Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

PURPOSE: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab. DESIGN: Multicenter, retrospective, observational cohort study. PARTICIPANTS: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab. METHODS: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit. MAIN OUTCOME MEASURES: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement. RESULTS: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8). CONCLUSIONS: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Teprotumumab for the Treatment of Recalcitrant Thyroid Eye Disease.

PURPOSE: Teprotumumab, an insulin-like growth factor 1 receptor monoclonal antibody, is FDA-approved to treat thyroid eye disease (TED). The initial clinical trials excluded patients with previous orbital irradiation, surgery, glucocorticoid use (cumulative dose >1 gm), or prior biologic treatment. Information on the use of teprotumumab for patients who failed prior therapy is limited. Our purpose is to characterize the efficacy of teprotumumab for the treatment of recalcitrant TED. METHODS: This is a multicenter retrospective study of all patients treated with teprotumumab for moderate-to-severe TED after failing conventional therapy with corticosteroids, orbital radiation, surgical decompression, biologics, or other steroid-sparing medications. Treatment failure was defined as an incomplete response to or reactivation after previous treatment. Only patients who received at least 4 infusions of teprotumumab were included in the analysis. Primary outcome measures comprised proptosis response (≥2 mm reduction in the study eye without a similar increase in the other eye), clinical activity score (CAS) response (≥2-point reduction in CAS), and diplopia response (≥1 point improvement in Gorman diplopia score in patients with baseline diplopia) following treatment. Adverse events and risk factors for recalcitrant disease were also evaluated. RESULTS: Sixty-six patients were included in this study, 46 females and 20 males. Average age was 59.3 years (range 29-93). The mean duration of disease from TED diagnosis to first infusion was 57.8 months. The proptosis, CAS, and diplopia responses in this recalcitrant patient population were 85.9%, 93.8%, and 69.1%, respectively. Patients experienced a mean reduction in proptosis of 3.1 ± 2.4 mm and a mean improvement in CAS of 3.8 ± 1.6. Patients who underwent prior decompression surgery experienced a statistically significant decrease in diplopia response (46.7% vs. 77.5%, p = 0.014) and proptosis response (75.0% vs. 90.9%, p = 0.045) when compared with nondecompression patients. Additionally, there were no significant differences in proptosis, CAS, and diplopia responses between patients with acute (defined as disease duration <1 year) versus chronic (disease duration ≥1 year) TED. While most adverse events were mild to moderate, 4 patients reported serious adverse events related to persistent hearing loss. CONCLUSIONS: Patients with recalcitrant TED demonstrated a significant improvement after teprotumumab in each of the primary study outcomes. The degree of proptosis reduction, diplopia response, and CAS improvement in the recalcitrant group were similar to those of treatment-naïve patients from the pivotal clinical trials. Patients with a prior history of orbital decompression, however, demonstrated poor improvement in diplopia and less reduction in proptosis than surgery naïve patients. These results indicate that teprotumumab is a treatment option for the treatment of patients with TED recalcitrant to prior medical therapies.

Advances in the Treatment of Thyroid Eye Disease Associated Extraocular Muscle Myopathy and Optic Neuropathy.

PURPOSE OF REVIEW: To review emerging treatments for thyroid eye disease (TED) associated extraocular muscle myopathy and dysthyroid optic neuropathy (DON). RECENT FINDINGS: Emerging targeted biologic therapies may alter the disease course in TED. Teprotumumab, a type I insulin-like growth factor receptor inhibitor, is the most recent addition to the treatments available for TED-associated extraocular muscle myopathy causing diplopia. Small studies also suggest a potential therapeutic benefit for DON. Various recent studies have also expanded our knowledge on conventional TED therapies. The therapeutic landscape of TED and its sequelae has evolved in recent years. New targeted therapies have the potential to reduce the extraocular muscle and orbital volume expansion which can lead to diplopia and vision loss from optic nerve compression. Longer term efficacy and durability data is needed to determine the role biologics, such as teprotumumab, should play in the treatment of TED patients compared to the current standard of care.

#PlasticsTwitter: The Use of Twitter Data as a Tool for Evaluating Public Interest in Cosmetic Surgery Procedures.

BACKGROUND: Plastic surgeons are increasingly turning to social media to market their services. The newly released Twitter Academic Research Product Track (TARPT) database provides free, customizable analysis of keywords that are included in tweets on the Twitter platform. The TARPT tool may provide valuable insight into public interest in cosmetic surgery procedures. OBJECTIVES: The aim of this study was to determine TARPT's utility in tracking and predicting public interest in cosmetic surgery procedures and to examine temporal trends in tweets related to cosmetic facial and body procedures. METHODS: The TARPT tool was used to calculate the total number of tweets containing keywords related to 10 facial cosmetic procedures and 7 cosmetic body procedures from 2010 to 2020. Annual volumes for respective procedures were obtained from annual statistics reports of The Aesthetic Society from 2010 to 2020. Tweet volumes and procedure volumes were compared by univariate linear regression, taking P < 0.05 as the cutoff for significance. RESULTS: Variations in tweet volume were observed. Univariate linear regression analysis demonstrated statistically significant positive correlations between tweet volumes and procedure volumes for 7 search terms: "eyelid lift," "facelift," "lip injections," "mastopexy," "butt lift," "butt implants," and "liposuction." Many procedure-related keywords were not significant, demonstrating the importance of careful selection of Twitter search terms. CONCLUSIONS: The TARPT database represents a promising novel source of information for plastic surgeons, with the potential to inform marketing and advertising decisions for emerging trends in plastic surgery interest before these patterns become apparent in surgical or clinical volumes.

#CosmeticsTwitter: Predicting Public Interest in Nonsurgical Cosmetic Procedures Using Twitter Data.

BACKGROUND: The utilization of social media in plastic surgery is expanding. The Twitter Academic Research Product Tract (TARPT) database provides plastic surgeons the opportunity to monitor public interest in plastic surgery procedures. Previously, TARPT was shown to be effective in tracking public interest in surgical cosmetic facial and body procedures. OBJECTIVES: The authors sought to determine the ability of the TARPT tool to track and predict public interest in nonsurgical cosmetic procedures and to examine temporal public interest trends in nonsurgical cosmetic procedures. METHODS: The authors employed the TARPT tool to calculate the total number of tweets containing keywords related to 15 nonsurgical cosmetic procedures from 2010 to 2020. Annual case volumes were obtained for each of the 15 procedures from annual reports provided by the American Society of Plastic Surgeons. Univariate linear regression was employed to compare tweet volumes and procedure volumes, with P < 0.05 as a threshold for significance. RESULTS: Univariate linear regression revealed significant positive correlations between tweet volumes and American Society of Plastic Surgeons procedure volumes for 10 search terms representing 6 nonsurgical cosmetic procedures: "xeomin," "microdermabrasion," "facial filler," "fat filler," "fat injections," "fat transfer," "hyaluronic acid filler," "hyaluronic acid injection," "HA filler," and "PRP filler." Thirty-two search terms did not demonstrate a significant relationship. CONCLUSIONS: The TARPT tool is an informative data source for plastic surgeons with the potential to guide marketing and advertising strategies, and monitor public interest in nonsurgical cosmetic procedures, helping surgeons respond to patients' evolving needs.

Design of a novel continuous flow reactor for low pH viral inactivation.

Insufficient mixing in laminar flow reactors due to diffusion-dominated flow limits their use in applications where narrow residence time distribution (RTD) is required. The aim of this study was to design and characterize a laminar flow (Re 187.7-375.5) tubular reactor for low pH viral inactivation with enhanced radial mixing via the incorporation of curvature and flow inversions. Toward this aim, the reactor described here, Jig in a Box (JIB), was designed with a flow path consisting of alternating 270° turns. The design was optimized by considering the strength of secondary flows characterized by the Dean No., the corresponding secondary flow development length, and the reactor turn lengths. Comprehensive CFD analysis of the reactor centerline velocity profile, cross-sectional velocity, and secondary flow streamlines confirmed enhanced radial mixing due to secondary flows and changes in flow direction. For initial CFD and experimental studies the reactor was limited to a 16.43 m length. Pulse tracer studies for the reactor were computationally simulated and experimentally generated to determine the RTD, RTD variance, and minimum residence time for the tracer fluid elements leaving the reactor, as well as to validate the computational model. The reactor was scaled length wise to increase incubation time and it was observed that as the reactor length increases the RTD variance increases linearly and the dimensionless RTD profile becomes more symmetrical and tighter about the mean residence time.

Teprotumumab-Related Hyperglycemia.

CONTEXT: Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials. OBJECTIVE: Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort. METHODS: This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months. RESULTS: Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up. CONCLUSION: While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.

Oral Corticosteroids for Teprotumumab-Related Hearing Loss: A Case Report.

Teprotumumab is a novel insulin-like growth factor-1 receptor inhibitor approved for the treatment of thyroid eye disease, but growing reports of hearing loss require further investigation. To date, an effective protocol for managing hearing loss in this setting has not been determined. Here, we present the first report of the resolution of teprotumumab-related hearing loss with prompt oral prednisone. A 70-year-old woman on teprotumumab experienced sudden hearing loss and tinnitus after her first infusion. An audiogram demonstrated a mild down-sloping to moderately severe mixed conductive and sensorineural hearing loss that was promptly treated with prednisone 60 mg for 6 days with a 1-week gradual taper. An audiogram 3 weeks later demonstrated return of hearing to normal thresholds, and the whole teprotumumab treatment course was completed without further issue. This case highlights the importance of audiometric monitoring, prompt identification of hearing symptoms, and the potential for oral steroids to reverse teprotumumab-related hearing loss.

Vitreofoveal Traction Associated With Pilocarpine for Presbyopia.

Vuity (pilocarpine HCL ophthalmic 1.25%) was approved for the treatment of presbyopia in October 2021. Previous case series have reported the presence of vitreofoveal traction and retinal detachment following pilocarpine administration, but this was not reported in the recent randomized control trials assessing the efficacy of Vuity. The authors report a case of a woman of 65 years who developed vitreomacular traction immediately following the first administration of Vuity, review the literature, and present considerations regarding screening and management of patients starting Vuity. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:410-411.].

Hearing Dysfunction After Treatment With Teprotumumab for Thyroid Eye Disease.

PURPOSE: To characterize the frequency, severity, and resolution of hearing dysfunction in patients treated with teprotumumab for thyroid eye disease (TED). DESIGN: Prospective observational case series. METHODS: Ophthalmic examination and adverse event assessment, including otologic symptoms, were performed at baseline, after infusions 2, 4, and 8, and at 6-month follow-up in consecutive patients who received at least 4 teprotumumab infusions. Laboratory test results were collected at baseline and during treatment. Audiometry, patulous eustachian tube (PET) testing, and otolaryngology evaluation were obtained for patients with new or worsening otologic symptoms, with a subset obtaining baseline and posttreatment testing. RESULTS: Twenty-seven patients were analyzed (24 females, 3 males, average 56.3 years old). Twenty-two patients (81.5%) developed new subjective otologic symptoms, after a mean of 3.8 infusions (SD 1.8). At 39.2-week average follow-up after the last infusion, most patients with tinnitus (100%), ear plugging/fullness (90.9%), and autophony (83.3%) experienced symptom resolution, whereas only 45.5% (5 of 11) of patients with subjective hearing loss/decreased word comprehension experienced resolution. Six patients underwent baseline and posttreatment audiometry, 5 of whom developed teprotumumab-related sensorineural hearing loss (SNHL) and 1 patient also developed PET. Three of the 5 patients with teprotumumab-related SNHL had persistent subjective hearing loss at last follow-up. A prior history of hearing loss was discovered as a risk factor for teprotumumab-related SNHL (P = .008). CONCLUSIONS: Hearing loss is a concerning adverse event of teprotumumab, and its mechanism and reversibility should be further studied. Until risk factors for hearing loss are better understood, we recommend baseline audiometry with PET testing and repeat testing if new otologic symptoms develop. Screening, monitoring, and prevention guidelines are needed.

Impact of Dean Vortices on the Integrity Testing of a Continuous Viral Inactivation Reactor.

We propose a standard protocol for integrity testing the residence-time distribution (RTD) in a "Jig in a Box" design (JIB)-a previously described tortuous-path, tubular, low-pH, continuous viral inactivation reactor, ensuring that biopharmaceutical products will be incubated for the required minimum residence time, tmin . tmin is the time by which just 0.001% of the total product containing virus has exited the incubation chamber (i.e., t0.00001 ). This t0.00001 is selected to ensure a >4-log reduction in viral load. As current tracers and in-line analytical technologies may not be able to detect tracers at the 0.001% level, an alternative approach is required. The authors describe a method for deriving tmin from t0.005 (i.e., the time at which 0.5% of the product has emerged from the reactor outlet) and an experimentally confirmed offset value, toffset = t0.005 -t0.00001 . The authors also evaluate tracer candidates-including 100-nm-diameter gold nanoparticles, dextrose, monoclonal antibody, and riboflavin-for pre-process acceptability and the effects of viscosity, molecular diffusion coefficient, and particle size. The authors show that a JIB will yield tmin and RTDs that are nearly identical for multiple tracers due to Dean vortex induced mixing. Results indicate that almost any small-molecule tracer that is generally recognized as safe can be used in pre-use integrity testing of a continuous viral inactivation reactor under the Deans values (De) of 119-595.

Design, construction, and optimization of a novel, modular, and scalable incubation chamber for continuous viral inactivation.

We designed, built or 3D printed, and screened tubular reactors that minimize axial dispersion to serve as incubation chambers for continuous virus inactivation of biological products. Empirical residence time distribution data were used to derive each tubular design's volume equivalent to a theoretical plate (VETP) values at a various process flow rates. One design, the Jig in a Box (JIB), yielded the lowest VETP, indicating optimal radial mixing and minimal axial dispersion. A minimum residence time (MRT) approach was employed, where the MRT is the minimum time the product spends in the tubular reactor. This incubation time is typically 60 minutes in a batch process. We provide recommendations for combinations of flow rates and device dimensions for operation of the JIB connected in series that will meet a 60-min MRT. The results show that under a wide range of flow rates and corresponding volumes, it takes 75 ± 3 min for 99% of the product to exit the reactor while meeting the 60-min MRT criterion and fulfilling the constraint of keeping a differential pressure drop under 5 psi. Under these conditions, the VETP increases slightly from 3 to 5 mL though the number of theoretical plates stays constant at about 1326 ± 88. We also demonstrated that the final design volume was only 6% ± 1% larger than the ideal plug flow volume. Using such a device would enable continuous viral inactivation in a truly continuous process or in the effluent of a batch chromatography column. Viral inactivation studies would be required to validate such a design. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:954-965, 2017.