In this study, the mean LOM in patients with TED significantly improved throughout the follow-up after treatment; however, a group of patients showed no improvement in LOM. A higher initial titer of TSAb was associated with a poor prognosis for the recovery of LOM. The mean initial TSAb concentration of the not-improved group was 66.4% higher than that of the improved group. In addition, the diplopia grade at 1 year after treatment was significantly lower in the improved group than in the not-improved group, while the pre-treatment diplopia grade, pre-treatment LOM, and mean rectus muscle thickness did not significantly differ in the two groups.
The mean age at the initial visit was 54.6 years in male patients and 53.3 years in female patients in this study. It was much higher than the mean age (42.8 years in men and 41.7 years in women) of Korean patients with dysthyroid TED from the multicentral epidemiological study involving patients in 24 centers.12 This was consistent with other studies that reported a significantly higher mean age in patients with restrictive myopathy.7,13 The female-to-male ratio was 0.85:1 for restrictive myopathy in this study. This contrasted with the female-to-male ratio of all 652 patients with TED during the study period (3.88:1). In Woo et al.’s Korean multicenter study, the female-to-male ratio (3.9:1) was compatible with that of all the 652 patients. The female-to-male ratio of patients with restrictive myopathy has been reported to be lower (1-1.74:1) than that of all patients with TED. 14-16
According to several studies, smoking is strongly associated with the development of TED and unfavorable clinical outcomes. Current smokers had more than twice the odds ratio or relative risk of TED development than those who had never smoked or past smokers. Current smokers also showed a higher incidence of proptosis, diplopia, and total ophthalmopathy, but no differences in clinical manifestations and clinical outcomes in some reports.17 In our study, the smoking factor was not related to the prognosis of restrictive myopathy, which contrasted with other studies reporting worse ocular motility prognosis in smokers.18,19 The limitations of our study were the small sample size and the inclusion of only the initial smoking status.
Of note, the proportion of patients with euthyroid orbitopathy was 15.4%. This was higher than that of other epidemiologic studies conducted more than a decade ago: 5.0–7.3% of euthyroid orbitopathy patients with TED of all the stages.20-22 According to a study by Yoon et al. the proportion of euthyroid orbitopathy was 14.7%, and euthyroid orbitopathy was known to take a milder form of TED, although the prevalence of restrictive myopathy was not significantly different from that of hyperthyroid TED.23 Euthyroid orbitopathy was diagnosed when typical clinical signs of TED and high autoantibody titers of TSHR-Ab or TSAb were observed without any evidence of preceded dysthyroid disease. The higher proportion of euthyroid orbitopathy in our study may be related to the recent trend of routine autoantibody testing for the diagnosis of TED. Further studies are needed to establish the relationship between euthyroid orbitopathy and restrictive myopathy.
Muscle thickness is known to be related to the degree of extraocular muscle motility restriction in patients with active-phase TED.10 The correlation between the cross-sectional area of the vertical rectus muscles in the CT scan and the vertical angle of deviation of the eye was previously reported.24 However, in search of prognostic factors of restrictive myopathy on the pre-treatment CT scans, we could not find any significant factors. The type and number of involved muscles and the muscle thickness at initial presentation did not affect the recovery of the limitation of muscle movement. Since initial pre-treatment CT scans were only used in this study, imaging studies compatible with the 1-year clinical status could not be evaluated in this study.
Since all the patients in this study met the moderate-to-severe TED classification by EUGOGO, the treatment recommendations of EUGOGO were adopted.3 Eighty percent of patients received IV methylprednisolone as a first-line treatment after a thorough discussion of the treatment course and side effects. Patients who could not follow the treatment schedule took oral steroid treatment as the first treatment. Orbital radiotherapy and oral prednisolone treatments were administered to 35.4% and 33.8% of the patients, respectively (Table 1). The proportion of patients who received IV methylprednisolone was higher in the improved group, but the difference was not significant (P = 0.16). Although there are debates on the efficacy of orbital radiotherapy for TED, it has been accepted as an effective treatment option for restrictive myopathy related to TED.3 However, in our study, the proportion of patients who underwent radiotherapy in the improved and not-improved groups were not different. A limitation of our study is that a few patients received radiation therapy, and there may have been a selection bias for treatment decisions.
During the longitudinal analysis, the treatment outcomes were evaluated chronologically (Table 4). Notably, the LOM of the improved group did not show any improvement until after 9 months of follow-up, whereas the CAS in both groups decreased after 3 months of follow-up. This implies that the restoration of LOM takes time after treatment even though the inflammatory signs decrease during the early post-treatment period. Therefore, we need to follow-up on patients with restrictive myopathy for a long time after immunosuppressive treatment to determine the effect of treatment. Interestingly, the diplopia grade decreased in the improved group after 3 months of follow-up: quality of vision can improve from the early post-treatment period even if LOM does not recover at all.
Some studies have categorized the severe TED subtypes and demonstrated the association of TSHR-Ab and TSAb with the severity of restrictive myopathy in TED.13,25 Our study is worthwhile because it focused solely on the prognosis of restrictive myopathy. A high titer of TSAb may be predictive of a poor prognosis for restrictive myopathy, as our study shows; moreover, if the titer of TSAb does not diminish through the follow-up, it may also contribute to a poor prognosis in restrictive myopathy. Therefore, checking the concentration of TSAb during follow-up may be important for prognosticating restrictive myopathy.26 Our study is worthwhile because it focused solely on the prognosis of restrictive myopathy. A high titer of TSAb may be predictive of a poor prognosis for restrictive myopathy, as our study shows; moreover, if the titer of TSAb does not diminish through the follow-up, it may also contribute to a poor prognosis in restrictive myopathy. Therefore, checking the concentration of TSAb during follow-up may be important for prognosticating restrictive myopathy.
TSHR-Ab, including TSAb and TSHR binding inhibitory immunoglobulins and other autoantibodies, activate helper T-cells, which, in turn, activate B-cells to express autoantibodies or become autoactivated T-cells.27,28 High TSAb concentrations are related to severe inflammatory responses; therefore, conventional systemic steroid treatment or radiotherapy may not be sufficient to control the status with high pre-treatment TSAb concentrations. Subsequent studies focusing on the treatment response of patients with high TSAb restrictive myopathy using other immunosuppressants and novel biologic agents are required.3,29
This study was designed as a retrospective study and performed at a single tertiary care center in Korea. The limitations of this study are referral bias, uncontrolled treatment options, and the small sample. Further multicenter studies with larger sample sizes may be required to confirm our findings.
In conclusion, patients with TED and restrictive myopathy who had higher pre-treatment TSAb titers showed poorer responses to treatment. Pre-treatment and regular TSAb follow-up may be beneficial for predicting the prognosis of restrictive myopathy in patients with TED.