Recent advances in thyroid orbitopathy treatment: A narrative review

Pathological changes in thyroid orbitopathy

Thyroid-associated orbitopathy (TO) is characterized by several pathological changes that contribute to its clinical manifestations.^[4], ^[5] These changes include orbital inflammatory infiltration, de novo adipogenesis, upregulated synthesis of glycosaminoglycans (GAGs), and differentiation of orbital fibroblasts into myofibroblasts.

Orbital inflammatory infiltration

The inflammatory process in TO is marked by the infiltration of orbital tissues by mononuclear cells, predominantly T cells (mainly CD4+), monocytes, and macrophages.^[6], ^[7], ^[8] This pattern of infiltration supports the notion that TO is chiefly a T cell-mediated disease. In some cases, mast cells and dendritic cells are also present.^[9], ^[10] The severity of TO is often linked with the degree of inflammatory cell infiltration, with active and severe stages showing more prominent infiltration by CD4+ T cells and monocytes/macrophages.^[11] The clinical activity score (CAS), which measures disease activity, is positively correlated with the extent of lymphocytic and macrophage infiltration.

De novo adipogenesis

De novo adipogenesis refers to the formation of new adipose tissue within the orbital connective tissue. This process primarily affects the extraocular muscles, leading to an increase in orbital fat volume while sparing the muscle fibers. The expansion of orbital fat contributes to the characteristic proptosis (bulging eyes) seen in TO patients.^[12]

Upregulated synthesis of glycosaminoglycans (GAGs)

Orbital fibroblasts in TO produce increased amounts of hydrophilic GAGs, such as hyaluronan (HA). These molecules attract water, leading to tissue edema and further expansion of orbital tissues. The accumulation of GAGs is a significant factor in the development of tissue swelling and discomfort experienced by TO patients.^[13]

Differentiation of orbital fibroblasts into myofibroblasts

Orbital fibroblasts can differentiate into myofibroblasts, which are cells that contribute to extracellular matrix deposition and tissue fibrosis. This differentiation process is influenced by various cytokines and growth factors. The resulting fibrosis and remodeling of orbital tissues are responsible for many of the chronic changes observed in TO, including restricted eye movements and strabismus (misalignment of the eyes). ^[14]

Interaction of T and B cells in TO

The autoimmune response in TO involves complex interactions between T cells and B cells. Antigen-presenting cells, such as B cells and dendritic cells, play a crucial role in initiating the immune response. These cells present thyroid-stimulating hormone receptor (TSHR) peptides to T cell receptors on autoreactive T helper cells, triggering the activation of both T and B cells. This activation results in the production of TSHR antibodies and various pro-inflammatory cytokines, which amplify and sustain orbital inflammation. These immune responses also promote the activation, proliferation, and differentiation of orbital fibroblasts, contributing to the pathological changes observed in TO.^[15], ^[16]

Roles of T cells in TO

CD4+ T cells dominate the inflammatory milieu in TO and can be classified into several subtypes, including Th1, Th2, Th17, and regulatory T (Treg) cells. Each subtype plays a distinct role in the immune response and disease progression.^[17], ^[18]

Th1 cells

Th1 cells are involved in cell-mediated immunity and produce pro-inflammatory cytokines such as IL-1β, IL-2, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). These cytokines activate orbital fibroblasts, promoting their proliferation and enhancing the production of GAGs. The activation of Th1 cells is crucial in the early stages of TO, contributing to the initiation and maintenance of inflammation.^[19]

Th2 cells

Th2 cells are associated with humoral immunity and produce cytokines such as IL-4, IL-5, IL-10, and IL-13. These cytokines mediate the production of autoantibodies, tissue remodeling, and fibrosis. Th2-mediated responses become more prominent in the later stages of TO, contributing to chronic tissue changes and fibrosis.^[20]

Th17 cells

Th17 cells have emerged as an important subset of CD4+ T cells due to their pro-inflammatory and pro-fibrotic properties. Th17 cells produce cytokines such as IL-17A, which positively correlate with disease activity and severity in TO. IL-17A enhances the secretion of pro-inflammatory cytokines and promotes the differentiation and proliferation of orbital fibroblasts. Th17 cells play a significant role in perpetuating inflammation and fibrosis in TO.^[21]

Regulatory T (Treg) cells

Treg cells possess immunoregulatory functions and are essential for maintaining immune tolerance. However, their role in TO is complex and not fully understood. There is conflicting evidence regarding the correlation between peripheral blood Treg levels and TO activity, severity, and treatment response. Further research is needed to elucidate the precise role of Treg cells in TO.^[22]

Orbital fibroblasts as key effector cells

Orbital fibroblasts play a central role in mediating the pathological changes in TO. These fibroblasts are activated by various stimuli, including cytokines, growth factors, and interactions with immune cells.^[23], ^[24] Once activated, orbital fibroblasts produce pro-inflammatory cytokines and chemokines, attracting more inflammatory cells to the orbit. The interaction between CD40 on fibroblasts and CD40L on T cells further activates and proliferates fibroblasts, contributing to tissue remodeling and fibrosis.

Hyaluronan production

One of the critical functions of orbital fibroblasts in TO is the overproduction of hydrophilic GAGs, particularly hyaluronan (HA).^[25] HA production is stimulated by the activation of TSHR and various inflammatory mediators such as IL-1, TNF-α, IFN-γ, transforming growth factor-beta (TGF-β), platelet-derived growth factors (PDGF), and prostaglandins. The accumulation of HA in orbital tissues leads to edema and tissue expansion, contributing to the clinical symptoms of TO.

Adipogenesis and fibrosis

Orbital fibroblasts can differentiate into adipocytes (fat cells) or myofibroblasts under different stimuli. The balance between these two pathways influences the extent of tissue remodeling in TO. Thy1- fibroblasts (preadipocytes) have a strong capacity to differentiate into mature adipocytes, a process enhanced by PPARγ agonists (e.g., rosiglitazone), IL-1β, IL-6, and pro-adipogenic prostaglandins. In contrast, Thy1+ fibroblasts can differentiate into myofibroblasts under the influence of TGF-β, contributing to extracellular matrix deposition and fibrosis.^[26] The relative proportion of Thy1- and Thy1+ fibroblasts determines the extent of adipogenesis and fibrosis in the orbital tissues.

Oxidative stress in TO

Oxidative stress, defined as an imbalance between the production and elimination of reactive oxygen species (ROS), is a significant mechanism in the pathogenesis of TO. In vitro studies have shown higher levels of hydrogen peroxide (a potent ROS inducer) in TO orbital fibroblasts compared to controls, while levels of antioxidants such as glutathione peroxidase are reduced.^[27] ROS promote the proliferation of orbital fibroblasts, the release of GAGs, and the secretion of pro-inflammatory cytokines and various inflammatory molecules. Environmental factors like cigarette smoking exacerbate oxidative stress, worsening TO symptoms. Antioxidant treatments, such as selenium supplementation, have shown promise in managing mild TO.

Genetic susceptibility and epigenetics

Genetic predisposition plays a substantial role in TO, with several genetic loci associated with Graves' disease. Recent studies have identified epigenetic modifications, such as DNA methylation and non-coding RNA alterations, that correlate with TO severity and response to treatment.^[28] These epigenetic changes influence immune regulation, fibrosis, and adipogenesis, contributing to the complex pathogenesis of TO.

Animal models and gut microbiome

Recent advances in animal models of TO, particularly using TSHR immunization in mice, have provided valuable insights into the disease's mechanisms. These models have helped elucidate the role of T cell immunity and the gut microbiome in TO pathogenesis.^[29], ^[30] Studies have shown significant differences in gut microbiota composition between TO patients and controls, suggesting a potential link between gut health and TO.

Gut microbiome

The gut microbiome has been extensively studied in various human diseases, and its role in TO is gaining attention. Studies have demonstrated altered gut microbiota composition in TO patients, with reduced diversity and specific changes in bacterial populations. For example, TO patients show increased proportions of Bacteroidetes and reduced proportions of Firmicutes. These changes in gut microbiota are associated with disease activity and severity, indicating a potential role of the gut microbiome in TO pathogenesis.

Recent large-scale studies, such as the Investigation of Novel Biomarkers and Definition of the Role of the Microbiome In Graves' Orbitopathy (INDIGO) consortium, have compared the gut microbiome in TO patients, GD patients, and healthy controls.^[31] Preliminary analysis revealed significant differences in gut microbiota composition among these groups, suggesting that the gut microbiome may contribute to the pathogenesis of TO and GD. Further research is needed to explore the therapeutic potential of targeting the gut microbiome in TO.

Animal models

Animal models of TO, particularly using TSHR immunization in mice, have expanded our understanding of the disease's mechanisms. These models mimic the clinical and pathological features of TO, providing valuable insights into the role of T cell immunity and the gut microbiome in disease development. For example, studies have shown that modifying the gut microbiota in mouse models can alter the disease phenotype of TO, supporting the pivotal role of gut microbiota in the pathogenesis of GD and TO.

Clinical utility and relevance of TSHR antibodies

TSHR antibodies (TSHR-Ab) are crucial biomarkers in the diagnosis and management of GD and TO. These antibodies can be classified into three functional subtypes: TSHR stimulating antibody (TSAb), TSHR blocking antibody (TBAb), and neutral TSHR-Ab. Serum TSHR-Ab levels are typically measured by immunoassays, which are highly sensitive and specific for detecting these antibodies. ^[32], ^[33] However, functional assessment of TSHR-Ab activity requires cell-based bioassays.

Diagnosis and differential diagnosis

TSHR-Ab measurement is essential for diagnosing GD and TO. TSAb is more sensitive and specific than TBII in diagnosing TO, making it a valuable marker for differentiating TO from other orbital diseases, especially when clinical or radiological features are inconclusive.^[34], ^[35]

Predicting development of TO

Persistent TSHR-Ab positivity at baseline and during serial dilutional analysis can identify GD patients who are at risk of developing TO.^[36], ^[37] A predictive score incorporating parameters such as CAS, TBII level, duration of hyperthyroid symptoms, and smoking habit can help predict the risk of TO development in GD patients without TO at presentation.

Disease monitoring and predicting disease course

TSHR-Ab levels correlate positively with clinical features of TO and negatively with the duration of the disease. High TSAb levels are associated with increased disease activity and severity, including the risk of developing dysthyroid optic neuropathy.^[38], ^[39] Monitoring TSHR-Ab levels can help clinicians identify patients who need urgent therapy and guide treatment decisions.

Signaling Pathways in TO

Understanding the signaling pathways involved in TO is crucial for developing targeted therapies. The activation of TSHR and insulin-like growth factor-1 receptor (IGF-1R) plays a significant role in the pathogenesis of TO.^[40] These receptors form a functional complex and interact through crosstalk, enhancing the activation of orbital fibroblasts and promoting the production of pro-inflammatory cytokines and GAGs.

TSHR signaling pathway

TSHR activation triggers multiple signaling pathways, including the G protein Gαs-cAMP-PKA pathway and the PI3K-Akt-mTOR pathway. The Gαs-cAMP-PKA pathway leads to the activation of cAMP-dependent protein kinase A (PKA), which phosphorylates transcription factors such as cAMP-response element binding protein (CREB).^[41], ^[42] CREB binds to the promoters of hyaluronan synthase-2 (HAS2), leading to increased HA production. The PI3K-Akt-mTOR pathway, activated by TSHR and IGF-1R, regulates HA production and adipogenesis in orbital fibroblasts.

IGF-1R signaling pathway

IGF-1R activation also plays a critical role in TO pathogenesis. IGF-1R forms a physical and functional complex with TSHR, mediated by β-arrestin 1.^[43] This crosstalk enhances the activation of orbital fibroblasts and promotes the production of pro-inflammatory cytokines and GAGs. IGF-1-induced HA secretion is inhibited by IGF-1R kinase inhibitors or blocking antibodies, highlighting the potential of targeting IGF-1R in TO therapy.^[44]

Corticosteroids

Corticosteroids have long been the mainstay of treatment for moderate to severe active thyroid orbitopathy due to their potent anti-inflammatory effects. High-dose intravenous corticosteroids are preferred over oral administration because they offer a better therapeutic response with fewer side effects. Pulsed intravenous methylprednisolone is commonly used, and recent studies have refined dosing regimens to maximize efficacy and minimize adverse effects. Despite their effectiveness, corticosteroids are associated with significant side effects, especially with prolonged use, necessitating the development of alternative therapies.^[45]

Immunosuppressive agents

Immunosuppressive agents such as azathioprine, mycophenolate mofetil, and methotrexate have been employed as steroid-sparing agents. These drugs help control the autoimmune response by inhibiting the proliferation of immune cells and reducing inflammation. Mycophenolate mofetil, in particular, has shown promise in reducing disease activity and improving clinical outcomes with a relatively favorable safety profile.^[46]

Antioxidants

Oxidative stress is a significant factor in the pathogenesis of thyroid orbitopathy. It exacerbates inflammation and tissue damage within the orbit. Antioxidants have thus been investigated for their potential to mitigate these effects.

Selenium

Selenium is one of the most well-studied antioxidants in the context of thyroid orbitopathy. Its use has been associated with improved outcomes in patients with mild to moderate disease. Selenium supplementation has been shown to reduce inflammation and oxidative stress markers, improve quality of life, and slow the progression of thyroid orbitopathy. Clinical trials have supported its efficacy, making it a valuable adjunct in managing the disease.^[47]

Vitamin E

Vitamin E is another antioxidant that has shown potential benefits in reducing oxidative stress and inflammation. Although less extensively studied than selenium, vitamin E supplementation may help ameliorate some of the symptoms associated with thyroid orbitopathy.

Immunosuppressive agents

Immunosuppressive agents have been employed to manage the immune dysregulation and inflammation inherent in thyroid orbitopathy. These agents, though nonspecific, can modulate the immune response and reduce disease activity.

Mycophenolate mofetil (MMF)

Mycophenolate mofetil (MMF) is an immunosuppressive drug that inhibits the proliferation of T and B lymphocytes. It has been used as a steroid-sparing agent in thyroid orbitopathy, particularly for patients who are refractory to corticosteroids or who experience significant side effects from steroid therapy. MMF has demonstrated efficacy in reducing disease activity and improving clinical outcomes with a relatively favorable safety profile.

Cyclosporine

Cyclosporine is a calcineurin inhibitor that suppresses T cell activity. It has been used in thyroid orbitopathy for its immunomodulatory effects. While effective in some cases, cyclosporine is associated with significant side effects, including nephrotoxicity and hypertension, which limit its long-term use.^[48]

Azathioprine

Azathioprine is an immunosuppressive agent that interferes with DNA synthesis, thereby inhibiting the proliferation of immune cells. It has been used in the management of thyroid orbitopathy, particularly as a second-line agent when corticosteroids are ineffective or not tolerated. Azathioprine can be beneficial in reducing inflammation and disease activity, but it requires careful monitoring due to its potential for serious side effects, including bone marrow suppression and hepatotoxicity.

Statins

Statins, widely known for their cholesterol-lowering effects, have also been recognized for their anti-inflammatory and immunomodulatory properties. These characteristics make them a potential therapeutic option in thyroid orbitopathy. Statins inhibit the enzyme HMG-CoA reductase, leading to reduced cholesterol synthesis. Beyond their lipid-lowering effects, statins also modulate the immune response by reducing the expression of inflammatory cytokines and adhesion molecules, as well as by promoting anti-inflammatory pathways.

Emerging evidence suggests that statins may help reduce the inflammation and progression of thyroid orbitopathy. Studies have shown that statin use is associated with lower disease activity scores and improved clinical outcomes. However, more extensive clinical trials are needed to establish their definitive role in the treatment of thyroid orbitopathy.

Targeted molecular therapies

Recent advances in understanding the molecular mechanisms underlying thyroid orbitopathy have led to the development of targeted therapies. These therapies aim to specifically inhibit the pathways and molecules driving the disease process, offering a more precise and potentially more effective treatment approach.

Tumor necrosis factor α (TNF-α) inhibitors

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine implicated in various autoimmune diseases, including thyroid orbitopathy. TNF-α inhibitors are biologic agents designed to neutralize this cytokine, thereby reducing inflammation and autoimmune activity.

Infliximab and adalimumab

Infliximab and adalimumab are monoclonal antibodies that target TNF-α. These agents have been used successfully in other autoimmune conditions such as rheumatoid arthritis and Crohn's disease. In thyroid orbitopathy, preliminary studies and case reports suggest that TNF-α inhibitors may reduce inflammation and disease activity, improving symptoms such as proptosis and diplopia. However, their use in thyroid orbitopathy remains off-label, and further research is needed to establish their efficacy and safety in this context.^[49]

Teprotumumab

Teprotumumab, an IGF-1R antagonist, represents a significant breakthrough in the treatment of thyroid orbitopathy. It is the first drug specifically approved for this condition. Clinical trials have shown that teprotumumab can dramatically reduce proptosis, improve diplopia, and enhance the quality of life for patients with active thyroid orbitopathy. Its introduction has revolutionized the management of the disease, offering a highly effective targeted therapy.^[49]

Small molecule inhibitors

Small molecule inhibitors targeting specific signaling pathways involved in thyroid orbitopathy, such as JAK inhibitors and BTK inhibitors, are under investigation. These inhibitors offer the potential to modulate immune responses and reduce inflammation with greater specificity and fewer side effects.

Gene therapy

Gene therapy represents a novel approach to treating thyroid orbitopathy by directly targeting the genetic and molecular mechanisms underlying the disease. Techniques such as CRISPR-Cas9 gene editing and RNA interference (RNAi) are being explored to modulate gene expression and immune responses.

Cellular therapies

Cellular therapies, including the use of mesenchymal stem cells (MSCs) and regulatory T cells (Tregs), are being investigated for their potential to modulate immune responses and promote tissue repair. Early studies have shown promising results, but further research is needed to establish their safety and efficacy in clinical practice.^[49]

Biologic therapies

Biologic therapies represent one of the most significant advances in the treatment of thyroid orbitopathy. These therapies target specific molecules involved in the disease pathogenesis, offering a more precise approach compared to traditional immunosuppressive agents.

Teprotumumab

Teprotumumab represents a breakthrough in the treatment of thyroid orbitopathy. It is a human monoclonal antibody that targets the IGF-1R, which is overexpressed in the orbital fibroblasts of patients with the disease. By inhibiting the IGF-1R signaling pathway, teprotumumab reduces inflammation, tissue expansion, and fibrosis. Clinical trials have shown remarkable efficacy in reducing proptosis, improving diplopia, and enhancing the quality of life in patients with active thyroid orbitopathy. The FDA approved teprotumumab in 2020, making it the first drug specifically indicated for thyroid eye disease. Its introduction has transformed the therapeutic landscape, offering hope to patients with severe and refractory disease. ^[50], ^[51], ^[52]

Rituximab

Rituximab is a monoclonal antibody that targets CD20 on B cells, leading to their depletion. Since B cells play a crucial role in the autoimmune response by presenting antigens and producing autoantibodies, rituximab has been investigated for its potential in treating thyroid orbitopathy. Clinical trials have shown mixed results, with some studies reporting significant improvement in disease activity and others showing no benefit over placebo. The variability in response highlights the need for further research to identify patient subgroups that may benefit most from rituximab therapy.^[53]

Tocilizumab

Tocilizumab, an IL-6 receptor antagonist, has been explored for its role in reducing inflammation in thyroid orbitopathy. IL-6 is a pro-inflammatory cytokine implicated in the pathogenesis of the disease. Clinical trials have demonstrated that tocilizumab can significantly reduce disease activity and improve symptoms in patients who are refractory to corticosteroids. Its safety profile is generally favorable, although the risk of infections remains a concern.^[54], ^[55]

Orbital decompression surgery

Orbital decompression surgery aims to create more space within the orbit to relieve pressure on the optic nerve and reduce proptosis. Traditional approaches involved removing parts of the orbital bones, which carried significant risks of complications such as diplopia and hypoglobus (eye sinking). Recent advances include the development of endoscopic and minimally invasive techniques, which offer better precision and reduced morbidity.

Endoscopic orbital decompression

Endoscopic techniques allow surgeons to access the orbit through the nasal cavity, minimizing external incisions and reducing postoperative complications. These techniques provide excellent visualization of the orbital apex and medial orbital wall, enabling precise bone removal and fat excision. Studies have shown that endoscopic orbital decompression is effective in reducing proptosis and improving optic neuropathy with a lower risk of complications compared to traditional approaches.

Strabismus surgery

Strabismus surgery is performed to correct misalignment of the eyes, which is a common complication of thyroid orbitopathy due to fibrosis and muscle involvement. Advances in strabismus surgery include the use of adjustable sutures and intraoperative imaging techniques.

Adjustable suture technique

The adjustable suture technique allows for postoperative adjustment of the muscle position, improving the precision of eye alignment and reducing the risk of overcorrection or undercorrection. This technique is particularly useful in patients with unpredictable muscle behavior due to fibrosis.

Intraoperative imaging

Intraoperative imaging techniques, such as intraoperative optical coherence tomography (OCT) and ultrasound biomicroscopy, provide real-time visualization of the extraocular muscles and surrounding tissues. These technologies enhance the accuracy of muscle placement and improve surgical outcomes by allowing for immediate assessment and correction of any misalignment.

Eyelid surgery

Eyelid surgery addresses the cosmetic and functional issues associated with eyelid retraction and lagophthalmos (inability to close the eyelids). Advances in eyelid surgery include novel techniques for levator muscle recession and Müller muscle resection.

Levator muscle recession

Levator muscle recession involves repositioning the levator muscle to lower the upper eyelid and reduce the staring appearance characteristic of thyroid orbitopathy. Recent techniques, such as graded recession and posterior approach, offer more precise control over eyelid position and reduce the risk of complications like overcorrection.

Müller muscle resection

Müller muscle resection targets the sympathetically innervated muscle fibers responsible for upper eyelid retraction. By resecting a portion of the Müller muscle, surgeons can achieve a more natural eyelid position and improve the overall appearance. Advances in this technique include minimally invasive approaches and the use of laser technology to enhance precision and reduce recovery time.

Supportive measures and multidisciplinary care

Supportive measures play a crucial role in managing the symptoms and improving the quality of life of patients with thyroid orbitopathy. A multidisciplinary approach involving endocrinologists, ophthalmologists, oculoplastic surgeons, and other healthcare professionals is essential for comprehensive care.

Lubrication and ocular surface management

Dry eye and exposure keratopathy are common complications of thyroid orbitopathy. Frequent use of artificial tears, lubricating ointments, and moisture chamber goggles can alleviate symptoms and protect the ocular surface. In severe cases, punctal plugs or surgical procedures like tarsorrhaphy may be necessary to reduce corneal exposure and prevent damage.

Smoking cessation

Smoking is a significant risk factor for the development and progression of thyroid orbitopathy. Smoking cessation is strongly recommended for all patients, as it can reduce disease activity and improve treatment outcomes. Counseling and support services should be offered to assist patients in quitting smoking.

Psychological support

The psychosocial impact of thyroid orbitopathy can be profound, leading to anxiety, depression, and social isolation. Psychological support, including counseling and support groups, is essential for addressing these issues and improving patients' overall wellbeing. Healthcare providers should assess the psychological needs of their patients and provide appropriate referrals to mental health professionals when necessary.

The treatment landscape for thyroid orbitopathy continues to evolve, with ongoing research aimed at identifying new therapeutic targets and improving existing treatments. Several promising areas of investigation include.