OFs are integral effector cells in TED, contributing significantly to this condition’s characteristic soft tissue swelling. OFs are typically located in the interstitial spaces between muscle fibers, orbital fibers, and connective tissue, playing a critical role in TED’s pathogenesis and progression (10). These cells are divided into CD34+ and CD34- subtypes, with CD34+ OFs absent in healthy individuals’ orbits but comprising approximately 30% of OFs in TED patients (11). CD34+ OFs exhibit significantly higher TSHR and thyroid peroxidase mRNA levels than CD34- OFs (12, 13). Studies have shown that activated OFs in TED patients respond robustly to pro-inflammatory cytokines and growth factors, secreting elevated levels of interleukins (IL-1α, IL-1β, IL-6, IL-8), macrophage chemotactic protein-1 (MCP-1), and transforming growth factor-β (TGF-β), thereby exacerbating inflammation (14). Additionally, OFs can proliferate and differentiate into myofibroblasts and adipocytes, produce excessive glycosaminoglycans, and promote adipogenesis. They also actively interact with mononuclear cells, producing chemokines and cytokines that perpetuate orbital inflammation. Consequently, OFs are crucial in initiating and maintaining TED-related inflammation and tissue remodeling (15).

Recent research has focused on the involvement of IGF-1R and TSHR in the pathogenesis of TED. TSHR is TED’s most common pathogenic antigen, expressed in orbital connective tissues and extraocular muscles. While its expression is low in cultured OFs and normal orbital fat tissue, it is significantly elevated in the orbital tissues of TED patients (16). The expression level of TSHR correlates closely with the clinical activity and severity of TED (17). IGF-1R, a receptor tyrosine kinase, is broadly expressed in human cells, including OFs, and plays a crucial role in immune regulation, making it a therapeutic target in autoimmune diseases (18).

In female mouse models of TED, OFs exhibit high levels of IGF-1R expression and increased adipogenesis. Compared to control animals, IGF-1 stimulation significantly elevates hyaluronic acid secretion through IGF-1R activation (19). In TED patients, OFs express high levels of IGF-1R, which regulate lymphocyte trafficking, hyaluronic acid production, and fat accumulation and define the phenotypes and functions of T and B lymphocytes (20, 21). Furthermore, IgG from Graves’ disease patients activates IGF-1R, leading to inappropriate expression of inflammatory factors, hyaluronic acid production, and OF activation (22). These studies indicate that IGF-1R is an autoantigen in TED, contributing to the disease’s pathogenesis and immune system modulation. The IGF system, a complex network comprising ligands (IGF-1, IGF-2, and insulin), receptors (IGF-1R, IGF-2R, and insulin receptor), and IGF-binding proteins, is a fascinating study area. IGF-1 and IGF-2, the primary players, exert their effects through IGF-1R (23), a transmembrane glycoprotein dimer (heterotetramer) that shares structural similarities with the insulin receptor. The mature IGF-1R protein’s extracellular region, which includes elements of the α and β subunits, is involved in ligand binding. In contrast, the intracellular region contains the tyrosine kinase domain of the β subunit (24). IGF-1R, a receptor tyrosine kinase family member, is widely expressed in various human tissues and participates in numerous physiological processes such as growth and development, metabolism, energy consumption, and immune surveillance (25, 26).

At physiological ligand concentrations, IGF-1R undergoes significant structural rearrangement upon binding a single ligand and exerts its effects through two significant signaling pathways:

Studies have shown that the stimulating TSHR monoclonal antibody M22 in TED fibroblast tissues can directly activate TSHR and trigger IGF-1R signaling, immediately increasing hyaluronic acid secretion (27). Recent research confirms that stimulating TSHR antibodies can induce IGF-1R phosphorylation and activate both TSHR and IGF-1R signaling pathways. ANTAG3, a selective TSHR antagonist, can inhibit both IGF-1R-dependent and IGF-1R-independent pathways, proving more effective than the IGF-1R inhibitory antibody 1H7 in suppressing TED-Ig-induced hyaluronic acid secretion (28). These findings suggest that activating or blocking TSHR can simultaneously trigger or inhibit IGF-1R signaling pathways, ultimately affecting hyaluronic acid synthesis. TSHR and IGF-1R co-localize on the membranes of orbital cells, forming a protein complex that interacts physiologically and functionally (29). This suggests that the signaling pathways of IGF-1R and TSHR may overlap and interact, jointly contributing to the pathogenesis of TED.

Among the adverse reactions to teprotumumab, hearing impairment is particularly concerning. Teprotumumab, a biological agent that inhibits the IGF-1 pathway by targeting IGF-1R, disrupts critical signaling pathways in cochlear cells that rely on IGF-1 signaling for survival and proliferation ( Figures 1a, b , 2 ). The PI3K/Akt and Ras/Raf/MEK/ERK pathways, typically activated by IGF-1, support cochlear cell function. By blocking IGF-1’s interaction with IGF-1R, teprotumumab disrupts these pathways, impairing cochlear cell survival and contributing to hearing loss.

Hearing impairment associated with teprotumumab appears to involve both sensorineural and conductive components. Sensorineural impairments are linked to the inhibition of IGF-1 signaling in cochlear cells, while conductive impairments are likely due to dysfunction in the Eustachian tube, typically reversible (30, 31).

In clinical trials, approximately 10% of patients receiving teprotumumab reported hearing-related adverse events. In phase II and III trials for TED, 8 cases (9.5%) of hearing-related adverse reactions were reported in the teprotumumab group (0 cases in the placebo group); in the extension study of the phase III trial (32), 5 cases (10.9%) were reported. These events included hearing loss (5 cases), deafness (3 cases), tinnitus (3 cases), and Eustachian tube dysfunction (2 cases). In the OPTIC trial, 12 patients (9.9%) reported hearing-related adverse events, most of which were mild and resolved after treatment discontinuation (33).

Findings from observational studies highlight the importance of baseline hearing conditions. In a prospective study, 22 out of 27 patients (81.5%) receiving teprotumumab reported new subjective ear symptoms, but only 45.5% of those with hearing loss achieved full recovery (34). Importantly, Sears et al. (34) found that 46% of patients with post-treatment hearing issues had baseline hearing impairments.

Additionally, Douglas et al. (35) demonstrated that patients without baseline hearing dysfunction did not develop significant hearing impairment from teprotumumab treatment, underscoring the need for careful monitoring in high-risk populations.

Objective audiometric assessments, as highlighted by Keen et al. (36) and Douglas et al. (35), are critical for accurately evaluating the incidence and severity of hearing-related adverse effects. Sears et al. (34) noted that relying on subjective reports may introduce bias, making objective assessments more reliable.

Teprotumumab-related hearing impairment may also be associated with other disabling diseases, including cognitive decline, dementia, and depression (37). Research indicates that Graves’ Disease (GD) patients have a higher risk of hearing impairment, with studies showing IGF-1 deficiency in some GD patients (32, 38, 39). Several published cases have demonstrated persistent and potentially permanent sensorineural hearing loss related to teprotumumab (40, 41).

The U.S. prescribing label for TEPEZZA^® (teprotumumab) recommends conducting hearing evaluations before, during, and after treatment, emphasizing the importance of monitoring high-risk patients (42).

Teprotumumab treatment has been associated with significant blood glucose fluctuations in some patients. The hypothalamus and pituitary gland regulate the secretion of various hormones, including growth hormone, which plays a vital role in glucose regulation. Under normal conditions, IGF-1 binds to IGF-1R on cells in the hypothalamus and pituitary gland ( Figures 3a, c ), providing negative feedback to inhibit growth hormone secretion, thereby maintaining stable glucose levels. However, teprotumumab inhibits IGF-1R, disrupting this negative feedback mechanism and increasing growth hormone secretion. Elevated growth hormone promotes glucose production in the liver through glycogenolysis and gluconeogenesis ( Figure 3b ) and increases insulin resistance, making it harder for insulin to lower blood glucose levels. Through these mechanisms, teprotumumab induces blood glucose fluctuations and hyperglycemia in some patients, especially early in treatment ( Figure 3d ). This complex mechanism may explain why some patients experience significant blood glucose fluctuations after receiving teprotumumab treatment.

Some patients experience significant blood glucose fluctuations after receiving teprotumumab treatment, especially early in treatment (43). Dysregulation of the hypothalamic-pituitary axis may lead to elevated serum glucose levels. Inhibition of IGF-1R can reduce the feedback inhibition on growth hormone secretion, increasing growth hormone levels, glucose production, and insulin resistance. Lee et al. (44) suggested that hyperglycemia is an adverse reaction due to the partial homology between IGF-1R and the insulin receptor. The indirect impact on insulin receptor signaling might also play a role, as IGF-1R inhibitors block the insulin receptor, preventing insulin from binding to its receptor, thereby inhibiting cellular glucose uptake and leading to hyperglycemia (45).

In a recent study analyzing three clinical trials (46), among 121 TED patients receiving teprotumumab, 8 cases (6.6%) of hyperglycemia were reported in the treatment group compared to no cases in the placebo group. This incidence of hyperglycemia was notably higher in patients with pre-existing diabetes or impaired glucose tolerance. Additionally, among 10 patients with a history of diabetes or impaired glucose tolerance, 5 (50%) developed hyperglycemia-related adverse events. In contrast, among the 74 patients without glucose tolerance impairment, only 3 cases (4.1%) of hyperglycemia were observed. Most hyperglycemic events occurred in patients with diabetes or impaired glucose tolerance, and all cases were managed with adjustments to their diabetes medication or with additional glucose-lowering therapy. These findings highlight that teprotumumab’s hyperglycemia-related adverse effects predominantly affect those with pre-existing glucose metabolism issues, emphasizing the importance of regular blood glucose monitoring for high-risk patients, such as those with diabetes or impaired glucose tolerance (3). Shah et al. (47) reported a case of a 56-year-old female TED patient who developed hyperglycemia symptoms three weeks after the first infusion of teprotumumab, eventually leading to a hyperosmolar hyperglycemic state (HHS). This case underscores the potential for teprotumumab to induce significant hyperglycemia in high-risk patients and highlights the need for vigilant monitoring and prompt management in such cases. Furthermore, the drug manufacturer has clearly stated in the prescription information that the incidence of hyperglycemia is approximately 10% in TED patients receiving teprotumumab.

Monitoring blood glucose levels in patients receiving teprotumumab treatment is crucial, with particular attention to high-risk groups (patients with prediabetes, diabetes, the elderly, and high-risk populations). If necessary, antidiabetic medications should be used to control blood glucose levels. Before starting treatment, patients should undergo fasting blood glucose and HbA1c testing to assess their baseline glucose control. As Douglas et al. (48) recommended, close collaboration between ophthalmologists and endocrinologists is essential to address the potential risk of hyperglycemia, and patients with poorly controlled diabetes should aim to stabilize HbA1c levels before initiating teprotumumab treatment.

During treatment, it is essential to increase the frequency of blood glucose monitoring, adjusting based on baseline diabetes status and other risk factors. Patients are most susceptible to hyperglycemia early in the treatment course, as highlighted by the incidence data from controlled trials (49). Proactive measures should be taken to control hyperglycemia effectively, such as daily fasting and postprandial blood glucose monitoring during initial treatment weeks, with weekly follow-ups to adjust antidiabetic medication dosages as necessary (50). Future studies are warranted to further analyze the incidence and management of severe hyperglycemia and HHS in patients treated with teprotumumab.

Research indicates an inverse correlation between serum IGF-1 levels and the severity of several autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD) (51–53). Although the etiology of IBD remains unclear, active IBD patients typically exhibit reduced serum IGF-1 levels (54), which may be secondary to gastrointestinal dysfunction and acquired growth hormone resistance (55). Under normal physiological conditions, IGF-1, stimulated by growth hormone, promotes cell proliferation, somatic growth, and cellular synthesis processes. IGF-1R, expressed on intestinal epithelial cells and smooth muscle cells, facilitates the regulation of growth and function of adjacent intestinal epithelial cells by IGF-1 derived from intestinal mesenchymal cells (56). In the gastrointestinal tract, IGF-1 is crucial for promoting mucosal proliferation and repair, preventing apoptosis, supporting mucosal barrier function, and mitigating inflammation (57–59). Thus, it is hypothesized that inhibiting IGF-1R could reduce IGF-1 levels in both serum and gastrointestinal tissues. The IGF-1 reduction caused by teprotumumab’s inhibition of IGF-1R may mimic conditions observed in IBD patients, potentially leading to similar gastrointestinal symptoms and signs. However, it should be noted that the current clinical trial data have not established a direct association between teprotumumab and IBD reactivation. The majority of reported diarrhea cases did not specify IBD as an underlying condition, suggesting that gastrointestinal adverse events associated with teprotumumab may not necessarily indicate IBD causation. As stated in the prescribing label (60), “Exacerbation of Preexisting Inflammatory Bowel Disease (IBD): Monitor patients with preexisting IBD for flare of disease; discontinue TEPEZZA if IBD worsens.” This underscores the potential risks of teprotumumab in IBD patients and the importance of monitoring but does not confirm causation between teprotumumab and IBD exacerbation.

Clinical data on diarrhea incidence highlight a 13% occurrence rate among patients receiving teprotumumab. In the phase II trial for TED, 14% (6/43) of patients treated with teprotumumab experienced diarrhea, including two cases where patients with a history of colitis had significant disease exacerbation during treatment (3). Consequently, IBD patients were excluded from the phase III trial, and the FDA was advised to list IBD as a precautionary contraindication rather than a strict contraindication. Additionally, spontaneous case reports, such as that by Ashraf et al., described a TED patient with a family history of IBD who developed new-onset IBD during teprotumumab treatment (61). Similarly, Safo et al. (62) reported a case involving a 46-year-old female who developed bloody diarrhea and urgency following five infusions of teprotumumab, which ultimately led to a diagnosis of ulcerative colitis (UC) confirmed by colonoscopy and biopsy. However, it is essential to note that individual case reports cannot establish a causal link between teprotumumab and IBD development, as spontaneous reports alone lack the statistical strength required for causation.

Based on these observations, it is critical to exercise caution with teprotumumab in patients with a history of IBD or a family history of autoimmune diseases. Thorough screening of patients’ autoimmune disease history, particularly family history, is not just recommended but essential prior to initiating treatment. Patients identified with a personal or family history of IBD should be informed of the potential risks associated with the medication. During treatment, close monitoring for acute gastrointestinal symptoms, such as gastrointestinal bleeding, abdominal pain, and diarrhea, is essential. If signs of IBD exacerbation, such as persistent severe diarrhea or hematochezia, occur, gastroenterological evaluation is strongly advised, and consideration should be given to discontinuing teprotumumab infusion.

Research indicates that IGF-1 is crucial for skeletal muscle growth, repair, and prevention of degradation (63, 64). Inhibiting IGF-1R can lead to muscle cramps. Precisely, IGF-1 activates the PI3K/Akt pathway. Upon binding to its receptor IGF-1R, IGF-1 stimulates the intracellular PI3K/Akt signaling cascade. This pathway promotes protein synthesis and enhances cellular growth and proliferation by upregulating the activity of the mammalian target of rapamycin (mTOR). Additionally, it inhibits the FoxO (Forkhead Box O) transcription factors responsible for protein degradation. Furthermore, IGF-1 activates muscle satellite cells, which can differentiate into myoblasts following muscle injury, thus promoting muscle repair and regeneration (65).

In phase II and III trials for TED, muscle cramps were the most common adverse reaction to teprotumumab (25%) (3). Most cases were mild, with five moderate cases reported, but none required treatment discontinuation. The lower limbs were the most frequently affected area, with no clinically relevant laboratory abnormalities detected. It’s reassuring to know that treatment measures for muscle cramps may include massage, Epsom salt baths, or supplementation with magnesium, calcium, and potassium (66). Adequate hydration and using muscle relaxants are also effective in alleviating symptoms when necessary.

Infusion reactions induced by teprotumumab, although not fully understood, are believed to arise from cytokine release following antibody-antigen interactions (67). As with many human monoclonal antibodies, infusion reactions with teprotumumab are typically mild, though severe cases have been observed. In the Phase III trial (4), two patients experienced infusion reactions; one reaction occurred during the initial infusion, which was managed effectively within two hours, and the infusion was discontinued. After premedication and a reduced infusion rate, another patient completed the trial without further severe reactions. Both cases underscore the need for a well-prepared clinical environment to address potential infusion-related adverse events.

Management protocols recommend immediate cessation of infusion upon recognition of a reaction, followed by assessment of vital signs and monitoring of airway status. According to recent recommendations by Kang et al. (68), once symptoms subside, premedication with antihistamines, acetaminophen, and corticosteroids, along with a slower infusion rate, may reduce the severity of subsequent reactions. In moderate reactions, gradual resumption of the infusion may be considered, although all patients should be closely monitored.

For severe reactions, rapid intervention is paramount. Patients should receive oxygen supplementation and, if necessary, bronchodilators, epinephrine, antihistamines, and corticosteroids. Emergency response protocols recommend that infusion centers maintain ready access to resuscitation equipment and that staff are trained to recognize and manage severe infusion reactions promptly. This approach minimizes risk and enhances patient safety during treatment.

Given the potential for infusion reactions, particularly during the initial infusion or within 90 minutes of administration, it is essential to inform patients of these risks beforehand. Patients should be educated to recognize early symptoms, such as flushing, nausea, headache, or shortness of breath, and to notify healthcare staff immediately if symptoms occur. Clear communication with patients allows for swift intervention, minimizing the risk of severe outcomes.