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The New England Journal of Medicine May 2017Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.
METHODS
We conducted a multicenter, double-masked, randomized, placebo-controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid-associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves' ophthalmopathy-specific quality-of-life questionnaire. Adverse events were assessed.
RESULTS
In the intention-to-treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug-related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes.
CONCLUSIONS
In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997 .).
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Diabetes Complications; Double-Blind Method; Exophthalmos; Female; Graves Ophthalmopathy; Humans; Hyperglycemia; Immunologic Factors; Intention to Treat Analysis; Logistic Models; Male; Middle Aged; Quality of Life; Receptor, IGF Type 1
PubMed: 28467880
DOI: 10.1056/NEJMoa1614949 -
Ophthalmology Apr 2022To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate teprotumumab safety/efficacy in patients with thyroid eye disease (TED) who were nonresponsive or who experienced a disease flare.
DESIGN
The Treatment of Graves' Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves' Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial.
PARTICIPANTS
Patients who previously received placebo (n = 37) or teprotumumab (n = 14) in OPTIC.
METHODS
OPTIC nonresponders or those who flared (≥2-mm increase in proptosis, ≥2-point increase in clinical activity score [CAS], or both) during follow-up were treated for the first time (previous placebo patients) or re-treated with teprotumumab in OPTIC-X with 8 infusions over 24 weeks.
MAIN OUTCOME MEASURES
Proptosis response and safety. Secondary outcomes included proptosis, CAS, subjective diplopia, and quality-of-life.
RESULTS
Thirty-three of 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean ± standard deviation, -3.5 ± 1.7 mm) when treated with teprotumumab in OPTIC-X. The responses were equivalent to the OPTIC study. In these responders, proptosis, CAS of 0 or 1, and diplopia responses were maintained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at follow-up week 48. The median TED duration was 12.9 months versus 6.3 months in those treated with teprotumumab in the OPTIC study. Of the 5 OPTIC teprotumumab nonresponders re-treated in OPTIC-X, 2 responded, 1 showed a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatment early. Of the OPTIC teprotumumab responders who experienced flare, 5 of 8 patients (62.5%) responded when re-treated (mean proptosis reduction, 1.9 ± 1.2 mm from OPTIC-X baseline and 3.3 ± 0.7 mm from OPTIC baseline). Compared with published double-masked trials and their integrated follow-up, no new safety signals were identified. Mild hearing impairment was reported; 4 events occurred during the first course of treatment, and 2 events reoccurred after re-treatment.
CONCLUSIONS
Patients with TED of longer disease duration responded similarly to those treated earlier in the disease course. Patients with an insufficient initial response or flare may benefit from additional teprotumumab therapy. No new safety risk was identified; however additional postmarketing pharmacovigilance is ongoing.
Topics: Antibodies, Monoclonal, Humanized; Diplopia; Exophthalmos; Graves Ophthalmopathy; Humans
PubMed: 34688699
DOI: 10.1016/j.ophtha.2021.10.017 -
The Journal of Clinical Endocrinology... Nov 2023Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED).
OBJECTIVE
We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED.
DESIGN
Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials.
SETTING
Multicenter.
PARTICIPANTS
Patients with moderate-to-severe, active TED.
INTERVENTION
In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks.
MAIN OUTCOME
Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial).
RESULTS
The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation.
CONCLUSIONS
These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.
Topics: Infant, Newborn; Humans; Graves Ophthalmopathy; Quality of Life; Antibodies, Monoclonal; Exophthalmos; Immunoglobulin G; Double-Blind Method; Treatment Outcome
PubMed: 37390454
DOI: 10.1210/clinem/dgad381 -
Deutsches Arzteblatt International Sep 2022
Topics: Humans; Exophthalmos
PubMed: 36507730
DOI: 10.3238/arztebl.m2022.0128 -
Clinical Endocrinology Jun 2022In Graves' disease (GD), autoantibodies to the thyroid stimulating hormone receptor (TSHR) cause hyperthyroidism. The condition is often associated with eye signs...
TSH receptor specific monoclonal autoantibody K1-70 targeting of the TSH receptor in subjects with Graves' disease and Graves' orbitopathy-Results from a phase I clinical trial.
OBJECTIVES
In Graves' disease (GD), autoantibodies to the thyroid stimulating hormone receptor (TSHR) cause hyperthyroidism. The condition is often associated with eye signs including proptosis, oedema, and diplopia (collectively termed Graves' orbitopathy [GO]). The safety profile of K1-70 (a human monoclonal TSHR specific autoantibody, which blocks ligand binding and stimulation of the receptor) in patients with GD was evaluated in a phase I clinical trial.
PATIENTS AND STUDY DESIGN
Eighteen GD patients stable on antithyroid drug medication received a single intramuscular (IM) or intravenous (IV) dose of K1-70 during an open label phase I ascending dose, safety, tolerability, pharmacokinetic and pharmacodynamic (PD) study. Immunogenic effects of K1-70 were also determined.
RESULTS
K1-70 was well-tolerated in all subjects at all doses and no significant immunogenic response was observed. There were no deaths or serious adverse events. Increased systemic exposure to K1-70 was observed following a change to IV dosing, indicating this was the correct dosage route. Expected PD effects occurred after a single IM dose of 25 mg or single IV dose of 50 mg or 150 mg with fT3, fT4, and TSH levels progressing into hypothyroid ranges. There were also clinically significant improvements in symptoms of both GD (reduced tremor, improved sleep, improved mental focus, reduced toilet urgency) and GO (reduced exophthalmos measurements, reduced photosensitivity).
CONCLUSIONS
K1-70 was safe, well tolerated and produced the expected PD effects with no immunogenic responses. It shows considerable promise as a new drug to block the actions of thyroid stimulators on the TSHR.
Topics: Antithyroid Agents; Autoantibodies; Graves Disease; Graves Ophthalmopathy; Humans; Receptors, Thyrotropin
PubMed: 35088429
DOI: 10.1111/cen.14681 -
Frontiers in Endocrinology 2020Graves' Orbitopathy (GO) is an autoimmune orbital disorder usually presenting as a sequala of autoimmune thyroid disease. The presence of GO is associated with increased... (Review)
Review
Graves' Orbitopathy (GO) is an autoimmune orbital disorder usually presenting as a sequala of autoimmune thyroid disease. The presence of GO is associated with increased psychological burden and, in severe cases may cause blindness. While most patients with GO present with bilateral disease, asymmetric or unilateral GO may affect a significant proportion of patients diagnosed with GO. Older age, male sex, active and severe disease correlate with asymmetric disease. However, the exact mechanisms causing asymmetry remain elusive. Herein, we review the literature on asymmetric GO and highlight its differences compared with bilateral GO.
Topics: Age Factors; Animals; Graves Disease; Graves Ophthalmopathy; Humans; Sex Factors
PubMed: 33391188
DOI: 10.3389/fendo.2020.611845 -
Journal of Neuro-ophthalmology : the... Sep 2016We describe 2 unique cases of visual symptoms occurring during mastication in patients with lateral orbital wall defects. A 57-year-old man reported intermittent double...
We describe 2 unique cases of visual symptoms occurring during mastication in patients with lateral orbital wall defects. A 57-year-old man reported intermittent double vision and oscillopsia after a right fronto-temporal-orbito-zygomatic craniotomy with osteotomy of the lesser wing of the sphenoid for a complex invasive pituitary adenoma. Proptosis of the right globe was present only during mastication. Computed tomography (CT) revealed a bony defect in the right lateral orbital wall. A 48-year-old man presented with transient diplopia and scotoma in the right eye elicited by chewing. CT and magnetic resonance imaging demonstrated a bilobed lesion connecting the temporal fossa to the orbit through a defect in the right lateral orbital wall. The regional neuroanatomy and pathophysiology as pertaining to these cases are discussed.
Topics: Craniotomy; Diplopia; Exophthalmos; Humans; Magnetic Resonance Imaging; Male; Mastication; Middle Aged; Orbit; Postoperative Complications; Sphenoid Bone; Tomography, X-Ray Computed
PubMed: 26919071
DOI: 10.1097/WNO.0000000000000354 -
The Journal of Clinical Endocrinology... Dec 2023Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Early 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.
OBJECTIVE
We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.
METHODS
This 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.
RESULTS
A 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.
CONCLUSION
Teprotumumab 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.
Topics: Adult; Humans; Antibodies, Monoclonal, Humanized; Exophthalmos; Graves Ophthalmopathy; Inflammation; Protein Kinase Inhibitors; Double-Blind Method
PubMed: 37925673
DOI: 10.1210/clinem/dgad637 -
BMJ Case Reports Dec 2019
Topics: Adult; Conservative Treatment; Exophthalmos; Humans; Magnetic Resonance Imaging; Male; Orbital Diseases; Varicose Veins
PubMed: 31818898
DOI: 10.1136/bcr-2019-232887 -
Acta Ophthalmologica Sep 2022Graves' orbitopathy (GO) is a rare condition in children often considered to be a less severe condition than at an older age. The aim of our study was to analyse if... (Observational Study)
Observational Study
PURPOSE
Graves' orbitopathy (GO) is a rare condition in children often considered to be a less severe condition than at an older age. The aim of our study was to analyse if there are any factors that distinguish paediatric from adult GO in order to provide guidelines for assessing and managing paediatric GO.
METHODS
Study design is a multicentre retrospective observational case series; 115 paediatric patients diagnosed with GO who visited our university medical centres in the Netherlands and Iran between 2003 and 2019 were submitted for complete ophthalmological examinations, serological testing and/or orbital imaging. Main outcome measures focussed on the natural course and clinical picture as well as medical and surgical treatment in paediatric GO.
RESULTS
Clinical findings included proptosis (n = 97; 84.3%), eyelid retraction (n = 77; 67%) and diplopia (n = 13; 11.3%). Ninety-two patients (80%) presented with mild disease, 21 (18.3%) with moderate-severe disease and two (1.7%) with severe GO. Five patients (4.3%) underwent intravenous glucocorticoids and 25 patients underwent orbital decompression surgery. Strabismus surgery due to primary involvement of extraocular muscles was performed in two patients (1.7%). Overall, rehabilitative surgical treatment was planned in 31 patients (26.9%) with inactive disease. Two patients experienced reactivation of the disease.
CONCLUSION
Despite the fact that paediatric and adult GO are considered two separate entities, they might be the same disease with two different clinical phenotypes. Paediatric GO population presents with a comparable clinical picture regarding both soft tissue involvement and proptosis, which may require surgical intervention. Proptosis was present in the majority of paediatric GO patients. Orbital decompression was performed in 21.7% of patients.
Topics: Decompression, Surgical; Exophthalmos; Graves Ophthalmopathy; Humans; Orbit; Retrospective Studies
PubMed: 34951116
DOI: 10.1111/aos.15084