2000 (13) edrebo 2002 (14) Kimball 2002 (15) Kruljac 2015 (16) Tota l coho rt Mal es Age Grou p ATD Adults Carbima zole or PTU Adults Carbima zole or PTU Tx Duration (mean) Definition of Remission 18 mo Euthyroid 6 months after ATD 12 mo Euthyroidism achieved during ATD treatment Adults S mo Euthyroid 6 months after ATD Adults MMI mo Euthyroidism achieved during ATD treatment Liu 2015 (25) 133 D Adults MMI mo Euthyroid 12 months after ATD Mohlin 2014 (26) Anagnostis 2013 (27) Dauksiene 2013 (28) Adults 96% MMI, 4% PTU Adults MMI or carbima zole 6 mo Euthyroidism achieved during ATD treatment 38.6 mo Euthyroidism achieved during ATD treatment Adults S 28 mo Euthyroid 12 months after ATD Leger 2012 (30) Childr en Ishtiaq 2010 (29) Cinemre 2009 (17) Glaser 2008 (18) Cappelli 2007 (19) Quadbeck 2005 (20) Benker 1998 (21) Chiou 1995 (22) Carbima zole Adults Carbima zole 24.5 mo Euthyroid 18 months after ATD 6-18 mo Euthyroidism achieved during ATD treatment 26 4 Adults PTU 18 mo Euthyroidism achieved during ATD treatment Childr en PTU and L- thyroxin e Adults MMI mo 2 y Euthyroid 12months after ATD Euthyroid 48 months after ATD Adults S mo Euthyroidism achieved during ATD treatment 313 D Adults MMI 1 y Euthyroid 12 months after ATD Follow up Mean 9 months after ATD 13.4 to 41.7 mo after ATD 6 months after ATD 80 weeks from start of ATD 1 year after ATD Median 2.6 years, max 10 years Mean 56.7 months, range months 1 year after ATD Median 10.4 years Total 18 months from start of ATD Total 18 months from start of ATD 1 year after ATD Total 120 months 2 years after ATD Mean 4.3 years Adults S 28.1mo D 3 years after ATD Tajiri 1991 (23) 44 3 Adults MMI 5-16 mo Euthyroidism achieved during ATD treatment Greer 1977 (24) Adults MMI 4.7 mo Euthyroidism achieved during ATD treatment Magri 2016 (31) Adults S mo Euthyroid 3months after ATD D Mean 29 months Total 5 years after ATD Is Male Gender a egative Predictor for Remission Y Y Y ATD, anti-thyroid drugs, MMI, mercaptizole, PTU, propyltiouracil.

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