Thyroid Eye Disease: Do Biologics hold the key to better outcomes in this complex autoimmune disease?


Published on MedED:  19 February
Type of article: Summary Article
MedED Catalogue Reference: MOT006

Compiler: Linda Ravenhill
SourcesL JAMA Ophthalmology, EJE, Therapeutic Advances In Ophthalmology, DrugBankonline 



 

Thyroid Eye Disease (TED) - also known as Grave's ophthalmology - is a complex autoimmune condition characterised by progressive inflammation which causes a "..remodelling of the orbital soft tissues and periorbital areas." (pg2) 5
 
The condition is relatively rare. The European Group on Graves' orbitopathy (EUGOGO) estimates its incidence at 0.54–0.9 cases per 100 000 / year in men, and 2.67–3.3 cases per 100 000 / year in women.
 
TED is usually diagnosed on clinical presentation in the presence of active thyroid disease. This poses a clinical challenge, in large part due to the misperception that the condition occurs only in the presence of hyperthyroidism, specifically Graves' disease. According to researchers Men, Kossler & Wester et al., as many as 20% of patients can present with TED symptoms prior to developing thyroid dysfunction. They further state that while most TED patients develop hyperthyroidism (90%), 4–5% will develop hypothyroidism, and as many as 5–6% may exhibit euthyroidism.5

Effective management of these patients has proven as challenging as making a diagnosis. Therapeutic options have been limited: oral glucocorticoids for mild cases: intravenous methylprednisolone (IVMP) for moderate-to-severe cases; and a combination of IV methylprednisolone and mycophenolate sodium for the long-term treatment of patients with more complicated TED.1


Most clinicians acknowledge that these treatments do not always result in the desired or complete outcomes for patients with moderate-to-severe cases of TED.8  
 
Historically, TED research centred on the role of Thyroid Stimulating Hormone Receptor (TSHR) in the development of the condition. More recently, researchers began to focus on the role of inflammatory mediators in the underlying disease process; the most likely of which is insulin-like growth factor-1 (IGF-1). 

Insulin-like growth factor-1 receptor (IGF-1R) - a cell surface protein - appears to be upregulated in TED patients. When combined with TSHR – the central antigen thought to be responsible for TED – they form a complex signalling partnership.
8

This shift in the understanding of the underlying aetiology of TED focused the search for treatment options on the development of biologic therapies. Men, Kossler & Wester state:


  "Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches." (pg1)5
 
Tep
rotumumab - the first biologic developed for the treatment of TED - is the result of this new focus.  

Termed a "breakthrough" therapy by the FDA and approved for use in  July 2020
, teprotumumab is an IgGI monoclonal antibody that inhibits the IGF-1R/TSHR signalling pathway, thereby reducing "...the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED." (pg1) 5, 2
 
Two large clinical trials - conducted by Smith, Kahal, &  Etza et al., and Douglas, Kahaly & Patel et al. -  showed that the biologic was associated with a clinically significant reduction in inflammatory proptosis and diplopia over 24 weeks, demonstrating its effectiveness as a treatment choice.
7,4  However, research comparing treatment efficacy with teprotumumab to treatment with the current standard protocol of IVMP had not been conducted. Douglas, Dailey, and Subramanian et al., the authors of a recent paper published in JAMA Ophthalmology in February 2022, set out to address this question.3

Their study - a meta-analysis - set out to determine firstly, the improvements in proptosis and diplopia in patients on the most recommended IVMP treatment protocol, according to literature research; and secondly, using a match-adjusted indirect comparison study, to compare these results to results obtained in patients on teprotumumab and those on a placebo.
 
They found that 1) when compared to the placebo, IVMP is associated with a slight change from baseline in proptosis and a modest change in diplopia; and 2) when compared to IVMP, teprotumumab was associated with more significant improvements in proptosis, and patients were "twice as likely to have a 1 grade or higher reduction in diplopia." 
(E1)3
 
While further studies are required, based on this research, in cases of moderate-severe TED, biologics such as teprotumumab may indeed hold the key to unlocking better outcomes for patients afflicted with this debilitating condition.
 
References:
1.Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021;185(4):G43-G67. Published 2021 Aug 27. doi:10.1530/EJE-21-0479 Accessed 18 Feb 2022
2.Drugbank.com: Teprtoumumab.  https://go.drugbank.com/drugs/DB06343. Accessed 18 Feb 2022
3.Douglas RS, Dailey R, Subramanian PS, et al. Proptosis and Diplopia Response With Teprotumumab and Placebo vs the Recommended Treatment Regimen With Intravenous Methylprednisolone in Moderate to Severe Thyroid Eye Disease: A Meta-analysis and Matching-Adjusted Indirect Comparison. JAMA Ophthalmol. Published online 17 February 2022. doi:10.1001/jamaophthalmol.2021.6284  Accessed 18 Feb 2022
4.Douglas  RS., Kahaly  GJ., Patel  A.,  et al.  Teprotumumab for the treatment of active thyroid eye disease. ?N Engl J Med. 2020;382(4):341-352. doi:10.1056/NEJMoa1910434   Accessed 19 February 2022
5.Men, C. J., Kossler, A. L., & Wester, S. T. (2021). Updates on the understanding and management of thyroid eye disease. Therapeutic advances in ophthalmology, 13, 25158414211027760. https://doi.org/10.1177/25158414211027760 Accessed 18 Feb 2022 
6.Smith  TJ, Kahaly  GJ, Ezra  DG,  et al.  Teprotumumab for thyroid-associated ophthalmopathy. ?N Engl J Med. 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949PubMedGoogle ScholarCrossref
7.Smith TJ, Janssen JA. Building the Case for Insulin-Like Growth Factor Receptor-I Involvement in Thyroid-Associated Ophthalmopathy. Front Endocrinol (Lausanne). 2017;7:167. Published 2017 Jan 3. doi:10.3389/fendo.2016.00167.  Accessed 19 February 2022

Contributor: Linda Ravenhill
Linda Ravenhill is a medical professional with an MA in Journalism. She has worked in the medical, technology and digital development spaces for over 25 years, & has a particular interest in the impact of technology on the delivery of healthcare in the Sub-Saharan Africa region.

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