Stan, Marius N.

Abstract Background Autonomously functioning thyroid nodules (AFTNs) constitute 5% to 7% of thyroid nodules and represent the second most common cause of hyperthyroidism following Graves’ disease. Currently, radioactive iodine (RAI) and surgery are the standard treatment options, and both incur a risk of postprocedural hypothyroidism and other surgery and radiation-related complications. Methods This work aimed at assessing the efficacy of radiofrequency ablation (RFA) as an alternative treatment option for resolving hyperthyroidism and the nodule volume rate reduction (VRR) and its associated adverse events. Results A total of 22 patients underwent RFA for a solitary AFTN. Seventy-two percent (n = 16) had subclinical hyperthyroidism, 9% (n = 2) had overt hyperthyroidism, and 18% (n = 4) were biochemically euthyroid on antithyroid medication. Average pretreatment TSH was 0.41 mIU/L (SD = 0.98) and free T4 1.29 ng/dL (SD = 0.33). Following a single RFA session, hyperthyroidism resolved in 90.9% (n = 20) and average VRR (61.13%) was achieved within 3 to 6 months following the ablation. Except for 1 nodule, none of the nodules grew during the follow-up period (16.5 months). Two patients (9%) developed transient tachycardia requiring short-term beta-blocker therapy, and 2 developed mild hypothyroidism requiring levothyroxine therapy. Two patients developed recurrent hyperthyroidism and elected to undergo lobectomy and repeat RFA respectively. No serious adverse effects were noted in this cohort. Conclusion RAI and/or surgery represent the standard of care for toxic adenomas, but RFA shows excellent efficacy and safety profile. Therefore, at centers with RFA expertise, it should be considered an alternative treatment strategy, avoiding radiation and surgery-related complications.

Abstract Disclosure: C.A. Conover: None. L.K. Bale: None. D. Hamadi: None. M. Stan: ; Tourmaline, Genentech, Third Rock Ventures, ArgenX, Septerna, OrthoDi. ; Horizon, Immunovant, Lassen, Sling. Background: Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Studies revealed an interaction between thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor-I receptor (IGF-IR) that is essential in promoting TED pathogenesis. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. PAPP-A is metalloprotease that can increase pericellular IGF bioavailability through specific cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. We propose that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitory antibodies attenuates IGF-IR signaling in TED with fewer side effects. Methods: Informed consent was obtained from TED patients undergoing surgery in Mayo Clinic operating suites in Rochester, MN. Retro-orbital tissue was collected from 19 TED patients and 2 control subjects for fibroblast isolation and culture and was performed in a sterile tissue culture facility. TED and control fibroblasts were treated with pro-inflammatory cytokines, and flow separation of CD34- and CD34+ orbital fibroblasts was done, the latter representing infiltrating fibrocytes into the orbit in TED. Main outcome measured were PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. Results: Primary cultured cells showed that PAPP-A is expressed in orbital fibroblasts from TED patients but not in control subject fibroblasts and were markedly increased by pro-inflammatory cytokines stimulation. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A’s proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. CD34+ orbital fibroblasts represent 80% of cells in culture from TED patients, and approximately 70% of these cells were accountable for PAPP-A and IGF-IR expression. Conclusion: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis. Presentation: 6/2/2024

Abstract Context Proptosis in thyroid eye disease (TED) can result in facial disfigurement and visual dysfunction. Treatment with insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. Objective To test the hypothesis that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitors attenuates IGF-IR signaling in TED. Informed consent was obtained from patients with TED undergoing surgery, and retro-orbital tissue was collected for fibroblast isolation and culture. Operations were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility. Retro-orbital tissue was collected from 19 patients with TED. Methods Treatment of TED fibroblasts with proinflammatory cytokines. Flow separation of CD34− and CD34+ orbital fibroblasts, the latter representing infiltrating fibrocytes into the orbit in TED. PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway, and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status, and associated PAPP-A and IGF-IR expression were measured. Results Proinflammatory cytokines markedly increased PAPP-A expression in TED fibroblasts. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A's proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from patients with TED. TED fibroblasts that were CD34+ represented ∼80% of the cells in culture and accounted for ∼70% of PAPP-A and IGF-IR–expressing cells. Conclusion These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.

Introduction: Graves’ disease (GD) is known to cause menstrual changes and has been linked to infertility in women. This can be due to the increased production of androstenedione and testosterone induced by the excess thyroid hormone. However, screening for sex hormone levels in all women diagnosed with GD to identify patients more likely to have infertility is not cost-effective and not clinically indicated. AI-augmented ECG can identify the signature of female with an AUC of 0.97. In this model, AI- ECG gives a probability number between 0-100% of being female, with higher numbers indicating high probability of being female. Hypothesis: We hypothesized that this inexpensive AI ECG tool is reflective of hormonal levels and the resulting changes in menstrual cycle and fertility associated with GD in women. Methods: Patients diagnosed with GD (2009-2019) at our institution were included. Three intervals were identified: 1) Before GD: >2 months before GD diagnosis 2) During GD: within 2 months before GD and before attaining euthyroidism 3) After GD: after attaining euthyroidism. The matched-pairs t-test was used to compare probability of being a female; patients acted as their own controls. A subset analysis was done on females <45 years at GD diagnosis to study the association between female probability during GD and menstrual changes (defined as shorter, lighter, or newly irregular menstrual cycles). Results: 154 females with ECGs both before and during GD were identified. AI ECG female probability decreased with GD diagnosis (85% vs. 77%, P<.001). On the other hand, 137 females with GD had ECGs during and after GD. Female probability increased after attaining euthyroidism (76% vs 83%, P=.005). Moreover, 72 females <45 years were identified; 30 (42%) developed menstrual changes and had significantly lower AI-ECG female probability [77 (58-94)% vs 98 (92-100)%, P<.001] Conclusions: AI-enabled ECG signature of female gender in women was altered by GD and was associated with menstrual changes, likely reflecting changes in sex hormone levels. Future studies to confirm its role in screening for infertility in women with GD are needed.

AbstractContextEarly inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials.ObjectiveWe present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.MethodsThis randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed.ResultsA total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (−2.41 [0.228]) than with placebo (−0.92 [0.323]), difference −1.48 (95% CI −2.28, −0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths.ConclusionTeprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Abstract Disclosure: K.N. Rachmasari: None. P. Thapa: None. D. Sighoko: Employee; Self; Horizon Therapeutics. L. Abdul Jabbar: None. M.N. Stan: None. Objective: To describe the epidemiology of Thyroid Eye Disease (TED). Methods: A population-based cohort of all Olmsted County, Minnesota, residents who had newly diagnosed TED between April 3, 2002, and December 31, 2021, was identified through the medical diagnostic index of the Rochester Epidemiology Project. Individuals aged 18 years and older were included. Incidence rates and point prevalence were calculated. Results: We identified 137 incident patients, of whom 124 (90.5%) were female (p &lt; 0.0001). The overall incidence was 6.24 cases/100,000 person-years in Olmsted County, corresponding to 6.25 cases/100,000 person-years for the US population (age and sex adjusted incidence). Women had higher incidence (10.94 cases/ 100,000 person-years) compared to men (1.22 cases/100,000 person-years). The distribution of incidence rates by ten-year age groups demonstrated peak incidence rates in the age groups 70 to 79 years (17.94 cases/100,000 person-years for women compared with 4.04 cases for men). The majority of cases (77/137) occurred between 50-79 years of age. No clear trend was identified for the yearly incidence between 2002 and 2021. The overall estimated point prevalence per 100,000 was 65.6 (95% CI, 57.8 – 72.9). Prevalence was 117.6 (95% CI, 96.5 – 141.4) for females and 11.2 (95% CI, 5.1 – 21.2) for males (p &lt; 0.0001). Conclusions: Incidence rates for TED remained stable and significant over the last 2 decades. Majority of disease burden is present after the age of 50 with the peak between 70-79 years, a decade later than in the previous study from our population (1). Based on reported incidence and prevalence of Graves’ disease (2), our data indicates that TED continues to affect about 20-30% of that population and appropriate resources should be devoted to furthering education, management, and research into this condition. References: 1. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 1995;120(4):511-7, doi:10.1016/s0002-9394(14)72666-2 2. Hussain YS, Hookham JC, Allahabadia A, et al. Epidemiology, management and outcomes of Graves' disease-real life data. Endocrine 2017;56(3):568-578, doi:10.1007/s12020-017-1306-5 Presentation: Friday, June 16, 2023

Abstract Disclosure: R.S. Douglas: Consulting Fee; Self; Horizon Therapeutics plc, Immunovant, Viridian. S. Couch: None. S.T. Wester: Advisory Board Member; Self; Horizon Therapeutics plc. Consulting Fee; Self; Immunovant, Sling. B. Fowler: Consulting Fee; Self; Horizon Therapeutics plc. C. Liu: Other; Self; Walter Kluwer Health. P. Subramanian: Consulting Fee; Self; Gensight, Horizon Therapeutics plc, Viridian. R. Tang: Consulting Fee; Self; Viridian, Alexion, Valenza. Research Investigator; Self; Viridian, Horizon Therapeutics plc, Novartis, Immunovant, Vasaragen. Speaker; Self; Serono Speaker Journal Club. Q.T. Nguyen: None. K. Hsu: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. M. Karon: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. M.N. Stan: Consulting Fee; Self; Immunovant, Horizon Therapeutics plc, Sling, Genentech, ArgenX. Background: Thyroid eye disease (TED) is characterized by expansion of peri- and retro-orbital fat and muscle, often resulting in disfiguring proptosis (eye-bulging) and diplopia (double vision) which may persist chronically. Teprotumumab, an inhibitor of the insulin-like growth factor-1 receptor, demonstrated improvements in proptosis, diplopia, inflammation and quality of life in clinical trials in patients with TED history of short duration (6-13 months), and active disease (clinical activity score [CAS] ≥4). In a published study of 31 patients with CAS≤3 and TED duration &gt;2 years, teprotumumab reduced proptosis, diplopia and inflammation.1 We have undertaken the first randomized, placebo (PBO)-controlled trial to evaluate teprotumumab in patients with chronic/inactive/low CAS TED. The trial has completed randomization with results available in May 2023. Here we report characteristics of the randomized patients. Methods: The trial (NCT04583735) is being conducted in 11 centers in the United States. Key inclusion criteria were age≥18 years, TED duration ≥2 years but &lt;10 years and CAS≤1 in both eyes, ≥3mm proptosis from baseline and/normal for sex and race, or no progression in proptosis or diplopia or new inflammatory symptoms in the preceding year. Patients must have been euthyroid or mildly hypo/hyperthyroid, and not require surgical intervention through the trial. Patients could not have received teprotumumab previously, or steroids within 3 weeks before screening. Patients were randomized 2:1 to receive 8 infusions of teprotumumab (10 mg/kg for the first infusion and 20 mg/kg for the remaining 7 infusions) or PBO once every 3 weeks. The primary endpoint is improvement in proptosis (mm) as compared with PBO from baseline at Week 24. Other endpoints include percentage of proptosis responders (improvement of ≥2mm), diplopia responders (improvement of ≥1 grade in diplopia on the Bahn-Gorman scale, 0-3), and improvement in Graves’ Ophthalmopathy- Quality of Life (GO-QoL), all at Week 24. Adverse events (AE) and AE of special interest will be reported. Results: 62 patients were randomized. 80.6% are female, mean (SD) age was 48.7 (14.94) years. 54.8% are White, 24.2 %, Black or African American, and 12.9%, Asian. Mean (SD) TED duration was 5.2 (1.77) years. 87.1% are never/former smokers. At baseline, mean (SD) proptosis in the study eye was 24.4 (2.94) mm, and mean (SD) CAS was 0.4 (0.49). 27.4% had binocular diplopia with a mean diplopia score of 2. The mean overall GO-QoL score was 63.9 indicating similar disutility as observed in the acute trial population (previously published). Results from this 24-week trial will be presented. Conclusions: Despite a long duration of TED and low “activity”, patients enrolled in this trial have high levels of proptosis and impaired quality of life at baseline. Presentation: Saturday, June 17, 2023

Abstract Disclosure: R.S. Douglas: Consulting Fee; Self; Horizon, Immunovant, Viridian. Research Investigator; Self; Horizon. S. Couch: Research Investigator; Self; Horizon. S.T. Wester: Advisory Board Member; Self; Horizon. Consulting Fee; Self; Immunovant, Sling. Research Investigator; Self; Horizon. B.T. Fowler: Consulting Fee; Self; Horizon. Research Investigator; Self; Horizon. C. Liu: Research Investigator; Self; Horizon. Other; Self; Royalties from Wolters-Kluwer. P. Subramanian: Consulting Fee; Self; Horizon, Gensight, Viridian. Research Investigator; Self; Horizon. R. Tang: Consulting Fee; Self; Viridian, Alexion, Valenza. Research Investigator; Self; Horizon, Viridian, Novartis, Immunovant, Vasaragen. Speaker; Self; Serono Journal Club. Q.T. Nguyen: Research Investigator; Self; Horizon. R.N. Maamari: Research Investigator; Self; Horizon. K. Hsu: Employee; Self; Horizon. Stock Owner; Self; Horizon. M. Karon: Employee; Self; Horizon. Stock Owner; Self; Horizon. M. Stan: Consulting Fee; Self; Septerna Inc, Third Rock Ventures LLC, Genentech, MedicXi Ventures, ArgenX US Inc, Tourmaline Bio, Lassen Therapeutics, Ortho Clinical Diagnostics, Siemens Healthcare, Tolmar Inc, OSE, Immunotherapeutics, Roivant Sciences. Research Investigator; Self; Horizon, Immunovant, ValenzaBio, Sling Therapeutics. Background: Early inflammatory thyroid eye disease (TED) gives way to chronic disease which may lead to long-term disfiguring proptosis (eye-bulging). Teprotumumab, an IGF-1 receptor inhibitor, significantly improved signs and symptoms of newly diagnosed TED (6-13 months) with active disease (clinical activity score [CAS] ≥4) in prior studies. We present data from the first randomized, placebo (PBO)-controlled trial (NCT04583735) with teprotumumab in chronic/low CAS TED, where disease has not regressed. Methods: Pts met all following criteria: ≥18 yrs, TED 2-10 yrs, inactive disease or &gt;1 yr without progression in proptosis/diplopia/new symptoms, baseline (BL) CAS≤1, increased proptosis ≥3mm before TED or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab and no steroids within 3 wks of screen. Pts received teprotumumab or PBO once every 3 wks for 21 wks. Primary endpoint was improvement in proptosis(mm) from BL at Wk 24 vs PBO. Secondarily proptosis responders (≥2mm improvement), diplopia responders (≥1 grade improvement on Gorman scale 0-3) with resolved diplopia (grade 0) and improvement in Graves’ Ophthalmopathy-QoL (GO-QoL) visual function (VF) and appearance (AP) subscales were assessed. Treatment-emergent adverse events (TEAE) and AEs of special interest are reported. Study was solely sized/powered for proptosis. Results: 62 pts were randomized 2:1 (ITT, teprotumumab:42; PBO:20), 80.6% were female, mean(SD) age was 48.7(14.94) yrs. Mean(SD) TED duration was 5.2(1.8) yrs. 87.1% were never/former smokers. At BL, mean(SD) proptosis was 24.4(2.94) mm, mean CAS was 0.4, and 29% (teprotumumab, n=14, PBO, n=4) had diplopia with a mean score ∼2. 93%(39) of teprotumumab pts completed the study. At Wk 24, proptosis improvements from BL were significantly greater in the teprotumumab group [2.41 (0.228) mm] vs PBO [0.92(0.323) mm], P&lt;.001. Proptosis response was observed in 26/42 (62%) of teprotumumab pts vs 5/20 (25%) of PBO, P=.01. Diplopia improvement was observed in 6/14 (43%) teprotumumab pts with resolved diplopia in 4(29%) vs 2/4(50%) in PBO and 1(25%) resolved. Significantly greater improvement from BL was observed on GO-QoL-VF for teprotumumab (8.73) vs PBO (2.41), P=.03. Change from BL on AP was 10.03 vs 7.19, P= .65. TEAEs proportions were similar: 33/41(80.5%) of teprotumumab, and 16/20(80%) of PBO pts. Hyperglycemia was reported in 6(15%) vs 2(10%) and hearing impairment in 9(22%) vs 2(10%), respectively. There were two AE discontinuations: teprotumumab (left ear conductive hearing loss with congenital anomaly) and PBO (infusion related). Conclusions: For the first time in pts with longstanding TED and low CAS/inflammation, a medical therapy, teprotumumab, produced significant improvement in proptosis as compared with PBO supporting its use regardless of TED duration or activity. The safety profile was comparable to that previously reported. Presentation: Saturday, June 17, 2023

Abstract Disclosure: M. Dhanasekaran: None. A.A. Rajwani: None. M.R. Castro: None. J.C. Morris: None. J. Schmitz: None. R.A. Lee: None. M. Callstrom: None. M. Stan: None. Context: Autonomously functioning thyroid nodules (AFTNs) constitutes 5% of thyroid nodules and is the second most common cause of hyperthyroidism following Graves’ Disease. Untreated hyperthyroidism is associated with adverse cardiovascular and skeletal complications. Currently, radioactive iodine (RAI) and surgery are the standard treatment options for AFTNs, and both incur a risk of post-procedural hypothyroidism. To overcome this and other surgery/radiation-related complications, radiofrequency ablation (RFA) has been utilized in multiple countries (for both toxic and non-toxic thyroid nodules). It has been shown to induce significant nodule volume reduction along with restoration of normal thyroid function in many AFTNs. Methods: We present a single-center experience using RFA as an alternative treatment modality for AFTNs. The study's primary aim was to assess the efficacy of RFA in normalizing thyroid hormone concentration and restoring the euthyroid state. In addition, we analyzed the efficacy of RFA in nodule volume rate reduction (VRR) and its associated adverse events. Results: A total of 22 consecutive patients (17 F and 5 M) underwent RFA for a solitary AFTN (hot nodule in thyroid uptake and scan) under variable degrees of general anesthesia. 72% (n=16) had subclinical hyperthyroidism, 9% (n=2) had overt hyperthyroidism, and 18% (n=4) were biochemically euthyroid on anti-thyroid drugs (ATD). The mean age at the time of ablation was 52.09 years (SD= 14.6), with a mean BMI of 27.36 kg/m2 (SD= 4.67). Average pre-treatment TSH was 0.41 mIU/L (SD= 0.980) and free T4 1.29 ng/dl (SD= 0.33). The thyroid function was assessed after a single RFA session. TSH normalized in all patients within 3-6 months following the ablation. All four patients on ATD pre-treatment discontinued therapy within three months following the procedure. The average VRR (62.54%) was achieved within 3-6 months following the RFA, and importantly, none of the nodules grew back during the follow-up period (up to 24 months). Two patients (9%) developed transient tachycardia requiring short-term beta-blocker therapy, and two (9%) developed mild hypothyroidism requiring levothyroxine therapy. One patient, euthyroid post RFA, developed recurrent hyperthyroidism 45 months later and elected to undergo lobectomy. No serious adverse effects were noted in this cohort. Conclusions - RAI and/or surgery represent the standard of care for toxic adenomas but RFA shows excellent efficacy along with an excellent safety profile. Therefore at centers with RFA expertise it should be considered an alternative treatment strategy, avoiding radiation and surgery-related complications. Presentation Date: Saturday, June 17, 2023