Selenium in the treatment of mild-to-moderate Graves’ orbitopathy: A 5-year Prospective Controlled Cohort Study

doi:10.21203/rs.3.rs-3430851/v1

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Research Article

Selenium in the treatment of mild-to-moderate Graves’ orbitopathy: A 5-year Prospective Controlled Cohort Study

https://doi.org/10.21203/rs.3.rs-3430851/v1

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Journal Publication

published 10 Jan, 2024

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Purpose

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease. However, limited studies have investigated the actual efficacy of selenium in GO therapy. This longitudinal study explored the effect of selenium on QOL and prognosis of patients with mild-to-moderate GO.

Methods

We conducted a 5-year prospective controlled cohort clinical trial to determine the effect of selenium on 74 patients with mild-to-moderate GO. Patients received selenium yeast or placebo orally for 6 months and were followed up at 6 months and at 5 years by biochemical examination, ophthalmologist evaluation and QOL questionnaire to assess oculopathy and QOL.

Results

(1) During a follow-up period of 3–6 months, in the selenium group, the symptoms of tearing, grittiness and conjunctival congestion improved (P < 0.01); clinical activity scores and total GO-QOL scores increased relative to baseline (P < 0.01); TRAb was decreased at the 6-month evaluation (P = 0.003); and patients treated with selenium had a higher rate of improvement and a lower rate of worsening than patients treated with placebo (P < 0.05). (2) Exploratory evaluations at 6 months after drug withdrawal confirmed the earlier results; further changes included alleviation of blurred vision and diplopia symptoms in the selenium group (P < 0.01). (3) At the 5-year follow-up, compared with baseline, ocular symptoms and signs, proptosis, clinical activity scores, TRAb level and total GO-QOL scores in both the selenium and placebo groups were significantly improved (P < 0.01).

Conclusion

Six months of selenium supplementation may effectively change the early course of mild-to-moderate GO, but this regimen makes no difference in long-term outcomes.

Graves’ orbitopathy

Selenium

Quality of life

Prospective study

Graves’ orbitopathy (GO), also called thyroid eye disease or thyroid-associated ophthalmopathy, is the main extrathyroidal manifestation of Graves’ disease (GD)(1). The prevalence of GO is 90–300/100 000 population, with mild and nonprogressive cases occurring more commonly and severe and sight-threatening cases rarely(2–4). Patients with GO may present with various symptoms, such as dry and gritty ocular sensation, photophobia, tearing, double vision, redness of the eyelid and retrobulbar oppressive feeling(5). GO can not only change the appearance of patients, threaten vision, and significantly affect quality of life (QOL) but also pose a public health burden, even in mild cases(6, 7).

Treatment strategy is determined by the clinical activity, severity and duration of GO(1). The Clinical Activity Score (CAS) is the best validated scoring system. Evaluation of treatment outcome should be standardized by both a subjective assessment of quality of life through the disease-specific GO-QOL questionnaire and an objective evaluation by ophthalmologists at a fixed time interval following the end of the intervention(8, 9)In mild GO, the majority of patients experience spontaneous resolution of eye manifestations, so a wait-and-see strategy and local treatments seem to be sufficient. However, a small number of GO cases can even progress to severe forms, and patients may then experience a profound impact on quality of life(10).

Selenium is a trace mineral that has been shown to play a crucial role in maintaining immune-endocrine function, metabolism and cellular homeostasis(11). The thyroid gland is rich in selenium, which, in the form of selenocysteine, is incorporated into selenoproteins. Some of these selenoproteins contribute to the antioxidant defense of the thyroid by removing oxygen free radicals(12). Studies have shown that increased generation of reactive oxygen species may be involved in the pathogenesis of GO(3), so selenium is recommended in clinical practice for GO(1, 13). Several studies have investigated the actual efficacy of selenium in GO therapy. Marcocci et al.(14) reported that compared to a placebo group, a 6-month course of selenium administration improved quality of life, relieved ocular symptoms, and reduced the risk of developing severe forms of the disease in patients with mild GO. A European survey also indicated that selenium supplementation should be used in patients with both mild and moderate-to-severe GO(11). However, no studies have been performed outside of Europe, especially in nonselenium-deficient areas. The effects of selenium therapy on the long-term prognosis of GO have not yet been studied.

In this study, we report the results of a 5-year prospective, population-based cohort clinical trial aiming to evaluate whether selenium supplementation is beneficial for quality of life and prognosis in the Han population with mild-to-moderate Graves’ orbitopathy in nonselenium-deficient areas of northern China.

The longitudinal study was a randomized, double-blind, placebo-controlled clinical trial conducted in a 2:1 ratio that lasted for 5 years, including 6 months of intervention, followed by 6 months and 5 years of follow-up. It was carried out in the Department of Endocrinology, The First Hospital of China Medical University, from 2015 to 2021. It mainly aimed to determine whether selenium, compared with placebo, could affect the course of mild-to-moderate GO and improve patients’ quality of life.

In our study, we selected patients with euthyroidism or subclinical thyroid function to minimize the impact of thyroid dysfunction on quality of life. Relevant history and demographic data were gathered from all the enrolled participants, and they were randomly assigned to orally take selenium (46 patients, 100 µg, twice daily) or placebo (28 patients, 100 µg, twice daily) without knowing which drug they were taking. They underwent comprehensive biochemical examination, ophthalmic and endocrine assessment, completed the disease-specific GO-QOL questionnaire at baseline (week 0) and had 4 follow-up visits (after 3, 6, 12 and 60 months). The effect of selenium on the prognosis (improvement, unchanged and deterioration) of Graves’ orbitopathy was evaluated by comparing the GO-QOL total score between the selenium therapy group and the placebo group. Detailed assessments are described in the Supplementary Appendix.

Study participants

From 2015 to 2016, a total of 74 patients (27 men and 47 women) with mild-to-moderate Graves’ orbitopathy who were treated at the Department of Endocrinology of the First Affiliated Hospital of China Medical University were recruited. They were randomly assigned to take selenium (46 patients) or placebo (28 patients) orally. In the selenium group, 23 patients were followed up, and 23 were lost at 5 years, while in the placebo group, 18 patients were followed up, and 10 were lost at 5 years. Patients in both groups were lost at follow-up time points of 3 months, 6 months, 1 year, and 5 years, as shown in Fig. 1. For a description of the assessment of GO activity and severity and the inclusion and exclusion criteria, see the Supplementary Appendix.

Assessment and laboratory measurements

Exophthalmos was measured with an exophthalmos instrument (No. 6 Vision Technology Company, Suzhou, China). Electrochemiluminescence immunoassay on a Cobas 601 analyzer (Roche Diagnostic, Switzerland) was used to test serum TSH, thyroid peroxidase antibody (TPOAb), thyroglobulin antibodies (TgAb) and TSH receptor antibodies (TRAb) for each sample. TSH: 0.27–4.2 IU/ml; FT3: 3.1–6.8 pmol/L; FT4: 12–22 pmol/L; TgAb: 0-115 IU/ml; TPOAb: 0–34 IU/ml; TRAb: 0-1.75 IU/l. Serum selenium concentrations were measured in duplicate using inductively coupled plasma‒mass spectrometry (ICP‒MS, Perkin-Elmer SCIEX ELAN 6000, US). Blood serum was diluted 40-fold with an acidic solution consisting of nitric acid (1%), X-Triton (0.1%), and 1-butanol (0.8%). A calibration curve was established from 1 to 400 µg/L (r² > 0.99). The limit of detection was 0.5 µg/L. The between-run coefficient of variation (CV) was 6.59%, and the within-run CV was < 2%. Selenium yeast tablet (trade name “Xavier”) is a new national drug produced by Mudanjiang Lingtai Pharmaceutical Co., Ltd., and it is a selenoprotein with yeast as a carrier. Each selenium yeast tablet (70 mg) contained 50 µg selenium, approval No.: GyzzH10940161.

Statistical analysis

Calculations were performed using SPSS software (version 22.0; SPSS, Inc. Chicago, IL, USA). Variables that were not normally distributed were expressed as medians with interquartile ranges (IQRs) and analyzed using the Mann‒Whitney U test for comparison of two groups. Variables that were normally distributed are expressed as the means ± SDs and were analyzed using the T test for comparison of two groups. The T test and the Mann‒Whitney U test were used to evaluate differences in the selenium and placebo groups at follow-up and baseline. Categorical variables presented as counts and percentages were analyzed by the chi-square test. P < 0.05 was considered statistically significant.

Demographic characteristics at baseline

The average ages at baseline for the selenium group and placebo group were 42.76 ± 12.22 years and 44.14 ± 12.71 years, respectively. The general characteristics of the participants are presented in Table 1. There was no significant difference between the two groups with respect to age, sex, proportion of smokers, proportion of patients who received antithyroid drugs or I131 treatment, thyroid function or TRAb level. Similarly, for ocular symptoms and signs, the CAS and GO-QOL scores were comparable. At the 5th year of follow-up, there was no difference in the baseline characteristics between the lost and the participants in the selenium and placebo groups (P༞0.05) (Supplementary Table 1).

Table 1

Demographic characteristics at baseline
Group	Selenium (n = 46)	Placebo (n = 28)	P
Age(Y)	42.76 ± 12.22	44.14 ± 12.71	0.643
Sex(F/M)	30/16	17/11	0.696
Smoking N/Y	18/20	8/20	0.356
Clinical Activity Score	2.845 ± 1.38	2.71 ± 1.21	0.674
Visual functioning Score	55.77 ± 29.52	64.42 ± 28.59	0.220
Psychosocial functioning Score	54.21 ± 27.55	56.70 ± 25.74	0.701
Total scores of GO-QOL	54.99 ± 24.94	60.56 ± 22.35	0.336
TSH(mIU/L)	1.53(0.35–2.51)	1.48(0.19–2.94)	0.811
FT4	13.53(11.09–15.37)	14.67(12.34–16.82)	0.087
FT3	4.45(3.82–5.13)	4.71(4.26–5.23)	0.187
TRAb(IU/L)	6.01(2.32–14.91)	4.35(0.65–17.18)	0.467
TPOAb(mIU/L)	18.72(7.10-174.58)	32.67(1.99-30.00)	0.682
TgAb(mIU/L)	11.91(1.99–29.99)	13.80(7.86–30.33)	0.480
TPOAb(+/-)	16/46(34.78%)	9/28(32.14%)	0.816
TgAb(+/-)	7/46(15.22%)	1/28(3.57%)	0.118
Retrobulbar oppressive feeling(%)	29/46(63.04%)	18/28(64.29%)	0.914
Pain on attempted upward or downward gaze (%)	25/46(54.35%)	15/28(53.57%)	0.948
Tearing(%)	36/46(78.26%)	23/28(82.14%)	0.687
Photophobia (%)	36/46(78.26%)	23/28(82.14%)	0.687
Grittiness (%)	31/46(67.39%)	23/28(82.14%)	0.166
Double vision (%)	25/46(54.35%)	18/28(64.29%)	0.401
Blurred vision (%)	33/46(71.74%)	16/28(57.14%)	0.198
Swelling of eyelids (%)	9/43(20.9%)	4/22(18.2%)	0.793
Swelling of the caruncle (%)	3/43(7.00%)	0/22(0.0%)	0.205
Data were presented as M ± SD or medians (interquartile ranges) or n (%) as appropriate.
Abbreviations: TSH, thyroid-stimulating hormone; FT4, free thyroxine;FT3, Free Triiodothyronine; TPOAb,
thyroid peroxidase antibody; TgAb, thyroglobulin antibody .

Ocular symptoms and signs

Ocular symptoms and signs were evaluated by ophthalmologists at enrollment, and the proportion of patients with swelling of eyelids and conjunctival congestion was relatively high, accounting for almost 50–60% of the total number of eyes. Starting at 3 months of intervention, compared with the placebo group, the symptoms of tearing and grittiness were significantly improved in the selenium group (16.3% vs. 0.0%, χ² = 17.391, P = 0.000; 20.9% vs. 0.0%, χ² = 23.46, P = 0.000, respectively) (Fig. 2A). At the 6-month evaluation in the selenium group, grittiness was further improved, and conjunctival congestion was significantly relieved (44.4% vs. 5.6%, χ² = 28.1, P = 0.000) compared with patients in the placebo group (Fig. 2B). At 6 months after drug withdrawal (12 months), further changes were improvements in blurred vision and double vision in the selenium group (35.7% vs. 10.5%, χ² = 5.52, P = 0.019; 21.4% vs. 0.0%, χ² = 23.22, P = 0.000, respectively) (Fig. 2C). At the last visit (5 years), the ocular symptoms and signs in the two groups were both significantly improved compared with the baseline (P < 0.01), and there were no differences between the two groups (P༞0.05) (Fig. 2D). Proptosis was significantly improved in both the selenium and placebo groups (P = 0.01, P = 0.026, respectively) (Fig. 2E). There was no significant difference in eyelid aperture between the two groups at the 4 follow-up visits (Fig. 2F).

Assessment of clinical activity score

As shown in Fig. 3A, starting at 3 months of intervention, compared with baseline, the clinical activity score decreased gradually in patients treated with selenium, while that in the patients in the placebo group decreased gradually after 6 months of withdrawal (12 months). As shown in Table 2, compared with the placebo group, the change of clinical activity score decreased more significantly in the selenium group at 6 months of intervention and at 6 months after drug withdrawal (12 months). At 5 years of follow-up, there was no significant difference in the change in the clinical activity score between enrollment and the end of follow-up between the two groups (P > 0.05).

Table 2

Change of clinical activity score before and after study treatment
Groups	Change at 3 mo	Change at 6 mo	Change at 12 mo	Change at 60-mo
Selenium	0.70 ± 1.17	1.04 ± 1.09	1.29 ± 0.91	1.78±·1.31
placebo	0.32 ± 0.89	0.00 ± 1.08	0.52 ± 1.22	1.33 ± 1.24
P	0.186	0.003*	0.049*	0.272
Data were presented as M ± SD, for changes in the Clinical Activity Score,comparisons of selenium and placebo were calculated with the use of t-test. *P < 0.05

TRAb

As shown in Fig. 3B, there was no significant decrease in TRAb levels in either group after 3 months of intervention. At 6 months of intervention and 6 months after drug withdrawal, TRAb levels in the selenium group decreased from 6.01 IU/l at baseline to 2.41 IU/l at 6 months and 2.59 IU/l at 12 months (P = 0.003, P = 0.019, respectively), while there was no difference in the placebo group. At the 5th year of follow-up,TRAb levels were decreased significantly from baseline in both groups, from 6.01 IU/l to 0.71 IU/l in the selenium group (P = 0.000) and from 4.22 IU/l to 1.00 IU/l in the placebo group (P = 0.037).

Evaluation of GO-QOL

The GO-QOL questionnaire completed by the patients indicated that 54.80% of patients with GO had impairment in visual function during cycling (51.72%), driving (52.52%), reading (65.52%), watching TV (63.22%) and restricted daily life (77.01%); 64.92% of patients suffered from social mentality disorders because of their appearance. After 3 months of intervention, visual functioning scores in the selenium group were significantly increased from baseline (P = 0.015 at 3 months, P = 0.045 at 6 months, P = 0.000 at 1 year, P = 0.029 at 5 years). In the placebo group, visual functioning scores increased only at the 5th year of follow-up (P = 0.009) (Fig. 3C). Psychological functioning scores were significantly increased from baseline in both groups only at the 5th year of follow-up (P = 0.000 in the selenium group, P = 0.029 in the placebo group) (Fig. 3D). The total calculated QOL score increased significantly in the selenium group from 3 months to 5 years after withdrawal, whereas it increased only at the 5th year of follow-up in the placebo group (P < 0.05) (Fig. 3E).

At 3 months, 6 months, and 12 months of follow-up, a significantly greater proportion of patients in the selenium group had an improved quality of life compared with those in the placebo group (P < 0.05, Table 3). At the 5th year of follow-up, there was no significant difference in the prognosis of GO patients between the selenium and placebo groups (P > 0.05). There were no differences in psychological functioning between the two groups at any point during follow-up.

Table 3

Effect of selenium on the prognosis of GO at 4 follow-ups
	Selenium	Placebo	P
Prognosis (3-mo)	n = 39	n = 21
Total GO-QOL
Improved	19/39(48.72%)	3/21(14.29%)	0.008*
Unchanged	14/39(35.90%)	14/21(66.67%)	0.023*
worse	6/39(15.38%)	4/21(19.05%)	0.717
Visual functioning scores
Improved	20/39(51.28%)	3/21(14.29%)	0.005*
Unchanged	14/39(35.90%)	14/21(66.67%)	0.023*
worse	5/39(12.82%)	4/21(19.05%)	0.519
Psychological functioning scores
Improved	16/39(48.84%)	5/21(22.73%)	0.182
Unchanged	12/39(34.88%)	9/21(45.45%)	0.349
worse	1139(16.27%)	7/21(31.82%)	0.679
Prognosis (6-mo)	n = 27	n = 17
Total GO-QOL
Improved	20/27(74.07%)	7/17(41.18%)	0.029*
Unchanged	4/27(14.81%)	3/17(17.65%)	0.942
worse	3/27(11.11%)	7/17(41.18%)	0.020*
Visual functioning scores
Improved	17/27(62.96%)	8/17(47.06%)	0.300
Unchanged	8/27(29.63%)	2/17(11.76%)	0.169
worse	2/27(7.41%)	7/17(41.18%)	0.007*
Psychological functioning scores
Improved	16/27(59.26%)	7/17(41.17%)	0.145
Unchanged	5/27(18.52%)	4/17(23.53%)	0.688
worse	6/27(22.22%)	6/17(35.29%)	0.222
Prognosis (1 year)	n = 14	n = 19
Total GO-QOL
Improved	7/14(50.00%)	3/19(15.79%)	0.035*
Unchanged	6/14(42.86%)	8/19(42.11%)	0.966
worse	1/14(7.14%)	8/19(42.11%)	0.026*
Visual functioning scores
Improved	7/14(50.00%)	3/19(15.79%)	0.035*
Unchanged	3/14(21.43%)	9/19(47.37%)	0.126
worse	4/14(28.57%)	7/19(36.84%)	0.618
Psychological functioning
Improved	6/14(42.86%)	6/19(31.58%)	0.506
Unchanged	5/14(35.71%)	6/19(31.58%)	0.803
worse	3/14(21.43%)	7/19(36.84%)	0.341
Prognosis (5 years)	n = 23	n = 18
Total GO-QOL
Improved	21/23(91.30%)	15/18(83.33%)	0.439
Unchanged	1/23(4.35%)	1/18(5.56%)	0.859
worse	1/23(4.35%)	2/18(11.11%)	0.409
Visual functioning
Improved	19/23(82.61%)	12/18(66.67%)	0.238
Unchanged	2/23(8.70%)	5/18(27.78%)	0.107
worse	2/23(8.70%)	1/18(5.56%)	0.702
Psychological functioning
Improved	21/23(91.30%)	14/18(77.78%)	0.224
Unchanged	1/23(4.35%)	1/18(5.56%)	0.859
worse	1/23(4.35%)	3/18(16.67%)	0.187
For changes in the prognosis, comparisons of selenium and placebo were calculated with the use of the chisquare test. *P < 0.05

Selenium concentration

The serum selenium concentration increased significantly after 3 months of selenium supplementation (P = 0.000, Table 4).

Table 4

Selenium concentration before and after selenium supplement
	0-mo	3-mo	P
	n = 46	n = 39
Selenium(ug/L)	77.51 ± 16.23	133.47 ± 29.18	0.000*
Data were presented as M ± SD, *P༜0.05

Other interventions

During the 5-year follow-up period, 5 people in the selenium group and 4 people in the placebo group received intravenous glucocorticoid treatment, and there was no significant difference between the two groups (21.74% vs. 22.22%, χ² = 0.001, P = 0.970). Two patients in the selenium group and 3 patients in the placebo group received orbital decompression, and there was no significant difference between the two groups (8.70% vs. 16.67%, χ² = 0.599, P = 0.439).

According to the findings of this prospective cohort study of Chinese adults, 6 months of selenium therapy for mild-to-moderate Graves’ orbitopathy has been shown to be beneficial both during the treatment period and 6 months after drug withdrawal. These improvements mainly emphasize ocular involvement and quality of life. However, the long-term effects of selenium supplementation were not observed at the 5-year follow-up.

Studies have shown that quality of life is markedly decreased in patients with GO(26–29). This was confirmed in our study. As assessed by the GO-QOL questionnaire completed by the participants at enrollment, more than half of patients had a total QOL score less than 60, while nearly 80% had a total QOL score less than 80. Almost 2/3 of patients suffered from psychological functioning disorders because of their appearance. In the interim, 28.67% of the patients still had impairment in visual function. Marcocci et al. (14) found that selenium plays a positive role in GO, and selenium supplementation can improve the quality of life of GO patients. Our findings are similar to those of Marcocci et al. Both studies found that the beneficial effects of selenium on quality of life appeared at 6 months and persisted for at least 6 months after drug withdrawal, with the minor difference that in our study, the benefit occurred as early as 3 months after the intervention began. Patients experienced significant improvements in quality of life as a result of improved visual function, which also indicates that in the early stage of GO, all patients, except for severe cases, may benefit from 6 months of selenium therapy, as previously suggested in the findings of Roberto Negro’s study that the majority of patients with GO, whether mild, moderate or severe, should be treated with selenium as adjuvant therapy(11). More study is needed.

Europe is a selenium-deficient region, although the selenium concentration was not measured. We are not located in a selenium-deficient region, but our previous study observed that the serum selenium concentration of GO patients was significantly lower than that of healthy controls (22). Graves’ orbitopathy is an autoimmune disorder associated with increased oxidative stress(15). In vitro studies have confirmed the contribution of oxygen free radicals to changes occurring in the orbit(16). TSH receptor antibodies (TRAbs) have been shown to be involved in the pathogenesis and course of GO and are strongly correlated with activity and severity(17–19). Studies have shown that selenium plays an active role in GO because of its antioxidant and immunoregulatory abilities(13, 20, 21). In this study, starting from 3 months of intervention, patients treated with selenium had better improvement in ocular symptoms and signs and a gradual decline in clinical activity score and TRAb levels, even after drug withdrawal, which was not seen in the placebo group. In another study(23), a correlation between TRAb levels and the clinical activity score was also found. Therefore, we considered that selenium might reduce the CAS and improve ocular symptoms by reducing TRAb levels. The correlation between CAS and quality of life has also been discussed (26, 31–34). Our study showed that visual functioning and total quality of life scores increased after 3 months of selenium therapy, which was consistent with the timing of improvement in ocular symptoms and CAS. Thus, the early improvements in quality of life attributable to selenium supplementation were probably associated with the reduction in CAS. At any follow-up point, there was no difference in mental function between the two groups, reflecting that the early improvement in quality of life is related to the improvement in visual function and the reduction in CAS. However, the quality of life in the placebo group did not recover 1 year after GO diagnosis, suggesting the benefits of early selenium supplementation for GO patients.

Whether mild-to-moderate GO is a remitting disease or even a transient event during Graves' disease remains unknown. The clinical features in more than half of GO patients improved spontaneously. The course of GO usually follows the curve initially described by Rundle decades ago, where an initial progressive deterioration occurs, lasting 6–24 months and reflecting an autoimmune process, and then reaches a plateau, which represents a spontaneous slow improvement that may last 12 months(24, 25). Another innovation of this study is that, for the first time, we discuss the effects of selenium therapy on the long-term prognosis of GO. Our findings demonstrated that ocular symptoms and signs, proptosis, clinical activity score, TRAb level and total scores of GO-QOL were significantly improved from baseline in most patients in both the selenium and placebo groups at the 5th year of follow-up, with no significant differences between the two groups; there was no difference in the serum selenium concentration in the two groups, probably reflecting the natural progression of GO, which becomes less active or inactive. Additionally, although few patients have long-term functional impairment due to GO, the experience of GO can still impact quality of life. More than one-third of patients in the current investigation were still unhappy with their ultimate appearance(30). In this study, after five years of observation, a total of 52.38% of patients still suffered from social mentality disorders regardless of whether they had been treated with selenium. This suggests that even for patients with mild GO, new therapeutic approaches still need to be developed.

The obvious strength of our study was the 5-year long-term prospective follow-up design, which allowed for longitudinal evaluation of selenium therapy on the quality of life of GO patients. In addition, this study was conducted in a nonselenium-deficient area. Consistent with EUGOGO guidelines, early administration of selenium for 6 months in patients with mild to moderate GO is associated with early improvement in symptoms and quality of life. Selenium supplementation had no significant effect on the long-term prognosis of GO patients, and the final quality of life of GO patients was still lower than that of healthy people, suggesting that more therapies need to be developed. Our study has limitations. First, we lost a subset of patients during 5 years of follow-up. However, as we can see from the analysis, there was no difference in the baseline characteristics between those lost and the participants in the selenium and placebo groups. Ultimately, we were unable to determine whether the lost patients stopped coming because of aggravation or remission. Second, we did not test the serum selenium concentration of patients in the placebo group at enrollment and at 3 months, so we could not compare it with that of the patients in the selenium supplement group. Third, similar to Marcocci et al(14), we only administered selenium to mild-to-moderate GO patients for 6 months without long-term supplementation, so we do not know the effect of long-term supplementation.

In conclusion, our study indicates that six months of selenium therapy for mild-to-moderate Graves’ orbitopathy can significantly alleviate ocular symptoms, reduce ocular activity and improve quality of life in the early stages of the disease. Selenium supplementation may effectively change the early course of mild-to-moderate Graves’ orbitopathy, but this regimen makes no difference to the long-term outcomes.

Statements & Declarations

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

This study was approved by the Ethics Committee of China Medical University and registered in the China Clinical Trial Registry (Registration Number: CHICTR-IOR-15005855). All the participants signed informed consent forms before enrollment. The study will be implemented and reported in line with the STROBE statement.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Data Availability

All datasets generated during and analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Acknowledgments

We would like to thank all the participants of this study.

Author Contributions

YSL and ZYS conceived of and designed the study; CYW, JQ, SSL and Sichen Piao organized the study and conducted the statistical analysis. Second authors JQ, SSL, and Sichen Piao contributed equally. All authors contributed to the acquisition, analysis, or interpretation of data. YSL, ZYS and CYW drafted the manuscript. All authors revised the report and approved the final version before submission. No competing financial interests exist.

Funding

This work was supported by the National Natural Science Foundation of China (81570709, 82270833，82300886). the Science Research Fund Project of Education Department of Liaoning Province (General Project) (LJKZ0742), and the Science Research Fund Project of Shenyang Science and Technology Bureau [2011] (21, F11-262-9-23).

L. Bartalena, G.J. Kahaly, L. Baldeschi, C.M. Dayan, A. Eckstein, C. Marcocci, M. Marinò, B. Vaidya, W.M. Wiersinga, The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur. J. Endocrinol. 185, G43–g67 (2021)
L. Bartalena, E. Piantanida, D. Gallo, A. Lai, M.L. Tanda, Epidemiology, Natural History, Risk Factors, and Prevention of Graves' Orbitopathy. Front. Endocrinol. Nov. 30, 11:615993 (2020)
L. Bartalena, L. Baldeschi, K. Boboridis, A. Eckstein, G.J. Kahaly, C. Marcocci, P. Perros, M. Salvi, W.M. Wiersinga, The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur. thyroid J. 5, 9–26 (2016)
L. Bartalena, L. Baldeschi, A. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M. Mourits, P. Perros, K. Boboridis, A. Boschi, N. Currò, C. Daumerie, G.J. Kahaly, G.E. Krassas, C.M. Lane, J.H. Lazarus, M. Marinò, M. Nardi, C. Neoh, J. Orgiazzi, S. Pearce, A. Pinchera, S. Pitz, M. Salvi, P. Sivelli, M. Stahl, von G. Arx, W.M. Wiersinga, Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur. J. Endocrinol. 158, 273–285 (2008)
R.S. Bahn, Graves' ophthalmopathy. N. Engl. J. Med. 362, 726–738 (2010)
W.M. Wiersinga, Quality of life in Graves' ophthalmopathy. Best Pract. Res. Clin. Endocrinol. Metab. 26, 359–370 (2012)
K.A. Ponto, S. Merkesdal, G. Hommel, S. Pitz, N. Pfeiffer, G.J. Kahaly, Public health relevance of Graves' orbitopathy. J. Clin. Endocrinol. Metab. 98, 145–152 (2013)
C.B. Terwee, F.W. Dekker, M.P. Mourits, M.N. Gerding, L. Baldeschi, R. Kalmann, M.F. Prummel, W.M. Wiersinga, Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin. Endocrinol. 54(3), 391–398 (2001)
L. Bartalena, W.M. Wiersinga, Proposal for Standardization of Primary and Secondary Outcomes in Patients with Active, Moderate-to-Severe Graves' Orbitopathy. Eur. thyroid J. 9, 3–16 (2020)
W. Wiersinga, M. Žarković, L. Bartalena, S. Donati, P. Perros, O. Okosieme, D. Morris, N. Fichter, J. Lareida, von G. Arx, C. Daumerie, M.C. Burlacu, G. Kahaly, S. Pitz, B. Beleslin, J. Ćirić, G. Ayvaz, O. Konuk, F.B. Törüner, M. Salvi, D. Covelli, N. Curro, L. Hegedüs, T. Brix, Predictive score for the development or progression of Graves' orbitopathy in patients with newly diagnosed Graves' hyperthyroidism. Eur. J. Endocrinol. 178, 635–643 (2018)
R. Negro, L. Hegedüs, R. Attanasio, E. Papini, K.H. Winther, A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Graves' Hyperthyroidism and Graves' Orbitopathy. Eur. thyroid J. 8, 7–15 (2019)
M. Ventura, M. Melo, F. Carrilho, Selenium and Thyroid Disease: From Pathophysiology to Treatment. Int. J. Endocrinol. 2017, 1297658 (2017)
G. Lanzolla, M. Marinò, C. Marcocci, Selenium in the Treatment of Graves' Hyperthyroidism and Eye Disease. Front. Endocrinol. 11, 608428 (2021)
M. Weissel, Selenium and the course of mild Graves' orbitopathy. N. Engl. J. Med. 365, 769–770 (2011). author reply 770 – 761
G.J. Kahaly, Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J. Clin. Endocrinol. Metab. 105, 3704–3720 (2020)
L. Bartalena, M.L. Tanda, E. Piantanida, A. Lai, Oxidative stress and Graves' ophthalmopathy: in vitro studies and therapeutic implications. BioFactors (Oxford, England). 19, 155–163 (2003)
T. Diana, K.A. Ponto, G.J. Kahaly, Thyrotropin receptor antibodies and Graves' orbitopathy. J. Endocrinol. Investig. 44, 703–712 (2021)
A. George, T. Diana, J. Längericht, G.J. Kahaly, Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves' Orbitopathy. Front. Endocrinol. Feb. 2, 11:629925 (2021)
D. Łacheta, P. Miśkiewicz, A. Głuszko, G. Nowicka, M. Struga, I. Kantor, K.B. Poślednik, S. Mirza, M.J. Szczepański, Immunological Aspects of Graves' Ophthalmopathy. Biomed. Res. Int. 2019, 7453260 (2019)
J.C. Avery, P.R. Hoffmann, Selenium, Selenoproteins, and Immunity. Nutrients Sep 1;10(9):1203 (2018)
M. Almanza-Monterrubio, L. Garnica-Hayashi, A. Dávila-Camargo, Ã. Nava-Castañeda, Oral selenium improved the disease activity in patients with mild Graves' orbitopathy. J. Fr. Ophtalmol. 44, 643–651 (2021)
Y. Liu, S. Liu, J. Mao, S. Piao, J. Qin, S. Peng, X. Xie, H. Guan, Y. Li, Z. Shan, W. Teng, Serum Trace Elements Profile in Graves' Disease Patients with or without Orbitopathy in Northeast China. Biomed. Res. Int. 2018, 3029379 (2018)
F. Nicolì, G. Lanzolla, M. Mantuano, I. Ionni, B. Mazzi, M. Leo, A. Sframeli, C. Posarelli, M.N. Maglionico, M. Figus, M. Nardi, C. Marcocci, M. Marinò, Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves' orbitopathy. J. Endocrinol. Investig. 44, 581–585 (2021)
F. Menconi, M.A. Profilo, M. Leo, E. Sisti, M.A. Altea, R. Rocchi, F. Latrofa, M. Nardi, P. Vitti, C. Marcocci, M. Marinò, Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited. Thyroid Jan. 24(1), 60–66 (2014)
P. Anagnostis, K. Boboridis, F. Adamidou, M. Kita, Natural course of mild Graves' orbitopathy: is it a chronic remitting or a transient disease? J. Endocrinol. Investig. 40, 257–261 (2017)
E. Hoppe, A.C.H. Lee, D. Hoppe, G.J. Kahaly, Predictive Factors for Changes in Quality of Life after Steroid Treatment for Active Moderate-to-Severe Graves' Orbitopathy: A Prospective Trial. Eur. thyroid J. 9, 313–320 (2021)
M. Lumyongsatien, B. Keeratidamkerngsakul, K. Pornpanich, S. Vangveeravong, P. Saonanon, D. Wiwatwongwana, P. Mahaisavariya, O. Aryasit, K. Pongpirul, Development and psychometric properties of the Thai Graves' ophthalmopathy quality of life (GO-QOL) questionnaire. Journal of patient-reported outcomes Dec 31;4(1):1 (2019)
D. Villagelin, J. Romaldini, J. Andrade, R. Santos, A. Milkos, P. Teixeira, L.S. Ward, Evaluation of Quality of Life in the Brazilian Graves' Disease Population: Focus on Mild and Moderate Graves' Orbitopathy Patients. Front. Endocrinol. 10, 192 (2019)
C.M. Riguetto, A.M. Neto, M.A. Tambascia, D.E. Zantut-Wittmann, The relationship between quality of life, cognition, and thyroid status in Graves' disease. Endocrine. 63, 87–93 (2019)
G.B. Bartley, V. Fatourechi, E.F. Kadrmas, S.J. Jacobsen, D.M. Ilstrup, J.A. Garrity, C.A. Gorman, Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology. 103, 958–962 (1996)
Y.J. Choi, H.T. Lim, S.J. Lee, S.Y. Lee, J.S. Yoon, Assessing Graves' ophthalmopathy-specific quality of life in Korean patients. Eye (London, England). 26, 544–551 (2012)
I.C. Lin, C.C. Lee, S.L. Liao, Assessing quality of life in Taiwanese patients with Graves' ophthalmopathy. J. Formos. Med. Assoc. 114(11), 1047–1054 (2015)
C.Y. Weng, Z.F. Li, S.D. Hu, Y.S. Luo, X.T. Feng, Q. Zhong, Q. Zhang, J. Shen, Evaluation of quality of life in patients with Graves orbitopathy and its influencing factors. Zhonghua nei ke za zhi. 58, 577–583 (2019)
L.C. Delfino, A. Zunino, V. Sapia, M. Croome, V. Ilera, A.T. Gauna, Related quality of life questionnaire specific to dysthyroid ophthalmopathy evaluated in a population of patients with Graves' disease. Archives of endocrinology and metabolism. 61, 374–381 (2017)

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Selenium in the treatment of mild-to-moderate Graves’ orbitopathy: A 5-year Prospective Controlled Cohort Study

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Abstract

Purpose

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Introduction

Materials and Methods

Study participants

Assessment and laboratory measurements

Statistical analysis

Results

Demographic characteristics at baseline

Ocular symptoms and signs

Assessment of clinical activity score

TRAb

Evaluation of GO-QOL

Selenium concentration

Other interventions

Discussion

Conclusion

Declarations

References

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