Abstract
Background:
Thyroid eye disease (TED) is an autoimmune inflammatory condition affecting the orbit and ocular surface, often leading to proptosis, diplopia, and evaporative dry eye. Tear film instability, eyelid retraction, and lagophthalmos contribute significantly to ocular surface dysfunction in TED. Smoking is a major risk factor that worsens disease severity and reduces treatment response.
Objectives:
To evaluate ocular surface changes, treatment responses, and risk factors—including smoking—in patients with TED, and to assess the effects of different therapeutic modalities.
Design:
Retrospective observational cohort study.
Methods:
This retrospective study analyzed the records of 365 patients with TED followed between 2014 and 2021. Complete clinical data were available for 362 patients. Ocular parameters, including TBUT, OSDI, Oxford staining score, MRD-1, MRD-2, and Hertel exophthalmometry, were evaluated at baseline and follow-up. Treatment modalities included antithyroid drugs, corticosteroids, selenium supplementation, RAI, and surgery. Data were compared between smokers and nonsmokers.
Results:
Among 362 patients (76% female), 105 (29%) were smokers. TED severity and persistent dry eye symptoms were significantly higher among smokers (p < 0.05). Posttreatment, significant improvements were observed in TBUT, OSDI, and Oxford scores (p < 0.05). Selenium supplementation showed potential benefit. CAS decreased significantly over follow-up (from 7.7% to 4.7% active cases, p < 0.05). TED progression was observed in 18.7% of patients receiving RAI therapy. Surgical intervention rates were low.
Conclusion:
TED causes notable ocular surface dysfunction and dry eye symptoms, particularly in smokers. Medical and surgical treatments provide effective disease control, while selenium appears promising for disease stabilization. Smoking cessation and early multidisciplinary management are critical to improving outcomes.
Plain language summary
Thyroid eye disease (TED) is an autoimmune condition affecting the tissues around the eyes, often seen in people with thyroid disorders, especially hyperthyroidism. TED can cause symptoms such as eyelid retraction, swelling, redness, bulging eyes (proptosis), and in severe cases, vision problems due to optic nerve compression. Additionally, many patients experience dry eye symptoms, including irritation, foreign body sensation, and discomfort due to tear film instability. This study aimed to examine the eye-related changes in TED, identify risk factors affecting disease severity, and evaluate treatment outcomes. We retrospectively analyzed data from 365 TED patients at a specialized eye clinic. We assessed eye measurements, tear film stability using the tear breakup time (TBUT) test, and ocular surface damage through the Oxford staining scale. We also investigated the effects of smoking and different treatment options, including corticosteroids, selenium supplementation, radioactive iodine (RAI) therapy, and surgical interventions. The majority of patients (76%) were female, and 95.6% had hyperthyroidism. After treatment, significant improvements were observed in dry eye symptoms, TBUT, and ocular surface health. However, smoking (28.5% of patients) was linked to more severe TED and poorer treatment response. Selenium supplementation (31.77% of patients) appeared to help stabilize the disease. In contrast, 18.7% of patients who received RAI therapy experienced worsening of their TED. Our findings highlight the importance of early intervention, smoking cessation, and a multidisciplinary approach to TED management. TED not only affects the orbital tissues but also contributes to dry eye disease, making comprehensive eye care essential. Future research should focus on optimizing treatment strategies to prevent complications and improve patient outcomes.
Keywords
Introduction
Thyroid eye disease (TED), also known as Graves’ orbitopathy, is an autoimmune inflammatory disorder affecting orbital and periorbital tissues. Although most frequently associated with hyperthyroidism, it can also occur in euthyroid or hypothyroid individuals. 1 TED commonly presents with eyelid retraction, periorbital edema, conjunctival injection, and proptosis. In 3%–5% of cases, serious complications such as corneal ulceration, compressive optic neuropathy, and vision-threatening inflammation may develop. 2
TED is a relatively uncommon yet clinically significant condition, with an estimated prevalence ranging from 90 to 300 per 100,000 individuals and an annual incidence of 4–5 per 100,000 population. Although TED affects approximately 25%–40% of patients with Graves’ disease, only a small subset (5%–6%) develop moderate-to-severe forms requiring aggressive intervention. While women are more frequently affected, men tend to present with more severe disease at older ages. Over recent decades, the burden of TED has declined, likely due to earlier diagnosis and better management of modifiable risk factors such as smoking and thyroid dysfunction. 3 A recent meta-analysis confirmed that TED is present in roughly 40% of patients with Graves’ disease, with marked variation across regions-58% in Oceania, 44% in Asia, and 38% in Europe-likely reflecting ethnic, behavioral, and healthcare system differences. The most prevalent clinical features are lid retraction and proptosis, with diplopia occurring in approximately one-third of cases. 4 Furthermore, TED most frequently occurs in the fifth to sixth decades of life, with two distinct age peaks—40–44 and 60–64 years in women, and 45–49 and 65–69 years in men—and tends to present at an older age and with greater severity in male patients. 3 Although most cases develop in the context of hyperthyroidism, TED can also arise in euthyroid or hypothyroid individuals, particularly in those with chronic autoimmune thyroiditis.3,5 Well-recognized modifiable risk factors include cigarette smoking—the strongest predictor of disease severity and poor treatment response—thyroid dysfunction (both hyper- and hypothyroidism), and RAI therapy without glucocorticoid prophylaxis.3,5 Early identification and control of these factors, combined with risk-based screening and prompt multidisciplinary management, are essential to reduce the likelihood of progression to moderate-to-severe disease and to improve functional and quality-of-life outcomes3,5
The pathophysiology involves autoantibody-mediated activation of the TSH receptor in orbital fibroblasts, leading to fibroblast proliferation, cytokine release, and adipogenesis. This cascade contributes to orbital volume increase, soft tissue inflammation, and restrictive strabismus due to extraocular muscle fibrosis.2–7
Among risk factors, smoking is the most well-established, known to worsen disease severity and reduce treatment efficacy. 8
Disease activity is typically assessed using the Clinical Activity Score (CAS), with a CAS ⩾3 indicating active inflammation. Severity classification by the European Group on Graves’ Orbitopathy (EUGOGO) is based on eyelid retraction, proptosis, diplopia, and optic nerve involvement. 9
Ocular surface dysfunction is a common consequence of TED and is primarily driven by tear film instability caused by proptosis, lagophthalmos, and eyelid retraction. This leads to evaporative dry eye symptoms such as foreign body sensation, photophobia, and ocular discomfort. Disruption of tear film homeostasis may result in corneal epithelial damage, reduced visual quality, and increased risk of corneal ulceration.10,11
Management of TED requires a multidisciplinary approach. Achieving euthyroidism is fundamental and may involve antithyroid drugs, RAI therapy, or thyroidectomy. 12 Selenium supplementation has also shown potential benefits in mild cases due to its anti-inflammatory properties. 13
Although several recent studies have highlighted the association between disease activity and ocular surface alterations in TED, there is still a lack of large-scale, clinically integrated data assessing the interplay between dry eye parameters, disease severity, treatment response, and risk factors such as smoking and radioiodine therapy.14–16 The present study adds to the existing literature by providing a comprehensive analysis of clinical and ocular surface changes in a large TED cohort, with particular emphasis on how treatment modalities and modifiable risk factors influence both symptomatology and disease course.
Accordingly, the aim of this study is to assess ocular surface alterations, relevant risk factors, and treatment outcomes in patients with TED.
Materials and methods
This single-center retrospective cohort study analyzed the medical records of 365 patients diagnosed with TED, who were followed at the Ophthalmology Clinic of Dışkapı Yıldırım Beyazıt Training and Research Hospital between 2014 and 2021. Although 365 patients were initially included, complete clinical and ocular surface data were available for 362 patients, who were subsequently included in the statistical analyses. Cases with incomplete clinical or ocular surface data were excluded from the final analysis. Ethical approval was obtained, and the study was conducted in accordance with the principles of the Declaration of Helsinki.
All consecutive patients who met the inclusion criteria during the study period were enrolled to minimize selection bias. Inclusion criteria were a confirmed TED diagnosis based on clinical and radiological findings and the availability of complete ophthalmological and systemic data. Patients with ocular surface disorders unrelated to TED, such as Sjögren’s syndrome or severe blepharitis, were excluded. In addition, those with a history of previous ocular surgeries, except for orbital decompression or strabismus surgery due to TED, and patients with systemic diseases that could affect ocular surface parameters, such as uncontrolled diabetes mellitus, were not included in the study. Patients with other causes of orbital inflammation (e.g., idiopathic orbital inflammation, infection, lymphoma, or granulomatous disease) were excluded based on clinical and radiologic findings. Potential sources of bias, including selection and information bias, were minimized by applying standardized diagnostic criteria, consistent examination protocols, and reviewing complete medical records.
Ophthalmological assessments included proptosis measurement using Hertel exophthalmometry, eyelid position evaluation through interpalpebral distance (IPD) and margin reflex distances (MRD-1, MRD-2), ocular motility assessment, diplopia testing, and color vision testing using Ishihara plates. Ocular surface evaluations were performed using multiple parameters. Tear film stability was assessed through tear breakup time (TBUT) measurements, where a fluorescein sodium strip was applied, and patients were instructed to blink three times before maintaining forward gaze. The first appearance of a tear film break was recorded, and the mean of three consecutive measurements was taken. Ocular surface damage was evaluated using the Oxford grading scale, ranging from 0 to 5. Dry eye symptoms were assessed using the 12-item Ocular Surface Disease Index (OSDI) questionnaire, administered at baseline and final follow-up. 17
Patients received various treatment modalities, including medical therapy with antithyroid drugs, corticosteroids, and selenium supplementation at a dose of 200 µg/day for 6 months. In most cases, systemic therapy for thyroid dysfunction (antithyroid drugs, RAI therapy, or thyroidectomy) had been initiated by endocrinology services prior to referral to our ophthalmology clinic. Upon referral, ocular involvement was managed by the ophthalmology team, which provided ocular surface treatment, systemic or local corticosteroid therapy where indicated, and surgical interventions such as orbital decompression in patients with significant proptosis or optic nerve compression, and strabismus surgery in those with restrictive diplopia. In selected severe cases, coordination with radiation oncology was undertaken for orbital radiotherapy. This collaborative approach, involving different specialties at various stages of the disease, ensured that patient care was consistent with a multidisciplinary management model.
Diplopia was evaluated based on documentation in the clinical records. The presence or absence of diplopia was assessed in primary gaze during ophthalmologic examination. When available, Hess screen charting or field of binocular single vision tests were also used and recorded.
Smoking status was recorded, and patients were classified as smokers (current daily or occasional smokers) or nonsmokers (individuals who had never smoked). Former smokers were not included in the study population. The impact of smoking on TED severity was assessed using the CAS, where a score of three or more indicated active TED, and the EUGOGO classification, which categorized patients into mild, moderate, or severe disease groups. 9
Statistical analyses were performed using IBM SPSS Statistics 22.0 (Armonk, NY, USA). Descriptive statistics were presented as mean ± standard deviation (SD) or percentage (%). Comparisons of continuous variables between baseline and follow-up were performed using the paired t-test for normally distributed data and the Wilcoxon signed-rank test for non-normally distributed data. Comparisons between independent groups, such as smokers and nonsmokers, were conducted using the Mann-Whitney U test or independent t-test, depending on data distribution. Categorical variables were analyzed using the chi-square test or Fisher’s exact test when applicable. A p-value of less than 0.05 was considered statistically significant.
Results
A total of 365 patients diagnosed with TED were initially included in the study; however, complete clinical data were available in 362 patients, who were included in the subgroup and statistical analyses. The mean follow-up duration was 56.3 ± 59.5 months, ranging from 3 to 360 months. The majority of patients were female (76%), and 95.6% had hyperthyroidism, while 4.4% were hypothyroid, and 0.8% were euthyroid. TED was present in 189 patients (52.2%) at baseline.
Baseline and final follow-up ophthalmological measurements, including Hertel exophthalmometry, IPD, and margin reflex distances (MRD-1, MRD-2), are summarized in Table 1.
Interpupillary distance, marginal reflex, and Hertel measurements (baseline and follow-up).
Tear film stability and ocular surface health improved following treatment. Post-treatment improvements were observed in OSDI scores (10.99 ± 16.99 to 7.8 ± 13.6, p < 0.001), TBUT, and Oxford staining scores (p < 0.05). (Table 2) Tear film stability and ocular surface health improved following treatment. Significant improvements were observed in TBUT (OD and OS), OSDI scores (10.99 ± 16.99 to 7.8 ± 13.6, p < 0.001), and Oxford staining scores (1.42 ± 0.81 to 1.21 ± 0.76, p = 0.04). These changes are detailed in Table 2.
Changes in tear film stability and ocular surface parameters, including TBUT, OSDI, and Oxford grading scores.
OSDI, Ocular Surface Disease Index; TBUT, Tear Breakup Time.
Among the modifiable and nonmodifiable risk factors known to influence the course of TED—including age, gender, thyroid dysfunction, radioiodine therapy, and selenium status—smoking was notably prevalent in our cohort. Of the 362 patients, 105 (29.0%) were identified as smokers. Smoking was significantly associated with increased TED severity and reduced treatment responsiveness. At the initial visit, 11 smokers (10.5%) had clinically active disease (CAS ⩾ 3), compared to 5.1% of nonsmokers (p = 0.04). Persistent dry eye symptoms were observed in 37 smokers (35.2%) versus 17.4% of nonsmokers (p = 0.01).
Treatment modalities varied among patients, with 341 (94.2%) receiving medical therapy, including corticosteroids and antithyroid drugs. A total of 71 (19.6%) patients underwent thyroidectomy, while 32 (8.8%) received radioactive iodine (RAI) therapy. Intravenous methylprednisolone therapy was administered to 18 patients (4.9%) with active, moderate-to-severe TED, in accordance with EUGOGO guidelines, 6 as part of first-line anti-inflammatory treatment. Orbital decompression surgery was performed in seven patients (1.9%), including five bony and two fat decompressions.
Strabismus surgery was performed in five patients (1.4%) due to restrictive diplopia. Selenium supplementation was provided to 115 patients (31.8%) for 6 months at a dose of 200 µg/day, showing potential benefits in stabilizing TED progression. A summary of all treatment modalities, including monotherapies and combination approaches, is presented in Table 3 to enhance clarity and facilitate interpretation.
Summary of treatment modalities administered to patients with thyroid eye disease.
At the initial visit, 28 patients (7.7%) had clinically active TED (CAS ⩾ 3). At the final follow-up, 17 patients (4.7%) remained clinically active, indicating a statistically significant reduction in disease activity following treatment (p < 0.05).
Among the 31 patients who received topical cyclosporine, the mean OSDI score decreased from 14.2 ± 12.7 to 9.4 ± 11.2 (p = 0.08). TBUT improved from 4.1 ± 1.6 s to 5.3 ± 2.1 s (p = 0.09). Although the improvements were more prominent than in the non-cyclosporine group, the differences did not reach statistical significance.
Among the 32 patients (8.8%) who received RAI therapy, TED progression was observed in six patients (18.7%). These patients exhibited worsening of proptosis and ocular surface symptoms. In this subgroup, the mean CAS increased from 2.0 ± 0.63 at baseline to 3.2 ± 0.75 at final follow-up (p = 0.04).
Discussion
TED is a complex autoimmune disorder affecting both orbital and ocular surface structures, significantly impacting patients’ visual function and quality of life. The pathogenesis involves autoantibody-mediated activation of orbital fibroblasts, leading to inflammatory cytokine release, glycosaminoglycan accumulation, and orbital fat expansion.1,2 These processes contribute to proptosis, restrictive strabismus, and ocular surface dysfunction, which were key findings in our study.
Our results confirm that TED is strongly associated with evaporative dry eye, characterized by reduced TBUT, increased corneal staining, and elevated OSDI scores. 18 This aligns with prior studies indicating that orbital soft tissue expansion and eyelid retraction exacerbate tear film instability by increasing ocular surface exposure and tear film osmolarity.19,20
Following treatment, we observed a significant improvement in TBUT and Oxford staining scores (p < 0.05) and a reduction in OSDI scores (p < 0.001), suggesting enhanced tear film stability and symptom relief. Similar findings have been reported in the literature, indicating that TED-directed therapies improve ocular surface integrity by reducing orbital inflammation and restoring eyelid function. 21
Topical cyclosporine was used in 8.6% of patients, and although a trend toward improved ocular surface parameters was noted, the difference was not statistically significant (p = 0.08). Previous studies suggest that cyclosporine, when combined with corticosteroids, enhances the treatment response in TED-related dry eye, likely due to its immunomodulatory and anti-inflammatory effects.22,23 However, further randomized trials are needed to confirm its efficacy.
Smoking is a well-established exacerbating factor in TED, associated with increased disease severity, poorer corticosteroid response, and higher relapse rates following RAI therapy.24–26 In our study, smokers had higher rates of active TED (CAS ⩾ 3) and persistent dry eye symptoms compared to nonsmokers (p < 0.05), reinforcing the necessity of smoking cessation in TED management.27,28 Although the impact of smoking cessation during follow-up could not be assessed due to incomplete retrospective documentation, previous studies have consistently demonstrated that cessation improves TED outcomes and should be strongly encouraged in clinical practice. 9
Although prior studies have linked RAI therapy in smokers to higher TED exacerbation rates, 29 our study did not demonstrate a statistically significant difference in disease worsening between smokers and nonsmokers post-RAI. This suggests that larger prospective studies are needed to clarify the interaction between smoking and post-RAI TED progression. This study further confirms that smoking is a key risk factor for TED severity, contributing to persistent ocular surface damage and poorer treatment response.
Selenium supplementation has been proposed as a potential adjunct therapy in TED due to its antioxidant properties and immune-modulating effects. 30 In our study, 31.8% of patients received selenium (200 μg/day for 6 months), and disease stabilization was noted. Prior randomized trials have demonstrated a reduction in TED progression and an improvement in quality of life with selenium supplementation.31–33 However, the optimal dose, duration, and mechanism of action remain subjects of ongoing research, necessitating further clinical investigations.
TED management requires a multidisciplinary approach, integrating endocrinology, ophthalmology, and, in severe cases, orbital surgery. In our cohort, 94.2% of patients received medical therapy, with a statistically significant reduction in CAS scores following treatment (p < 0.05), indicating effective disease control.
RAI was administered to 8.8% of patients. While prior studies suggest RAI may trigger TED exacerbation.33,34 Our study observed a TED progression rate of 18.7% following RAI, consistent with reported literature. To mitigate this risk, glucocorticoid prophylaxis should be considered in high-risk patients undergoing RAI therapy. 35
Surgical intervention was performed in a limited subset of patients. Orbital decompression was indicated for cases with optic nerve compression or severe proptosis (1.9%), while strabismus surgery was performed in 1.4% of patients due to restrictive diplopia. The relatively low number of surgical interventions in our cohort may be explained by the predominance of mild-to-moderate disease, favorable response to medical therapies, and patient preference. In some cases, patients with surgical indications declined the procedures. These rates align with prior studies indicating that most TED cases can be effectively managed medically, with surgical intervention reserved for refractory cases. 36
One of the key strengths of this study lies in its large real-world cohort (n = 362) and the integration of standardized diagnostic tools—including CAS, Hertel exophthalmometry, TBUT, and Oxford staining scale—to comprehensively assess both orbital and ocular surface parameters. Unlike prior reports7,18 focusing on either structural or symptomatic features, this study uniquely evaluates how treatment modalities (e.g., corticosteroids, selenium supplementation, and radioiodine therapy) and modifiable risk factors such as smoking influence TED severity and ocular surface integrity. In addition, the inclusion of follow-up measurements enables assessment of treatment response in a routine clinical setting, adding to the practical value of the findings.
This study has several limitations. First, the retrospective design may have led to incomplete data capture. To mitigate bias, we included only patients with complete ophthalmologic and systemic records in the statistical analyses; nonetheless, some degree of selection bias cannot be ruled out. Second, smoking status was based on self-report, which may underestimate its impact. Third, the absence of a randomized control group limits causal inferences regarding selenium’s efficacy, though the observed trends align with recent prospective studies.
Conclusion
TED imposes a significant burden on both orbital structures and the ocular surface, often manifesting as dry eye symptoms, diplopia, and visual impairment. Our findings underscore the importance of early recognition, smoking cessation, and individualized treatment planning. The observed benefit of selenium supplementation, alongside steroid therapy, supports its consideration in the routine management of mild-to-moderate TED. These results contribute meaningful clinical insight and reinforce the need for prospective studies targeting treatment optimization and risk stratification.
