The role of mycophenolate mofetil in the therapy of thyroid eye disease

Abstract

Thyroid eye disease (TED) is an autoimmune disorder that can threaten vision loss. In 90% cases, it is related to Graves’ disease, and in 10% cases, it occurs with euthyroidism or with chronic autoimmune thyroiditis. It is the leading cause of orbital pathology in adults. The TED treatment remains challenging for clinicians, particularly in moderate-to-severe or sight-threatening forms of the disease. One-third of TED patients experience a relapse despite the corticosteroids as a first-line treatment. Some patients show poor response or even no response to the treatment. There are many adverse effects associated with chronic use of intravenous methylprednisolone (IVMP). There is a need for new, efficient therapeutic methods, such as immunomodulating drugs like mycophenolate mofetil (MMF). This paper describes the role and potential efficiency of MMF application in TED by its direct action on TED pathogenic mechanisms. The introduction of MMF in the second-line treatment helps decrease the level of clinical symptoms and the risk of chronic complications, while causing only a small number of adverse events. Nevertheless, it should be noted that there are no unified guidelines available for consolidating treatment focused on maintaining remission after the first dose of IVMP. Moreover, clinical knowledge on the use of MMF application in TED is still limited, and further research is needed. Nonetheless, the available evidence is promising and MMF may play a vital role in future therapeutic strategies.

Plain language summary

Thyroid orbitopathy also known as Graves’ orbitopathy is a condition in which soft tissues of the orbit are targeted by the body’s immune system. The antibodies that are produced in this disease target the TSH receptor (TSHR) in the thyroid, but can also affect the tissues of the orbit. Then cells called fibroblasts, that are responsible for the production of collagen and other connective tissue components, are activated. It leads to inflammation, swelling and the orbital tissues enlargement, including the extraocular muscles and adipose tissue. As a consequence, intraocular pressure is elevated, which can cause exophthalmos, double vision, eyelid swelling and ocular pain. Treatment is recommended when the disease is active and causes symptoms. The severity of the disease determines the treatment strategy. In mild cases, selenium supplementation is usually sufficient, while in moderate and severe manifestations medications that suppress the immune system such as corticosteroids and mycophenolate mofetil (MMF) are used. In this paper we describe the role of MMF as a immunosuppressive drug used in thyroid eye disease treatment. Its role may be important and the data gathered is promising.

Introduction

Thyroid eye disease (TED) is a serious, progressive autoimmune condition that can threaten vision loss. In 90% of the cases, it is related to Graves’ disease (GD), and in 10% of the cases, it occurs in patients with normal thyroid function or chronic autoimmune thyroiditis. ¹ TED is a self-limiting disease; patients with TED often progress from the active to the quiescent phase within 1–3 years, with a 5%–10% risk of future recurrence. Once TED is diagnosed, the treatment should be initiated immediately. ²

Epidemiology of TED

Studies indicate that between 25% and 40% of patients with GD experience TED. ³ This condition is five times more common in women than in men. ⁴ However, men rather than women suffer from severe forms of the disease, and they face a higher risk of vision loss, particularly in older age. The incidence of TED is 16 cases per 100,000 females and 2.9 cases per 100,000 males. ⁵ In the cases of severe TED, the ratio of females to males is approximately 1:4. ⁶ About 5%–6% of all TED patients require aggressive treatment, mostly those with moderate and severe cases of the disease. ⁷ Several risk factors contribute to the development of TED, although the exact genetic background remains unclear. Cigarette smoking is a significant environmental risk factor. ⁸ Other important and potentially modifiable risk factors are thyroid dysfunction (including both hyperthyroidism and hypothyroidism), radioactive iodine (RAI) therapy (without accompanying low-dose steroid prophylaxis), and elevated levels of thyrotropin receptor (TSHR) antibodies. ⁹ RAI therapy is an adjuvant treatment for differentiated thyroid cancers—papillary and follicular thyroid cancer, it is also a treatment method for TED GD patients. Glucocorticosteroids (GCs) are used to avoid early, intermediate, and late adverse effects of RAI therapy. In patients with GD with TRAb levels higher than 8.8 IU/L and in smokers, there is a risk of Graves orbitopathy exacerbation reaching 32% in benign orbitopathy. To avoid a deterioration of GD, prednisone prophylaxis is introduced. The dose of prednisone varies from 0.3 to 0.5 mg/kg/day, and it is tapered over 3 months.^10,11

Pathophysiology of TED

Initially, an abnormal immune response is triggered against antigens shared by the thyroid gland and orbital tissues. A key mechanism at the beginning of the disease involves the activation and binding of the antibodies to a receptor complex composed of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R).^12,13 This interaction induces activation and proliferation of orbital fibroblasts. ¹⁴ There is a positive correlation between the titer of TSHR antibodies and the intensity of the inflammatory process that endocrinologists use to assess the activity and severity of the disease. ¹⁵ Activated fibroblasts possess the capacity to produce large amounts of glycosaminoglycans (GAGs), primarily hyaluronic acid. Their excessive production leads to uncontrolled orbital tissue expansion. ¹⁶ This creates a disproportion between the orbital capacity and its contents, which can impinge upon important structures such as the orbital nerve, veins, and lymphatic vessels. As a result, intraocular pressure (IOP) may increase, extraocular muscle mobility may be impaired, and proptosis can occur. ¹

The first stage of the TED pathogenesis is an active inflammatory phase with an inflammation of the orbit. Afterward, there is a plateau phase. In this phase, the inflammation remains at a constant level. The third one and final is the gradual resolution of inflammation. In the last phase, fibrosis of the extraocular muscles progresses, and the adipose tissue volume increases. An enhanced cell migration facilitates the progression of fibrosis in TED. Transforming growth factor beta 1 (TGF-β1) causes upregulation of collagen production and formation. Moreover, TGF-β triggers the differentiation of Thy-1-positive fibroblasts into myofibroblasts. The total duration of these processes is usually 12–18 months, but it may vary individually.^17–19

Concurrently, orbital tissues undergo infiltration by immune cells, predominantly CD4+ T lymphocytes, B lymphocytes, and macrophages. Pro-inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ are secreted. ¹⁶ Then it comes to proliferation, migration, and differentiation of fibroblasts into adipocytes or myofibroblasts, which actively secrete extracellular matrix (ECM) components such as collagen types I and III, fibronectin, and GAGs. ²⁰ A key mediator of fibrosis that promotes the differentiation of fibroblasts into myofibroblasts through the induction of alpha-smooth muscle actin expression is TGF-β, particularly the TGF-β1 isoform. Recent scientific reports also highlight the involvement of CD34⁺ bone marrow-derived fibrocytes, which infiltrate the orbit and differentiate into fibroblasts. These cells express the TSHR and class II major histocompatibility complex molecules, contributing both to autoantigen presentation and local tissue remodeling. ²¹ These changes contribute to hypertrophy and fibrosis of the extraocular muscles, leading to their stiffening and permanent damage. As a consequence, restrictive ophthalmopathy develops. It is characterized by limited ocular motility, diplopia, and persistent proptosis. ²⁰

Contemporary treatment options in TED

Before commencing treatment, the activity and severity of TED should be assessed. To determine the activity of the disease—Clinical Activity Score (CAS) is used. The CAS is a 7-point scale, in which a single point is assigned for each feature described below. The first is spontaneous orbital pain, the second is gaze-evoked orbital pain. Eyelid swelling due to TED is also assessed. One point is also given when the eyelid erythema appears. Another assessed feature is also conjunctival redness, considered to be caused by TED. We also evaluate the presence of chemosis and inflammation of the caruncle or plica. When it comes to ongoing monitoring, another 3 symptoms and 3 points may be given—each for 1 feature: the increase in proptosis greater than or equal to 2 mm, a decrease in acuity equivalent to 2 Snellen chart lines, and a decrease in uniocular excursion in any direction greater than or equal to 8 degrees. During initial visit CAS greater than or equal to 3 is considered active TED and during the ongoing monitoring CAS 4 is considered active TED. ²² To describe TED severity as mild, moderate-to-severe, or sight-threatening, the European Group of Graves’ Orbitopathy (EUGOGO) system is commonly used. The Vision, Inflammation, Strabismus, and Appearance (VISA) system may be utilized to assess both activity and severity. ²³

Mild cases of TED do not require pharmacological treatment and supportive measures are introduced. These methods include lubricating the eyes, using moisture goggles, wearing sunglasses, and elevating the head during sleep to reduce swelling. These measures help to alleviate dryness and irritation. ²⁴ Among the patients with a selenium deficiency, its supplementation with a daily dose of 200 mcg may be effective. ²⁵ It also seems that the clinical course of TED may be influenced by dysbiosis of oral and intestinal microbiota. Nowadays, the subject of oral hygiene is brought up more often in discussions about various autoimmune diseases. Although, emerging reports suggest that dysbiosis of the oral and gut microbiota may influence the clinical course of TED and that oral cavity sanitation may reduce symptoms in selected patients. However further well-designed studies are needed to confirm these observations and clarify the underlying mechanisms. ²⁶ Moreover, there are some studies that indicate beneficial effects of aloe vera juice. ²⁷ In smoking patients and in patients exposed to second-hand smoke, it has been proven that smoking can exacerbate thyroid orbitopathy and prolong the active phase of the disease. It is crucial to quit smoking and to avoid exposure in these patients. ²⁸ Smoking may also reduce the thyroid orbitopathy treatment effectiveness. ²⁹ It is important to note that mild thyroid orbitopathy often passes and many patients do not require active medical intervention beyond supportive care and lifestyle modifications. ³⁰

The main principle in the treatment of GD with TED is to reverse hyperthyroidism. ³¹

This is typically achieved by using antithyroid drugs, preferably metamizole, and in some cases, radioiodine therapy (RAI). ³² However, RAI is not recommended for moderate-to-severe cases of TED.^33,34 Additionally, even when thyroid hormone levels are well controlled, it is still possible to experience orbital symptoms associated with GD. ³⁵

Contemporarily, intravenous (i.v.) glucocorticoids are considered as a first-line therapy in patients with moderate-to-severe TED. ³⁶ Typically, patients receive 4.5 g of methylprednisolone over 12 weeks, usually given as 0.5 mg i.v. weekly for 6 weeks and then 0.5 g weekly during another 6 weeks. ³⁷ The total dose should not exceed 8 g to avoid potentially severe toxicity associated with a risk of severe hepatotoxicity. ³⁸ Oral glucocorticoids are less effective and can more often cause adverse effects. ³⁹ Constant surveillance of patients receiving steroids is required. The other drugs approved for the treatment of moderate-to-severe cases of TED are monoclonal antibodies, ⁴⁰ including teprotumumab (TEP)—which targets IGF-1R, tocilizumab (TCZ)—which targets the interleukin-6 receptor (IL-6-R) and rituximab (RTX)—which targets CD20 antigen on B-cells.^41,42 Another immunotherapeutic that has emerged as an option in the treatment of TED is mycophenolate mofetil (MMF). ⁴³

Review of the role of MMF in the therapy of TED

MMF is an ester of mycophenolic acid. ⁴⁴ It is an immunosuppressant, primarily used to prevent allograft rejection after solid-organ transplantation. ⁴⁵ It is a fermentation product of several Penicillium species.^46,47 For the first time, it was used in the 1970s in the treatment of psoriasis. ⁴⁸ Mycophenolic acid inhibits de novo purine synthesis, resulting in antiproliferative effects on T and B lymphocytes. The primary mode of action of MMF is the noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme crucial for the de novo synthesis of guanosine-based nucleotides. ⁴⁹ In this way, it suppresses cell-mediated immune response and antibody formation. Moreover, it inhibits the expression of adhesion molecules and the recruitment of lymphocytes and monocytes to the site of inflammation. ⁴⁸ MMF is applied in various fields of medicine, such as dermatology, nephrology, rheumatology, transplantation, and endocrinology.^50–53 The suggested dosage in TED equals 1 g twice a day, while in renal graft rejection, 3 g once a day. ⁴⁷

Action of MMF in TED

The uncontrolled activation of orbital fibroblasts and their proliferation are the major causes of TED. The factors leading to this condition are mainly the autoantibodies directed against TSHR and IGF-1R. Once activated, the fibroblasts begin producing pro-inflammatory cytokines, including IL-6, and hyaluronans. This environment triggers an inflammatory response, in which T lymphocytes and macrophages are involved. As these reactions amplify, there is an excessive deposition of ECM and fat accumulation in the periorbital space. ¹⁹ Activated CD4+ T lymphocytes produce a variety of adhesion molecules. Chemokines and adhesion molecules, which are important in many autoimmune diseases and are stimulated by orbital fibroblasts, mediate the lymphocyte entry into orbital tissue and drive the inflammatory response in TED.^54,55

The combination of the inflammation and fibrosis leads to tissue damage and scarring, resulting in the clinical manifestations of TED, including proptosis, diplopia, and eyelid swelling. A part of MMF’s mode of action is its influence on T cell and B cell proliferation through inhibition of IMPDH. This leads to the suppression of cell-mediated immune responses and antibody formation. The administration of MMF in TED reduces the production of autoantibodies and helps control the inflammatory process, leading to symptom relief. ⁵⁶

Comparison of MMF with other drugs used in TED treatment

In the treatment of moderate-to-severe TED, IV steroids are readily available and inexpensive. They are indicated as first-line drugs by EUGOGO. The use of IV steroids reduces inflammation and improves disease symptoms. This treatment has been associated with a decrease in CAS and inactivation of TED in up to 59% of patients. ³⁶ Nonetheless, up to 20%–25% of clinically active moderate-to-severe TED patients do not respond to the treatment or experience a relapse after the treatment discontinuation. ⁵⁷ In a study performed by Kahaly et al., ⁵⁸ oral steroids were a worse choice than i.v. steroids, since their efficacy reached about 51% in comparison to 77% in patients treated with i.v. steroids. ³⁹ In patients with a lack of response, with suboptimal improvement, or with clinical deterioration after 6–8 weeks of intravenous glucocorticosteroids (IVGC) treatment, physicians should consider discontinuing therapy and initiating alternative therapeutic strategies.

TEP is a monoclonal antibody directed against IGF-1R. The studies showed that it has a great efficacy in reducing proptosis, improving diplopia, and lowering the CAS. This drug has been approved by the US regulatory authorities since 2020. In June 2025, the European Commission issued a positive opinion regarding its use for the treatment of moderate-to-severe TED.^59,60 It has a good safety profile with a low incidence of serious adverse events. ⁶¹ However, the high cost of TEP—approximately $360,000 per course of the treatment has raised concerns about its cost-effectiveness. TEP was found to have the highest cost per unit of quality-of-life (QOL) improvement compared to other treatment methods for TED. ⁶²

TCZ is also an example of a monoclonal antibody with proven effectiveness in TED. ⁶³ It is directed against IL-6-R. By blocking the IL-6-R, TCZ reduces inflammation and the production of other pro-inflammatory cytokines; moreover, it slows down tissue remodeling and fibrosis in the orbit. This may help to reduce the severity of TED symptoms such as exophthalmos and eyelid retraction. ⁶⁴ Pampín-Sánchez et al. ⁶⁵ suggest that it could be an alternative drug in the treatment of steroid-resistant patients. For now, TCZ remains an alternative and a second-line treatment for patients in whom conventional therapy has failed, or for those who have persistent and recurring symptoms.

RTX is a monoclonal antibody that targets the CD20 receptor on B-lymphocytes. By reducing the number of B cells, RTX may help inhibit inflammation and decrease the degree of proptosis. ⁶⁶ Studies showed that RTX may be effective in improving the CAS and reducing the severity of TED. ⁶⁷ RTX may cause adverse effects like infusion reactions, and the evidence for its safety compared to steroids or a placebo is uncertain. ⁶⁸ RTX is currently considered a valid second-line treatment option for patients with TED who are unresponsive to previous interventions or have disease reactivation. ⁶⁹

Although data from randomized controlled trials are limited and inconsistent, it is indicated that RTX may be effective in achieving disease inactivation and preventing relapses longer than 1 year, especially in patients with a disease duration of less than 9 months.

MMF is used as a second-line immunosuppressive agent in the treatment of TED, particularly in active conditions and in moderate to sight-threatening cases. Among the patients treated with MMF, the QOL scores improve, and CAS scores decrease. MMF has been shown to reduce inflammation in TED patients, as indicated by a decrease in TRAb and IL-6 levels over time. ⁷⁰ Long-term studies suggest that MMF can maintain its efficacy over extended periods, with some patients showing sustained improvement even after 72 weeks of treatment. ⁴³

The MMF is considered a relatively safe drug. The most common side effects are not severe and easily manageable; they include gastrointestinal issues, headaches, dizziness, difficulty sleeping, tremors, and rashes. The most serious and concerning side effects are related to the immunosuppressive properties of MMF, which weaken the immune system. This feature may increase the risk of infections and allergic reactions. Moreover, MMF can affect blood cell counts and may lead to side effects such as fatigue or easy bruising. Routine blood tests are recommended to monitor these changes. However, the incidence of serious side effects is low.^71,72 If it comes to long-term risks, MMF may increase the risk of developing progressive multifocal leukoencephalopathy, a rare and usually fatal brain condition, as well as certain types of cancer, such as lymphoma and skin cancer. ⁷³

Physicians should follow specific criteria before initiating second-line treatment with immunomodulatory drugs. Patients with TED who show no response or only a partial response to intravenous methylprednisolone (IVMP) in monotherapy require treatment intensification. Certain markers can help predict treatment response and identify patients who may benefit from adjuvant treatment. One of the factors is thyroid-stimulating immunoglobulin (TSI). Its elevated concentration concerns 98% of patients with untreated active TED. There is a strong correlation between its level and the disease activity and severity. Patients included in the study by Zloto et al., who required second-line treatment after unsuccessful IVMP monotherapy, had higher baseline and post-first-line TSI concentrations. These patients may benefit from dual therapy and require more precise monitoring. ⁷⁴

Until now, there have a few studies that have examined the efficacy of combined MMF with systemic GCs treatment compared to conventional treatment using only GCs. For this purpose, measurable indicators such as CAS scale, proptosis, visual acuity (VA), IOP, diplopia, and QOL were used. These studies provided important observations, including improvements in QOL, reductions in the severity of symptoms and ophthalmological signs. This combined treatment was more effective in a large group of patients, leading to significant improvements in CAS, proptosis, and diplopia. The addition of MMF in the treatment led to more effective control of local inflammation. These studies also showed a higher incidence of adverse events in the groups treated only with corticosteroids than in the other groups of patients. However, different results were obtained regarding VA and IOP. Data containing key findings are included in Table 1).^43,70,74,75

Table 1.

Summary of original studies with the use of MMF among patients with TED.

Study parameter	Quah Qin Xian et al. 43	Rajabi et al. 75	Li et al. 70	Zloto et al. 74
Study group	- 20 patients	- 242 patients	- CG—30 patients - EG—30 patients	- 47 patients enrolled - 21 patients recommended a second-line treatment: (6 patients—MMF, 7—rituximab, - 4—second course of IVMP, 1—tocilizumab)
Treatment method	- MMF initiation phase (500 mg increasing up to 2 g for 52 weeks, 12 weeks i.v.). - Maintenance phase (doses of ⩾1.5 g). - Weaning phase (1 g tapered down to 750 mg then 500 mg).	- Oral prednisolone (20 mg started and gradually tapered, reduction of 5 mg/week for 3 weeks, continued at a dose of 5 mg daily + 500 mg of MMF added orally twice per day). - The treatment continued for 3 months until clinical response and discontinued. - Prednisolone withdrawn abruptly, the dosage of MMF was reduced gradually by 500 mg for 1 month and discontinued.	- CG (methyloprednisolone 500 mg intravenously once a week, six times, followed by methyloprednisolone 250 mg intravenously once a week, six times) - EG (0.25 g oral MMF added to the treatment from the control group, 0.36 g twice daily for 24 weeks)	- First-line treatment with IVMP i.v. (500 mg weekly for 6 weeks followed by 250 mg weekly for additional 6 weeks). - Second-line treatment with MMF/rituximab/IVMP, tocilizumab)
Results	- Clinical efficacy in patients without DON with active moderate-severe TED in 100% patients at 24 weeks, 87.5% at 52 weeks, 83.3% at 78 weeks. Significant reduction in CAS scores: - baseline CAS: 2.78 ± 1.99 - at 24 weeks CAS: 0.50 ± 0.58 - at 52 weeks CAS: 0.50 ± 0.82 - at 78 weeks CAS: 1.00 ± 1.30 Statistical significance at all time points during treatment was p < 0.01. Diplopia (Gorman scale) improvement: - baseline: 2.33 ± 1.32 - at 24 weeks: 0.63 ± 0.50 - at 52 weeks: 1.13 ± 0.84 - at 78 weeks: 1.83 ± 1.30 Statistical significance at all time points during treatment was p = 0.03. VA in worse eye improvement: - baseline: 0.13 ± 0.19 - at 24 weeks: 0.04 ± 0.22 - at 52 weeks: 0.11 ± 0.27 - at 78 weeks: 0.00 ± 0.14 No statistically significant difference (p > 0.05). - Improvements in patients with DON in 90% at 24 weeks, 100% at 52 weeks, and 100% at 78 weeks. Significant reduction in CAS scores: - baseline CAS: 2.55 ± 1.54 - CAS at 24 weeks: 0.83 ± 1.27 - CAS at 52 weeks: 1.00 ± 1.17 - CAS at 78 weeks: 0.63 ± 0.95 Statistical significance at all time points during treatment was p < 0.001. Diplopia (Gorman scale) improvement: - baseline: 2.64 ± 0.99 - at 24 weeks: 1.50 ± 1.22 - at 52 weeks: 1.43 ± 1.29 - at 78 weeks: 1.75 ± 1.53	- The clinical response rate was 67.7% on the 3rd month, 94.2% on the 12th month. Significant reduction in CAS scores: - baseline CAS: 5.4 ± 0.2 - 3rd month CAS: 2.8 ± 1.1 - 12th month CAS: 1.5 ± 1.2 - CAS improved in 70.6% on the 3rd month, 92.5% on the 12th month. Statistical significance at all time points during treatment was p < 0.001. - Proptosis response improved: 52% on the 3rd month, 83% on the 12th month. The mean proptosis value decreased (in worse eye): - baseline: 21.5 ± 1.8 - 3rd month: 20.3 ± 1.7 (p = 0.002) - 12th month: 18.4 ± 2.0 (p < 0.001) - Diplopia in Gorman Scale—improved in 73.9% patients at the 3rd month, 94.21% at 12th month.	- The clinical effective rates at 12 and 24 weeks in the EG higher than the CG: (p < 0.05). CG: - In the CG after 12 weeks of treatment CAS scores, bilateral lid fissure width decreased and right eye VA increased compared with those before treatment (p < 0.05). Improvement of parameters in the CG: 1. CAS: - baseline CAS: 4.4 ± 0.81 - at 12 weeks CAS: 3.00 ± 0.91 (p < 0.05) - at 24 weeks CAS: 2.13 ± 0.94 (p < 0.05) 2. Proptosis (in worse eye): - baseline: 20.73 ± 2.05 - at 12 weeks: 19.87 ± 1.61 - at 24 weeks: 19.00 ± 0.98 (p < 0.05) Changes in IOP and VA (both in the worse eye) were not significant in CG: 3. IOP: - baseline: 21.43 ± 3.96 - at 12 weeks: 20.33 ± 1.73 (p > 0.05) - at 24 weeks: 20.10 ± 1.49 (p > 0.05) 4. VA: - baseline: 0.64 ± 0.18 - at 12 weeks: 0.73 ± 0.16 (p < 0.05) - at 24 weeks: 0.77 ± 0.14 (p < 0.05) 5. Pre- and post-treatment TRAb concentrations—a significant decrease in CG: - baseline TRAb concentration in CG: 16.53 ± 9.41 - at 24 weeks: 7.17 ± 3.51 (p > 0.05) EG: - In the EG after 12 weeks of treatment the QOL score and VA increased, CAS score, IOP, lid width and proptosis decreased compared with before treatment (p < 0.05). Improvement of parameters in the EG: 1. CAS: - baseline CAS: 4.23 ± 0.90 - CAS at 12 weeks: 2.90 ± 1.00 (p < 0.05) - CAS at 24 weeks: 1.83 ± 0.83 (p < 0.05) 2. Proptosis (in worse eye): - baseline: 20.77 ± 2.82 - at 12 weeks: 19.13 ± 2.03 (p < 0.05) - at 24 weeks: 17.63 ± 1.16 (p < 0.05)	- CAS decreased in patients undergoing second-line treatment compared to the CAS before: - baseline CAS: 6.00 - at 5 weeks CAS: 2.96 - at 12.2 weeks CAS: 1.81 Statistical significance: p < 0.001. - TSI levels at baseline: higher in second-line vs responders • Second-line group: 2135% • First-line group (good IVMP response): 1159% • Statistical significance: p = 0.05
	Statistical significance at all time points during treatment was p < 0.001. VA in worse eye improvement: - baseline: 0.45 ± 0.42 - at 24 weeks: 0.42 ± 0.42 - at 52 weeks: 0.40 ± 0.45 - at 78 weeks: 0.33 ± 0.48 Statistical significance at all time points during treatment was p = 0.02.	Diplopia (Gorman Scale)—significant reduction: - baseline: 1.5 ± 1.2 - 3rd month: 0.3 ± 0.7 - 12th month: 0.1 ± 0.3 Statistical significance at all time points during treatment was p < 0.001. - Changes in IOP and VA were not significant (all p-values were >0.05).	Changes in IOP and VA (both in the worst eye) were not significant in EG: 3. IOP: - baseline: 20.27 ± 3.20 - at 12 weeks: 18.80 ± 1.97 (p < 0.05) - at 24 weeks: 17.70 ± 1.09 (p < 0.05) 4. VA: - baseline: 0.67 ± 0.24 - at 12 weeks: 0.81 ± 0.19 (p < 0.05) - at 24 weeks: 0.91 ± 0.17 (p < 0.05) 5. Pre- and post-treatment TRAb concentrations—a significant decrease in EG: - baseline TRAb concentration: 17.38 ± 9.52 - TRAb concentration at 24 weeks: 4.46 ± 2.99 (p < 0.05)	- TSI levels after treatment: • Second-line group: 2201% • Responders: 986% • Statistical significance: p = 0.043 - patients with second-line treatment had higher baseline and post-first-line treatment serum TSI levels

CAS, Clinical Activity Score; CG, control group; DON, dysthyroid optic neuropathy; EG, experimental group; IOP, intraocular pressure; i.v., intravenous; IVMP, intravenous methylprednisolone; MMF, mycophenolate mofetil; QOL, quality of life; TED, thyroid eye disease; TSI, thyroid-stimulating immunoglobulin; VA, visual acuity.

Current place of MMF in TED treatment recommendations

Choosing a suitable drug requires a thorough consideration of many different factors, including sex, age, and pregnancy. ⁷⁰ Other important factors to consider in the decision on an appropriate treatment selection are the assessment of the disease activity and severity. In this decision-making process, scales like CAS, EUGOGO, and VISA are useful. First-line treatment involves the use of corticoids. However, it is not only impossible to use these medicines in all patients, but also not equally effective in all cases. In recent years, researchers and clinicians have become focused on monoclonal antibodies; however, MMF is yet another alternative. MMF has been applied for many years now in various medical conditions. Its usage is well established in the prevention of transplant rejection. It has been shown that MMF is highly specific for the treatment of TED. MMF has been found to be significantly more effective than prednisone in the treating TED, with fewer adverse effects. ⁷⁵ The clinical efficacy of combination therapy with MMF and glucocorticoids in TED treatment was higher than that of glucocorticoid treatment alone. ³⁹

Conclusion

TED is a progressive, sight-debilitating condition, usually associated with GD. It manifests with proptosis, diplopia, and eyelid swelling. Its treatment remains a challenging task, even currently. MMF appears to be a safe and effective therapeutic option for TED. Its usage in TED has recently gained attention, and it may be recommended to administer it alongside corticosteroids to enhance its efficacy. Compared to monoclonal antibodies, MMF is relatively inexpensive and readily available. Adverse effects are uncommon, and there are few contraindications. Given these advantages, MMF should be considered more frequently as a treatment option for TED. However, there is a need for new studies comparing IV steroid treatment and other common methods with MMF therapy. Additionally, new alternative treatment regimens—including MMF for patients who do not respond to conventional medications—should be explored.