Grave's orbitopathy (GO) is the most common extrathyroidal manifestation of Grave's disease and one of the most prevalent orbital disorders in adults (1–3). Signs and symptoms include eyelid retraction, proptosis, motility restriction, exposure keratopathy, and even vision loss, associated with a significant decrease in the quality of life of patients. As an autoimmune disease, GO follows a two-stage process, with an active inflammatory stage followed by an inactive fibrotic stage (2, 3). Anti-inflammatory treatment is usually considered effective during the active stage, but it has little value during the inactive stage (1, 4). Therefore, an accurate and objective assessment of inflammatory activity is essential to determine the appropriate treatment for GO.

The clinical activity score (CAS), based on inflammatory signs and symptoms, has been widely used for GO evaluation and as a criterion and guideline for therapeutic management (1). However, the acute inflammatory involvement of EOM or orbital fat may fail to be adequately assessed, especially when diplopia or motility impairment is not present (5–8). Moreover, diplopia and strabismus can be induced by either inflammation in the active stage or fatty degeneration and fibrosis in the inactive stage. MRI is another useful modality for GO imaging by the nature of its superior soft tissue contrast and no ionizing radiation. Especially, T2-weighted images can assist in staging and deciding treatment. However, the overall accuracy is still limited (9). Thus, a more precise assessment of EOM inflammatory activity is needed.

Currently, ^99mtechnetium (^99mTc)-labeled diethylene triamine pentaacetic acid (DTPA) orbital single-photon emission computed tomography/computed tomography (SPECT/CT) or SPECT has proven to be a valuable method for the detection of inflammation in GO (5, 10). Theoretically, DTPA is uniformly distributed throughout the extracellular space, binds to polypeptides in the extracellular fluid, and does not cross the blood-tissue barrier. The amount of ^99mTc-DTPA accumulation in the soft tissue of orbital cavity (mainly in the EOMs) is directly proportionate to the activity of the inflammation with associated hyperpermeability and breakdown of blood-tissue barrier (5, 11). This may explain the high uptake of ^99mTc-DTPA in GO due to inflammation. Moreover, it provides not only visual but also semi-quantitative information about the activity of the disease. Although DTPA SPECT/CT imaging in patients with GO has been validated in some cases (10, 11), a systematic evaluation of the DTPA uptake of EOMs has not been validated. The aim of our study was to examine the SPECT/CT parameters of EOMs for assessing the inflammatory activity of GO, and to evaluate the role in predicting the efficacy of treatment.

The notable results of this study were as follows: (1)we found significantly higher uptake and thickening of EOM evaluated by orbital SPECT/CT in patients with active GO than in patients with inactive GO. These parameters appeared useful for the differentiation disease activity between inactive and active GO; (2) the UR of EOMs as determined from SPECT/CT at baseline provided the independent and incremental values for the prediction of response following PGT.

To date, the CAS is the most commonly used clinical scale to determine the indication and duration of anti-inflammatory treatment. However, it presents some limitations that reflect ocular surface inflammation and has certain subjectivity. Orbital CT can provide information on exophthalmos and fat and muscle enlargement, which can be useful for diagnosis. The current study showed that the thickness of four EOMs in the active GO group were greater than those in the inactive GO group and control group, consistent with previous studies (13, 14). Additionally, we found that abdominal enlargement of the EOMs, especially the inferior and medial rectus muscles, was most common in GO. Although the thickness of the EOMs could reflect the stage of GO, the involvement of each EOM can occur in different phases, and it may be difficult to identify which EOM is in the inflammatory phase by clinical assessment alone. Therefore, it is challenging to evaluate the inflammatory activity from CT measurement.

Orbital ^99mTc-DTPA SPECT has been used to evaluate autoimmune inflammation of the retro-bulbar area in patients with GO for many years (5, 11). However, only the retro-orbital area of a SPECT image could be analyzed for the assessment of inflammation, without allowing for a more precise indication of which EOM is involved. In addition, physiological uptake in adjacent nasal sinuses can sometimes lead to falsely positive accumulation in the retro-orbital cavity. Thus, our study aimed to evaluate the EOMs of GO using a hybrid SPECT/CT method. SPECT/CT depiction of EOM inflammation may help clinicians to accurately evaluate the inflammatory staging of GO (10, 13). Our findings showed that the UR of EOM, especially the medial and inferior rectus muscles, in the active GO group was higher than that in the inactive GO group and the control group, suggesting that the UR has a potential for the evaluation of inflammatory infiltration within EOMs.

The European Group of Grave's Orbitopathy (EUGOGO) recommended systemic GC treatment for patients with moderate-to-severe GO as the first-line therapy (1, 15–18). However, medications can cause many side effects. Previous studies have found that periocular injections of GC were safe and effective in mild-to-moderate GO without causing serious complications (10). In clinical practice, the classification of clinical outcomes following GC therapy in GO has not been consistent: some patients with mild GO had significant improvements with local steroid therapy (5, 10), but a portion of patients with moderate-to-severe GO did not respond to systemic steroids (9, 19). This heterogeneity could be attributed to the presence of fibrosis and residual inflammation not detectable by current imaging modalities. Thus, it is essential to accurately evaluate the degree of inflammation and select the appropriate time for treatment.

In this study, we evaluated the predictive value of DTPA SPECT/CT for the efficacy of PGT in GO. Our results showed that the UR and thickness of EOMs all significantly dropped after treatment in the responders. However, in the non-responders, the UR of EOMs remained unchanged after treatment, even if the thickness of the superior and lateral rectus muscles decreased after the treatment. Additionally, it appeared that the UR of EOMs provided independent and incremental information for the prediction of response following PGT. These findings suggested that GO was likely to improve significantly with PGT in patients with high inflammatory burden at baseline.

What is also interesting is that this study suggests that initial CAS may not predict improvement following PGT. This can be explained by the fact that only patients with mild GO and elevated DTPA uptake, in spite of having low CAS (2–3 points), were included for analysis. This was because based on our previous study (10), patients with GO and CAS below 3 points might also benefit from PGT as long as the SPECT/CT showed DTPA activity in the eyes. Moreover, another reason is that CAS is judged on the basis of eye signs and symptoms in anterior segment, while SPECT/CT reflects activity in the posterior orbital segment, the major site of inflammation deposit. Thus, we speculated that patients with high uptake ratio of EOMs would, thus, be recommended to receive PGT, which would be superior to the conventional CAS score methods.

This study has several limitations. First, no uniform consensus regarding the definition of treatment response exists, and various factors (such as the CAS) complicate the objective evaluation of inflammatory activity. Second, partial volume effect remains one of the major degrading factors that hamper quantitative accuracy in SPECT imaging, particularly for small structures. Further studies using PET/CT will be needed to validate this finding, as PET/CT has a higher spatial resolution than SPECT/CT. Third, our study concerned only the predictability of DTPA SPECT/CT for the efficacy of periocular steroid treatment in patients with GO, and evaluation of the efficacy of systemic steroid treatment in patients with GO, thus, needs to be further investigated.

Orbital ^99mTc-DTPA SPECT/CT provided a reliable and feasible technique for assessing the inflammatory activity of EOMs in patients with GO. The UR of EOMs could be used as an objective index for evaluating the therapeutic efficacy in patients with GO.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Xiangya Hospital (No. 202101021). The patients/participants provided their written informed consent to participate in this study.

CZJ participated in study design and data analysis and interpretation, performed the statistical analysis, and drafted the manuscript. ZLD and JH collected the imaging data. HYD and JT contributed to editing and review of the manuscript. MZ and XHL contributed to study design and editing and review of the manuscript. All the authors read and approved the submitted version.

This study was supported by the National Natural Science Foundation of China (No. 81901784 to MZ) and Hunan Provincial Clinical Technology Innovation Project (No. 2020SK53705 to MZ).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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