A 2017 SURVEY OF THE CLINICAL PRACTICE PATTERNS IN THE MANAGEMENT OF RELAPSING GRAVES DISEASE

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1 ENDOCRINE 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 A 2017 SURVEY OF THE CLINICAL PRACTICE PATTERNS IN THE MANAGEMENT OF RELAPSING GRAVES DISEASE EP Shlomit Koren, M.D. 1,4 Miriam Shteinshnaider, M.D. 1, Karen Or, M.D. 1, Dror Cantrell, M.D. 1,3 Carlos A. Benbassat, M.D. 1,4 Ronit Koren, M.D. 1,2,4 From: 1 Endocrine Institute, 2 Dept. of Internal Medicine A, 3 Dept. of Internal Medicine C, Assaf Harofeh Medical Center, Zerifin, Israel and 4 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Running title: Management of Graves disease relapse Corresponding author: Shlomit Koren, MD Endocrine Institute Assaf Harofeh Medical Center, Zerifin , Israel shlomitks@gmail.com Key words: Thyroid, Survey, Grave s disease

2 Abstract Objective: Previous surveys from different world regions have demonstrated variations in the clinical management of Graves' disease (GD). We aim to investigate the clinical approach to GD relapse among endocrinologists. Methods: Electronic questionnaires were ed to all members of the Israeli Endocrine Society. Questionnaires included demographic data and different scenarios regarding treatment and follow up of patients with GD relapse. Results: The response rate was 49.4% (98/198). For a young male with GD relapse, 68% would restart ATD (98% methimazole) while 32% would refer to radioactive iodine (RAI) treatment. Endocrinologists who treat >10 thyroid patients a week, tended to choose ATDs over RAI (p=0.04). In the case of GD relapse with ophthalmopathy, 50% would continue ATDs, while 22.4% would recommend RAI treatment and 27.6% surgery. Most endocrinologists (56%) would continue ATDs for months. Seventy-five percent would monitor complete blood count and liver function (39% for the first month and 36% for 6 months), and 44% would recommend a routine neck ultrasound. In a case of thyrotoxicosis due to a 3 cm hot nodule, most endocrinologists (70%) would refer to RAI ablation, 46.4% without and 23.7% with a previous fine needle aspiration. No significant differences were found regarding gender, years of board certificate, or work environment. Conclusion: Our survey demonstrates diverging patterns in the diagnosis and management of GD Relapse that correlates well with previous surveys from other countries on GD naïve patients and a less than optimal adherence to recently published clinical guidelines.

3 Abbreviations: GD = Graves' disease; RAI = radioactive iodine; ATDs = anti-thyroid drugs; ATA = American Thyroid Association; CBC = complete blood count; LFT = liver function tests; TFTs = thyroid function tests; MMI = methimazole; PTU = propylthiouracil; TSI = thyroid stimulating immunoglobulin; GO = Graves ophthalmopathy. Introduction Graves disease (GD) is the most common cause of hyperthyroidism. It is an autoimmune disease caused by thyroid-stimulating antibodies. Despite its prevalence, treatment of GD is still a matter of controversy. Once diagnosis is established, one of three alternatives needs to be selected: radio-active iodine (RAI) ablation, surgery or anti-thyroid drugs (ATDs). Decision making should involve benefits, drawbacks, potential side effects, logistics and local expertise (1). Treatment should follow comprehensive discussion with the patient (2). Clinical practice differs in different parts of the world. For example, ATDs are favored in Japan, Taiwan, Europe and Latin America, while RAI and ATD are equally favored in the United States (3, 4). Recurrence after an initial course of ATDs is common and associated with environmental, genetic, immune and clinical parameters. While accepted treatment in such a case would be RAI or surgery, prolonged low-dose ATDs is emerging as a reasonable approach (5). Previous surveys on GD have demonstrated variations in clinical practice relating to diagnostic modalities, treatment options and follow-up strategies, both between and within countries. A survey conducted in Spain demonstrated that while in the past surgery was the treatment of choice, ATDs have become more popular, with RAI being the preferred choice

4 for recurrence (6). A large 2011 survey, comprising 730 respondents, from the American Thyroid Association (ATA), the Endocrine Society and the American Association of Clinical Endocrinologists showed that ATDs were preferred as initial treatment in 53.9% of responders, followed by 45% who would choose RAI as first choice. In that survey, routine monitoring of liver enzymes and complete blood count (CBC) was advocated by almost half of the respondent, This survey, however, did not include reference to a recurrence or relapse of GD (7). Negro et al found significant differences in clinical practice with regard to diagnosis, management and monitoring of patients with GD among Italian endocrinologists compared to Europeans and North American colleagues (8). Again, most surveys did not address the scenario of relapsing GD. Therefore, we conducted a survey among endocrinologists in Israel to investigate current approaches in the management of a first GD relapse. Methods During September-December 2016 an electronic survey was ed to 198 longstanding members of the Israeli Endocrine Society. A web-based survey platform service was used to administer the survey (SurveyMonkey, Palo Alto, CA, USA). Two reminders were sent after the first , each two-week apart. The study was approved by the local institutional ethics committee. Survey design The survey, designed by the study authors (see supplementary data), included 9 questions related to the choice of therapy and follow up of an index case: a 40-year-old male with a first relapse of GD (Table 1). The survey included another question to assess the impact of hyperthyroid etiology on decision making. In addition, the survey included one question on

5 demographic data of the responders (gender, work environment, number of years holding endocrinology board certification, and number of thyroid patients/week). Questions were either multiple choice or yes/no questions. Statistical analysis Statistical calculations were performed with the statistical software SPSS version 19 (SPSS, Inc. Chicago, IL, USA) computerized program. The continuous variables are presented as means and standard deviations, and the categorical variables as percentages. Differences in demographic and categorical baseline characteristics were analyzed with chisquare or Fisher s exact test; for continuous variables we used the independent t-test or Mann- Whitney test, as appropriate. A P value of <0.05 was defined as statistically significant. Results Demographics of respondents We received 98 (49.4%) responses out of 198 s sent. The demographic characteristics of the 98 responders are shown in Table 2. Forty-two responders were male (43%) and 56 (57%) female with an average of 11.8 ± 10.1 years since their endocrine board accreditation. Most responders had over 10-years of experience. Overall 72.4% responders reported that they work in a hospital environment, with most responders (61.2%) treating more than 10 thyroid patients per week. Preferred primary treatment modality in the index case Given the scenario of a 40-year-old man with clinical and laboratory evidence of GD relapse, with no evidence of Graves ophthalmopathy and no history of smoking (Table 1), the initial treatment of choice was as follows: 67.7% would start with ATDs and follow-up with thyroid function tests (TFTs), compared to 32.3% who would start with ATDs followed by RAI

6 ablation. None would refer to surgery at this stage (answer 1.c. supplementary data). Interestingly, we found that more experienced endocrinologist )those reported to see >10 thyroid patients per week) tended to choose ATD over RAI therapy compared to less experienced endocrinologists (75% vs. 55.2% for ATD and 25% vs. 44.7% for RAI, respectively; p=0.042) (Figure 1, panels A-C). No significant differences were found regarding working environment or years in practice. When asked about their approach when two months later the patient becomes euthyroid while on ATDs, 34% would continue ATD therapy, while 64.3% would offer the patient RAI treatment now. Again, more experienced endocrinologists (>10 thyroid patients per week) would choose to continue ATDs rather than RAI treatment, (43% vs. 21% for ATDs and 56.6% vs. 76.3% for RAI, respectively; p=0.043). Preferred drug and doses for ATD therapy Among the 98 respondents, 98% would select methimazole (MMI) and 2% propylthiouracil (PTU). The preferred starting dose of MMI for the index case was 20 mg once daily by 74.5% of the respondents, 30 mg once daily by 19.4%, and 40 mg once daily by 4%. Two percent would stop treatment after TSH normalization, 7% would continue treatment for another 3-6 months after TSH become normal, 23.5% would continue treatment for a further 6-12 months, 55% would continue ATD treatment for an extra months, and 11% would keep a low maintenance ATD dose indefinitely (Figure 2, panel A). Adverse event monitoring policy After instituting ATD therapy, 39% of respondents would monitor CBC and LFTs for the first month, and 36% for 6 months, while 25% would not monitor WBC and LFTs routinely (Figure 2, panel B). If a patient being treated with MMI developed pruritus and/or skin rash, 26.5% of respondents would add antihistamine therapy, 18% would switch to PTU, 6% would

7 stop treatment immediately and resume either MMI or PTU three weeks later, whereas 47% would re-offer the patient RAI treatment at this point. Variation 1- Newly diagnosed (naïve) male with GD and no GO Among respondents, 56% would recommend routine neck ultrasound while 44% would not. In addition, 65% would recommend routine thyroid stimulating immunoglobulin (TSI) measurements. Variation 2 - GD first relapse with concurrent ophthalmopathy The index case was modified to include moderate Graves ophthalmopathy. Respondents were asked about their preferred primary treatment modality in such scenario (Figure 1, panel D). With this modification of the index case, 27.5% would offer the patient surgery, 22.5% would offer RAI treatment with prednisone, while 50% would continue ATD therapy (p<0.001). (Figure 1, panel E) Variation 3 - Persistent thyrotoxicosis due to a 3.1 cm single right toxic nodule Tirads 4a The first approach to a 40-year old male with persistent thyrotoxicosis due to a 3.1 cm single toxic nodule, revealed that 70.1% of responders would refer to RAI ablation, 15.4% would treat with ATDs and 14.4% would refer to surgery, as first treatment choice. If the treatment of choice was RAI, 23.7% would refer to FNA before therapy (Table 3). Discussion The optimal diagnosis and treatment options for GD remain a matter of controversy. Moreover, the ATA's most current guidelines lack recommendations for management of its recurrence (1). In recent years several surveys from different parts of the world have shed light on accepted common practice regarding diagnosis, treatment choice and monitoring practices for patients with GD (6-12). However, most surveys did not address the case of GD

8 relapse nor did they analyze the association between physicians' characteristics and clinical approach. In this study we investigated the clinical approach to GD relapse among Israeli endocrinologists and the association between clinical experience and work environment and response to the relevant clinical questions. We found that ATD was the first choice of treatment for uncomplicated GD relapse for most responders, particularly among more experienced endocrinologists. For our index case the surgical option was discarded by all the responders as first choice in GD relapse but rises significantly when GO was present. Surgery and RAI were similarly considered when the cause of thyrotoxicosis in the index case was a toxic adenoma (28% vs 32%, respectively, p=ns) As recommended in current clinical guidelines (1), the almost unanimous selection of MMI over PTU was also seen in other surveys and is not surprising. During the past decade data concerning PTUs hepatotoxicity led to a black box warning issued by the FDA in 2009 (13). The main role of PTUs is in treatment of hyperthyroidism during the first trimester of pregnancy and in thyroid storm (14). In accordance with surveys from Europe and Italy, we found ATD to be the first-choice for most respondents (67.7% in our survey vs. 83.8% in a 2013 European survey, and 77.1% in a 2015 Italian survey) (8, 12). The lower rate of ATDs used as first choice in our study can be largely explained by the fact that our index case presented with relapsing GD, while the other surveys were done for naïve cases. Another explanation may be that we choose a young male rather than young female for our index case. Allahabadia et al. studied 536 patients with GD and found lower remission rates for males than females and for patients younger than 40 years old (15). Interestingly, we found that more experienced physicians tended to treat with ATDs more often, possibly reflecting a more conservative approach based on longer experience.

9 Nearly 80% of Israeli endocrinologists maintain routine monitoring of CBC and LFTs during ATD treatment, half of them during the first month and half over the first 6 months. With such approach, which resemble that of their Italian colleagues, Israeli endocrinologist do monitor CBC and LFTs more frequently than reported in previous surveys (7, 8, 10, 12). This policy deviates from the ATA guidelines which recommends only baseline CBC and LFTs prior to initiating ATD, specifying that evidence is not sufficient to recommend for or against routine monitoring of CBC and LFTs (1). We do agree that routine monitoring is probably unjustified as most side effects are minor and transient, while the more serious ones are unpredictable over a time-curve (14, 16). In a newly diagnosed male with suspected GD most responders (65%) would recommend TSI measurement regardless of GO diagnosis and more than half would order a neck ultrasound. The ATA guidelines recommend measurement of TSI if diagnosis is not apparent on clinical and initial biochemical evaluation, and do not recommend routine neck US (1). TSI testing is more popular in Europe than in North America and was recommended by 77% of responders in a previous survey (7). In Israel TSI is not covered by health insurance, which might explain the lower rate of TSI testing in our study. Neck ultrasound would be performed by 56% of Israeli endocrinologists, compared to near 90% of Italian and French endocrinologists, and only 25% of endocrinologists in North America, that probably do rely more on thyroid scan (8, 11). Primary therapy for a patient with GD complicated with Graves' ophthalmopathy remains a challenge, since it is suggested that RAI therapy tends to aggravate this condition (17), prompting the concomitant use of glucocorticoids to ameliorate or prevent such a risk (18). The ATA guidelines recommend against RAI for the treatment of hyperthyroidism in patients with active or severe GO. They endorse ATDs or surgery with no clear preference between

10 them (1). Similar to surveys from North America, Europe, Italy and the Middle East (7-9, 12); when GO was added to our index case, we observed a strong shift (0% to 28%) towards the surgical approach. A strong shift was also seen when persistent hyperthyroidism was caused by toxic adenoma instead of GD, with RAI been then the first choice The epidemiology of GD or GD relapse in Israel compared to other countries is unknown. Israel is an industrialized state with a developed healthcare system. In the last decade several sea-water desalinization plants became fully functional. Thus, the iodine status of the Israeli population has changed significantly, as seen in a recently published 2017 National Iodine Survey (19). Unexpectedly, the desalinization program seems to have slightly lowered the Israeli iodine sufficiency level (19). Limitations of our study include the small number of responders and the lack of previous data regarding common practice in naïve GD patients in Israel. Nevertheless, our study adds novel data regarding the approach to relapsing GD and corroborates the large and worldwide variance in clinical practice published from other countries, despite current published guidelines. Also, this is the first survey to evaluate the association between physicians' characteristics and clinical approach to GD relapse. Moreover, given the lack of Israeli clinical guidelines on the management of GD we hope the present study will serve in promoting such a task. Overall, we found the management of relapsing GD to be quite similar to that of a first episode, as reflected in other surveys. Interestingly, more experienced endocrinologists tend to choose ATDs over definitive treatment. We conclude that the approach to GD in Israel parallel the one followed in Italy and other European countries, also in the case of a first relapse.

11 References 1. Ross DS, Burch HB, Cooper DS, et al American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26: Brito JP, Castaneda-Guarderas A, Gionfriddo MR, et al. Development and Pilot Testing of an Encounter Tool for Shared Decision Making About the Treatment of Graves' Disease. Thyroid. 2015;25: Wartofsky L, Glinoer D, Solomon B, Lagasse R. Differences and similarities in the treatment of diffuse goiter in Europe and the United States. Exp Clin Endocrinol. 1991;97: Kornelius E, Yang YS, Huang CN, et al. The Trends of Hyperthyroidism Treatment in Taiwan: A Nationwide Population-Based Study. Endocr Pract. 2018;24: Villagelin D, Romaldini JH, Santos RB, Milkos AB, Ward LS. Outcomes in Relapsed Graves' Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment. Thyroid. 2015;25: Escobar-Jimenez F, Fernandez-Soto ML, Luna-Lopez V, Quesada-Charneco M, Glinoer D. Trends in diagnostic and therapeutic criteria in Graves' disease in the last 10 years. Postgrad Med J. 2000;76: Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical practice patterns in the management of Graves' disease. J Clin Endocrinol Metab. 2012;97: Negro R, Attanasio R, Grimaldi F, Guglielmi R, Papini E, Ame, et al. A 2015 Italian Survey of Clinical Practice Patterns in the Management of Graves' Disease: Comparison with European and North American Surveys. Eur Thyroid J. 2016;5:112-9.

12 9. Beshyah SA, Khalil AB, Sherif IH, et al. A Survey of Clinical Practice Patterns in Management of Graves Disease in the Middle East and North Africa. Endocr Pract. 2017;23: Cox SC, Tamatea JA, Conaglen JV, Elston MS. The management of Graves' disease in New Zealand N Z Med J. 2016;129: Goichot B, Bouee S, Castello-Bridoux C, Caron P. Survey of Clinical Practice Patterns in the Management of 992 Hyperthyroid Patients in France. Eur Thyroid J. 2017;6: Bartalena L, Burch HB, Burman KD, Kahaly GJ. A 2013 European survey of clinical practice patterns in the management of Graves' disease. Clin Endocrinol (Oxf). 2016;84: Akmal A, Kung J. Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity. Expert Opin Drug Saf. 2014;13: Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352: Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab. 2000;85: Sundaresh V, Brito JP, Wang Z, et al. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab. 2013;98: Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Engl J Med. 1992;326:

13 18. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. 1998;338: Ovadia YS, Arbelle JE, Gefel D, et al. First Israeli National Iodine Survey Demonstrates Iodine Deficiency Among School-Aged Children and Pregnant Women. Thyroid. 2017;27: Supplemental Material Survey for adult endocrinologists 1. What would be your next step, in addition to symptomatic therapy (betablockers)? 1. Start ATD and follow up TSH in one month 2. Start ATD and refer to radioiodine therapy 3. Start ATD and refer to surgery 2. If you decide to start ATD 1. start PTU 100 mg X3 2. Start PTU 150 mg X3 3. Start Mercaptizole (methimazole) 20 mg X1 4. Start Mercaptizole (methimazole) 30 mg X1 5. Start Mercaptizole (methimazole) 40 mg X1 3. What would be your adverse event monitoring policy? 1. Routine monitoring of WBC and liver function tests for the first month 2. Routine monitoring of WBC and liver function tests monthly for the first 6 months 3. Routine monitoring of WBC and liver function tests is not needed

14 4. The patient was started on ATD treatment. On a follow-up visit 2 months later, his symptoms improved as well as his laboratory results: TSH 0.06 miu/l, FT4 18 pmol/l, and FT3 4.8 pmol/l. Now that the patient is euthyroid, would you offer him a definitive treatment? 1. Yes, I would offer this patient a surgery 2. Yes, I would offer this patient radioiodine treatment 3. No, I will continue ATD therapy and follow up 5. The patient refuses definitive treatment and prefers to continue ATD. After ruling out definitive treatment, when would you stop ATDs? 1. When TSH become normal months after TSH become normal months after TSH become normal months after TSH become normal 5. Will keep low maintenance dose indefinitely 6. The patient is on Mercaptizole (methimazole) and develops Pruritus and skin rash 1. You will add anti-histaminics 2. You will down titrate dose 3. You will switch to PTU 4. You will stop and resume PTU or MMI 3 weeks later 5. You will re-offer him surgery 6. You will re-offer him RAI treatment 7. If the same patient had moderate Graves ophthalmopathy, would you offer this patient a definitive treatment? 1. Yes, I would offer this patient a surgery 2. Yes, I would offer this patient radioiodine treatment with prednisone 3. No, I will continue ATD therapy and follow up 8. In a case of newly diagnosed male with GD would you recommend 1. Routine neck US. (Yes, No) 2. Routine TSI measurement. (Yes, No)

15 9. Same patient with persistent thyrotoxicosis due to a 3.1 cm single right toxic nodule Tirads 4a. Your recommendation will be 1. Treat with ATDs and do FNA 2. Treat with ATDs without FNA 3. Refer to RAI ablation after short course of ATD and FNA 4. Refer to RAI ablation after short course of ATD without FNA 5. Refer to surgery after short course of ATD and FNA 6. Refer to surgery after short course of ATD without FNA 10. Demographics of Responders 1. Gender (1-male; 2-female) 2. Years of board certification in endocrinology 3. Work environment (1-Hospital, 2-Community, 3-both) 4. Number of thyroid patients you see per week

16 Table 1. Index case A 40-year-old male without any significant past medical history presented with a first relapse of GD. He was diagnosed with Graves 2 years ago and was treated with ATD for 1 year. He became euthyroid 5 months from diagnosis and continued to receive a low dose regimen of ATDs for an additional 7 months. He had no signs of ophthalmopathy and no history of smoking. He was on regular follow up and was euthyroid until the current visit. Today, he complains of heat intolerance, sweating and weight loss. Physical examination reveals an anxious man weighing 70 kg, tachycardia, hyper-reflexia, warm and moist hands with tremors, and no signs of ophthalmopathy. Neck palpation reveals a twice- enlarged diffuse non-tender goiter. ECG was normal except for sinus tachycardia 104/min. Lab tests showed undetectable TSH with FT4 36 pmol/l (normal pmol/l) and FT3 9 pmol/l (normal pmol/l).

17 Table 2. Characteristics of respondents Respondents (n=98) Females 57% Hospital practice 72.4% Community practice 26.5% Years in practice, mean ± SD 11.8 ± years in practice 30.6% 5-10 years in practice 27.6% 10+ years in practice 41.8% Thyroid patients per week, mean ±SD 21.1 ± thyroid patients per week 38.8% 10+ thyroid patients per week 61.2% Table 3. Management of thyrotoxicosis due to a 3.1 cm single right toxic nodule Tirads 4a FNA Treat with ATD Refer to RAI ablation Refer to surgery With n (%) 13 (13.4%) 23 (23.7%) 9 (9.3%) Without n (%) 2 (2%) 45 (46.4%) 5 (5.1%) FNA, fine needle aspiration; ATD, anti-thyroid drugs; RAI, radioactive iodine

18 Fig 1A-D Fig 1E

19 Fig 2