Literature
Clinical Pearls & Morning Reports
Published January 22, 2020
In the trial by Douglas et al., was teprotumumab effective in reducing proptosis and diplopia in patients with clinically active thyroid eye disease?
Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition. In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, Douglas et al. investigated the efficacy and safety of teprotumumab, an insulin-like growth factor I receptor inhibitor, as compared with placebo in patients with clinically active thyroid eye disease. Read the Original Article here.
Clinical Pearls
Q: What are some of the manifestations of thyroid eye disease?
A: Thyroid eye disease is a rare, debilitating autoimmune disease. The disease course transitions from an active progressive period characterized by inflammation to a stable and fibrotic (inactive) period after 1 to 3 years. Remodeling of the orbit and upper face results in diverse presentations, including dry eyes, increased lacrimation, local irritation, and eyelid retraction in mild cases, but it can also manifest as pronounced proptosis, diplopia (due to uneven motility restriction), and optic nerve compression, with potential vision loss in more severe disease.
Q: What are some of the factors involved in the pathogenesis of thyroid eye disease?
A: Autoantibodies (thyroid-stimulating immunoglobulins) targeting the thyrotropin receptor drive hyperthyroidism in Graves’ disease, but data indicate that additional autoantigens and antibodies are involved in the development of thyroid eye disease. The insulin-like growth factor I receptor (IGF-IR), which is overexpressed by orbital fibroblasts and B and T cells in Graves’ disease and thyroid eye disease, plays a central role. Thyrotropin receptors and IGF-IRs form physical and functional complexes that cause thyroid eye disease, including hyaluronan accumulation and cytokine expression, resulting in inflammation, edema, and expansion of extraocular muscle and adipose tissue. Teprotumumab, a fully human monoclonal antibody, attenuates signaling initiated at either receptor, thereby blocking pathologic immune responses in active thyroid eye disease.
Morning Report Questions
Q: In the trial by Douglas et al., was teprotumumab effective in reducing proptosis and diplopia in patients with clinically active thyroid eye disease?
A: The primary and all secondary outcomes were better among those who received teprotumumab than among those who received placebo. The primary outcome was a proptosis response (defined as a reduction in proptosis of ≥2 mm from baseline in the study eye without a corresponding increase of ≥2 mm in the fellow eye) at week 24. With respect to the primary outcome, 83% of the patients in the teprotumumab group had a proptosis response, as compared with 10% of the patients in the placebo group (between-group difference, 73 percentage points; 95% CI, 59 to 88; P<0.001). A diplopia response (i.e., a reduction in diplopia of ≥1 grade) was observed in a higher percentage of patients in the teprotumumab group than in the placebo group at the first visit and each subsequent visit.
Q: What were some of the adverse events of special interest in the trial by Douglas et al.?
A: Adverse events of special interest that occurred in less than 5% of the patients in either trial group within 21 days after the last dose included the development of hyperglycemia in two patients (<5%) in the teprotumumab group (both cases were mild). Hearing impairment was reported in five patients in the teprotumumab group: two had hypoacusis, which resolved; one had deafness, which resolved; one had autophony (bilateral intermittent echoing of the patient’s own voice that occurred in conjunction with sore throat), which resolved; and one had mild patulous eustachian tube, which resolved. Five patients (four women) in the teprotumumab group had a body-weight loss of at least 5.0 kg during the trial.