There is need for alternative treatment to circumvent current treatment limitations
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 flashes2,3. 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 antibodies3,6. 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 TED3,6.
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:
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 proptosis3.
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.
Iyza F. Baig
Baig is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.
Pascoe is affiliated with McGovern Medical School at The University of Texas Health Science Center in Houston (UTHealth), Houston.
Andrew G. Lee, MD
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.
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, CurrÃ² 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.