Medication for Thyroid Eye Disease

Written by Christina Young and Edited by Olivia Cooper

Hyperthyroidism is a condition that affected about 1-2% of the U.S. population in 2016 and is characterized by symptoms of weight loss, temperature sensitivity, fatigue, anxiety, and polydipsia, or abnormal thirst [1]. The syndrome is caused by increased activity of the thyroid gland, an organ in one’s neck that typically produces hormones necessary for metabolism and maintaining many functions in the body. The main regulator of the thyroid gland is the rate of iodine uptake; iodine is a common mineral in many foods, such as seafood and salt, and is converted to thyroid hormones [2]. Hyperthyroidism is a general term referring to unregulated iodine uptake, and can be caused by a number of factors, including inflammation of the thyroid gland, and most prominently, Graves’ Disease. Graves’ Disease is characterized by the production of antibodies that attack one’s thyroid gland and other tissues, causing greater uptake of iodine and therefore, imbalances of thyroid hormones [2]. One major effect of Graves’ Disease induced hyperthyroidism is the onset of Graves’ Ophthalmopathy, also called Thyroid Eye Disease (TED), which affects roughly 30% of those with Graves’ Disease [3] [4]. Patients with TED may experience symptoms including bulging eyes, light sensitivity, retinal pressure, and vision loss in addition to symptoms of hyperthyroidism [3].

Recently, the FDA has approved a drug, teprotumumab, that targets the onset of TED and the disease’s progression. Teprotumumab targets the IGF-I pathway, a cascade of cellular proteins and signaling that typically activates growth hormones. When this pathway is disrupted, some cells are unable to maintain themselves. In the event of this lack of regulation, cells are more easily attacked by antibodies involved in Graves’ Disease and can lead to the onset of TED [5]. Based on a global study that looked at the effectiveness of this drug in 2019, the use of teprotumumab suggested significant decreases in the eye-bulging symptom in patients over the course of 21 weeks [6]. Acting as a competitor against the hormones that would typically activate the IGF-I pathway, teprotumumab reduced attacks on retinal tissue. While there is no current treatment for TED, the discovery of this drug is projected to alter the approach to TED from physicians and patients alike, although it does have its limits. The study followed patients for 21 weeks and had them self-report on the effects of the drug on their symptoms, which introduces a subjective bias to how the drug could be evaluated. Also, the researchers did not provide any long-term follow-up on patients, which is especially concerning for 5% of study participants who reported adverse effects [6]. 

Previous work has been done to find a suitable treatment for TED, with the consideration of a number of different drugs with different mechanisms of actions to target different characteristics of the disease. Ciclosporin was one of the earliest drugs proposed for use against TED, although due to the toxicity of the drug in high doses, it was not approved as a treatment for the disease. Later drugs such as rituximab, which was aimed at reducing immune cell numbers, and tocilizumab, which reduced inflammation and should reduce the gathering of antibodies to tissues, were also proposed and rejected due to insufficient evidence of efficacy [7]. Today, teprotumumab is the first approved drug for the treatment of TED, and has so far shown significant improvement in the symptoms of patients with the disease, although the long term effects and work on TED treatments is still on-going.

References:

1. De Leo, S., Lee, S.L., Braverman, L.E. (2016). Hyperthyroidism. Lancet, 388: 906-918. 
2. “Graves’ Disease.” Mayo Clinic, Mayo Clinic, https://www.mayoclinic.org/diseases-conditions/graves-disease/symptoms-causes/syc-20356240. Accessed 6 Nov 2020.
3. “Graves’ Eye Disease.” American Thyroid Association, American Thyroid Association, https://www.thyroid.org/graves-eye-disease/. Accessed 7 Nov 2020.
4. Cawood, T., Moriarty, P., O’Shea, D. (2004). Recent developments in thyroid eye disease. BMJ, 329: 385.
5. Smith, T.J., Huetwell, E.G.K., Hegedus, L., Douglas, R.S. (2012). Role of IGF-1 pathway in the pathogenesis of Graves’ orbitopathy. Best Practice & Research in Clinical Endocrinology & Metabolism, 26: 291-302.
6. Douglas, R.S., Kahaly, G.J., Patel, A., Sile, S., Thompson, E.H.Z., Perdok, R., Fleming, J.C., Fowler, B.T., Marcocci, C., Marino, M., Antonelli, A., Dailey, R., Harris, G.J., Eckstein, A., Schiffman, J., Tang, R., Nelson, C., Salvi, M., Wester, S., Sherman, J.W., Vescio, T., Holt, R.J., Smith, T.J. (2020). Teprotumumab for the Treatment of Active Thyroid Eye Disease. The New England Journal of Medicine, 382: 341-352.
7. Khong, J.J., McNab, A. (2020). Medical treatment in thyroid eye disease in 2020. British Journal of Ophthalmology, 7: 1161.