Evaluation of corticoresistance in patients with Thyroid Eye Disease and use of Rituximab as a second-line treatment

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We evaluate the usefulness of CAS and TSI as predictors and/or post-treatment markers of corticoresistance in patients with TED and the effect of Rituximab in second-line treatment. Methods: We enrolled 236 patients with an active TED into this retrospective single-tertiary-center cohort study. All patients were initially treated with high-dose systemic glucocorticoids. Rituximab was later administered to 29 of 42 corticoresistant patients. Results: The CAS of the corticoresistant patients was significantly higher both before (p = 0.0001) and after (p = <0.0001) first-line treatment compared to the corticosensitive group. ROC analysis established the cut-point value as CAS ≥ 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve of 82.8%. In 22 patients treated with Rituximab, CAS gradually decreased to zero values without reactivation during extended follow-up. There was no difference in the TSI of corticosensitive and corticoresistant patients before or after first-line therapy. Conclusion : CAS ≥ 2, after first-line treatment, could be used as a corticoresistance marker. Corticoresistant patients should be subject to long-term follow-up for early detection of reactivation to reduce the delay to second-line treatment. Rituximab is a well-tolerated choice of second-line treatment and has a long-lasting effect on disease activity. Although TSI is a valuable biomarker of Graves’ disease and TED activity, according to our results, TSI cannot be used as a marker of corticoresistance. thyroid eye disease clinical activity score immunosuppressive treatment corticoresistance corticosensitivity Rituximab Figures Figure 1 Figure 2 Figure 3 Key Message High-dose intravenous glucocorticoids are the standard first-line treatment for active, moderate to severe and severe thyroid eye disease. Corticoresistant patients could be detected using a clinical activity score ≥ 2 after first-line treatment. Rituximab was a well-tolerated choice of second-line treatment and had a long-lasting effect on disease activity. INTRODUCTION Thyroid eye disease (TED) is a progressive autoimmune inflammatory disease of soft orbital tissues closely related to thyroid autoimmunity. Orbital and periorbital changes can lead to visual impairment, limitation of eye movement, diplopia and appearance changes. All of these severely affect TED patients' quality of life (QoL) in both their visual functioning and appearance aspects [ 1 ] [ 2 ]. The time of TED presentation differs among patients [ 3 ] [ 4 ]. The clinical activity score (CAS) evaluates the disease activity in everyday clinical practice. Its characteristics make CAS easily assessed by clinical examination without requiring laboratory or imaging methods or any special medical equipment [ 5 ]. EUGOGO classifies the severity of the disease into three degrees: mild, moderate to severe, and sight-threatening (including DON and corneal breakdown) [ 6 ] [ 7 ]. One of the TED activity biomarkers is the level of TSH receptor antibodies (TRAb). Its stimulating fraction, thyroid-stimulating immunoglobulin (TSI, or stimulatory TSH-R antibodies, TSAb), is ideally detected by cell-based bioassays, which can differentiate the functionality type of the antibodies (stimulating, neutral or blocking). This method is, however, not routinely available and so-called “bridging” immunoassays are thereby commonly used [ 8 ] [ 9 ]. The standard first-line treatment for active, moderate to severe and severe TED are high-dose intravenous glucocorticoids (ivGC), sometimes also combined with mycophenolate-mofetil [ 10 ]. Unfortunately, some patients either do not respond to standard first-line treatment or their TED reactivates sometime after treatment termination. In these corticoresistant (CR) patients, a chimeric mouse/human antibody, Rituximab (RTX), is listed in the EUGOGO guidelines as a valid second-line treatment [ 6 ]. However, dosing schemes vary among authors [ 6 ] [ 11 – 17 ]. Monoclonal antibodies directed against IGF-1R Teprotumumab, the first-line and only FDA-approved treatment for TED, are currently unavailable in Europe [ 18 ]. Another option with a documented effect on eye muscle motility and/or diplopia is orbital radiotherapy combined with glucocorticoids [ 6 ]. In urgent states, like DON, eyeball subluxation or severe corneal exposure is the surgery (orbital decompression) inevitable choice. Otherwise, to correct strabismus, proptosis, lid malposition or chronic orbital congestion, surgery should be postponed to disease activity disappearance [ 18 ]. Early recognition of CR patients could minimize the time gap between the first- and second-line treatment, enabling them to achieve the highest possible quality of life. In this study, we evaluate the usefulness of CAS and TSI as predictors and/or post-treatment markers of corticoresistance in patients with TED. MATERIALS AND METHODS In this retrospective single-tertiary-center cohort study, we included 236 patients (159 women and 77 men, 18–85 years of age) with an active moderate-to-severe TED from our register, who were all initially treated with high-dose systemic corticosteroids (methylprednisolone) between 2007 and 2022. Patients with an initially severe form of TED requiring acute orbital decompression were excluded from the study. For more information, see Table 1. ivGC administration was performed during three short hospitalizations over three months. Patients obtained different cumulative doses of 7.5 g, 6 g and 4.5 g, and singularly different doses of ivGC as the EUGOGO recommendations changed over the time period of the study. In between the hospitalizations, patients received decreasing doses of oral prednisone (tapering from 20 mg daily). In our study, we use the term “corticosensitive” for patients whose response to first-line treatment was complete (objective/subjective significant change in activity) – any signs of reactivation were observed, and no other medical intervention due to active disease was needed. The term “corticoresistant” is used when the response to first-line treatment was incomplete, or TED reactivated and medical intervention was needed. RTX was administered intravenously to 29 CR patients during short hospitalization in a single dose of 100 mg, which was repeated if clinically needed. Twenty-five patients received a cumulative dose of 100 mg, two had a cumulative dose of 200 mg, and two had a cumulative dose of 400 mg of RTX. After both first- and second-line treatments, all patients were educated about the signs and symptoms of TED reactivation. The schematization of retrograde patient recruitment and their distribution into subgroups is summarized in Fig. 1. Biochemical analyses were performed from peripheral venous blood samples obtained at admission, before hospital discharge and at scheduled checkups. Thyroid-stimulating immunoglobulin (TSI, IU/L) levels were determined immunologically (LEIA) using the Immulite 2000 analyzer (Siemens Healthineers, Germany). The activity of the disease was assessed according to a standardized 7-point CAS (Clinical Activity Score) scale by the same clinical ophthalmologist [ 6 ]. All data was expressed as mean ± standard deviation (SD) or median and interquartile range (IQR), as specified. For data analyses, both parametric and non-parametric methods were used. The Shapiro-Wilk test was utilized to test the data distribution. Paired T-tests, Mann-Whitney paired tests and receiver operating characteristics (ROC) analyses were performed as appropriate. Statistical significance was set as p < 0.05. All tests were performed, and figures were created using GraphPad Prism 8.4.3.686 for Windows (San Diego, California, USA). RESULTS Demographic Of 194 CS patients, 69% were women aged 51.5 ± 13.1 years; the CR group comprised 42 patients, of which 60% were women aged 51.7 ± 14.1 years; the groups did not differ in gender and age at first-line treatment, lateralization of TED, cumulative dose of ivGC administered and smoking status. 55% of CS patients were smokers before the start of the treatment, and 15% were smoking at the end; in the CR group there were 72.5% smokers before, and 9.5% during the treatment. A total thyroidectomy was undertaken by 88% of CS patients and 78.5% of CR patients. In the CS group, significantly more patients underwent thyroid gland radioiodine ablation as a part of euthyroidism restoring therapy (p = 0.0031). The groups neither differed in the duration of TED before first-line treatment nor the time from diagnosis of thyroid disease and TED development. Decompressive surgery was performed in 5 CS (due to chronic non-active exophthalmos more than six months after ivGC) and 24 CR patients; of these, 13 patients were indicated to urgent decompression (due to severe TED, and those did not receive RTX)ꓼ 11 CR patients were in second-line treated with RTX, whereby decompression was performed in two of them as a form of corrective surgery due to chronic non-active exophthalmos, four of them in between ivGC and RTX, and five of them within six months from the last RTX dose due to absence of clinical response or reactivation (RTX resistant/nonsensitive). The group characteristics are summarized in Table 1. Effect of first-line treatment The median CAS of the CS patients dropped after first-line treatment from 3 (IQR: 2–4) to 1 (IQR: 0–1); in CR patients it dropped from 4 (IQR: 3–5) to 3 (IQR: 1–4). We found that the CR patient CAS was significantly higher both before (p = 0.0001) and after (p = < 0.0001) first-line treatment when compared to the CS group. ROC analysis of the CAS at the end of first-line treatment in CR and CS patients computed a CAS cut point value of 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve 82.8% with a positive predictive value of 0.915. Detailed CAS values are shown in Table 2 and Figure 2. In CS patients, CAS did not correlate with the TED duration prior to the treatment, r = -0.07 (p = 0.346), nor after the end of first-line treatment, r = -0.111 (p = 0.129). Similarly, in CR patients, CAS did not correlate with the duration of TED prior to the treatment, r = -0.196 (p = 0.252), nor after the end of first-line treatment, r = -0.232 (p = 0.15). Effect of second-line treatment In the 29 patients who, as a second-line treatment, obtained low dose RTX (RTX subgroup), the median time between the end of first-line treatment (ivGC) and reactivation (RTX dose) was 96 days (IQR: 52.5–261.5). 69% were women, 51.61 ± 14.6 years of age, 65.5% of which smoked before and 7% of which during the treatment, which is not different from the CS group. Eleven of them underwent decompression, as explained above. In 22 patients treated by RTX, CAS gradually decreased to zero values without any signs of reactivation during extended follow-up (median 832 days, IQR: 420.5–1455) (Figure 3). TED reactivated in seven patients after RTX in a median of 114 days (IQR: 45–1014). There was no difference in the rate of reactivations after RIT from the rate after ivGC (p = 0.81). TSI of CR and RTX-treated patients dropped from a median of 4.89 (IQR: 0.66–22.3) to 2.31 (IQR: 0.36–8.44) after first-line treatment (p = 0.22) and later to 1.86 (IQR: 0.1–7.41) after RTX (p = 0.12). TSI of the CS subgroup dropped from a median of 3.64 (IQR: 0.95–8.13) to 1.29 (IQR: 0.38–3.37) (p = 0.0034). There was no significant difference between the TSI of the CS and CR patients before (p = 0.46) or after first-line therapy (p = 0.56). DISCUSSION Evaluating corticoresistance is critical both before and after first-line treatment for patients predicted to be CR to avoid the potential side effects of first-line therapy and delays in providing effective therapy. Furthermore, CR patients should be offered second-line treatment as early as possible. We wish to offer our patients the chance to maintain as high a quality of life as possible by minimizing the time between TED development and effective treatment. Moreover, possible adverse events of each treatment type could be avoided. The current EUGOGO guidelines recommend evaluating the effect of the treatment by assessing a subjective primary outcome (patient-reported outcome) and an objective primary outcome (clinician-reported outcome). A recently revised composite index was suggested. “Improvement in ≥ 2 features in one eye without deterioration in the other might be considered a positive response to treatment” [ 6 ]. This guideline does not explicitly define nonresponding patients. Perez-Moreiras et al. use the term “corticosteroid resistant” for patients with incomplete response (defined as a CAS improvement < 2) to at least three doses of 500 mg of ivGC or recurrence of TED, defined as an increase in CAS ≥ 1 after treatment with ivGC [ 27 ]. We found that the CR patients’ CAS was significantly higher before and after the first-line treatment than the CS group. Performed ROC established the cut-point value as CAS was ≥ 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve of 82.8%. Therefore, we suggest CAS ≥ 2 after first-line treatment as a possible marker of corticoresistance and that patients with higher CAS should be subject to regular long-term follow-up. Early recognition of the ineffectiveness of the first-line treatment or reactivation of the disease could enable early access to the second-line treatment. It is essential to follow up high-risk patients after successful therapy and, in case of reactivation, offer them personalized additional treatment based on their medical and personal history and preferences to maintain as high quality of life as possible with the best clinical outcome. When evaluating TSI, another possible marker of corticoresistancy in our cohort, we did not find a significant difference between CS and CR patients. Mourits, Prummel et al. showed that the outcome of glucocorticoid treatment was not related to the total duration of TED [ 5 ] [ 19 ] [ 20 ], which is also true for rituximab treatment [ 15 ]. Similarly, we did not find any correlation between the length of TED prior to treatment and CAS at the beginning or end of first-line treatment. Moreover, CS and CR patients did not differ in the length of TED before first-line treatment. TSI of the CR patients treated with RTX in the second-line did not change significantly, although it dropped after first-line treatment and after RTX; none of these decreases were significant from the pre-treatment value. The TSI of the CS subgroup dropped significantly after first-line therapy. CR and CS groups did not differ in TSI values. Although TSI is a valuable, highly sensitive biomarker of Graves’ disease and TED activity, according to our results, TSI cannot be used as a marker of corticoresistance. However, given that TSI values were not available for all time points in our cohort, we can assume that if data from larger samples was analyzed, the statistical significance and strength of evidence could differ [ 21 ] [ 22 ] [ 23 ]. We found a higher distribution of patients treated by radioiodine in the CS than in the CR. However, radioactive iodine usage and oxidative stress are relevant risk factors for TED development and progression. We supposed this difference was mainly caused by the recruitment of patients over a long time while the guidelines on TED treatment and thyroid gland dysfunction were changing. Several studies reported the long-term positive effect of RTX on TED [ 24 ]. In the second part of our study, we followed 29 corticoresistant patients who reactivated after first-line treatment in the median of 96 days. Low-dose RTX (100 mg) was reported to be effective as TED first-line treatment [ 11 ], but also as a second-line treatment in previously corticoresistant TED patients [ 25 ]. Lower doses lead to a reduction in the risk of potential side effects. One of the reported potential adverse severe events is DON, which must be monitored and treated appropriately. While treating our CR patients with low-dosed RTX as second-line treatment (a single dose was 100 mg per cycle), we did not observe any significant side effects, and RTX was well tolerated in all of them. It should be noted that four of them were after orbital decompression before RTX. As one of the main goals of this study, we focused on CAS evolution over time in TED patients. As mentioned above, CAS was significantly higher in RTX-treated patients both before and after first-line treatment. We could see the long-term positive effect of RTX documented by the gradual, significant and long-term decrease of CAS to zero values. In patients who do not sufficiently respond to RTX as a second-line treatment and show high activity of the disease and/or several eye and sight impairments, urgent orbital decompression should be considered [ 6 ] [ 26 ]. From our RTX subgroup, two patients underwent decompression as a form of corrective surgery due to chronic non-active exophthalmos, five due to the absence of clinical response or reactivation, and four in between the treatment cycles. Decompression as a corrective surgery due to chronic non-active exophthalmos was performed in five CS patients. Urgent orbital decompression must be performed in the event of DON cases unresponsive to ivGC [ 2 ] [ 6 ]. Thirteen CR patients were indicated for decompression (less than six months from the end of treatment) due to the persisting activity and severity of the disease after first-line treatment. This study has several limitations. As we serve as a referral center, we included TED patients treated with ivGC in other hospitals, some of which were administered “unusual” cumulative doses of ivGC. Due to our study’s retrospective design, the observed effect of Rituximab could be affected by the delayed effect of previous treatment or by the natural course of the disease described by Rundle [ 28 ]. Also, we could not provide a predictive solution for corticoresistency before initiating ivGC. On the contrary, this sample represents the largest cohort of patients describing sequentially the effect of first- and second-line treatment in the same patients and, therefore, describing TED development over time as we see in our real-life patients. Based on our data, CR patients could be detected by CAS score after first-line treatment ≥ 2. These patients should be subject to long-term follow-up for early detection of reactivation. Timely diagnosis would allow them early access to second-line treatment and enhance their chances of reaching the best treatment effect and final quality of life. RTX is a well-tolerated choice of second-line treatment and, even in low doses, has a long-lasting effect on disease activity, as documented by the progressive and long-term decrease of CAS. Nevertheless, further research is still needed to find markers of corticoresistance prior to ivGC. Declarations ETHICAL APPROVAL Informed consent was obtained from all individual participants included in the study. The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hospital Olomouc (Ref. No. 49/23). Funding: This work was supported by the Ministry of Health of the Czech Republic – Conceptual development of research organization (FNOL, 00098892) and Grant No. NU21J-01-00017. All rights are reserved. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Author Contribution KP performed data analysis, and drafted the manuscript. JS designed the work, performed data analysis, and drafted the manuscript. RD collected the data. MR Jr. performed data analysis. DK designed the work and substantively revised the manuscript. MK designed the work, and substantively revised the manuscript. All authors reviewed the manuscript References Kahaly, G., Petrak, F., Hardt, J., Pitz, S., Egle, U.: Psychosocial morbidity of Graves' orbitopathy. Clinical Endocrinology (2005). https://doi.org/10.1111/j.1365-2265.2005.02352.x Terwee, C., Dekker, F., Mourits, M., et al: Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clinical Endocrinology (2001). https://doi.org/10.1046/j.1365-2265.2001.01241.x McAlinden, C.: An overview of thyroid eye disease. Eye and Vision (2014). https://doi.org/10.1186/s40662-014-0009-8 Perros, P., Hegedüs, L., Bartalena, L., et al: Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement. Orphanet Journal of Rare Diseases (2017). https://doi.org/10.1186/s13023-017-0625-1 Mourits, M., Prummel, M., Wiersinga, W., Koornneef, L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clinical Endocrinology (1997). https://doi.org/10.1046/j.1365-2265.1997.2331047.x Bartalena, L., Kahaly, G., Baldeschi, L., et al: The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. European Journal of Endocrinology (2021). https://doi.org/10.1530/EJE-21-0479 Bartalena, L., Baldeschi, L., Dickinson, A., et al: Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid (2008). https://doi.org/10.1089/thy.2007.0315 Kahaly, G., Diana, T.: TSH Receptor Antibody Functionality and Nomenclature. Front. Endocrinol (2017). doi:10.3389/fendo.2017.00028 Smith, T. J., Hegedüs, L.: Graves' Disease. New England Journal of Medicine (2016). https://doi.org/10.1056/NEJMra1510030 Kahaly, G., Riedl, M., König, J., et al: Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. The Lancet Diabetes & Endocrinology (2018). https://doi.org/10.1016/S2213-8587(18)30020-2 Salvi, M.: Small Dose of Rituximab for Graves Orbitopathy: New Insights Into the Mechanism of Action. Archives of Ophthalmology (2012). https://doi.org/10.1001/archopthalmol.2011.1215 Supronik, J., Szelachowska, M., Kretowski, A., Siewko, K.: Rituximab in the treatment of Graves' orbitopathy: latest updates and perspectives. Endocrine Connections (2022). https://doi.org/10.1530/EC-22-0303 Vannucchi, G., Campi, I., Covelli, D., et al: Effect of a very low dose of Rituximab on active moderate-severe Graves' orbitopathy: an interim report. Endocrine Abstracts (2015). https://doi.org/10.1530/endoabs.37.GP.27.05 Stan, M., Salvi, M.: MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves' orbitopathy – lessons from randomized control trials. European Journal of Endocrinology (2017). https://doi.org/10.1530/EJE-16-0552 Campi, I., Vannucchi, G., Muller, I., et al: Therapy With Different Dose Regimens of Rituximab in Patients With Active Moderate-To-Severe Graves' Orbitopathy. Frontiers in Endocrinology (2022). https://doi.org/10.3389/fendo.2021.790246 Salvi, M., Vannucchi, G., Currò, N., et al: Efficacy of B-Cell Targeted Therapy With Rituximab in Patients With Active Moderate to Severe Graves' Orbitopathy: A Randomized Controlled Study. The Journal of Clinical Endocrinology & Metabolism (2015). https://doi.org/10.1210/jc.2014-3014 Karasek, D., Cibickova, L., Karhanova, M., Kalitova, J., Schovanek, J., Frysak, Z.: Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose Rituximab. Endokrynologia Polska (2017). https://doi.org/10.5603/EP.a2017.0040 Burch, H., Perros, P., Bednarczuk, T., et al: Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association. European Thyroid Journal (2022). https://doi.org/10.1530/ETJ-22-0189 Prummel, M., Berghout, A., Wiersinga, W., Mourits, M., Koornneef, L., Blank, L.: Randomised double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy. The Lancet (1993). https://doi.org/10.1016/0140-6736(93)92001-A Prummel, M., Mourits, M., Berghout, A., Krenning, E., van der Gaag, R., Koornneef, L., Wiersinga, W.: Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy. New England Journal of Medicine (1989). https://doi.org/10.1056/NEJM198911163212002 Diana, T., Ponto, K., Kahaly, G.: Thyrotropin receptor antibodies and Graves' orbitopathy. Journal of Endocrinological Investigation (2021). https://doi.org/10.1007/s40618-020-01380-9 George, A., Diana, T., Längericht, J., Kahaly, G.: Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves' Orbitopathy. Frontiers in Endocrinology (2021). https://doi.org/10.3389/fendo.2020.629925 Ponto, K., Kanitz, M., Olivo, P., Pitz, S., Pfeiffer, N., Kahaly, G.: Clinical Relevance of Thyroid-Stimulating Immunoglobulins in Graves' Ophthalmopathy. Ophthalmology, 118 (11), 2279-2285 (2011). Erdei, A., Paragh, G., Kovacs, P., et al: Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves' orbitopathy: A five-year follow-up study. Autoimmunity (2014). https://doi.org/10.3109/08916934.2014.939266 Du Pasquier-Fediaevsky, L., Andrei, S., Berche, M., Leenhardt, L., Héron, E., Rivière, S.: Low-Dose Rituximab for Active Moderate to Severe Graves’ Orbitopathy Resistant to Conventional Treatment. Ocular Immunology and Inflammation (2019). https://doi.org/10.1080/09273948.2018.1453078 Lucarelli, M., Shore, J.: Management of Thyroid Optic Neuropathy. International Ophthalmology Clinics (1996). https://doi.org/10.1097/00004397-199603610-00018 Perez-Moreiras, J., Gomez-Reino, J., Maneiro, J., et al: Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. American Journal of Ophthalmology (2018). https://doi.org/10.1016/j.ajo.2018.07.038 Rundle, F., Wilson, C.: Development and course of exophthalmos and ophthalmoplegia in Graves' disease with special reference to the effect of thyroidectomy. Clin Sci. 5 (3-4), 177-94 (1945) Tables Table 1: Patient information Number of patients Gender (female) Age at first-line treatment Cumulative dose of ivGC Smoker before treatment (active or passive) Smoker during treatment (active or passive) Lateralization (bilateral/right/left) Duration of Thyroid disease before TED (days) Duration of TED prior treatment (ivGC) (days) Total Thyroidectomy Radioiodine Decompression CS patients 194 134 (69%) 53 years 7.5g: 152, 6g: 33, 4.5g: 9 107 (55%) 30 (16%) bilateral: 151, right: 21, left: 22 median: 153, average: 1404 median: 163, average: 453 171 (88%) 91 (47%) 5 (3%) CR patients 42 25 (59%) 54.5 years 7.5g: 22, 6g: 10, 4.5g: 3 29 (69%) 4 (10%) bilateral: 35, right: 3, left: 4 median: 122.5, average: 1038 median: 124 average: 507 33 (79%) 9 (21%) 2 (5%) Table 2: CAS – descriptive statistics CS patients CR patients Rituximab-treated patients CAS start ivGC CAS end ivGC CAS start ivGC CAS end ivGC CAS start ivGC CAS end ivGC CAS start RTX CAS end RTX CAS 3 months after RTX CAS 6 months after RTX CAS 9 months after RTX CAS 12 months after RTX last available CAS Number of values 185 190 36 40 Number of values 25 27 29 29 15 17 19 17 29 Minimum 0 0 2 0 Minimum 2 0 1 0 0 0 0 0 0 25% Percentile 2 0 3 1 25% Percentile 2.5 1 3 1 1 1 0 0 0 Median 3 1 4 3 Median 4 3 4 2 2 1 1 0 0 75% Percentile 4 1 5 4 75% Percentile 5 4 4 3 3 2 1 0.5 0 Maximum 6 4 6 7 Maximum 6 6 6 5 5 3 2 1 4 Standard Deviation 1.15 0.78 1.30 1.73 Standard Deviation 1.33 1.52 1.09 1.14 1.33 0.83 0.60 0.43 0.83 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Nov, 2024 Read the published version in Endocrine → Version 1 posted Editorial decision: Revision requested 28 Aug, 2024 Reviews received at journal 27 Aug, 2024 Reviews received at journal 19 Aug, 2024 Reviewers agreed at journal 05 Aug, 2024 Reviewers agreed at journal 05 Aug, 2024 Reviewers invited by journal 05 Aug, 2024 Editor assigned by journal 16 Jul, 2024 Submission checks completed at journal 16 Jul, 2024 First submitted to journal 15 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4742070","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":337204134,"identity":"a33f4b9a-c0b1-4aa3-9864-093322da6c73","order_by":0,"name":"Klara Pekarova","email":"","orcid":"","institution":"University Hospital Olomouc","correspondingAuthor":false,"prefix":"","firstName":"Klara","middleName":"","lastName":"Pekarova","suffix":""},{"id":337204135,"identity":"98ebb0e5-4885-43eb-a5b0-95a221a393a6","order_by":1,"name":"Jan Schovanek","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie3QvQrCMBDA8QsBXZSu7VJf4UJBX8fiGrq4OHSIFHQRsrYgPoMuzpVAXfQNXLo4dXGr4OBXN+HQzSH/JYTw45IA2Gx/GFOvJW82Ex+g/Rs5BAD8u2ENmc6+IHx+zFkdn3zcH3dltsLI4cAuNXWxRTTkneIc4CEaic0Wx14C3HXJt0jkTJkwU7LvldtbuDbQAqSIrpBdn0RXg2u5xDcZUiSVCN0H0a7ss41qSE6SCk2nMIHjVoGXFhhmCUs8RRChpSjr2PgtR4rLIsZQt5Md+WNCwcctGDUDoEee2mw2m+3ZHZ+oTz937/U0AAAAAElFTkSuQmCC","orcid":"","institution":"University Hospital Olomouc","correspondingAuthor":true,"prefix":"","firstName":"Jan","middleName":"","lastName":"Schovanek","suffix":""},{"id":337204136,"identity":"08ec6f87-4ea3-4ec2-9009-8c2240575f7b","order_by":2,"name":"Roman Dohnal","email":"","orcid":"","institution":"University Hospital Olomouc","correspondingAuthor":false,"prefix":"","firstName":"Roman","middleName":"","lastName":"Dohnal","suffix":""},{"id":337204137,"identity":"2fe86969-8158-40e5-bd70-7c1a7f64d7f1","order_by":3,"name":"Martin Radvansky","email":"","orcid":"","institution":"VSB Technical University of Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Radvansky","suffix":""},{"id":337204138,"identity":"cdc8aa12-f87f-49e7-bed1-f385360f454c","order_by":4,"name":"David Karasek","email":"","orcid":"","institution":"University Hospital Olomouc","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Karasek","suffix":""},{"id":337204139,"identity":"e3954b4c-5790-4ee2-af7e-158808c1176c","order_by":5,"name":"Marta Karhanova","email":"","orcid":"","institution":"University Hospital Olomouc","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Karhanova","suffix":""}],"badges":[],"createdAt":"2024-07-15 10:06:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4742070/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4742070/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12020-024-04108-4","type":"published","date":"2024-11-28T15:57:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62633673,"identity":"34156f41-aeef-4f8b-8ecd-5dddcdd9114b","added_by":"auto","created_at":"2024-08-16 16:25:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":261834,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eScheme of patient subgroup distribution and treatment sequence\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4742070/v1/b3f9478785fbdb1c3b3e3c97.png"},{"id":62633671,"identity":"c0829349-cfe1-4ce3-bd80-89df8cba4041","added_by":"auto","created_at":"2024-08-16 16:25:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":116671,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eGraphs of CAS evolution after first-line treatment, start = before first-line treatment, end = after first-line treatment, a – CS patients, b – CR patients, c – CS and CR patients (median and interquartile range)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4742070/v1/57322132098dd63d8c4b02e5.png"},{"id":62633672,"identity":"31220014-82b4-4d5f-9f00-96db114fd3c1","added_by":"auto","created_at":"2024-08-16 16:25:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57761,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eCAS evolution over time in second-line Rituximab-treated patients\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4742070/v1/c131026749ef6f7fe559584d.png"},{"id":70388787,"identity":"d6ac62c5-f56f-4b1c-b4ff-7d4137277a87","added_by":"auto","created_at":"2024-12-02 17:27:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":726103,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4742070/v1/6c244404-ff28-4a7f-9a8f-f075807ab1f8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of corticoresistance in patients with Thyroid Eye Disease and use of Rituximab as a second-line treatment","fulltext":[{"header":"Key Message","content":"\u003cp\u003eHigh-dose intravenous glucocorticoids are the standard first-line treatment for active, moderate to severe and severe thyroid eye disease. Corticoresistant patients could be detected using a clinical activity score \u0026ge; 2 after first-line treatment. Rituximab was a well-tolerated choice of second-line treatment and had a long-lasting effect on disease activity.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eThyroid eye disease (TED) is a progressive autoimmune inflammatory disease of soft orbital tissues closely related to thyroid autoimmunity. Orbital and periorbital changes can lead to visual impairment, limitation of eye movement, diplopia and appearance changes. All of these severely affect TED patients' quality of life (QoL) in both their visual functioning and appearance aspects [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The time of TED presentation differs among patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The clinical activity score (CAS) evaluates the disease activity in everyday clinical practice. Its characteristics make CAS easily assessed by clinical examination without requiring laboratory or imaging methods or any special medical equipment [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. EUGOGO classifies the severity of the disease into three degrees: mild, moderate to severe, and sight-threatening (including DON and corneal breakdown) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. One of the TED activity biomarkers is the level of TSH receptor antibodies (TRAb). Its stimulating fraction, thyroid-stimulating immunoglobulin (TSI, or stimulatory TSH-R antibodies, TSAb), is ideally detected by cell-based bioassays, which can differentiate the functionality type of the antibodies (stimulating, neutral or blocking). This method is, however, not routinely available and so-called \u0026ldquo;bridging\u0026rdquo; immunoassays are thereby commonly used [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The standard first-line treatment for active, moderate to severe and severe TED are high-dose intravenous glucocorticoids (ivGC), sometimes also combined with mycophenolate-mofetil [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Unfortunately, some patients either do not respond to standard first-line treatment or their TED reactivates sometime after treatment termination. In these corticoresistant (CR) patients, a chimeric mouse/human antibody, Rituximab (RTX), is listed in the EUGOGO guidelines as a valid second-line treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, dosing schemes vary among authors [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Monoclonal antibodies directed against IGF-1R Teprotumumab, the first-line and only FDA-approved treatment for TED, are currently unavailable in Europe [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another option with a documented effect on eye muscle motility and/or diplopia is orbital radiotherapy combined with glucocorticoids [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn urgent states, like DON, eyeball subluxation or severe corneal exposure is the surgery (orbital decompression) inevitable choice. Otherwise, to correct strabismus, proptosis, lid malposition or chronic orbital congestion, surgery should be postponed to disease activity disappearance [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEarly recognition of CR patients could minimize the time gap between the first- and second-line treatment, enabling them to achieve the highest possible quality of life. In this study, we evaluate the usefulness of CAS and TSI as predictors and/or post-treatment markers of corticoresistance in patients with TED.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eIn this retrospective single-tertiary-center cohort study, we included 236 patients (159 women and 77 men, 18\u0026ndash;85 years of age) with an active moderate-to-severe TED from our register, who were all initially treated with high-dose systemic corticosteroids (methylprednisolone) between 2007 and 2022. Patients with an initially severe form of TED requiring acute orbital decompression were excluded from the study. For more information, see Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eivGC administration was performed during three short hospitalizations over three months. Patients obtained different cumulative doses of 7.5 g, 6 g and 4.5 g, and singularly different doses of ivGC as the EUGOGO recommendations changed over the time period of the study. In between the hospitalizations, patients received decreasing doses of oral prednisone (tapering from 20 mg daily).\u003c/p\u003e \u003cp\u003eIn our study, we use the term \u0026ldquo;corticosensitive\u0026rdquo; for patients whose response to first-line treatment was complete (objective/subjective significant change in activity) \u0026ndash; any signs of reactivation were observed, and no other medical intervention due to active disease was needed. The term \u0026ldquo;corticoresistant\u0026rdquo; is used when the response to first-line treatment was incomplete, or TED reactivated and medical intervention was needed. RTX was administered intravenously to 29 CR patients during short hospitalization in a single dose of 100 mg, which was repeated if clinically needed. Twenty-five patients received a cumulative dose of 100 mg, two had a cumulative dose of 200 mg, and two had a cumulative dose of 400 mg of RTX. After both first- and second-line treatments, all patients were educated about the signs and symptoms of TED reactivation. The schematization of retrograde patient recruitment and their distribution into subgroups is summarized in Fig.\u0026nbsp;1. Biochemical analyses were performed from peripheral venous blood samples obtained at admission, before hospital discharge and at scheduled checkups. Thyroid-stimulating immunoglobulin (TSI, IU/L) levels were determined immunologically (LEIA) using the Immulite 2000 analyzer (Siemens Healthineers, Germany). The activity of the disease was assessed according to a standardized 7-point CAS (Clinical Activity Score) scale by the same clinical ophthalmologist [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. All data was expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median and interquartile range (IQR), as specified. For data analyses, both parametric and non-parametric methods were used. The Shapiro-Wilk test was utilized to test the data distribution. Paired T-tests, Mann-Whitney paired tests and receiver operating characteristics (ROC) analyses were performed as appropriate. Statistical significance was set as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All tests were performed, and figures were created using GraphPad Prism 8.4.3.686 for Windows (San Diego, California, USA).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003ch2\u003eDemographic\u003c/h2\u003e\n\u003cp\u003eOf 194 CS patients, 69% were women aged 51.5\u0026nbsp;\u0026plusmn;\u0026nbsp;13.1 years; the CR group comprised 42 patients, of which 60% were women aged 51.7\u0026nbsp;\u0026plusmn;\u0026nbsp;14.1 years; the groups did not differ in gender and\u0026nbsp;age at first-line treatment, lateralization of TED, cumulative dose of ivGC administered and smoking status.\u0026nbsp;55% of CS patients were smokers before the start of the treatment, and 15% were smoking at the end; in the CR group there were 72.5% smokers before, and 9.5% during the treatment. A total thyroidectomy was undertaken by 88% of CS patients and 78.5% of CR patients.\u0026nbsp;In the CS group, significantly more patients underwent thyroid gland radioiodine ablation as a part of euthyroidism restoring therapy (p = 0.0031). The groups neither differed in the\u0026nbsp;duration of TED before first-line treatment nor the time from diagnosis of thyroid disease and TED development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDecompressive surgery was performed in 5 CS (due to chronic non-active exophthalmos more than six months after ivGC)\u0026nbsp;and 24 CR patients; of these,\u0026nbsp;13 patients were indicated to urgent decompression (due to severe TED, and those did not receive RTX)ꓼ\u0026nbsp;11 CR patients were in second-line treated with RTX, whereby decompression was performed in two of them as a form of corrective surgery\u0026nbsp;due to chronic non-active exophthalmos, four of them in between ivGC and RTX, and five of them within\u0026nbsp;six months from the last RTX dose due to absence of clinical response or reactivation (RTX resistant/nonsensitive). The group characteristics are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEffect of first-line treatment\u003c/h2\u003e\n\u003cp\u003eThe median CAS of the CS patients dropped after first-line treatment from 3 (IQR: 2\u0026ndash;4) to 1 (IQR: 0\u0026ndash;1); in CR patients it dropped from 4 (IQR: 3\u0026ndash;5) to 3 (IQR: 1\u0026ndash;4). We found that the CR patient CAS was significantly higher both before (p = 0.0001) and after (p = \u0026lt; 0.0001) first-line treatment when compared to the CS group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eROC analysis of the CAS at the end of first-line treatment in CR and CS patients computed a CAS cut point value of 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve 82.8% with a positive predictive value of 0.915. Detailed CAS values are shown in Table 2 and Figure 2.\u003c/p\u003e\n\u003cp\u003eIn CS patients, CAS did not correlate with the TED duration prior to the treatment, r = -0.07 (p = 0.346), nor after the end of first-line treatment, r = -0.111 (p = 0.129). Similarly, in CR patients, CAS did not correlate with the duration of TED prior to the treatment, r = -0.196 (p = 0.252), nor after the end of first-line treatment, r = -0.232 (p = 0.15).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEffect of second-line treatment\u003c/h2\u003e\n\u003cp\u003eIn the 29 patients who, as a second-line treatment, obtained low dose RTX (RTX subgroup), the median time between the end of first-line treatment (ivGC) and reactivation (RTX dose) was 96 days (IQR: 52.5\u0026ndash;261.5). 69% were women, 51.61 \u0026plusmn; 14.6 years of age, 65.5% of which smoked before and 7% of which during the treatment, which is not different from the CS group. Eleven of them underwent decompression, as explained above.\u003c/p\u003e\n\u003cp\u003eIn 22 patients treated by RTX, CAS gradually decreased to zero values without any signs of reactivation during extended follow-up (median 832 days, IQR: 420.5\u0026ndash;1455) (Figure 3). TED reactivated in seven patients after RTX in a median of 114 days (IQR: 45\u0026ndash;1014). There was no difference in the rate of reactivations after RIT from the rate after ivGC (p = 0.81).\u003c/p\u003e\n\u003cp\u003eTSI of CR and RTX-treated patients dropped from a median of 4.89 (IQR: 0.66\u0026ndash;22.3) to 2.31 (IQR: 0.36\u0026ndash;8.44) after first-line treatment (p = 0.22) and later to 1.86 (IQR: 0.1\u0026ndash;7.41) after RTX (p = 0.12). TSI of the CS subgroup dropped from a median of 3.64 (IQR: 0.95\u0026ndash;8.13) to 1.29 (IQR: 0.38\u0026ndash;3.37) (p = 0.0034). There was no significant difference between the TSI of the CS and CR patients before (p = 0.46) or after first-line therapy (p = 0.56).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eEvaluating corticoresistance is critical both before and after first-line treatment for patients predicted to be CR to avoid the potential side effects of first-line therapy and delays in providing effective therapy. Furthermore, CR patients should be offered second-line treatment as early as possible. We wish to offer our patients the chance to maintain as high a quality of life as possible by minimizing the time between TED development and effective treatment. Moreover, possible adverse events of each treatment type could be avoided.\u003c/p\u003e \u003cp\u003e The current EUGOGO guidelines recommend evaluating the effect of the treatment by assessing a subjective primary outcome (patient-reported outcome) and an objective primary outcome (clinician-reported outcome). A recently revised composite index was suggested. \u0026ldquo;Improvement in \u0026ge;\u0026thinsp;2 features in one eye without deterioration in the other might be considered a positive response to treatment\u0026rdquo; [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This guideline does not explicitly define nonresponding patients. Perez-Moreiras et al. use the term \u0026ldquo;corticosteroid resistant\u0026rdquo; for patients with incomplete response (defined as a CAS improvement\u0026thinsp;\u0026lt;\u0026thinsp;2) to at least three doses of 500 mg of ivGC or recurrence of TED, defined as an increase in CAS\u0026thinsp;\u0026ge;\u0026thinsp;1 after treatment with ivGC [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We found that the CR patients\u0026rsquo; CAS was significantly higher before and after the first-line treatment than the CS group. Performed ROC established the cut-point value as CAS was \u0026ge;\u0026thinsp;2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve of 82.8%. Therefore, we suggest CAS\u0026thinsp;\u0026ge;\u0026thinsp;2 after first-line treatment as a possible marker of corticoresistance and that patients with higher CAS should be subject to regular long-term follow-up. Early recognition of the ineffectiveness of the first-line treatment or reactivation of the disease could enable early access to the second-line treatment. It is essential to follow up high-risk patients after successful therapy and, in case of reactivation, offer them personalized additional treatment based on their medical and personal history and preferences to maintain as high quality of life as possible with the best clinical outcome. When evaluating TSI, another possible marker of corticoresistancy in our cohort, we did not find a significant difference between CS and CR patients.\u003c/p\u003e \u003cp\u003eMourits, Prummel et al. showed that the outcome of glucocorticoid treatment was not related to the total duration of TED [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which is also true for rituximab treatment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Similarly, we did not find any correlation between the length of TED prior to treatment and CAS at the beginning or end of first-line treatment. Moreover, CS and CR patients did not differ in the length of TED before first-line treatment.\u003c/p\u003e \u003cp\u003eTSI of the CR patients treated with RTX in the second-line did not change significantly, although it dropped after first-line treatment and after RTX; none of these decreases were significant from the pre-treatment value. The TSI of the CS subgroup dropped significantly after first-line therapy. CR and CS groups did not differ in TSI values. Although TSI is a valuable, highly sensitive biomarker of Graves\u0026rsquo; disease and TED activity, according to our results, TSI cannot be used as a marker of corticoresistance. However, given that TSI values were not available for all time points in our cohort, we can assume that if data from larger samples was analyzed, the statistical significance and strength of evidence could differ [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe found a higher distribution of patients treated by radioiodine in the CS than in the CR. However, radioactive iodine usage and oxidative stress are relevant risk factors for TED development and progression. We supposed this difference was mainly caused by the recruitment of patients over a long time while the guidelines on TED treatment and thyroid gland dysfunction were changing. Several studies reported the long-term positive effect of RTX on TED [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In the second part of our study, we followed 29 corticoresistant patients who reactivated after first-line treatment in the median of 96 days. Low-dose RTX (100 mg) was reported to be effective as TED first-line treatment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], but also as a second-line treatment in previously corticoresistant TED patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Lower doses lead to a reduction in the risk of potential side effects. One of the reported potential adverse severe events is DON, which must be monitored and treated appropriately. While treating our CR patients with low-dosed RTX as second-line treatment (a single dose was 100 mg per cycle), we did not observe any significant side effects, and RTX was well tolerated in all of them. It should be noted that four of them were after orbital decompression before RTX. As one of the main goals of this study, we focused on CAS evolution over time in TED patients. As mentioned above, CAS was significantly higher in RTX-treated patients both before and after first-line treatment. We could see the long-term positive effect of RTX documented by the gradual, significant and long-term decrease of CAS to zero values.\u003c/p\u003e \u003cp\u003eIn patients who do not sufficiently respond to RTX as a second-line treatment and show high activity of the disease and/or several eye and sight impairments, urgent orbital decompression should be considered [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. From our RTX subgroup, two patients underwent decompression as a form of corrective surgery due to chronic non-active exophthalmos, five due to the absence of clinical response or reactivation, and four in between the treatment cycles. Decompression as a corrective surgery due to chronic non-active exophthalmos was performed in five CS patients. Urgent orbital decompression must be performed in the event of DON cases unresponsive to ivGC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Thirteen CR patients were indicated for decompression (less than six months from the end of treatment) due to the persisting activity and severity of the disease after first-line treatment.\u003c/p\u003e \u003cp\u003eThis study has several limitations. As we serve as a referral center, we included TED patients treated with ivGC in other hospitals, some of which were administered \u0026ldquo;unusual\u0026rdquo; cumulative doses of ivGC. Due to our study\u0026rsquo;s retrospective design, the observed effect of Rituximab could be affected by the delayed effect of previous treatment or by the natural course of the disease described by Rundle [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Also, we could not provide a predictive solution for corticoresistency before initiating ivGC. On the contrary, this sample represents the largest cohort of patients describing sequentially the effect of first- and second-line treatment in the same patients and, therefore, describing TED development over time as we see in our real-life patients.\u003c/p\u003e \u003cp\u003eBased on our data, CR patients could be detected by CAS score after first-line treatment\u0026thinsp;\u0026ge;\u0026thinsp;2. These patients should be subject to long-term follow-up for early detection of reactivation. Timely diagnosis would allow them early access to second-line treatment and enhance their chances of reaching the best treatment effect and final quality of life. RTX is a well-tolerated choice of second-line treatment and, even in low doses, has a long-lasting effect on disease activity, as documented by the progressive and long-term decrease of CAS. Nevertheless, further research is still needed to find markers of corticoresistance prior to ivGC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eETHICAL APPROVAL\u003c/h2\u003e \u003cp\u003e Informed consent was obtained from all individual participants included in the study. The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hospital Olomouc (Ref. No. 49/23).\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was supported by the Ministry of Health of the Czech Republic \u0026ndash; Conceptual development of research organization (FNOL, 00098892) and Grant No. NU21J-01-00017. All rights are reserved.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting Interests:\u003c/strong\u003e \u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKP performed data analysis, and drafted the manuscript. JS designed the work, performed data analysis, and drafted the manuscript. RD collected the data. MR Jr. performed data analysis. DK designed the work and substantively revised the manuscript. MK designed the work, and substantively revised the manuscript. All authors reviewed the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKahaly, G., Petrak, F., Hardt, J., Pitz, S., Egle, U.: Psychosocial morbidity of Graves\u0026apos; orbitopathy. Clinical Endocrinology (2005). https://doi.org/10.1111/j.1365-2265.2005.02352.x\u003c/li\u003e\n \u003cli\u003eTerwee, C., Dekker, F., Mourits, M., et al: Interpretation and validity of changes in scores on the Graves\u0026apos; ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clinical Endocrinology (2001). https://doi.org/10.1046/j.1365-2265.2001.01241.x\u003c/li\u003e\n \u003cli\u003eMcAlinden, C.: An overview of thyroid eye disease. Eye and Vision (2014). https://doi.org/10.1186/s40662-014-0009-8\u003c/li\u003e\n \u003cli\u003ePerros, P., Heged\u0026uuml;s, L., Bartalena, L., et al: Graves\u0026apos; orbitopathy as a rare disease in Europe: a European Group on Graves\u0026apos; Orbitopathy (EUGOGO) position statement. Orphanet Journal of Rare Diseases (2017). https://doi.org/10.1186/s13023-017-0625-1\u003c/li\u003e\n \u003cli\u003eMourits, M., Prummel, M., Wiersinga, W., Koornneef, L. Clinical activity score as a guide in the management of patients with Graves\u0026apos; ophthalmopathy. Clinical Endocrinology (1997). https://doi.org/10.1046/j.1365-2265.1997.2331047.x\u003c/li\u003e\n \u003cli\u003eBartalena, L., Kahaly, G., Baldeschi, L., et al: The 2021 European Group on Graves\u0026apos; orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves\u0026apos; orbitopathy. European Journal of Endocrinology \u0026nbsp;(2021). https://doi.org/10.1530/EJE-21-0479\u003c/li\u003e\n \u003cli\u003eBartalena, L., Baldeschi, L., Dickinson, A., et al: Consensus statement of the European group on Graves\u0026apos; orbitopathy (EUGOGO) on management of Graves\u0026apos; orbitopathy. Thyroid\u0026nbsp;(2008).\u0026nbsp;https://doi.org/10.1089/thy.2007.0315\u003c/li\u003e\n \u003cli\u003eKahaly, G., Diana, T.: TSH Receptor Antibody Functionality and Nomenclature. Front. Endocrinol (2017). doi:10.3389/fendo.2017.00028\u003c/li\u003e\n \u003cli\u003eSmith, T. J., Heged\u0026uuml;s, L.: Graves\u0026apos; Disease. New England Journal of Medicine (2016). https://doi.org/10.1056/NEJMra1510030\u003c/li\u003e\n \u003cli\u003eKahaly, G., Riedl, M., K\u0026ouml;nig, J., et al: Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves\u0026apos; orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. The Lancet Diabetes \u0026amp; Endocrinology (2018). https://doi.org/10.1016/S2213-8587(18)30020-2\u003c/li\u003e\n \u003cli\u003eSalvi, M.: Small Dose of Rituximab for Graves Orbitopathy: New Insights Into the Mechanism of Action. Archives of Ophthalmology\u0026nbsp;(2012). https://doi.org/10.1001/archopthalmol.2011.1215\u003c/li\u003e\n \u003cli\u003eSupronik, J., Szelachowska, M., Kretowski, A., Siewko, K.: Rituximab in the\u0026nbsp;treatment of Graves\u0026apos; orbitopathy: latest updates and perspectives. Endocrine Connections\u0026nbsp;(2022). \u0026nbsp; \u0026nbsp; https://doi.org/10.1530/EC-22-0303\u003c/li\u003e\n \u003cli\u003eVannucchi, G., Campi, I., Covelli, D., et al:\u0026nbsp;Effect of a very low dose of Rituximab on active moderate-severe Graves\u0026apos; orbitopathy: an interim report. Endocrine Abstracts (2015).\u0026nbsp;https://doi.org/10.1530/endoabs.37.GP.27.05\u003c/li\u003e\n \u003cli\u003eStan, M., Salvi, M.: MANAGEMENT OF ENDOCRINE DISEASE: Rituximab therapy for Graves\u0026apos; orbitopathy \u0026ndash; lessons from randomized control trials. European Journal of Endocrinology (2017). https://doi.org/10.1530/EJE-16-0552\u003c/li\u003e\n \u003cli\u003eCampi, I., Vannucchi, G., Muller, I., et al: Therapy With Different Dose Regimens of Rituximab in Patients With\u0026nbsp;Active Moderate-To-Severe Graves\u0026apos; Orbitopathy. Frontiers in Endocrinology\u0026nbsp;(2022). https://doi.org/10.3389/fendo.2021.790246\u003c/li\u003e\n \u003cli\u003eSalvi, M., Vannucchi, G., Curr\u0026ograve;, N., et al: Efficacy of B-Cell Targeted Therapy With Rituximab in Patients With Active Moderate to Severe Graves\u0026apos; Orbitopathy: A Randomized Controlled Study. The Journal of Clinical Endocrinology \u0026amp; Metabolism (2015). https://doi.org/10.1210/jc.2014-3014\u003c/li\u003e\n \u003cli\u003eKarasek, D., Cibickova, L., Karhanova, M., Kalitova, J., Schovanek, J., Frysak, Z.: Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose Rituximab. Endokrynologia Polska (2017). https://doi.org/10.5603/EP.a2017.0040\u003c/li\u003e\n \u003cli\u003eBurch, H., Perros, P., Bednarczuk, T., et al: Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association. European Thyroid Journal (2022). \u0026nbsp;https://doi.org/10.1530/ETJ-22-0189\u003c/li\u003e\n \u003cli\u003ePrummel, M., Berghout, A., Wiersinga, W., Mourits, M., Koornneef, L., Blank, L.: Randomised double-blind trial of prednisone versus radiotherapy in Graves\u0026apos; ophthalmopathy. The Lancet (1993). https://doi.org/10.1016/0140-6736(93)92001-A\u003c/li\u003e\n \u003cli\u003ePrummel, M., Mourits, M., Berghout, A., Krenning, E., van der Gaag, R., Koornneef, L., Wiersinga, W.: Prednisone and Cyclosporine in the Treatment of Severe Graves\u0026apos; Ophthalmopathy. New England Journal of Medicine (1989). https://doi.org/10.1056/NEJM198911163212002\u003c/li\u003e\n \u003cli\u003eDiana, T., Ponto, K., Kahaly, G.: Thyrotropin receptor antibodies and Graves\u0026apos; orbitopathy. Journal of Endocrinological Investigation (2021). https://doi.org/10.1007/s40618-020-01380-9\u003c/li\u003e\n \u003cli\u003eGeorge, A., Diana, T., L\u0026auml;ngericht, J., Kahaly, G.: Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves\u0026apos; Orbitopathy. Frontiers in Endocrinology\u0026nbsp;(2021).\u0026nbsp;https://doi.org/10.3389/fendo.2020.629925\u003c/li\u003e\n \u003cli\u003ePonto, K., Kanitz, M., Olivo, P., Pitz, S., Pfeiffer, N., Kahaly, G.: Clinical Relevance of Thyroid-Stimulating Immunoglobulins in Graves\u0026apos; Ophthalmopathy. Ophthalmology, 118 (11), 2279-2285 (2011).\u003c/li\u003e\n \u003cli\u003eErdei, A., Paragh, G., Kovacs, P., et al: Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves\u0026apos; orbitopathy: A five-year follow-up study. Autoimmunity (2014). https://doi.org/10.3109/08916934.2014.939266\u003c/li\u003e\n \u003cli\u003eDu Pasquier-Fediaevsky, L., Andrei, S., Berche, M., Leenhardt, L., H\u0026eacute;ron, E., Rivi\u0026egrave;re, S.: Low-Dose Rituximab for Active Moderate to Severe Graves\u0026rsquo; Orbitopathy Resistant to Conventional Treatment. Ocular Immunology and Inflammation (2019). https://doi.org/10.1080/09273948.2018.1453078\u003c/li\u003e\n \u003cli\u003eLucarelli, M., Shore, J.: Management of Thyroid Optic Neuropathy. International Ophthalmology Clinics (1996). https://doi.org/10.1097/00004397-199603610-00018\u003c/li\u003e\n \u003cli\u003ePerez-Moreiras, J., Gomez-Reino, J., Maneiro, J., et al: Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. American Journal of Ophthalmology (2018). https://doi.org/10.1016/j.ajo.2018.07.038\u003c/li\u003e\n \u003cli\u003eRundle, F., Wilson, C.: Development and course of exophthalmos and ophthalmoplegia in Graves\u0026apos; disease with special reference to the effect of thyroidectomy. Clin Sci. 5 (3-4), 177-94 (1945)\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cem\u003eTable 1: Patient information\u003c/em\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"780\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.600770218228497%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003eGender (female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003eAge at first-line treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.911424903722722%\" valign=\"top\"\u003e\n \u003cp\u003eCumulative dose of ivGC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003eSmoker before treatment (active or passive)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.370988446726573%\" valign=\"top\"\u003e\n \u003cp\u003eSmoker during treatment (active or passive)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.75609756097561%\" valign=\"top\"\u003e\n \u003cp\u003eLateralization (bilateral/right/left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.012836970474968%\" valign=\"top\"\u003e\n \u003cp\u003eDuration of Thyroid disease before TED (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003eDuration of TED prior treatment (ivGC) (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003eTotal Thyroidectomy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003eRadioiodine\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.391527599486521%\" valign=\"top\"\u003e\n \u003cp\u003eDecompression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.600770218228497%\" valign=\"top\"\u003e\n \u003cp\u003eCS patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e134 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e53 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.911424903722722%\" valign=\"top\"\u003e\n \u003cp\u003e7.5g: 152, 6g: 33, 4.5g: 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003e107 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.370988446726573%\" valign=\"top\"\u003e\n \u003cp\u003e30 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.75609756097561%\" valign=\"top\"\u003e\n \u003cp\u003ebilateral: 151, right: 21, left: 22\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.012836970474968%\" valign=\"top\"\u003e\n \u003cp\u003emedian: 153, average: 1404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003emedian: 163, average: 453\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e171 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e91 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.391527599486521%\" valign=\"top\"\u003e\n \u003cp\u003e5 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.600770218228497%\" valign=\"top\"\u003e\n \u003cp\u003eCR patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e25 (59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e54.5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.911424903722722%\" valign=\"top\"\u003e\n \u003cp\u003e7.5g: 22, 6g: 10, 4.5g: 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003e29 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.370988446726573%\" valign=\"top\"\u003e\n \u003cp\u003e4 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.75609756097561%\" valign=\"top\"\u003e\n \u003cp\u003ebilateral: 35, right: 3, left: 4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.012836970474968%\" valign=\"top\"\u003e\n \u003cp\u003emedian: 122.5, average: 1038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.472400513478819%\" valign=\"top\"\u003e\n \u003cp\u003emedian: 124 average: 507\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.033376123234916%\" valign=\"top\"\u003e\n \u003cp\u003e33 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e9 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.391527599486521%\" valign=\"top\"\u003e\n \u003cp\u003e2 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 2: CAS \u0026ndash; descriptive statistics\u003c/em\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"777\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.640102827763496%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.154241645244216%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCS patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.154241645244216%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCR patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.053984575835475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"58.9974293059126%\" colspan=\"9\" valign=\"top\"\u003e\n \u003cp\u003eRituximab-treated patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003eCAS start ivGC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003eCAS end ivGC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003eCAS start ivGC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;CAS end ivGC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003eCAS start ivGC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003eCAS end ivGC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003eCAS start RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003eCAS end RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003eCAS 3 months after RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003eCAS 6 months after RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003eCAS 9 months after RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003eCAS 12 months after RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003elast available CAS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003eMinimum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003e25% Percentile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003e25% Percentile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003e75% Percentile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003e75% Percentile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003eMaximum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.627727856225931%\" valign=\"top\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.0397946084724%\" valign=\"top\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.006418485237484%\" valign=\"top\"\u003e\n \u003cp\u003e1.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.134788189987163%\" valign=\"top\"\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.878048780487805%\" valign=\"top\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e1.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.188703465982028%\" valign=\"top\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.21566110397946%\" valign=\"top\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.114249037227214%\" valign=\"top\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"thyroid eye disease, clinical activity score, immunosuppressive treatment, corticoresistance, corticosensitivity, Rituximab","lastPublishedDoi":"10.21203/rs.3.rs-4742070/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4742070/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eHigh-dose intravenous glucocorticoids are the standard first-line treatment in active, moderate to severe and severe thyroid eye disease (TED). We evaluate the usefulness of CAS and TSI as predictors and/or post-treatment markers of corticoresistance in patients with TED and the effect of Rituximab in second-line treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We enrolled 236 patients with an active TED into this retrospective single-tertiary-center cohort study. All patients were initially treated with high-dose systemic glucocorticoids. Rituximab was later administered to 29 of 42 corticoresistant patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The CAS of the corticoresistant patients was significantly higher both before (p = 0.0001) and after (p = \u0026lt;0.0001) first-line treatment compared to the corticosensitive group. ROC analysis established the cut-point value as CAS ≥ 2.5 with a sensitivity of 96.3%, specificity of 57.5% and area under the curve of 82.8%. In 22 patients treated with Rituximab, CAS gradually decreased to zero values without reactivation during extended follow-up. There was no difference in the TSI of corticosensitive and corticoresistant patients before or after first-line therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: CAS ≥ 2, after first-line treatment, could be used as a corticoresistance marker. Corticoresistant patients should be subject to long-term follow-up for early detection of reactivation to reduce the delay to second-line treatment. Rituximab is a well-tolerated choice of second-line treatment and has a long-lasting effect on disease activity. Although TSI is a valuable biomarker of Graves’ disease and TED activity, according to our results, TSI cannot be used as a marker of corticoresistance.\u003c/p\u003e","manuscriptTitle":"Evaluation of corticoresistance in patients with Thyroid Eye Disease and use of Rituximab as a second-line treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-16 16:25:03","doi":"10.21203/rs.3.rs-4742070/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-28T20:51:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-27T20:07:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-19T20:07:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217653883611197882745457384258542974834","date":"2024-08-05T17:30:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92011746900882311286116393237419047766","date":"2024-08-05T14:12:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-05T12:28:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-16T18:19:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-16T18:18:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2024-07-15T10:04:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3bc1aae8-36e3-4104-ae46-d36c262f0949","owner":[],"postedDate":"August 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T17:22:18+00:00","versionOfRecord":{"articleIdentity":"rs-4742070","link":"https://doi.org/10.1007/s12020-024-04108-4","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2024-11-28 15:57:50","publishedOnDateReadable":"November 28th, 2024"},"versionCreatedAt":"2024-08-16 16:25:03","video":"","vorDoi":"10.1007/s12020-024-04108-4","vorDoiUrl":"https://doi.org/10.1007/s12020-024-04108-4","workflowStages":[]},"version":"v1","identity":"rs-4742070","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4742070","identity":"rs-4742070","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}