Meta-Analysis

Proptosis and Diplopia Response With Teprotumumab and Placebo vs the Recommended Treatment Regimen With Intravenous Methylprednisolone in Moderate to Severe Thyroid Eye Disease: A Meta-analysis and Matching-Adjusted Indirect Comparison.

Authors: Raymond S Douglas, Roger Dailey, Prem S Subramanian...

IMPORTANCE

Thyroid eye disease can be a debilitating autoimmune disorder characterized by progressive proptosis or diplopia. Teprotumumab has been compared with placebo in randomized clinical trials, but not with intravenous methylprednisolone (IVMP), which sometimes is used in clinical practice for this condition.

OBJECTIVE

To conduct a matching-adjusted indirect comparison of teprotumumab vs IVMP vs placebo.

DATA SOURCES

Deidentified patient-level data from teprotumumab trials and aggregate-level data from literature on the most recommended regimen of IVMP.

STUDY SELECTION

PubMed and Embase were searched for randomized/observational studies using key terms and controlled vocabulary. Full texts of eligible articles were reviewed and cataloged.

DATA EXTRACTION AND SYNTHESIS

Conducted by 1 reviewer (R.A.Q.) and 1 verifier (R.B.), including study characteristics, eligibility criteria, baseline characteristics, and outcomes.

MAIN OUTCOMES AND MEASURES

Changes in proptosis by millimeter and diplopia response (percentage with ≥1 grade reduction) from baseline to week 12 in patients receiving IVMP and placebo, and to week 24 in patients receiving teprotumumab.

RESULTS

The search identified 1019 records, and 6 through manual searches, alerts, and secondary references. After excluding duplicates and screening full-text records, 12 IVMP studies were included in the matching-adjusted indirect comparison (11 for proptosis change [n = 419], 4 for diplopia response [n = 125], and 2 teprotumumab [n = 79] and placebo [n = 83] comparator studies). Treatment with IVMP resulted in a proptosis difference of -0.16 mm (95% CI, -1.55 to 1.22 mm) from baseline to week 12 vs placebo. The proptosis treatment difference between IVMP and teprotumumab of -2.31 mm (95% CI, -3.45 to -1.17 mm) favored teprotumumab. Treatment with IVMP (odds ratio, 2.69; 95% CI, 0.94-7.70) was not favored over placebo in odds of diplopia response; however, teprotumumab was favored over IVMP (odds ratio, 2.32; 95% CI, 1.07-5.03).

CONCLUSIONS AND RELEVANCE

This meta-analysis suggests that use of IVMP is associated with a small, typically not clinically relevant, change from baseline in proptosis vs placebo, with modest changes in diplopia. While this nonrandomized comparison suggests that use of teprotumumab, compared with IVMP, is associated with greater improvements in proptosis and may be twice as likely to have a 1 grade or higher reduction in diplopia, randomized trials comparing these 2 treatments would be warranted to determine if 1 treatment is superior to the other to a clinically relevant degree.

Topics: Antibodies, Monoclonal, Humanized; Diplopia; Exophthalmos; Graves Ophthalmopathy; Humans; Methylprednisolone

PubMed: 35175308
DOI: 10.1001/jamaophthalmol.2021.6284

Authors: Sebastian Paul, Frank Tost, Björn-Christian Hübner...

Topics: Humans; Exophthalmos

PubMed: 36507730
DOI: 10.3238/arztebl.m2022.0128

Authors: Mathias Tiedemann Svendsen, Georg Authried

Topics: Humans; Meningioma; Exophthalmos; Meningeal Neoplasms

PubMed: 37170741
DOI: No ID Found

Review

Authors: Grigorios Panagiotou, Petros Perros

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

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.

Authors: Jadwiga Furmaniak, Jane Sanders, Paul Sanders...

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

Review

Authors: Hans Olav Ueland, Mikael Thomassen Neset, Paal Methlie...

PURPOSE

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. Patients may be severely affected with eyelid retraction, exophthalmos, diplopia, pain, and threatened vision. Autoantibodies against thyroid-stimulating hormone receptor and insulin-like growth factor 1 receptor have shown associations with pathophysiological and clinical traits. Autoantibodies against thyroid-stimulating hormone receptor is in current clinical use as biomarker, but not with unambiguous diagnostic performance. A biomarker with high diagnostic accuracy and/or prognostic capability would be of immense value in diagnosing TED, especially in subclinical cases or when TED precedes the thyroid dysfunction. This article is a literature review on molecular biomarkers of TED.

METHODS

A literature search was performed using PubMed and Embase. Studies on molecular biomarkers in blood, tear fluid, and urine were included in the review.

RESULTS

Forty-six papers were included, of which 30, 14, and 2 studies on biomarkers in blood, tears, and urine, respectively. Fourteen of the papers evaluated the diagnostic performance of various biomarkers, 12 in blood and 2 in tears. Most studies evaluated single biomarkers, but 3 tested a panel of several markers. Except for autoantibodies against thyroid-stimulating hormone receptor, the reported diagnostic performances for the biomarkers were not confirmed in independent cohorts. In 32 studies, no or insufficient performance data were given, but the findings indicated involvement of various biologic mechanisms in TED including inflammation, oxidative stress, fibrosis, lipid metabolism, and ocular surface microflora.

CONCLUSIONS

Currently, serum autoantibodies against thyroid-stimulating hormone receptor is the only molecular biomarker with clinical utility in patients with TED. Several potential biomarkers have been investigated, and particularly panels of multiple biomarkers in tears are promising. To improve patient care, biomarkers in TED should be studied further.

Topics: Humans; Graves Ophthalmopathy; Biomarkers; Graves Disease; Autoantibodies; Thyrotropin

PubMed: 38054982
DOI: 10.1097/IOP.0000000000002466

Authors: I-Wen Chen, Cheng-Wei Lin

Topics: Amphotericin B; Antifungal Agents; Blindness; Brain Diseases; Debridement; Exophthalmos; Eye Diseases; Fatal Outcome; Female; Humans; Magnetic Resonance Imaging; Maxillary Sinusitis; Middle Aged; Mucormycosis; Optic Neuritis

PubMed: 31015350
DOI: 10.1503/cmaj.181210

Authors: Michael Stuart Howells, Rohit Sharma

Topics: Adult; Conservative Treatment; Exophthalmos; Humans; Magnetic Resonance Imaging; Male; Orbital Diseases; Varicose Veins

PubMed: 31818898
DOI: 10.1136/bcr-2019-232887

Authors: Pradeep Mettu, M Tariq Bhatti, Mays A El-Dairi...

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

Review

Authors: Rajat Maheshwari, Ezekiel Weis

Thyroid associated orbitopathy, also known as Graves' orbitopathy, is typically a self-limiting autoimmune process associated with dysthyroid states. The clinical presentation may vary from very mild disease to severe irreversible sight-threatening complications. Despite ongoing basic science and clinical research, the pathogenesis and highly effective therapeutic strategies remain elusive. The present article reviews the pathophysiology, clinical presentation, and management of this common, yet poorly understood disease, which remains a challenge to the ophthalmologist.

Topics: Exophthalmos; Graves Ophthalmopathy; Humans

PubMed: 22446901
DOI: 10.4103/0301-4738.94048