Considering use of teprotumumab in thyroid eye disease patients

Teprotumumab shows significant promise in the treatment of thyroid eye disease, and ophthalmologists should be aware of the drug as a viable therapeutic option

Grave’s disease is an autoimmune disease characterized by an autoantibody-stimulated thyroid gland leading to enlargement and hyperthyroidism. Features include increased heart rate, increased metabolic rate, and ocular abnormalities such as proptosis¹. Graves-mediated ophthalmopathy is also known as Thyroid Eye Disease (TED). Glucocorticoids and radiotherapy are the current mainstay of treatment for TED but are associated with inconsistent results and a variety of side effects such as urinary tract infections, glucose intolerance, Cushingoid features, and hot flashes^2,3. In addition, proptosis resolution is minimal when treating with glucocorticoids and radiotherapy³. If TED reaches the extent of compressive optic neuropathy, corneal exposure, or orbital congestion, decompression surgery is indicated, but evidence of its effectiveness is limited⁴.

In addition, a common postoperative complication is debilitating strabismus⁴. A possible therapeutic agent was rituximab, but trials have shown conflicting evidence regarding its effectiveness⁵. Therefore, there is a need for an alternative treatment that can circumvent the current treatment limitations.

The pathogenesis of Graves’ disease has been linked to the presence of TSHR antibodies^3,6. TSHRs are found in orbital tissues and orbital fibroblasts, and their stimulation has been linked to the accumulation of hyaluronan and the expansion of connective and fat tissue that leads to TED^3,6.

However, according to numerous in vitro studies, IGF-1R is also overexpressed in Graves’ disease, and autoantibodies recognizing and activating the IGF1R protein occurs in the condition as well³. Furthermore, Tsui et. al compared the levels of TSHR versus IGF1R protein expression in orbital fibroblasts of TED patients, and found that levels of IGF1R were much higher than TSHR levels, which were scantily expressed⁶. Evidence suggests that the activity of thyrotropin and thyroid stimulating antibodies depend on the activity of IGF-1R to some degree³.

Furthermore, through IGF-IR activation, fibroblasts have been shown to produce chemoattractants that cause infiltration of the orbital tissue by T cells and B cells⁶. IGF-IR and TSHR also form a receptor complex that when activated causes the activation of both receptors³. Because IGF-IR antibodies have been shown to mitigate the TSHR antibodies, blocking the stimulation of IGF-IR disrupts the pathway for the orbital tissues expansion of TED³.

Therefore, due to its potential role in the pathogenesis of TED, treatment with a human IGF-IR monoclonal antibody, teprotumumab, was proposed. In 2017, the results of a recent double blinded, randomized controlled trial of teprotumumab showed great promise in alleviating proptosis, diplopia in improving the quality of life of patients with TED3. To evaluate the efficacy of teprotumumab, a double-masked, randomized, multicenter, placebo-controlled trial was performed by Smith et al with three phases:

• A screening phase, lasting 2–6 weeks
• An intervention phase, lasting 24 weeks
• A follow-up phase, lasting 48 weeks Efficacy of treatment was measured by Clinical Activity Scores, Hertel exophthalmometer measurements, Graves’ ophthalmopathy-specific quality-of-life (GO-QO) score, and subjective diplopia assessment³.

Results showed that the difference between the trial group and the placebo group was apparent by week 6 with 43% of the teprotumumab group having a response in terms of the assessment factors listed above while only 4% of the placebo group experienced a response with a statistically significant difference between the two³. At week 24, 69% of the teprotumumab group and 20% of the placebo group experienced statistically significant reduction in assessment factors³.

Ultimately, the trial found that treatment with teprotumumab lead to statistically significant and clinically relevant reduction in subjective diplopia, Clinical Activity Score, proptosis, and GO-QOL (3).

The main adverse effect noted was hyperglycemia, which did not worsen after teprotumumab treatment3. In conclusion, the double-masked, randomized, multicenter, placebo-controlled trial by Smith et. al demonstrated that a 24-week course of teprotumumab benefits patients with moderate to severe Graves ophthalmopathy by enhancing quality of life as well as reducing their Clinical Activity Score and proptosis^3.

Although a similar reduction in proptosis can be achieved with decompression surgery, this drug doesn’t include the risk of recurrence or strabismus exacerbation³. The long-term benefits of teprotumumab are still in the process of being explored and future studies are required to establish its efficacy compared to glucocorticoids and assess the safety profile of the drug long term³. Based on these results however, teprotumumab shows significant promise in the treatment of TED, and ophthalmologists should be aware of the drug as a viable therapeutic option.

Disclosures:

Iyza F. Baig
E: iyza.baig@uth.tmc.edu
Baig is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.

Alexis Pascoe
E: alexis.pascoe@uth.tmc.edu
Pascoe is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.

Andrew G. Lee, MD
E: aglee@houstonmethodist.org
Dr. Lee is affiliated with Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston; Baylor College of Medicine, Houston; adjunct professor of ophthalmology; Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medical College, Houston; clinical professor, UTMB Galveston, TX and the UT M.D. Anderson Cancer Center, Houston; and adjunct professor of ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA. The authors did not indicate any proprietary interests relevant to the subject matter.

References:

1. Smith TJ, Hegedus L. Graves' Disease. The New England Journal of Medicine. 2016;375:1552-1565. doi:10.1056/NEJMra1510030.

2. Marcocci C, Luigi, Tanda ML, et al. Comparison of the Effectiveness and Tolerability of Intravenous or Oral Glucocorticoids Associated with Orbital Radiotherapy in the Management of Severe Graves Ophthalmopathy: Results of a Prospective, Single-Blind, Randomized Study. Journal of Clinical Endocrinology & Metabolism. 2001;86(8):3562-3567. doi:10.1210/jc.86.8.3562.

3. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for Thyroid-Associated Ophthalmopathy. The New England Journal of Medicine. 2017;376(18):1748- 1761. doi:10.1056/NEJMoa1614949

4. Wu CY, Niziol LM, Musch DC, Kahana A. Thyroid-Related Orbital Decompression Surgery: A Multivariate Analysis of Risk Factors and Outcomes. Ophthalmic Plastic and Reconstructive Surgery. 2017;33(3):189- 195. doi:10.1097/ iop.0000000000000699.

5. Salvi M, Vannucchi G, Currò N, et al. Efficacy of B-Cell Targeted Therapy With Rituximab in Patients With Active Moderate to Severe Graves Orbitopathy: A Randomized Controlled Study. The Journal of Clinical Endocrinology & Metabolism. 2015;100(2):422-431. doi:10.1210/jc.2014-3014.

6. Tsui S, Naik V, Hoa N, et al. Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves Disease. The Journal of Immunology. 2008;181(6):4397- 4405. doi:10.4049/jimmunol.181.6.4397.