Therapeutic effect of selective interleukin-2-inducible tyrosine kinase inhibitor in orbital fibroblasts from patients with Graves' orbitopathy.

Interleukin-2-inducible tyrosine kinase (ITK) is a crucial cytoplasmic protein in the T-cell signaling pathway. Here, we aimed to demonstrate the anti-inflammatory effect of the selective IL-2-induced tyrosine kinase inhibitor BMS-509744 (BMS) on Graves' orbitopathy (GO) in an in vitro model. ITK mRNA expression in orbital tissues from GO and normal controls was compared using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary cultured orbital fibroblasts from each group were pretreated with BMS and stimulated with interleukin (IL)-1ß to induce inflammatory reaction. ITK mRNA expression was evaluated using western blotting, and inflammatory cytokine production and downstream transcription factor expression were analyzed after pretreatment with BMS. ITK mRNA expression in GO tissues was significantly higher than that in normal control tissues. After stimulation with IL-1ß, ITK phosphorylation significantly increased in both GO orbital and normal control tissues. BMS inhibited IL-1ß-induced IL-8 expression in the GO orbital fibroblasts. BMS pretreatment significantly suppressed NF-κB phosphorylation in both GO and normal controls. The selective ITK inhibitor attenuates proinflammatory cytokine production and proinflammatory transcription factor phosphorylation in in vitro model of GO.

The Effect of Rho Kinase Inhibitors on In Vitro Human Orbital Preadipocytes.

PURPOSE: To identify the effects of Rho Kinase (ROCK) inhibitor medications on human orbital adipogenesis, fibroblast proliferation, and fibrosis. METHODS: Orbital adipose tissue was obtained from patients with Graves' ophthalmopathy (GO) as well as controls (non-GO or normal) after informed consent was done. These tissue samples were cultured and adipogenesis was initiated. Levels of Rho Kinase as well as cellular mediators of orbital inflammation and fibrosis. The same cultures and measurements were then repeated with the use of a ROCK inhibitor (KD025-ROCK2) to assess for changes in adipogenesis as well as markers associated with inflammation and fibrosis. RESULTS: Rho Kinase levels in GO tissue were more highly expressed than in controls. These levels were suppressed with the use of the ROCK inhibitor KD025. There was a dose-dependent reduction in differentiation of orbital adipocytes with the use of KD025. KD025 reduced the levels of fibrosis-related gene expression. Finally, there was a significant reduction of transforming growth factor beta mediated phosphorylation signaling pathways in the KD025-treated GO tissue. CONCLUSION: This study shows that the ROCK inhibitor, KD025, helps to reduce the expression of ROCK in GO tissue along with reducing orbital adipocyte differentiation as well as cell mediators involved in fibrosis that occurs in GO.

A comparison of proptosis reduction with teprotumumab versus surgical decompression based on fat-to-muscle ratio in thyroid eye disease.

PURPOSE: To explore if orbital fat-to-muscle ratio (FMR) is predictive of whether surgical decompression or teprotumumab leads to greater proptosis reduction in thyroid eye disease (TED). METHODS: A single-center retrospective cohort study comparing surgical decompression with teprotumumab according to FMR. All TED patients completing an 8-dose course of teprotumumab between January 2020 and September 2022 and all patients undergoing bony orbital decompression from January 2017 to December 2019 were included. Subjects were excluded if they were <18 years, received both surgical decompression and teprotumumab, or lacked orbital imaging. The primary exposure variable was teprotumumab or surgical decompression. The secondary exposure variable was baseline FMR. The primary outcome measure was change in proptosis (mm). RESULTS: Thirty-eight patients, mean age 53.5 years (±11.4), were included in the teprotumumab group and 160 patients, mean age 48 years (±11.1), in the surgical group. Average proptosis reduction after teprotumumab and surgical decompression was 3 mm (±1.44) and 5 mm (±1.75), respectively. The FMR was stratified at the median of 1.80. In subjects with FMR < 1.80, teprotumumab showed equivalent proptosis reduction compared to surgical decompression, -0.33 mm (SE 1.32) p = .802. In subjects with FMR ≥ 1.80, surgical decompression led to significantly more proptosis reduction than teprotumumab, 3.01 mm (SE 0.54), p < .001. CONCLUSIONS: Baseline FMR can be used to counsel patients as to proptosis reduction with teprotumumab versus surgery. Subjects with low FMR obtain comparable proptosis reduction with teprotumumab or surgery, whereas high FMR is associated with more significant proptosis reduction following surgery over teprotumumab.

Differential effects of teprotumumab treatment based on fat-to-muscle ratio in patients with thyroid eye disease.

PURPOSE: To characterize the distribution of fat-to-muscle ratio (FMR) across patients with thyroid eye disease (TED) and to assess the association between FMR and therapeutic response to teprotumumab. METHODS: A retrospective cohort study of patients completing a full course of teprotumumab for TED between January 2020 and March 2022 at a single tertiary referral center. Patients without baseline orbital imaging were excluded. Quantitative analysis of FMR was performed by manual segmentation of patients' imaging using OsiriX software. The primary outcome measure was change in clinical measurement of proptosis. Linear regression modelled change in proptosis against FMR. Statistical significance was set at p < .05. RESULTS: Twenty-two patients (3 M:19F) were included with a mean age of 49.4 ± 15.5 years. The FMR ranged from 1.11 to 6.54, mean 3.15 ± 1.30. The data did not deviate from a normal distribution (Shapiro-Wilk test for normality, p = .18). Pre- and post-treatment average proptosis measurements were 21.72 ± 3.56 mm and 18.81 ± 3.07 mm, respectively. Univariable linear regression demonstrated a 0.78 ± 0.36 mm greater reduction in proptosis for every 1 unit decrease in FMR (p = .038). CONCLUSIONS: Contrary to the traditional dichotomous characterization of TED into type 1 and type 2 phenotypes, orbital FMR may represent a continuum of disease manifestation, more closely following a normal rather than bimodal distribution. Furthermore, pre-treatment FMR is associated with response to teprotumumab; those with lower FMR experiencing a greater reduction in proptosis. This has implications for patient selection and counselling regarding the expected treatment outcome.

Quantitative assessment of increase in orbital volume after orbital floor fracture reconstruction using a bioabsorbable implant.

PURPOSE: To assess the postoperative changes in the orbital volume and the degree of enophthalmos after orbital floor fracture reconstruction using a bioabsorbable implant and to determine the predictors of postoperative orbital volume change. METHODS: Single-center, retrospective case series of 16 patients who underwent orbital floor fracture reconstruction using a bioabsorbable implant [poly(L-lactic acid)-poly(glycolic acid)/ß-tricalcium phosphate; Biobsorb ß®] were included. Three-dimensional volumetric calculations of orbit were determined using computed tomography scans and the degree of enophthalmos was assessed via Hertel exophthalmometry. Postoperative changes in the orbital volume and the degree of enophthalmos and their correlation were assessed. RESULTS: The mean volume of fractured orbits immediately after surgery was 22.26 ± 1.98 cm3, increasing to 23.67 ± 2.00 cm3 at 6-month follow-up (p < 0.001); the increased orbital volume was associated with postoperative deformation of the implant. The mean degree of enophthalmos was 0.09 ± 0.27 mm at 1-month follow-up, which increased to 0.66 ± 0.30 mm at 6-month follow-up (p = 0.001). Increase in orbital volume and enophthalmos progression showed a linear correlation (R = 0.682, p = 0.004). Patients with more herniated orbital tissue preoperatively showed increased postoperative orbital volume change (p = 0.015), whereas the size of the fracture area was not predictive of postoperative orbital volume change (p = 0.442). CONCLUSION: Increase in orbital volume by deformation of the bioabsorbable implant resulted in progressive enophthalmos during the postoperative follow-up period after orbital floor fracture reconstruction. Thus, careful selection of proper implants before surgery and close postoperative follow-up is needed for an optimal outcome.

Social determinants associated with loss of an eye in the United States using the All of Us nationwide database.

PURPOSE: To identify common factors associated with the loss of an eye using the NIH All of Us database. METHODS: In this case-controlled study, we extracted electronic health record and socio-demographic data for 231 cases of eye loss from All of Us enrollment sites. Controls (N = 924) matched the demographic characteristics of the 2020 United States Census. Bivariate analyses and multivariable logistic regression identified variables significantly associated with increased odds of eye loss. OUTCOME MEASURES: Medical and social determinants associated with increased odds of losing an eye. RESULTS: Among cases, the average age (standard deviation) was 60.1 (14.4) years. The majority (125, 54.1%) were male. 87 (37.7%) identified as African American, and 49 (21.2%) identified as Hispanic or Latino. Loss of eye was more likely in those with ocular tumor (odds ratio [OR] 421.73, 25 95% confidence interval [CI] 129.81-1959.80, p < .001), trauma (OR 13.38, 95% CI 6.64-27.43, p < .001), infection (OR 11.46, 95% CI 4.11-32.26, p = .001) or glaucoma (OR 8.33, 95% CI 4.43- 15.81, p < .001). African American (OR 2.39, 95% CI 1.39-4.09, p = .002) and Hispanic or Latino (OR 1.80, 95% CI 1.01-3.15, p = .04) participants were disproportionately affected. CONCLUSIONS: Racial and ethnic disparities exist among those with loss of an eye from underlying conditions. Addressing health inequities may mitigate the risk of this morbid outcome.

Gene expression profiles of pro-inflammatory mediators in the conjunctiva of patients with epiblepharon.

PURPOSE: To investigate the gene expression of pro-inflammatory mediators in the conjunctiva of pediatric patients with epiblepharon in a case-control study. METHODS: Twenty healthy controls and 15 pediatric patients with epiblepharon were enrolled from April 23, 2020 to June 15, 2020. Epiblepharon severity was divided into class I-III (least to moderate severity) and class IV (most severe). We obtained impression cytologic specimens from the medial palpebral conjunctiva of the participants to measure the gene expression of interleukin (IL)-1ß, IL-6, matrix metalloproteinase 9 (MMP9), and mucin 5AC (MUC5AC) using quantitative reverse transcription polymerase chain reaction. RESULTS: The mean age in the epiblepharon group was 9 years (range 7.5-11 years), and that in the healthy control group was 9.5 years (range 8-11.3 years). IL-1ß, IL-6, and MMP9 expression levels were 2.08 (p < 0.05), 2.11 (p < 0.05), and 2.48 (p < 0.05) fold higher, respectively, in the epiblepharon group than in the healthy control group. However, MUC5AC gene expression was not different between healthy subjects and patients with epiblepharon. IL-1ß, IL-6, and MMP9 expression levels in class IV patients were 1.32 (p < 0.05), 1.77 (p < 0.05), and 1.98 (p < 0.05) fold higher, respectively, than in class I-III patients. CONCLUSION: Epiblepharon may induce chronic inflammatory changes in the conjunctiva in addition to corneal epithelial damage. Therefore, early corrective surgery should be considered to prevent conjunctival inflammation.

4-Methylumbelliferone suppresses hyaluronan and adipogenesis in primary cultured orbital fibroblasts from Graves' orbitopathy.

PURPOSE: In Graves' orbitopathy (GO), hyaluronan secreted by orbital fibroblasts contributes to orbital tissue expansion. The goal of this research was to evaluate the potential benefit of 4-methylumbelliferone (4-MU), a hyaluronan synthase (HAS) inhibitor, in primary cultured orbital fibroblasts from Graves' orbitopathy. METHODS: We assessed the viability of orbital fibroblasts using a live/dead cell assay. Hyaluronan synthesis was evaluated by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qPCR). Adipogenesis was assessed by Oil Red O staining and qPCR of adipogenic transcription factors. RESULTS: In orbital fibroblasts treated with 4-MU (up to 1000 µM), cell viability was preserved by 90%. 4-MU significantly inhibited HAS gene expression and hyaluronan production (*P < 0.05). With respect to adipogenesis, 4-MU suppressed the accumulation of lipids and reduced the number of adipocytes, while decreasing expression of adipogenic transcription factors. CONCLUSIONS: 4-MU represents a promising new therapeutic agent for GO based on its ability to inhibit hyaluronan production and adipogenesis, without decreasing cell viability.

Anti-oxidative and anti-adipogenic effects of caffeine in an in vitro model of Graves' orbitopathy.

Oxidative stress and adipogenesis play key roles in the pathogenesis of Graves' orbitopathy (GO). In this study, the therapeutic effects of caffeine on the reduction of oxidative stress and adipogenesis were evaluated in primary cultured GO orbital fibroblasts in vitro. Orbital fibroblasts were cultured from orbital connective tissues obtained from individuals with GO. Intracellular reactive oxygen species (ROS) levels induced by hydrogen peroxide or cigarette smoke extract and the expression of anti-oxidative enzymes were measured after caffeine treatment. After adipogenic differentiation and caffeine treatment, cells were stained with Oil Red O and the levels of peroxisome proliferator activator γ (PPARγ), C/EBPα, and C/EBPß were determined by western blot analysis. Hydrogen peroxide and cigarette smoke extract increased the levels of intracellular ROS and anti-oxidative enzymes, which decreased in a dose-dependent manner upon pretreatment with caffeine in GO orbital fibroblasts. Oil Red-O staining results revealed a decrease in lipid droplets; furthermore, PPARγ, C/EBPα, and C/EBPß protein expression levels were inhibited upon treatment with caffeine during adipocyte differentiation. In conclusion, caffeine decreased oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. These findings may contribute to the development of new types of caffeine-containing pharmacological agents for use in the management of GO.

Proptosis as a Primary Symptom of Brain Arteriovenous Malformation.

Proptosis is a common yet cardinal symptom that may indicate the development of a wide range of diseases. Causes of proptosis are usually classified into vascular, inflammatory, endocrine, and neoplastic. Herein, the authors describe a case where proptosis manifested as the primary and only symptom of a massive brain arteriovenous malformation. Deprived of any other conventional symptoms and signs of a brain arteriovenous malformation, such as headaches, nausea, vision loss, increased ocular pressure, and so on, brain imaging played a key role in confirming the diagnosis of this patient. This case proclaims how imperative it is for ophthalmologists to consider the potential of brain arteriovenous malformation as a cause of proptosis and actively engage in brain imaging for diagnosis.

Lacrimal Drainage Obstruction and Gastroesophageal Reflux Disease: A Nationwide Longitudinal Cohort Study.

GOALS: This study aimed to evaluate the association between gastroesophageal reflux disease (GERD) and development of lacrimal drainage obstruction (LDO). BACKGROUND: It has been hypothesized that GERD may contribute toward the development of LDO. STUDY: This was a retrospective study of Koreans aged 40 to 79 years registered in the Korean National Health Screening Cohort from 2002 to 2013. Incident cases of LDO were identified according to the Korean Classification of Disease. We compared hazard ratios (HRs) for LDO between 22,570 patients with GERD and 112,850 patients without GERD by 1:5 propensity score-matched analysis. RESULTS: A total of 135,420 patients, representing 1,237,909 person-years, were evaluated. LDO developed in 1998 (8.9%) patients with GERD and 8565 (7.6%) patients without GERD (P<0.001). The incidence of LDO per 1000 person-years in patients with GERD was 9.7 and 8.3 in those without GERD; the age-adjusted and sex-adjusted HR was 1.17 (95% confidence interval, 1.11-1.23). This association between GERD and LDO was more pronounced among younger individuals (HR, 1.20 for patients 40 to 59-y old; HR, 1.12 for patients 60 to 79-y old) and among men (HR, 1.20 for men; HR, 1.14 for women). Patients with GERD had a higher risk of LDO than those without GERD, irrespective of history of proton-pump inhibitor use. In the sensitivity analysis, GERD patients with esophagitis had a higher risk of LDO than those without esophagitis. CONCLUSIONS: Our findings suggest that GERD is associated with an increased risk of subsequent LDO and that this effect is more pronounced among adults aged 40 to 59-years old and men.

Long-term outcome, relapse patterns, and toxicity after radiotherapy for orbital mucosa-associated lymphoid tissue lymphoma: implications for radiotherapy optimization.

OBJECTIVES: Although mucosa-associated lymphoid tissue lymphoma (MALToma) is sensitive to radiation therapy (RT), the optimal RT dose and treatment volumes have not been established. This study aimed to assess the relapse patterns and outcomes of patients with orbital MALToma who underwent RT and to suggest implications for optimized RT. METHODS: We reviewed 212 patients (246 orbits) diagnosed with orbital MALToma who received RT between 1993 and 2013. Median RT dose was 25.2 Gy. Generally, conjunctival and eyelid lesions were irradiated with electrons, whereas retrobulbar and lacrimal gland lesions with photons. Lens shielding was used for 70% of treated eyes, mainly conjunctival and eyelid tumors. RESULTS: Relapse occurred in 29 patients. Among 11 patients with local relapse (LR), 4 were attributed to insufficient dose (n = 2) and improper RT volume (n = 2). The 10-year LR, contralateral orbit relapse, and distant relapse rates were 8.6%, 12.8% and 4.9%, respectively. Twelve patients died of disease-specific causes (n = 1) and intercurrent diseases (n = 11). The 10-year relapse-free survival, overall survival, and cause-specific survival rates were 69.7%, 88.2% and 98.8%, respectively. Grade 3 cataracts and nasolacrimal duct obstruction were observed in 27 and 4 orbits, respectively. CONCLUSION: Low-dose RT with proper lens shielding is an appropriate treatment for orbital MALToma in terms of high disease control rate and acceptable morbidity. However, lower RT dose may be attempted to further reduce toxicity while maintaining excellent outcomes.

Semiautomated fabrication of a custom orbital prosthesis with 3-dimensional printing technology.

The fabrication of orbital prostheses is complex and time-consuming. A virtual orbital prosthesis and its negative mold are presented by using a 3D printer. This method avoids damage to the soft tissue or patient discomfort and reduces the time and skill required to fabricate a custom orbital prosthesis.

Lipidomic differentiation of Graves' ophthalmopathy in plasma and urine from Graves' disease patients.

Approximately 50% of patients with Graves' disease (GD) develop retracted eyelids with bulging eyes, known as Graves' ophthalmopathy (GO). However, no simple diagnostic blood marker for distinguishing GO from GD has been developed yet. The objective of this study was to conduct comprehensive profiling of lipids using plasma and urine samples from patients with GD and GO undergoing antithyroid therapy using nanoflow ultrahigh performance liquid chromatography electrospray ionization tandem mass spectrometry. Plasma (n = 86) and urine (n = 75) samples were collected from 23 patients with GD without GO, 31 patients with GO, and 32 healthy controls. Among 389 plasma and 273 urinary lipids that were structurally identified, 281 plasma and 191 urinary lipids were quantified in selected reaction monitoring mode. High-abundance lipids were significantly altered, indicating that the development of GD is evidently related to altered lipid metabolism in both plasma and urine. Several urinary lysophosphatidylcholine species were found to be increased (3- to 10-fold) in both GD and GO. While the overall lipid profiles between GD and GO were similar, significant changes (area under receiver operating curve > 0.8) in GO vs. GD were observed in a few lipid profiles: 58:7-TG and (16:1,18:0)-DG from plasma, 16:1-PC and 50:1-TG from urine, and d18:1-S1P from both plasma and urine samples. An altered metabolism of lipids associated with the additional development of ophthalmopathy was confirmed with the discovery of several candidate markers. These can be suggested as candidate markers for differentiating the state of GO and GD patients based on plasma or urinary lipidomic analysis. Graphical abstract.

Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves' orbitopathy.

OBJECTIVE: Graves' orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO. METHODS: Orbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL)-1ß, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed. RESULTS: IL-1ß exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1ß also induced the expressions of ICAM-1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor. CONCLUSION: S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.

Correction of Lower Eyelid Retraction Using Acellular Human Dermis During Orbital Decompression.

PURPOSE: To investigate the surgical outcome of grafting acellular human dermis compared with concurrent lower eyelid retractor recession during swinging eyelid orbital decompression for correction of lower eyelid retraction in patients with Graves' orbitopathy. METHODS: Institutional Review Board-approved retrospective nonrandomized study of 54 Graves' orbitopathy patients (95 eyes) from 2008 to 2012. Patients who received decompression were divided into 3 groups: Group 1 with conjunctival lengthening using 0.3-mm thickness AlloDerm (36 eyes), Group 2 with inferior retractor recession (33 eyes), and Group 3 with decompression only (26 eyes). Outcome measures included lower eyelid height, inferior sclera show, cosmetic appearance, and complications. RESULTS: Baseline clinical characteristics and the degree of improvement of exophthalmos were not different between groups. Preoperative MRD2 was higher in group 1 (8.0 mm) than in groups 2 (6.9 mm, p < 0.001) and 3 (6.6 mm, p < 0.001). Mean improvement of MRD2 as well as postoperative improvement of inferior scleral show at postoperative 4 to 6 months were significantly higher in group 1 (2.7 mm) than in groups 2 (1.8 mm, p < 0.001) and 3 (1.2 mm, p < 0.001). CONCLUSION: Simultaneous correction of lower eyelid retraction using thin AlloDerm during swinging eyelid orbital decompression maximizes improvement of lower eyelid retraction compared with concurrent inferior retractor recession.

A Prospective, Comparative Study of the Pain of Local Anesthesia Using 2% Lidocaine, 2% Lidocaine With Epinephrine, and 2% Lidocaine With Epinephrine-Bupivicaine Mixture for Eyelid Surgery.

PURPOSE: A mixture of 2% lidocaine with epinephrine and bupivacaine was developed to achieve the fast-onset anesthetic effect of lidocaine and the long-lasting effect of bupivacaine. The authors compared pain scores between 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture during local anesthesia for eyelid surgeries. METHODS: This was a double-blind, randomized, prospective, comparative study. In total, 120 consecutive patients (43 males, 77 females, mean age = 47.2 ± 21.2) who underwent bilateral eyelid surgery under subcutaneous anesthesia were asked to report pain scores for each eye during the first injection of anesthesia. Each patient was randomly assigned to receive 1 of the 3 anesthetic agents in 1 eyelid, and 1 of the remaining 2 agents in the other. RESULTS: The pH values of the 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture were 6.23 ± 0.21, 4.21 ± 0.37, and 3.87 ± 0.19, respectively. The pain scores of each were 4.3 ± 1.8, 5.1 ± 1.8, and 5.7 ± 1.9, respectively. The 2% lidocaine with epinephrine produced a statistically significantly higher pain score than 2% lidocaine (p = 0.044, generalized estimating equation method). The mixture also showed a significantly higher pain score than 2% lidocaine (p = 0.003, generalized estimating equation method). CONCLUSIONS: Epinephrine seemed to increase subjective pain scores. Compared with 2% lidocaine with epinephrine, 2% lidocaine with epinephrine-bupivicaine mixture was not significantly different in terms of subjective symptoms or pH.

Efficacy of combined orbital radiation and systemic steroids in the management of Graves' orbitopathy.

PURPOSE: To compare the efficacy and safety of combination therapy with orbital irradiation and systemic steroids versus steroid monotherapy in the management of active Graves' orbitopathy (GO). METHODS: The clinical charts of 127 patients with active inflammation due to GO who received intravenous steroid pulse therapy as a first-line treatment with or without orbital radiotherapy between 2010 and 2014 were reviewed. Patients were divided into two treatment groups: 1) combined orbital radiotherapy and steroid pulse therapy (SRT group) and 2) steroid pulse therapy only (ST group). Primary outcome measures included clinical activity score (CAS); NOSPECS classification; ocular motility impairment; and exophthalmos at 1, 3, 6, and 12 months after treatment. The secondary outcome measure was the change in orbital, extraocular muscle (EOM), and fat volume after treatment measured by orbit computed tomography. RESULTS: Sixty-eight patients were included in the SRT group, and 59 patients were in the ST group. In both treatments, CAS and NOSPECS were significantly reduced. In the comparison of the degree of change from baseline between the groups, the SRT group demonstrated more improvement in NOSPECS and scores of ocular motility. Orbital, EOM, and fat volume significantly decreased in the SRT group; however, only fat volume was reduced in the ST group. Compressive optic neuropathy after treatment developed in 0 % of the SRT group and 3.4 % (2/59) of the ST group. Reactivation of inflammation occurred in 11.8 % (8/68) of the SRT group and 28.8 % (17/59) of the ST group. CONCLUSIONS: Orbital radiotherapy in combination with steroid treatment significantly improved ocular motility by reducing EOM volume in patients with active GO.