Discussion
redness, caruncle swelling, CAS/active disease, diplopia, ±, TED, strabismus, fibrosis, conjunctival edema, −2.41, −3.5, orbital pain, proptosis, low disease activity
DIPLOPIA, POSITIVE, INFLAMMATION, DISEASE, STRABISMUS, FIBROSIS, PROPTOSIS, FATTY DEGENERATION, INFLAMMATORY DISEASE
TED activity historically has been assessed based on CAS, which includes the presence of eyelid and conjunctival edema or redness, caruncle swelling, and orbital pain in primary gaze or with eye movement. The presence of 3 or more of these has previously justified classifying patients with active or inflammatory disease (Patients can present with inflammatory or noninflammatory symptoms across the natural history of the disease for varying periods. Hence, the current notion that chronic patients are synonymous with longer-duration and asymptomatic disease needs re-evaluation. In a survey of patients without classic TED activity (ie, noninflammatory or low CAS), nearly identical percentages of these non-CAS signs and symptoms were seen in longer-duration (mean 9 years) vs shorter-lived (mean 1.4 years) disease, including proptosis, which was present in 59% vs 53%, respectively (TED is characterized by overexpression of IGF-1R on cell membranes of orbital fibroblasts and B- and T-cells (Since the initial successful trials and clinical experience with teprotumumab in reducing the symptoms of moderate to severe, high CAS/active disease, the drug has been reported efficacious in a wide array of patients with TED, including in case series of those with longer disease duration with low and higher CAS (This trial is unique in its placebo-controlled, masked design as well as in its population. It included patients with longer disease duration (mean of 5 years) manifesting proptosis, but with low inflammation (CAS ≤1), who were not candidates for surgery. Arguably, these patients may be more difficult to treat as they may manifest more fibrosis and be irremediable (Patients in this trial had a statistically significant decrease, as assessed by LS mean changes in mm of proptosis and a higher percentage of patients with a 2 mm reduction from baseline (62%) as compared with placebo. The mean observed change in proptosis at Week 24 with teprotumumab from baseline was −2.41 mm, which was smaller than that seen in the largest chronic TED case series published of 31 patients (−3.5 mm) with 90% having a 2 mm reduction at Week 24 (Per protocol assessments were consistent with the ITT analyses. Of note, the placebo-assigned patient who received an infusion of teprotumumab in error had a 3 mm improvement in proptosis, and 2 patients in the teprotumumab group missed the Week 18 assessment, possibly contributing to the transient dip in response rate at that time point.An important feature of this trial design was the inclusion of a placebo control arm, as natural changes in this long-duration, low CAS population are not well documented. Among patients who received placebo, 25% had a proptosis response at Week 24, which was still significantly lower than that observed with teprotumumab (62%).A reduction in volumes of both retro-orbital muscle and fat was observed in patients on teprotumumab who had MRI, indicating that both compartments are reduced by teprotumumab and contribute to the reduction in proptosis. Previously published studies demonstrated that, over time, there is an increase in orbital fat volume and a decrease in muscle volume, as well as an increase in intramuscular fatty degeneration, in those with longer-duration TED with low disease activity (Positive changes from baseline were noted with the GO-QOL overall (+9), Visual (+8.7) and Appearance (+10) subscales; however, when compared with placebo only the visual subscale reached statistical significance. This lack of significance for the appearance subscale was mostly due to a relatively high appearance-related improvement in the placebo group (+7). This interesting finding deserves further study. Previous data have suggested that patients can adapt to appearance-related changes over time but given the relatively long duration of TED in these patients, this seems unlikely, especially given the relatively poor GO-QOL Appearance subscale scores at baseline (40 in the placebo, and 46.4 in the teprotumumab group). In the only study of GO-QOL in chronic/low inflammation TED known to the authors with a similar duration of TED, appearance-related QOL was also noted to be worse than visually related QOL: Overall GO-QOL score of 60.5 ± 21.8, an appearance subscore of 58.6 ± 24.0, and a visual function subscore of 62.3 ± 25.1, indicating the heavy burden of appearance-related changes in these patients (A limitation was that only 14/42 (33%) teprotumumab and 4/20 (20%) placebo patients had diplopia at baseline, making this study underpowered to address potential impact on diplopia. The differences likely relate to a combination of this low power to ascertain benefit and that, by study design, patients were required to have stable disease with no history of prior decompression or strabismus surgery upon study entry. Therefore, patients with chronic diplopia would have had surgery or treatment previously and so would have been ineligible for the study. Another limitation was a short follow-up period (30 days), which did not allow for assessment of improvements over the longer term after completion of treatment.No new safety signals were identified in this study as compared to previous studies (