Erfolgreich durch internationale Zusammenarbeit

Endocrinology and Metabolism

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.24

Received 08 July 2026;
Accepted 11 August 2026;
Published 15 August 2026

BIOLOGIC THERAPIES IN THYROID EYE DISEASE: FROM IMMUNOPATHOGENESIS TO CLINICAL PRACTICE

Filip Chodań¹ , Krystian Domeracki¹ ,
Dagmara Laufer¹ , Olga Klimczak¹ ,
Estera Sośniecka¹ , Adam Miler¹

¹ Medical University of Silesia, Katowice, Poland

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  filip.ch3@wp.pl

ABSTRACT

Background

Thyroid Eye Disease is a complex autoimmune inflammatory disorder associated with Graves’ disease that may lead to orbital tissue remodeling, proptosis, diplopia and vision impairment. Although intravenous glucocorticoids remain the standard first-line therapy for active moderate-to-severe disease, their limited efficacy and adverse effects have stimulated the development of targeted biologic therapies.

Aim

This narrative review aims to summarize and critically evaluate current and emerging biologic therapies in thyroid eye disease, with particular emphasis on their immunopathogenic targets, clinical efficacy, safety, strength of evidence, and potential role in clinical practice.

Materials and methods

A structured literature search was conducted in PubMed, Google Scholar, and ClinicalTrials.gov for publications from 2021 to 2026, with earlier studies included selectively when they provided essential information on pathogenesis or biologic therapy. Clinical studies, experimental studies, systematic reviews, clinical guidelines, and relevant clinical trial registrations were considered. A total of 81 sources were included.

Results

Biologic therapies targeting key inflammatory pathways in thyroid eye disease have shown variable clinical efficacy. Teprotumumab demonstrated the strongest evidence, significantly reducing disease activity, proptosis and diplopia, with sustained therapeutic effects. Rituximab and tocilizumab primarily improved inflammatory activity, particularly in glucocorticoid-resistant disease, although rituximab showed inconsistent results across randomized trials. Emerging agents targeting IGF-1R, IL-6, TSHR, and FcRn pathways have shown promising preliminary outcomes, while IL-17 inhibitors failed to demonstrate clinical benefit.

Conclusions

Biologic therapies have expanded the treatment options available for patients with moderate-to-severe thyroid eye disease and represent an important step toward more personalized management. Teprotumumab currently has the strongest evidence for improving disease activity, proptosis, and diplopia, whereas the clinical roles of rituximab, tocilizumab, and emerging biologic agents remain less clearly defined. Treatment selection should consider the strength of the available evidence, expected clinical benefit, safety profile, and individual patient characteristics. High treatment costs and limited availability remain important barriers to broader implementation in routine clinical practice.

Keywords: Thyroid Eye Disease; Graves’ Orbitopathy; biologic therapy; teprotumumab; rituximab; tocilizumab; IGF-1 receptor; monoclonal antibodies.

INTRODUCTION

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves’ disease. It is a relatively rare disorder, occurring more frequently in women than in men, with an annual incidence of approximately 2.7–3.3 versus 0.5–0.9 cases per 100,000 individuals, respectively [1]. In most cases, the disease follows a mild and self-limiting course; however, a small proportion of patients develop more severe forms [1,2]. Moderate-to-severe and sight-threatening forms account for approximately 5–6% of all TED cases [1]. In recent decades, a decline in the prevalence of TED among patients with Graves’ disease, as well as a reduction in disease severity at presentation, has been observed. This trend is likely related to improved thyroid function control, earlier diagnosis, and reduced exposure to risk factors, particularly cigarette smoking [1,3].

The clinical presentation is characterized predominantly by proptosis, orbital tissue swelling, and pain, especially retrobulbar pain exacerbated by eye movements. Eyelid and conjunctival erythema are also common findings. In more advanced stages, patients may develop diplopia and sight-threatening complications, such as compressive optic neuropathy or corneal ulceration secondary to incomplete eyelid closure [1,4].

Thyroid eye disease is most commonly associated with hyperthyroidism in the course of Graves’ disease; however, it may also occur in patients with hypothyroidism, including Hashimoto’s thyroiditis, as well as in euthyroid individuals. A key element of patient assessment is the Clinical Activity Score (CAS), which distinguishes the active inflammatory phase from the inactive phase of the disease and therefore has direct implications for treatment selection [1]. Table 1 presents the parameters included in the CAS assessment.

Early diagnosis, smoking cessation, and maintenance of euthyroidism are essential for reducing the risk of TED progression. Smoking increases the risk and severity of the disease and reduces the response to immunosuppressive therapy [1,5–7]. Both hyperthyroidism and hypothyroidism may worsen ocular manifestations, while high TRAb levels are associated with a more severe disease course [5,8,9]. Radioactive iodine therapy may increase the risk of TED progression in susceptible patients, and prophylactic glucocorticoids should therefore be considered in high risk cases [8,10].

TED occurs more frequently in women, although men may develop more severe disease [11]. Hypercholesterolemia, diabetes mellitus, and low vitamin D levels have also been associated with less favourable clinical features or treatment outcomes in TED, although the strength and clinical significance of these associations remain uncertain [12–15].

Thyroid eye disease results from autoimmune activation of orbital fibroblasts, leading to inflammation and tissue remodeling. Binding of thyrotropin receptor antibodies to TSHR activates these cells, while functional interaction between TSHR and IGF-1R amplifies intracellular signaling. Activated orbital fibroblasts promote inflammatory cell recruitment and contribute to glycosaminoglycan production, adipogenesis, and fibrosis [16–18].

In active TED, the inflammatory response involves Th1 cells and mediators such as IL-1β, IFN-γ, and TNF-α, which promote orbital fibroblast activation, glycosaminoglycan synthesis, and tissue edema [19,20]. Th17 cells and IL-17A also contribute to persistent inflammation, adipogenesis, and fibrosis, whereas Th2-associated mediators and TGF-β may support humoral responses and tissue remodeling [20–23].

Follicular helper T cells contribute to TED pathogenesis through IL-21-mediated B-cell activation and enhanced TRAb production. B lymphocytes function both as autoantibody-producing cells and as antigen-presenting cells, thereby sustaining the autoimmune response [24,25]. IL-6 participates in the interaction between B cells, Tfh cells, Th17 cells, and orbital fibroblasts. Increased IL-6 concentrations have been detected in the serum and tears of patients with active TED and are associated with higher CAS values [26–30]. Proinflammatory cytokines, including IL-1β and IL-6, may promote adipogenic differentiation of orbital fibroblasts, whereas TGF-β and IL-11 contribute to myofibroblast differentiation and fibrotic tissue remodeling [31–34].

The management of TED includes restoration and maintenance of euthyroidism and complete smoking cessation [1,35,36]. Mild active disease is generally managed with local ocular measures, while a six month course of selenium may be considered in patients with recent onset disease, particularly in selenium deficient regions [1,37,38]. For active moderate to severe TED, intravenous methylprednisolone, commonly combined with mycophenolate sodium, remains a principal first line treatment [1]. The standard intravenous methylprednisolone regimen comprises a cumulative dose of 4.5 g administered over 12 weekly infusions. A cumulative dose of 7.5 g may be considered in more severe cases, while the total dose should not exceed 8 g per treatment course because of the risk of serious hepatic, cardiovascular, metabolic, and infectious complications [1,39–45].

Combination therapy with glucocorticoids and other immunosuppressive agents, such as mycophenolate sodium, cyclosporine, or azathioprine, increases therapeutic response rates and allows glucocorticoid dose reduction [46–48]. Sight-threatening dysthyroid optic neuropathy constitutes a medical emergency requiring immediate intervention. Failure to achieve adequate clinical improvement within a short time interval (1–2 weeks) represents an absolute indication for urgent orbital decompression surgery [1,49].

In a proportion of patients, conventional immunosuppressive therapies fail to provide sustained disease control or satisfactory improvement of symptoms, particularly diplopia and proptosis. Moreover, the risk of severe adverse effects, especially those associated with high-dose glucocorticoid therapy, highlights the need for the development of more selective treatments targeting the key immunopathogenic mechanisms of thyroid eye disease.

AIM AND OBJECTIVES

The aim of this narrative review is to summarize and critically evaluate current and emerging biologic therapies for thyroid eye disease, with particular emphasis on their immunopathogenic targets, clinical efficacy, safety, strength of evidence, and potential role in clinical practice.

The objectives are:

1. To describe the main immunopathogenic pathways in thyroid eye disease that serve as targets for biologic therapy.
2. To summarize the mechanisms of action of currently available and emerging biologic agents.
3. To evaluate their clinical efficacy, including effects on disease activity, proptosis, diplopia, ocular motility, and quality of life.
4. To assess their safety, limitations, strength of evidence, and potential role in the management of thyroid eye disease.

MATERIALS AND METHODS

This study was designed as a narrative review with a structured literature search.

A comprehensive search of the literature was conducted using the following freely accessible databases and sources: PubMed, Google Scholar, ClinicalTrials.gov. The search covered publications from 2021 to 2026. Earlier studies were included selectively when they provided essential data on pathogenesis or biologic therapy relevant to current clinical practice.

The search strategy was structured using Boolean operators. The main search query included combinations of the following terms: ("thyroid eye disease" OR "Graves' orbitopathy" OR "Graves' ophthalmopathy") AND ("biologic therapy" OR "monoclonal antibodies" OR “teprotumumab” OR “rituximab” OR “tocilizumab”). Additional terms such as “pathogenesis”, “clinical trial”, and “treatment outcomes” were used to refine the search where appropriate.

Inclusion criteria were as follows:

1. Articles published in English.
2. Clinical studies, randomized controlled trials, observational studies, relevant experimental studies, systematic reviews, clinical guidelines, and relevant clinical trial registrations addressing biologic therapy in thyroid orbitopathy.
3. Publications reporting mechanisms of action, disease activity, ophthalmological outcomes, clinical efficacy, safety, or the potential role of biologic therapies in clinical practice.

Exclusion criteria were as follows:

1. Articles not related to thyroid orbitopathy or not addressing biologic therapy.
2. Conference abstracts without full text, letters without original data, and publications lacking clinically relevant outcomes.
3. Duplicate publications.

The selection process included initial screening of titles and abstracts, followed by full text assessment for eligibility. A total of 81 sources were included in the final analysis. The selection process was descriptive and did not follow a formal systematic review protocol.

RESULTS

In view of the limitations of conventional therapies, increasing attention has been directed toward biologic agents targeting the key pathogenic mechanisms underlying thyroid eye disease.

Teprotumumab is a fully human monoclonal antibody directed against IGF-1R that acts at an early stage of the inflammatory cascade in TED. By inhibiting the IGF-1R/TSHR signaling axis, it reduces orbital fibroblast activation and suppresses the development of the inflammatory response, as indicated in Figure 1 [50]. Teprotumumab is currently the only biologic agent approved by the Food and Drug Administration (FDA) for the treatment of thyroid eye disease [51]. In a phase III randomized controlled trial involving patients with active moderate-to-severe TED of short duration (≤9 months) and baseline disease activity assessed by a CAS ≥4, intravenous teprotumumab resulted in a significantly greater reduction in proptosis compared with placebo (83% vs 10%; p<0.001). Treatment was also associated with significant reductions in CAS, improvement in diplopia, and enhanced quality of life [52,53]. In cases of relapse or inadequate response to initial therapy, retreatment may lead to clinically meaningful reductions in proptosis and diplopia [54]. Teprotumumab may also be effective in patients with longstanding, low-inflammatory TED, leading to significant improvement in proptosis; however, its effects on other clinical parameters, including diplopia and quality of life, remain less consistent [55]. Therapeutic benefits of teprotumumab have also been shown to persist after treatment completion [51,56]. In addition, the drug may reduce orbital asymmetry by producing greater improvement in the more severely affected orbit [57]. A meta-analysis demonstrated that teprotumumab is more effective than intravenous methylprednisolone in reducing proptosis in moderate-to-severe TED, highlighting its potential clinical advantage [58]. However, the high cost and limited availability of the therapy may represent substantial barriers to its implementation in routine clinical practice. The most commonly reported adverse events included infusion reactions, hyperglycemia, muscle spasms, diarrhea, and hearing impairment [52]. Hyperglycemia occurs predominantly in patients with diabetes or prediabetes, supporting the need for close glycemic monitoring during treatment [59]. Studies investigating a subcutaneous formulation of teprotumumab are currently ongoing, and preliminary findings suggest efficacy comparable to intravenous administration, potentially with greater treatment convenience [60].

According to current guidelines issued by the European Group on Graves’ Orbitopathy, the European Thyroid Association, and the American Thyroid Association, teprotumumab may be considered in patients with active moderate-to-severe TED, particularly in cases of marked proptosis, insufficient response to glucocorticoids, or glucocorticoid intolerance [1,61]. Other anti-IGF-1R antibodies are also under investigation. Lonigutamab, evaluated in phase I/II trials, has shown promising results in reducing disease activity and proptosis, while veligrotug is currently being assessed in phase III studies, with preliminary data suggesting potential improvements in proptosis, diplopia, and disease activity [62,63].

Rituximab is a monoclonal antibody directed against the CD20 antigen that induces B-cell depletion, thereby limiting their role in sustaining the inflammatory response in TED [64]. In a randomized clinical trial comparing rituximab with intravenous glucocorticoids in patients with active moderate-to-severe TED, both treatment regimens reduced disease activity; however, the effect was significantly greater in the rituximab group. The response rate reached 100% in rituximab-treated patients compared with 69% in the glucocorticoid group, and no disease reactivation was observed during follow-up in patients receiving rituximab. No significant differences were found in proptosis reduction or diplopia improvement. Both groups demonstrated significant reductions in serum TSH receptor antibody levels, although without significant differences between rituximab and glucocorticoids. Rituximab treatment was also associated with improved ocular motility and a lower number of surgical interventions, suggesting a potential disease-modifying effect [65]. However, another randomized controlled trial failed to demonstrate superiority of rituximab over placebo in patients with active moderate-to-severe TED. No significant differences were observed in disease activity reduction or other clinical outcomes, while treatment was associated with a higher incidence of adverse events [66].

As reflected in Figure 1, tocilizumab is a monoclonal antibody that blocks the interleukin-6 receptor (IL-6R), thereby inhibiting IL-6 signaling, which plays a major role in orbital fibroblast activation and amplification of the inflammatory response in TED. In a randomized controlled trial involving patients with active moderate-to-severe glucocorticoid-resistant TED, tocilizumab significantly increased the clinical response rate compared with placebo (93.3% vs 58.8%; p = 0.04). Tocilizumab treatment was also associated with a higher proportion of patients achieving low disease activity (CAS <3) and a significant reduction in proptosis compared with placebo [67]. Observational studies indicate that the therapeutic effects of tocilizumab may persist during long-term follow-up and may be accompanied by reduced TSH receptor antibody levels; however, its effect on diplopia remains inconclusive [68,69]. According to current guidelines, rituximab and tocilizumab may be considered as second-line therapies in selected patients with active moderate-to-severe TED, particularly in cases of inadequate response or intolerance to glucocorticoids [1,61].

Beyond tocilizumab, other agents targeting the IL-6 pathway are under investigation in TED, including antibodies directed against the IL-6 receptor, such as satralizumab (phase III), and antibodies targeting IL-6 itself, such as pacibekitug (TOUR006, phase II) [70,71]. Current evidence suggests that teprotumumab exerts the strongest effect on proptosis reduction among currently investigated biologic therapies, whereas rituximab and tocilizumab appear to primarily influence inflammatory disease activity.

Despite a strong pathophysiological rationale, IL-17 inhibitors such as secukinumab have failed to demonstrate clinical efficacy in TED, as confirmed in a phase III randomized trial that showed no significant improvement compared with placebo [72].

TNF-α inhibitors, including infliximab and adalimumab, have been used in isolated case reports involving patients with active, occasionally severe TED, resulting in reductions in pain, edema, and disease activity (CAS); however, randomized controlled trials confirming their efficacy are lacking [73–75].

Batoclimab, an FcRn receptor inhibitor, leads to a significant reduction in IgG antibody levels, including TRAb. Nevertheless, a randomized trial failed to demonstrate a significant improvement in proptosis compared with placebo, despite observed reductions in extraocular muscle volume and improvements in quality of life. The study was terminated prematurely because of an unexpected increase in serum cholesterol levels among treated patients [76].

LASN01 is a monoclonal antibody targeting the IL-11 receptor, leading to inhibition of fibrosis and hyaluronan production [77]. It is currently being evaluated in phase II clinical trials [78].

As shown in Figure 1, TSH receptor-blocking antibodies, such as K1-70, represent the most causally targeted therapeutic approach in TED, as they directly bind the receptor and prevent its activation by both TSH and TRAb [79]. Phase I studies and a case report demonstrated good tolerability and preliminary clinical efficacy, including improvement in TED manifestations such as proptosis reduction and decreased inflammatory activity [80,81].

DISCUSSION

The introduction of biologic therapies has substantially expanded the therapeutic landscape of thyroid eye disease, providing new treatment options for patients who respond inadequately to conventional immunosuppressive therapy. However, the currently available evidence indicates that biologic agents should not be regarded as interchangeable, as the strength of clinical evidence and therapeutic outcomes differ considerably between individual therapies [61,65–67,72,76].

Among the available biologic agents, teprotumumab is supported by the most robust clinical evidence and has demonstrated the most consistent efficacy across key clinical outcomes [51,56]. In contrast, evidence for rituximab and tocilizumab remains less consistent or is limited to selected clinical settings, while several emerging therapies have shown promising preliminary results but require confirmation in larger clinical trials [64,67,70–72,77,78]. These observations suggest that treatment selection should be based not only on the expected therapeutic effect but also on the clinical characteristics of individual patients.

Safety profiles also differ between individual biologic therapies and should be considered alongside efficacy. Teprotumumab has been associated with hearing impairment and hyperglycemia, particularly in patients with diabetes or prediabetes [52,59]. In one randomized trial, rituximab was associated with a higher incidence of adverse events than placebo [66]. Batoclimab treatment was associated with an unexpected increase in serum cholesterol levels, which contributed to the premature termination of the study [76]. These differences indicate that treatment selection and monitoring should take into account the specific safety profile of each agent and individual patient risk factors.

Limitations

The available evidence is limited by substantial heterogeneity among published studies, including differences in patient selection, disease duration, baseline inflammatory activity, outcome measures, and follow-up periods. Direct comparative studies between biologic therapies are lacking, long-term follow-up remains insufficient, and data on clinical predictors of treatment response are limited. These factors hinder reliable comparisons between individual agents, optimization of patient selection, and establishment of their precise roles within evidence-based treatment algorithms for thyroid eye disease.

CONCLUSION

Biologic therapies have expanded the treatment options available for patients with moderate-to-severe thyroid eye disease and represent an important step toward more personalized management. Teprotumumab currently has the strongest evidence for improvement in disease activity, proptosis, and diplopia, whereas the clinical role of other biologic agents remains less clearly defined. Treatment selection should therefore consider the strength of evidence, expected clinical benefit, safety profile, and individual patient characteristics. High treatment costs and limited availability remain important barriers to broader implementation in routine clinical practice.

DISCLOSURE

Author Contributions

Conceptualization and methodology: Filip Chodań, Krystian Domeracki. Investigation and data collection: Filip Chodań, Olga Klimczak, Dagmara Laufer. Formal analysis: Krystian Domeracki, Estera Sośniecka, Adam Miler. Writing – original draft: Filip Chodań, Krystian Domeracki, Olga Klimczak, Dagmara Laufer, Estera Sośniecka. Writing – review & editing: Krystian Domeracki, Adam Miler, Estera Sośniecka. Supervision: Filip Chodań.

All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

The authors received no external funding for this work.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

No new datasets were generated or analyzed in this narrative review.

Use of AI

Artificial intelligence tools, including ChatGPT and other OpenAI systems, were used to support language refinement, structural improvement, and the development of certain sections of the manuscript. All AI-generated content was thoroughly reviewed and verified by the authors.

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