Alexis Pascoe

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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 proptosis

. 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

. In addition, proptosis resolution is minimal when treating with glucocorticoids and radiotherapy

. If TED reaches the extent of compressive optic neuropathy, corneal exposure, or orbital congestion, decompression surgery is indicated, but evidence of its effectiveness is limited

In addition, a common postoperative complication is debilitating strabismus

. A possible therapeutic agent was rituximab, but trials have shown conflicting evidence regarding its effectiveness

. 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

. 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

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 well

. 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 expressed

. Evidence suggests that the activity of thyrotropin and thyroid stimulating antibodies depend on the activity of IGF-1R to some degree

Furthermore, through IGF-IR activation, fibroblasts have been shown to produce chemoattractants that cause infiltration of the orbital tissue by T cells and B cells

. IGF-IR and TSHR also form a receptor complex that when activated causes the activation of both receptors

. 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 TED

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 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 assessment

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 two

. At week 24, 69% of the teprotumumab group and 20% of the placebo group experienced statistically significant reduction in assessment factors

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

Although a similar reduction in proptosis can be achieved with decompression surgery, this drug doesn’t include the risk of recurrence or strabismus exacerbation

. 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 term

. 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.

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.

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. 

. 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. 

. 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. 

. 2008;181(6):4397- 4405. doi:10.4049/jimmunol.181.6.4397.

Articles

There is need for alternative treatment to circumvent current treatment limitations

Considering use of teprotumumab in thyroid eye disease patients 

A randomized controlled trial has demonstrated a viable contender for maintaining corticosteroid remission in GCA: the interleukin-6 (IL-6) receptor inhibitor, tocilizumab (TCZ).

Giant cell arteritis (GCA) is a systemic vasculitis that produces a granulomatous inflammation of large- and medium-sized-arteries, most commonly involving the aorta and extracranial branches of the carotid arteries.

Classically affecting patients over the age of 50 years, GCA is known to be the most common primary vasculitis affecting Western countries.

While headaches, myocardial infarction, stroke, and claudication of the jaw are important clinical manifestations of GCA5, those relevant to an ophthalmological perspective include transient ischemic visual symptoms and permanent blindness (e.g., ischemic optic neuropathy or central retinal artery occlusion).

Complications of the vasculitis can result from ischemia secondary to arterial occlusion, systemic inflammation, and aneurysm formation and rupture due to persistent arterial wall injury1 ; therefore, prompt and effective control of inflammation is essential. High-dose corticosteroids (e.g., 1–1.5 mg/kg of oral prednisone per day or intravenous (IV) methylprednisolone) should be considered urgently in the treatment of GCA. Earlier treatment may lead to more rapid symptomatic relief of headache, normalization of inflammatory markers, and reduction or prevention of vision loss after initiation.

While corticosteroids have significantly decreased the incidence of blindness in patients with GCA, studies have shown that vascular inflammation persists even after corticosteroid therapy, allowing for progressive occlusion of the affected vessels.

In addition, since the majority of patients tend to flare as corticosteroid dosage is reduced, long-term treatment with a slow reduction of steroids is thereby necessary.

Unfortunately, long-term corticosteroid use can lead to significant comorbidities such as infection, fractures, cataracts, diabetes, and even psychosis.

Consultation with the primary-care provider and/or rheumatologist may be necessary to help with treatment and management of side effects.

For this reason, the search for corticosteroid-sparing treatment regimens in GCA has been under way. Prior randomized controlled trials evaluating corticosteroid-sparing agents such as methotrexate and tumor necrosis factor inhibitors have failed or shown inconclusive or conflicting results.

However, a randomized controlled trial has finally demonstrated a viable contender for maintaining corticosteroid remission in patients with GCA: the interleukin-6 (IL-6) receptor inhibitor, tocilizumab (TCZ).

The rationale for blocking the receptor for IL-6 is based on the cytokine’s central role in regulating both innate and acquired immunities.3 Produced by T-cells, B-cells, endothelial cells, fibroblasts, and macrophages, IL-6 has been shown to be increased in inflamed arteries, potentiating the inflammatory responses of GCA.

A study by Weyand et al (2000) suggested that disease activity in GCA correlates with serum levels of IL-6, and that compared to erythrocyte sedimentation rate (ESR), IL-6 may be a more sensitive biological marker for disease activity in GCA patients who were untreated and treated with corticosteroids.

Consequently, numerous studies (including a phase II trial) examining TCZ were performed, and results suggested the high efficacy of the IL-6 receptor inhibitor in inducing and maintaining remission in GCA.

More recently, the results of the much awaited GiACTA trial, a 1-year, multicenter, randomized, controlled, double blind trial, show significant promise in the use of TCS for inducing and maintaining remission in GCA.

In the GiACTA trial, 251 patients were randomly assigned to one of four treatment groups

> 162 mg of subcutaneous TCZ weekly + 26- week prednisone taper (cumulative prednisone dose = 1,862 mg)
	> 162 mg of subcutaneous TCZ every two weeks + 26-week prednisone taper (cumulative prednisone dose = 1,862 mg)
	> Placebo + 26-week prednisone taper (cumulative prednisone dose = 3,296 mg)
	> Placebo + 52-week prednisone taper (cumulative prednisone dose = 3818 mg)

Sustained remission was defined as normalization of C-reactive protein (30 mm/hour) from week 12 to week 52 while adhering to prednisone taper.

Outcomes were measured at 52 weeks and included rates of corticosteroid-free remission maintained by each TCZ group compared with those of the placebo group treated with a 26-week prednisone taper and a 52-week taper prednisone taper.

Results of the GiACTA trial showed that by 52 weeks, 56% of patients receiving TCZ weekly and 53% of those receiving it biweekly had achieved and sustained remission, compared to 14% of the placebo group on the 26-week prednisone taper, and 18% of those on the 52-week prednisone taper.

Furthermore, 23% and 26% of those on TCZ weekly and biweekly had a flare, respectively, compared to 68% of those on the 26-week prednisone taper, and 49% of those on the 52-week taper.


	Safety of TCZ was also evaluated: 15% and 14% of the weekly and biweekly TCZ groups respectively reported serious adverse events, while those in the placebo 26-week taper and 52-week taper reported 22% and 25% adverse events respectively.

Infection was the most common adverse event in all groups, and occurred in 7% of those on weekly TCZ, 4% on biweekly TCZ, 4% of those on placebo and 26-week taper, and 12% of those on placebo and 52- week taper.

In conclusion, GiACTA trial has demonstrated with a 1-year, randomized, placebo controlled design that TCZ was more effective in sustaining corticosteroid-free remission than both placebo groups with 26- week and 52-week prednisone taper.

Furthermore, weekly treatment with TCZ resulted in better control of disease activity than biweekly TCZ.5 Some criticisms have arisen since publication of the GiACTA trial,

 and while further studies may be needed to characterize its long-term safety profile and efficacy, TCZ shows significant promise in the treatment of GCA.

Ophthalmologists should be aware of these newer agents including TCZ and should refer selected GCA patients for consideration of treatment in the appropriate clinical situation.

1. Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: Interleukin-6 as a biologic marker of disease activity. Arthritis and Rheumatism. 2000;43:1041-1048.

2. Villiger PM, Prof, Adler S, MD, Kuchen S, MD, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387:1921-1927.

3. Unizony SH, Dasgupta B, Fisheleva E, et al. Design of the tocilizumab in giant cell arteritis trial. International Journal of Rheumatology. 2013;2013:1–10.

4. Loricera J, Blanco R, HernÃ¡ndez JL, et al. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Seminars in Arthritis and Rheumatism. 2015;44:717-723.

5. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:317-328.

6. Ferfar Y, Mirault T, Desbois AC, et al. Biotherapies in large vessel vasculitis. Autoimmunity Reviews. 2016;15:544-551.

7. GonzÃ¡lez-Gay MA, Loricera J, Blanco R. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:1493.

8. Walker UA. Trial of Tocilizumab in Giant-Cell Arteritis. New England Journal of Medicine. 2017;377:1493- 1495

Alexis Pascoe

Articles

Considering use of teprotumumab in thyroid eye disease patients

Exploring tocilizumab for giant cell arteritis cases