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The New England Journal of Medicine Jan 2020Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.
METHODS
In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).
RESULTS
A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.
CONCLUSIONS
Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Diplopia; Double-Blind Method; Drug Administration Schedule; Exophthalmos; Graves Ophthalmopathy; Humans; Intention to Treat Analysis; Magnetic Resonance Imaging; Middle Aged; Orbit; Receptor, IGF Type 1; Self Report
PubMed: 31971679
DOI: 10.1056/NEJMoa1910434 -
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 -
Ophthalmic Plastic and Reconstructive...Congenital optic nerve cystic-like malformations associated with normally developed globes are extremely rare. We describe 3 children who presented since birth with...
Congenital optic nerve cystic-like malformations associated with normally developed globes are extremely rare. We describe 3 children who presented since birth with proptosis, and eye motility limitation. MRI showed in all cases that the intraorbital segment of the optic nerves was malformed with large cystic-like lesions in the intraconal segment of the orbit. In all cases, biopsies of the wall of the lesions were positive for glial fibrillary acidic protein. Since this protein is a neurobiomarker that exists only in astrocytes in the central nervous system, nonmyelinating Schwann cells of peripheral nerves, and enteric glial cells, we believe that these lesions represent true opticmeningoceles.
Topics: Astrocytes; Child; Exophthalmos; Glial Fibrillary Acidic Protein; Humans; Meningocele; Neuroglia; Optic Nerve; Schwann Cells
PubMed: 33229952
DOI: 10.1097/IOP.0000000000001864 -
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 -
Klinische Monatsblatter Fur... Dec 2021Orbital trauma is a common medical emergency with potentially sight-threatening complications. Due to the confined orbital conditions, any direct injury or...
Orbital trauma is a common medical emergency with potentially sight-threatening complications. Due to the confined orbital conditions, any direct injury or space-consuming lesion may cause serious tissue damage. Possible complications are orbital fractures, foreign body injuries, development of orbital compartment syndrome and traumatic optic neuropathy. Clinical signs include periorbital hematoma or emphysema, subconjunctival hemorrhage, proptosis, decreased ocular mobility, decreased vision, increased intraocular pressure and relative afferent pupillary defect. Ophthalmic status and low-dose CT-imaging provide key information regarding the therapeutic decision. Treatment options include surgical exploration, reconstruction or decompression or a conservative approach with anti-inflammatory or anti-glaucomatous medication. Rapid interdisciplinary diagnostics and therapy is critical for early detection and prevention of irreversible functional loss respectively. Considering the frequent association with life-threatening comorbidities diagnosis may be complicated.
Topics: Decompression, Surgical; Exophthalmos; Eye Injuries; Humans; Orbit; Orbital Diseases; Orbital Fractures
PubMed: 34798667
DOI: 10.1055/a-1669-0770 -
Journal of Pediatric Hematology/oncology Aug 2022
Topics: Exophthalmos; Humans; Iron; Sulfides
PubMed: 35797179
DOI: 10.1097/MPH.0000000000002491 -
Deutsches Arzteblatt International Sep 2022
Topics: Humans; Exophthalmos
PubMed: 36507730
DOI: 10.3238/arztebl.m2022.0128 -
Klinische Monatsblatter Fur... Sep 2023Malignant masses of the orbit include a large variety of neoplasms of epithelial or mesenchymal origin. The treatment of orbital malignancies is an essential...
Malignant masses of the orbit include a large variety of neoplasms of epithelial or mesenchymal origin. The treatment of orbital malignancies is an essential interdisciplinary field of medicine that integrates ENT medicine, facial surgery, plastic surgery, neurosurgery, oncology and radiology.The main symptom of malignant orbital masses is the exophthalmos. A symptom that can help to differentiate a benign from a malignant orbital mass can be the pain. The main diagnostic tool is the MRI including new sequences like DWI and DCE.After presenting symptoms and diagnostic strategies of malignant orbital masses, this article starts with the description of malignant epithelial neoplasms of the lacrimal gland. Furthermore, it describes new insights in orbital lymphomas, followed by the discussion of semimalignant orbital masses. Last but not least the text deals with malignant neoplasms of the skin that can grow secondarily in the orbit. Finally, the manuscript discusses orbital metastases.
Topics: Humans; Orbit; Orbital Neoplasms; Magnetic Resonance Imaging; Orbital Diseases; Exophthalmos
PubMed: 37586398
DOI: 10.1055/a-2129-1194 -
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 -
Survey of Ophthalmology 2021A 69-year-old woman developed a carotid-cavernous fistula (CCF) after firing a shotgun. Initially, the patient had mild visual symptoms, but later on developed prominent...
A 69-year-old woman developed a carotid-cavernous fistula (CCF) after firing a shotgun. Initially, the patient had mild visual symptoms, but later on developed prominent features of CCF including chemosis, proptosis, ophthalmoparesis and conjunctival injection . The fistula was embolized via an intravascular coiling procedure. We are unaware of another patient who developed a CCF due to blunt force from shotgun use.
Topics: Aged; Carotid-Cavernous Sinus Fistula; Conjunctival Diseases; Embolization, Therapeutic; Exophthalmos; Female; Humans
PubMed: 32628947
DOI: 10.1016/j.survophthal.2020.06.007