Thyroid eye disease (TED), also known as Graves’ orbitopathy, is driven by autoimmune processes that lead to orbital inflammation, oedema (inflammation due to fluid accumulation) and potential vision loss. Traditional management includes high-dose intravenous corticosteroids, orbital radiotherapy, PO steroids, orbital injections of steroids, observation, and surgery. For decades, management of thyroid eye disease (TED) relied largely on these interventions. However, the future of TED treatment lies in biologic therapies and personalized approaches with continued multidisciplinary collaboration to optimize patient care. But as with all novel approaches, it also brings new questions and concerns as it is important to have a comprehensive understanding before choosing biologics as a treatment option for TED.
What Are Biologic Therapies and Why They Matter for TED
Biologics are medications made from living cells or proteins and are designed to interfere with specific molecular targets such as receptors, cytokines, or immune cells rather than broadly suppressing the immune system. These novel agents for Thyroid Eye Disease aim to inhibit specific pathways implicated in orbital tissue inflammation, offering potentially greater efficacy and a more favorable safety profile than traditional approaches. In TED, some of the key molecular drivers that are targeted by biologics include the thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). Both these receptor proteins are found on orbital fibroblasts and immune cells. When such receptors are stimulated (by various inflammatory triggers), these orbital fibroblasts become activated and begin to produce and release inflammatory cytokines. This leads to hyaluronan (a type of connective tissue), fat expansion, and extraocular muscle swelling, leading to classic TED symptoms such as ocular pain, swelling, proptosis (protrusion of the eyes) and diplopia. By interrupting these pathways, biologics target the root of orbital expansion and inflammation rather than focusing only on symptomatic relief, thereby offering the possibility of better functional and cosmetic outcomes for patients with TED.
Key Biologics in TED
Teprotumumab (IGF-1R antagonist)
A significant advancement in biologics for TED management is teprotumumab, a human monoclonal antibody that inhibits the IGF-1R signaling cascade. Teprotumumab effectively reduces inflammation, hyaluronan accumulation, and fat deposition within the orbit, thereby mitigating proptosis and improving ocular symptoms such as pain, swelling, and diplopia. Collectively, these effects enhance quality of life by reducing disfigurement and providing symptomatic relief. Several randomized controlled clinical trials have demonstrated significant outcomes in patients with active moderate-to-severe TED (1). While teprotumumab is recognized as a major therapeutic advance, its safety has been well established, and ongoing post-marketing studies continue to monitor long-term effects, optimal timing, and benefits in later fibrotic stages to ensure it remains both safe and effective.
Tocilizumab (IL-6 receptor antagonist)
Tocilizumab is an anti-interleukin-6 (IL-6) receptor antibody that blocks the activity of IL-6, a pro-inflammatory cytokine that promotes inflammation in TED. Tocilizumab is particularly useful for patients who do not respond to corticosteroid therapy. In patients with moderate-to-severe corticosteroid-resistant TED, Tocilizumab reduced inflammation, improved clinical activity scores, and alleviated symptoms like pain, redness, and swelling (2).
Rituximab (CD20-directed B-cell therapy)
Rituximab acts on B cells, which are the key producers of autoantibodies and may be more effective than corticosteroids for active cases of TED. Studies show a significant decrease in clinical activity scores and inflammation in patients treated with RTX, with some research indicating that RTX may help induce a longer-lasting remission.
Emerging Biologics
Several other biologics that target more novel pathways in TED are currently in development and may further expand the treatment armamentarium. These include the neonatal Fc receptor, IL-17 receptor, TNF-α inhibitors and newer IGF-1R inhibitors.
Changes in Treatment Options for Patients and Clinicians
Earlier Window of Opportunity
Because biologics tackle the core mechanisms of disease, they are most effective if used during the active/inflammatory phase of TED i.e., before fibrosis becomes dominant. Hence there is a greater emphasis on prompt and early diagnosis of TED if biological interventions are to be opted for.
More Personalized Approach
Due to the availability of multiple biologic options (IGF-1R, IL-6, B cells, TNF-α etc), treatment can be tailored based on disease severity, underlying immune profile, patient comorbidities, prior response to steroids, and risk tolerance.
Better Functional & Cosmetic Outcomes
The effective outcomes with respect to meaningful reductions in proptosis and diplopia with biologics means fewer patients may end up needing extensive reconstructive surgery. Hence, improvements in quality of life, disfigurement, and diplopia all become realistic goals.
Shift in Standard of Care
Where once high-dose steroids were the default for moderate/severe TED, now biologics are being considered at much earlier stages, especially in patients at risk of vision compromise or significant disfigurement. This marks a positive evolution in treatment guidelines and consensus statements.
Practical Implications for Patients
Ask the Right Questions
When faced with a TED diagnosis, it is prudent to inquire about the following with your doctor:
- Is the disease currently in the active/inflammatory phase?
- Is the disease moderate-to-severe (for example, proptosis > 3-4 mm, double vision, optic nerve risk)?
- Should biologic therapy be initiated and if so, how soon, and which agent is likely best for me?
- What are the risks, side effects, cost, and monitoring requirements to be aware of for the specific biologic agent?
- Will surgery still be required (orbital decompression, eyelid repair)?
Biologics tend to work better when used early. Delay may reduce their efficacy if the disease has advanced to a fibrotic (scarred) stage. That said, ongoing evidence suggests even patients with longer-duration disease can benefit.
Side Effects and Monitoring
While safer than traditional broad immunosuppression, biologics come with certain risks such as increased blood sugar and heightened risks of infection due to immune suppression. Thus, immunologic labs, glucose monitoring, and coordination with your endocrinologist/ophthalmologist are an essential part of the follow-up workups when prescribed biologics. That said, the advantages of biologics far outweigh the inconvenience from these side effects, which, for the most part, are also manageable.
Costs and Access
Biologics can be expensive, and insurance coverage may vary. Patients should engage early with the treatment team and administrative support to understand financial pathways and access. Our care coordination team, with over 25 years of experience, offers expert guidance and support to help patients navigate their financial options.
Integration with Other Treatments
Biologic therapy does not always replace other treatments, and supportive care should still be continued. These include lubrication for dryness of the eyes, selenium shampoos for dandruff care, and smoking cessation. For thyroid eye disease (TED), it is also essential to manage the underlying thyroid condition. In select cases, radiation or surgery may be appropriate.
Future Directions with Biologics
Biologics are a recent addition to the toolkit for TED treatment and are constantly undergoing improvement. Better biomarkers and imaging assessments are needed for patient stratification to determine the best response. Combination therapies (e.g., biologic + low-dose steroid) are also being explored to see if outcomes can be optimized, along with a focus on developing oral formulations of the biologics, given that all current regimens are injectables (3).
Start Your Path to Advanced Biologic Care for TED
The treatment landscape of TED is undergoing a profound shift with biologic therapies being the preferred option for early-stage TED and disease that shows an indolent response to corticosteroid therapy. If you or a loved one has TED and is interested in discussing biologic options, do not hesitate to schedule an appointment with Dr. Raymond Douglas.
References
- Kulbay M, Tanya SM, Tuli N, Dahoud J, Dahoud A, Alsaleh F, Arthurs B, El-Hadad C. A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches. Int J Mol Sci. 2024;25(21). Epub 20241029. doi: 10.3390/ijms252111628. PubMed PMID: 39519180; PMCID: PMC11546489.
- Boutzios G, Chatzi S, Goules AV, Mina A, Charonis GC, Vlachoyiannopoulos PG, Tzioufas AG. Tocilizumab improves clinical outcome in patients with active corticosteroid-resistant moderate-to-severe Graves’ orbitopathy: an observational study. Front Endocrinol (Lausanne). 2023;14:1186105. Epub 20230622. doi: 10.3389/fendo.2023.1186105. PubMed PMID: 37424868; PMCID: PMC10327634.
- Men CJ, Kossler AL, Wester ST. Updates on the understanding and management of thyroid eye disease. Ther Adv Ophthalmol. 2021;13:25158414211027760. Epub 20210630. doi: 10.1177/25158414211027760. PubMed PMID: 34263138; PMCID: PMC8252358.
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