[Survey of the management of moderate to severe active Graves' orbitopathy at 28 metropolitan centers of excellence in France]. / État des lieux de la prise en charge de l'orbitopathie dysthyroidïenne modérée à sévère active en France à partir de 28 centres experts métropolitains.

INTRODUCTION: This study investigates the management of Graves'orbitopathy (GO) in France, at 26 university medical centers (CHU) as well as the Rothschild Foundation and the Quinze-Vingts national eye hospital in Paris. METHODS: The 28 metropolitan university medical centers were contacted by telephone or e-mail. The authors devised a 5-item questionnaire that explored the scheduling of multidisciplinary meetings, the existence or lack of a dedicated Graves' consultation service, the place of hospitalization, and first- and second-line treatments. RESULTS: Eighty-nine percent of hospital departments had a dedicated service for patients with GO, with 36% organizing multidisciplinary meetings. Intravenous corticosteroid therapy is still used as first-line treatment, while mycophenolate is used much less (14.3%), despite the new EUGOGO (European Group on Graves' orbitopathy) 2021 recommendations. For second-line treatment, tocilizumab is most commonly used (64%). Teprotumumab is available in France only on a compassionate basis, and its use is limited (18%). CONCLUSION: This study highlights the variability in practices and the importance of a multidisciplinary approach, while calling for national standardization of practices. Despite disparities in the application of recommendations, the emergence of second-line treatments such as tocilizumab and teprotumumab indicates a steady evolution in therapeutic options, although obstacles in terms of accessibility and cost remain.

Adverse event reporting of the IGF-1R monoclonal antibody teprotumumab: a real-world study based on the US food and drug administration adverse event reporting system.

Background: Teprotumumab, an IGF-1R monoclonal antibody, has shown significant efficacy in treating thyroid eye disease (TED). However, since teprotumumab was launched in 2020 and first approved in the United States, there were limited reports of post-marketing adverse events (AEs). In this study, we aimed to mine and analyze the AEs signals with teprotumumab on the basis of the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to provide instructions in clinical practice concerning adverse reactions and assistance in drug development and import/export into other countries. Methods: All AE reports were obtained from the FAERS database from the first quarter of 2020 to the fourth quarter of 2023. To comprehensively analyze the AEs, we applied four disproportionality analysis algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms. Results: A total of 687 reports from 200 patients related to administration of teprotumumab were obtained, and 78% of the cases was female. Signal detection of teprotumumab at the system organ class (SOC) level included gastrointestinal disorders, ear and labyrinth disorders, general disorders and administration site conditions, nervous system disorders, and musculoskeletal and connective tissue disorders. AEs that ranked top five at the preferred terms (PTs) level were muscle spasms, fatigue, tinnitus, headache, and deafness. The median time to those AEs onsets was 48 days (interquartile range 19.0-92.0 days) after administering drugs. Additionally, our results indicated the AEs in reproductive system and breast disorders because the prevalence of TED was more common in women. Conclusion: This study identified many AEs associated with teprotumumab and unveiled potential new AE signals. These results can provide valuable evidence for further clinical application of teprotumumab and are important in enhancing clinical medication safety.

Patterns of Teprotumumab-Induced Hearing Dysfunction: A Systematic Review.

OBJECTIVE: Hearing loss has been reported after administration of the monoclonal antibody teprotumumab. The purpose of this study was to review available evidence regarding the patterns of teprotumumab-related ototoxicity. DATA SOURCES: PubMed, EMBASE, and Cochrane Library. REVIEW METHODS: A systematic review was performed using standardized methodology. Studies were included if they included subjects who were prescribed teprotumumab. Exclusion criteria included non-English articles, abstracts, letters/commentaries, case reports, and reviews. Subjects without both pre- and posttreatment audiometric data were also excluded. Bias was assessed using the Mixed Methods Appraisal Tool. RESULTS: From an initial search of 76 articles, 7 studies reporting on 109 unique patients were included. Four studies were level 4 evidence, 1 study was level 3 evidence, and 2 studies were level 2 evidence. Mean age was 55 ± 14 years with a female predominance (64%). The most commonly reported symptoms were hearing loss (22%), followed by fullness (18%) and tinnitus (14%). In total, 41% of patients with available data met criteria for ototoxicity, all exhibiting shifts in the middle frequencies or higher. Fifteen (14%) patients underwent ultrahigh frequency audiometric testing and 8 (53%, 8/15) demonstrated shifts exclusively in this range. CONCLUSION: Ototoxicity may occur in patients treated with teprotumumab. Hearing loss occurs primarily in higher frequencies, and routine hearing screening with ultrahigh frequency testing may be warranted. The true incidence of ototoxicity with teprotumumab remains unknown, and more data is needed to elucidate underlying mechanisms and develop strategies to minimize risks.

Effects of Teprotumumab and Role of Human Leukocyte Antigens Markers in Patients With Thyroid Eye Disease.

OBJECTIVE: To evaluate the effects of teprotumumab on ophthalmologic and biochemical findings and assess potential genetic markers for response to treatment. METHODS: This is a retrospective study. Participants were 18-76 year old. All subjects were treated with teprotumumab. The primary outcome was the change in proptosis before and after teprotumumab treatment. Secondary outcomes include change in other ophthalmic measures and thyroid laboratory tests. Human leukocyte antigens (HLA) markers were analyzed for response to teprotumumab. RESULTS: Twenty-six patients were included in the final analysis. There was a significant decrease in thyroid stimulating immunoglobulin and thyrotropin receptor antibody levels and significant increases in glycated hemoglobin A1c, fasting glucose, and total T3 levels. There was also significant reduction in proptosis, clinical activity score, retinal nerve fiber layer thickness, ganglion cell analysis, and intraocular pressure. HLA haplotypes were distinct between responders and nonresponders, with HLA-DRB3 02:02:01G, HLA-DRB4 neg, and HLA-DQB1 02:01:01G demonstrating better response to teprotumumab and HLA-A 23:01:01G strongly correlating to nonresponse. CONCLUSIONS: Patients with both acute and chronic thyroid eye disease treated with teprotumumab had a significant reduction in thyroid stimulating immunoglobulin and thyrotropin receptor antibody levels and improvement in proptosis, clinical activity score, retinal nerve fiber layer and ganglion cell analysis thickness, and intraocular pressure. HLA may predict responders vs nonresponders. Further studies with longer duration and larger population comparing teprotumumab with steroids or other immunomodulatory agents (tocilizumab, rituximab, etc) may be helpful.

Assessment of hearing dysfunction in patients with Graves' disease and thyroid eye disease without or with teprotumumab.

IMPORTANCE: Thyroid eye disease (TED) negatively impacts quality of life. TED occurs predominantly in Graves' disease (GD). Teprotumumab improves TED but concern for hearing adverse events (AEs) has emerged. Hearing dysfunction is reported in thyroid autoimmune disease but the background prevalence in GD/TED without teprotumumab remains uncertain. OBJECTIVE: To quantify ear-related diagnostic codes/hearing AEs in GD, TED, and patients receiving teprotumumab by examining medical claims and clinical trials. DESIGN AND PARTICIPANTS: Deidentified claims for ear/labyrinth-related ICD-10 codes (KOMODO®) were examined in GD patients without TED, and TED patients without/with teprotumumab treatment. Hearing AE incidence/severity was evaluated in teprotumumab clinical trials. Graves' Ophthalmopathy QOL (GO-QOL) scores were compared in teprotumumab TED trial patients without/with hearing AEs. RESULTS: GD (469,720), TED (38,566) and teprotumumab-treated (967) patients were identified in the claims database. Ear-related codes (including those not specific for hearing) occurred in 24% GD, 33% TED, and 32% teprotumumab-treated patients. "Sensorineural hearing loss bilateral" was most frequent: 32,961/469,720 (7%) GD, 4,279/38,566 (11.1%) TED, and 104/967 (10.8%) teprotumumab patients. Pre-teprotumumab use,165 (17.1%) patients had ear-related codes while 98 (10.1%) had new ear-related codes post-treatment.Eight teprotumumab oncology trials revealed 8.1% (51/633) had Ear/Labyrinth Disorders with 2.1% (13) considered study-drug-related and 3.8% (24) hearing impairment/tinnitus-related AEs, with 1.3% (8) considered teprotumumab-related. Similar rates occurred in TED trials.GO-QOL improved in teprotumumab-treated patients without/with hearing AEs. Incidence/severity was consistent across patients with chronic and acute TED. CONCLUSIONS: These analyses indicate similar occurrence of hearing claims in patients with GD/TED alone as following teprotumumab treatment. Future analyses of incremental hearing risk from teprotumumab should utilize a priori study designs accounting for background hearing dysfunction in patients with GD/TED.

Reversible cerebral vasoconstriction syndrome due to teprotumumab: two case reports.

BACKGROUND: Reversible Cerebral Vasoconstriction Syndrome (RCVS) involves cerebral vasculature constriction and dilation. While the exact pathophysiology of RCVS is still not fully understood, there are multiple etiological factors suggested to be implicated in triggering RCVS. We report two RCVS cases potentially linked to teprotumumab. Case 1: A 59-year-old female with Graves' eye disease (GED) developed leg weakness and headache after initiating teprotumumab, and neuroimaging studies revealed multifocal cerebral vasospasm (CVS). Verapamil mitigated vasospasm and the patient overall improved. Case 2: A 71-year-old female with GED developed thunderclap headache two months after starting teprotumumab, with subarachnoid hemorrhage (SAH) and CVS revealed on neuroimaging studies. The patient improved on verapamil and was discharged without deficits. CONCLUSIONS: The temporal correlation between teprotumumab initiation and RCVS's symptom onset raises concern for the potential involvement of teprotumumab in triggering RCVS via disrupting cerebrovascular modulation. Further research is needed to investigate this proposed association.

Teprotumumab for thyroid eye disease in patients with hypothyroid/euthyroid state: a multicenter case series.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of acute and chronic thyroid eye disease (TED) related to hyperthyroidism. Given the lower incidence of TED associated with hypothyroidism / euthyroidism, there is a paucity of data regarding the efficacy of teprotumumab in this group. METHODS: In this multicenter study, consecutive patients who had been diagnosed with TED, presenting with either hypothyroidism or euthyroidism as their baseline thyroid dysfunction and treated with teprotumumab were included. All patients had measurements of proptosis, clinical activity scores (CAS), diplopia scores and four-point strabismus scores before and after therapy. RESULTS: Twenty-six patients met the inclusion criteria. Mean age was 48 ± 14 years old and mean duration of TED prior to treatment was 31 ± 43 months. All patients received 8 infusions. Mean (SD) reduction in proptosis for study orbits was 2.7 mm (1.8) (p < 0.05) and 1.8 mm (2.0) for the fellow orbit (p < 0.05). In the study orbit, mean (SD) CAS was 2.3 (1.3) before therapy and 1.0 (1.0) following therapy (p < 0.05). At baseline, mean (SD) diplopia score was 1.2 (1.1) and 0.9 (1.1) following therapy (p < 0.05). CONCLUSION: Teprotumumab reduces proptosis and inflammation in patients presenting with TED associated with hypothyroidism and euthyroidism. The results of this study highlight the potential for teprotumumab therapy in this subgroup and also provide a unique insight into the potential role of the IGF-1R in these patients.

The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up.

PURPOSE: To determine the rate of re-treatment in patients who receive a full course of teprotumumab therapy for thyroid eye disease (TED) and drivers of re-treatment. DESIGN: Multicenter retrospective study. PARTICIPANTS: All patients who received a full course of treatment and had available data at 1 year after initial treatment were included. METHODS: Charts were reviewed for the following information: age, sex, months since diagnosis of TED, smoking status, and prior treatments. Further, the clinical activity score (CAS), proptosis, and the Gorman diplopia score were reviewed at baseline, at the end of the first course, and at baseline for the second course in those who received it. A logistic regression model was created to review the drivers of re-treatment. MAIN OUTCOME MEASURES: Rate of re-treatment and the drivers of re-treatment. RESULTS: One hundred nineteen patients were included from 3 centers across the United States. The overall re-treatment rate was 24% (29/119). No difference was found among the 3 sites (P = 0.6). In univariable analyses, at baseline, no difference was found in proptosis (P = 0.07), diplopia score (P = 0.4), or duration of TED (P = 0.4) between patients who were re-treated and those not re-treated. From the re-treated group, 82% showed a significant proptosis response (≥ 2-mm reduction from baseline) after the initial course, whereas 68% of patients who were not re-treated showed a clinically significant proptosis response (P = 0.16). The mean ± standard deviation difference between the end of the first treatment and at baseline before the second treatment (in those who received it) was 2 ± 2 for CAS, 2 ± 4 mm for proptosis, and 1 ± 1 for diplopia score. Age was the only significant driver of re-treatment (P < 0.05). Re-treated patients were 7 years older than patients who were not re-treated (60 years vs. 53 years; P < 0.05). CONCLUSIONS: In patients receiving a full course of teprotumumab therapy, the rate of re-treatment was 24%. Age was the only driver of re-treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Thyroid Eye Disease: Advancements in Orbital and Ocular Pathology Management.

Thyroid Eye Disease (TED) is a debilitating autoimmune condition often associated with thyroid dysfunction, leading to significant ocular and orbital morbidity. This review explores recent advancements in the management of TED, focusing on both medical and surgical innovations. The introduction of Teprotumumab, the first FDA-approved drug specifically for TED, marks a pivotal development in medical therapy. Teprotumumab targets the insulin-like growth factor-1 receptor (IGF-1R), effectively reducing inflammation and tissue remodeling. Clinical trials demonstrate its efficacy in reducing proptosis and improving quality of life, making it a cornerstone in the treatment of active, moderate-to-severe TED. Surgical management remains critical for patients with chronic TED or those unresponsive to medical therapy. Advancements in orbital decompression surgery, including image-guided and minimally invasive techniques, offer improved outcomes and reduced complications. Innovations in eyelid and strabismus surgery enhance functional and cosmetic results, further improving patient satisfaction. The management of TED necessitates a multidisciplinary approach involving endocrinologists, ophthalmologists, oculoplastic surgeons, radiologists, and other specialists. This collaborative strategy ensures comprehensive care, addressing the diverse aspects of TED from thyroid dysfunction to ocular health and psychological well-being. Future directions in TED treatment include emerging pharmacological therapies targeting different aspects of the disease's pathophysiology and advanced surgical techniques aimed at enhancing precision and safety. This review underscores the importance of a personalized, multidisciplinary approach in managing TED, highlighting current advancements, and exploring potential future innovations to improve patient outcomes and quality of life.

Impact of Teprotumumab on Clinical Practice in Thyroid Eye Disease.

BACKGROUND: Following its Food and Drug Administration approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across 3 referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and 1 patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials.

Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.

Post-marketing Safety Concerns of Teprotumumab: A Real-World Pharmacovigilance Assessment.

PURPOSE: Teprotumumab is the only drug approval by The US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED), which targets the insulin-like growth factor-1 receptor. This study aimed to identify potential safety signals of teprotumumab by analyzing post-marketing safety data from the FDA Adverse Event Reporting System (FAERS) database in 2023. METHODS: The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered three or more. RESULTS: Total of 2158 cases were included in the analysis. Main safety signals identified were ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders and gastrointestinal disorders. Specifically, autophony (ROR [95% CI] = 4188.34 [1403.29-12500.8]), eyelid retraction (ROR [95% CI] = 2094.17 [850.69-5155.29]), deafness permanent (ROR [95% CI] = 1552.35 [789.07-3053.98]), deafness bilateral (ROR [95% CI] = 73.12 [41.14-129.97]), inflammatory bowel disease (ROR [95% CI] = 23.26 [13.46-40.19]), hyperglycaemic hyperosmolar nonketotic syndrome (ROR [95% CI] = 17.75 [5.70-55.28]) and amenorrhoea (ROR [95% CI] = 47.98 [36.22-63.54]) showed significant safety signals of teprotumumab. CONCLUSIONS: This study identified ear and labyrinth disorders, reproductive system and breast disorders, as specific safety signals of teprotumumab. Clinicians and pharmacists should be vigilant regarding these AEs. However, available data are currently insufficient, and further pharmacovigilance and surveillance are needed to fully understand this issue.

An observational study on the safety of teprotumumab based on FAERS database.

OBJECTIVE: Teprotumumab plays an important role in thyroid eye disease pathogenesis and progression. We intend to mine the adverse event (AE) signals from a relevant database, thereby contributing to the safe use of teprotumumab. METHODS: The data obtained from the ASCII data packages in the FAERS database from January 2020 to the second quarter of 2023 were imported into the SAS software (version 9.4) for data cleaning and analysis. Disproportionality analysis was performed using the reporting odds ratio (ROR) in conjunction with the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) omnibus standard method to detect positive signals. PARTICIPANTS: This retrospective observational study relied on adverse drug reactions reported to the FDA through FAERS, which is a standard public system for spontaneous reporting. RESULTS: Collectively, 2171 AE reports for teprotumumab were collected, among which 108 significant signals were identified involving 17 system organ classes. The SOC of ear and labyrinth disorders included the most AE signals and reports. Muscle spasms, fatigue, headache, nausea, diarrhea, alopecia, blood glucose increased, hypoacusis, tinnitus, and diabetes mellitus were the top ten PTs ranked by the frequency of reporting, meanwhile, the two high-strength signals of thyroid-stimulating immunoglobulin increase (ROR 662.89, 95% CI 182.40-2409.19) and gingival recession (ROR 125.13, 95% CI 79.70-196.45) were not documented in the drug instruction. Meanwhile, we found a higher risk of increased blood glucose, deafness, and decreased appetite for male patients, and headache for female patients. CONCLUSIONS: Clinical application of teprotumumab should be closely monitored for ototoxicity, nail abnormalities, and menstrual changes, as well as for AEs not mentioned in the drug instruction, including gingival recession, thyroid-stimulating immunoglobulin increase, and so on.

Orbital decompression surgery among Medicare beneficiaries in the post-teprotumumab era.

KEY POINTS: Utilization of orbital decompressions (ODS) increased (CAGR: +3.2%) from 2000 to 2019. FDA approved teprotumumab in January 2020; ODS utilization decreased (CAGR: -14.9%) from 2019 to 2022. In 2022, total spending was substantially higher for teprotumumab ($325 million) than surgery ($580,000).

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease.

Thyroid eye disease (TED) is a disfiguring autoimmune disease characterized by changes in the orbital tissues and is caused by abnormal thyroid function or thyroid-related antibodies. It is the ocular manifestation of Graves' disease. The expression of thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1 R) on the cell membrane of orbital fibroblasts (OFs) is responsible for TED pathology. Excessive inflammation is caused when these receptors in the orbit are stimulated by autoantibodies. CD34+ fibrocytes, found in the peripheral blood and orbital tissues of patients with TED, express immune checkpoints (ICs) like MHC II, B7, and PD-L1, indicating their potential role in presenting antigens and regulating the immune response in TED pathogenesis. Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, it can also lead to the occurrence of TED in some instances, suggesting the abnormality of ICs in TED. This review will examine the overall pathogenic mechanism linked to the immune cells of TED and then discuss the latest research findings on the immunomodulatory role of ICs in the development and pathogenesis of TED. This will offer fresh perspectives on the study of pathogenesis and the identification of potential therapeutic targets.

Side Effects and Adverse Events After Treatment With Teprotumumab for Thyroid Eye Disease: A Retrospective Observational Case Series.

As the use of teprotumumab for thyroid eye disease (TED) becomes more prolific, there remains a scarcity of literature regarding the associated side effects and adverse events of teprotumumab use. The authors present a single-center retrospective, observational case review of TED patients who received at least a single dose of teprotumumab infusion at the oculofacial plastic surgery service between February 2020 and July 2023. The most predominant recollected side effects were fatigue, brittle nails, dry eye symptoms, hair loss, muscle spasms, and dry mouth. Significant adverse events were limited to two cases of a blood clot and a single case of pulmonary embolism. This is the first retrospective study of patient-reported side effects and adverse events experienced by a cohort of teprotumumab users.

A Review of Novel Medical Treatments for Thyroid Eye Disease.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-insulin-like growth factor 1 receptor (anti-IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

Teprotumumab in thyroid eye disease.

Thyroid eye disease (TED) is an inflammatory condition involving the periocular and orbital soft tissues, affecting most commonly patients with hyperthyroid disorders. Traditional treatments used for the active phase of the disease range from conservative lubrication for mild symptoms to systemic immunomodulating drugs for moderate-to-severe symptoms. Teprotumumab (Tepezza) is a monoclonal antibody with an inhibitory effect on insulin-like growth factor 1 and is the first Food and Drug Administration (FDA) approved targeted medical therapy for reducing the inflammatory signs and symptoms associated with TED. Two large multicenter, randomized, double-masked, placebo-controlled trials have confirmed the efficacy and safety of teprotumumab in patients with active, moderate-to-severe TED. Recent reports and publications have also demonstrated the efficacy of teprotumumab in a wider range of patients. In this review, we summarize the clinical features and pathophysiology of TED, disease course, and traditional management methods. We further detail the development of teprotumumab, the founding studies that brought it to its FDA approval, adverse events profile, and ongoing as well as future investigations.

Rapid response of thyroid eye disease, peripheral edema, and acropathy to teprotumumab infusion.

Purpose: We present a case of rapid improvement in symptoms of thyroid eye disease and amelioration of worsening peripheral edema and acropathy with infusion of teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor. Observations: A 66 year old female with history of Hashimoto thyroiditis developed progressive thyroid eye disease (TED), peripheral edema, and acropathy attributable to acute Graves disease. Her signs and symptoms, refractory to oral steroid and diuretic therapy, rapidly improved following a standard dosing regimen of teprotumumab (one infusion 10 mg/kg then seven infusions 20 mg/kg) to resolution. Conclusions & importance: Teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor, is the first medication approved by the FDA for use in TED. Teprotumumab may contribute to the treatment of extraocular manifestations of Graves disease, chief among these peripheral soft tissue manifestations.

Severe Hyperglycemia with Teprotumumab for Treatment of Thyroid Eye Disease.

Introduction: Thyroid eye disease (TED) is a rare condition involving autoimmune-mediated inflammation of the orbit and periocular structures, which can result in many debilitating symptoms. Teprotumumab, a monoclonal antibody that targets the insulin-like growth factor 1 receptor, is gaining popularity for the treatment of TED. In fact, owing to its efficacy and side effect profile, some recommend that it be considered as a first-line therapy for patients with TED. While teprotumumab is often chosen due to its efficacy and relatively favorable side effect profile compared to other treatments, there is a known risk of hyperglycemia with this mechanism of action, which is well described through clinical trials in the oncology literature. Though all cases in the clinical trial study of teprotumumab were mild, there is growing evidence that its effect on blood sugar can be more profound. Case Presentation: We present a case of a well-controlled, recently diagnosed type 2 diabetic placed on teprotumumab for treatment of TED who developed life-threatening hyperglycemia. The case report provides evidence of hyperglycemic risk, as it highlights a patient's significant increase in hemoglobin A1C to 15.4 in addition to elevated serum glucose of 954 mg/dL while receiving teprotumumab. Conclusion: This case of severe hyperglycemia accentuates the need for more diligent, if not universal, glucose monitoring during teprotumumab treatment.