| BACKGROUND:Thyroid-associated ophthalmopathy (TAO) is a kind of orbital diseases caused by many factors, the incidence of which is in the first place among adult orbital diseases. The disease is characterized by proptosis, periorbital edema, conjunctival hyperemia and edema, ophthalmoplegia, and exposure keratitis, corneal ulceration, perforation, and optic nerve damage in severe cases. Clinically, TAO severely affects the appearance of the patients. In severe cases, the vision can also be affected. The incidence of TAO accounts for6%-10%of the patients with hyperthyroidism.The pathogenesis of thyroid-related eye disease is related to immunological, genetic and environmental factors.1.The relationship between various thyroid disease and TAO:90%of TAO patients suffered from hyperthyroidism. In the other patients,50%of them are associated with hypothyroidism, and among the euthyroid patients with immunological abnormalities, serum TRAb and TGAb (or TMAb) is positive in1/3and2/3patients respectively.2.Humoral immunity:Studies showed that there is a common epitope in thyroid and extraocular muscle membrane of orbital connective tissue. We have found one kind of64000antigen protein and its specific antibody in the TAO patients’ blood, which were expressed in the thyroid and extraocular muscle membrane, so64000antigen protein and its specific antibody may be related to the occurrence of thyroid-related eye disease. For the patients with64000antigen-antibody complex in their body, the possibility of suffered from thyroid disease and thyroid-related eye disease at the same time increased significantly.3.Cellular immunity and cytokines:The histological signs of TAO are the infiltration of lymphocytes in orbital connective tissue and extraocular muscles. Many researches showed that the proportion of orbital cytolytic T cells in TAO patients was significantly higher, including100%of the CD8+T cells and75%of the CD4+T cell clones. The lymphocytes infiltrated in the extraocular muscle and after the ball could secrete various cytokines, including interferon-γ (IFN-γ), interleukin-2(IL-2) and tumor necrosis factor-a (TNF-α). These cytokines could stimulate the proliferation of orbital fibroblasts and glycosaminoglycan (GAG) synthesis, thereby contributing to the incidence of thyroid-related eye disease. Moreover, the immunohistochemical results proved that, insulin-like growth factor (IGF) can be detected in the TAO patients’extraocular muscles, inflammatory infiltrate cells and fat cells within the orbit, IGF may also play a role in the incidence of thyroid-related eye disease.4.The role of fibroblasts:The proliferation of the fibroblast becomes active when influenced by IGF, fibroblast growth factor (FGF) and other cytokines, which secreted large amounts of glycosaminoglycan and led to proptosis when extraocular muscles and periorbital tissue swelled and intraocular pressure increased.5. Potential incentives:Studies had shown that smoking related with the onset and progression of thyroid-related eye disease. In addition, a large number of studies found that radioactive iodine treatment can affect thyroid-related eye disease and aggravate proptosis. The impact of thyroidectomy on exophthalmos was not confirmed. Several studies found that there was no significant difference of total thyroidectomy and subtotal thyroidectomy on the progression of the thyroid-related eye disease, and previous studies suggested that total thyroidectomy could improve the patients’proptosis. Therefore, the impact of thyroidectomy for thyroid-related eye disease needs to be further proved.TAO exhibits a female to male ratio of4:1, although women have a higher incidence, more severe diseases often affected elderly males.Thyroid eye disease typically has an active inflammatory phase subsiding over one to two years into an inactive fibrotic phase. After the inflammation subsides, patients may suffer permanent structural changes around the eyes, which required treatment. After entering stabilization period, active inflammation recurs in about1%of patients. Unfortunately, there is no reliable means of detection and signs that could be used to determine when the inactive phase began. When the clinical manifestations did not change for six months, it suggested that the patient has transferred from the active to inactive phase. It is important to recognize that the course of TAO in each patient is unique and may require different treatments. Some patients may have only mild proptosis while others have sudden onset of severe complications such as severe diplopia, proptosis and vision loss.Currently, there are a variety of treatments for the treatment of TAO. The three major treatment modalities of TAO are intravenous corticosteroid pulse therapy, radiation therapy and orbital decompression surgery. Glucocorticoid therapy is commonly used, although the side effects are often obvious. Moreover, as the deepening of researches concerning the pathogenesis of TAO, many kinds of new drugs such as octreotide, rituximab, peroxisome proliferator-activated receptor-γ antagonist, anti-IL-6receptor antibody and selenite are also used for the treatment of thyroid-associated ophthalmopathy, and much great progress have achieved so far. Currently, new immunosuppressive drugs are becoming a hotspot, which tend to have more significant effect and fewer side effects.OBJECTIVE:To search for effective treatment for Graves’ ophthalmopathy by analyzing the efficacy and safety of mycophenolate mofetil and other immunosuppressants for the treatment of Graves’ophthalmopathy (GO).METHODS:A total of115untreated GO patients were included in this study. All the patients were divided into group A, group B and group C. The patients in group A were given prednisone (n=30), the patients in group B were given tripterygium multi glycosides (T n, n=45), and those in group C were given mycophenolate mofetil (MMF, n=40). The duration of treatment is12weeks. The severity of disease and the response to therapy were quantitatively assessed according to the Ophthalmopathy Index Scoring System from Given-wilson (1989) with sensibly modified. Significant efficiency was defined if decrease of the score reached4or more in the ophthalmopathy index; If decrease of the score was between2and4, it was defined as efficiency; If the variation of the score did not exceed1, a lack of response was indicated. The patients who had hyperthyroidism were given antithyroid drugs (methimazole or propylthiouracil) therapy, the patients who had hypothyroidism were given levothyroxine therapy, the thyroid maintained in normal level, and avoid drug-induced hypothyroidism.RESULTS:1. After12-week therapy, one (3.3percent) of the30patients treated with glucocorticoid was significant effective,14(46.7percent) was effective, the other15(50.0percent) patients unchanged. In TⅡ group,15(33.3percent) of the45patients was significant effective,20(44.4percent) was effective, the other10(22.2percent) patients had no change. In mycophenolate mofetil group,21(52.5percent) of the40patients was significant effective,17(42.5percent) was effective, the remaining2(5.0percent) patients had no change. The efficacy of the drugs ranked from great to small as follows:mycophenolate mofetil, TⅡ and glucocorticoid, and the differences were statistically significant (P<0.05).2. None of the115patients had worsening of ophthalmopathy. Compared with integral value before treatment, after the treatment of TAO, the scores in each group all decreased to some extent after treatment (P＜0.01). The integral value decline in MMF group was (3.40±0.84) points, the integral value decline in T ii group was (2.76±1.51) points, and the integral value decline in glucocorticoid group was (1.67±1.09) points. The decreasing range were mycophenolate mofetil, TⅡ and glucocorticoid, respectively. Moreover, compared with the glucocorticoid group, the decrease of TAO integral value was greater than in the MMF group, and the difference was statistically significant (P<0.01); Compared with the T n group, the decrease of TAO integral value was greater than in the MMF group, and the difference was also statistically significant (P<0.05); Compared with the TⅡ group, the decrease of TAO integral value was smaller in glucocorticoid group, but there was no statistically significant difference (P＜0.01). The order of TAO integral value decline in each group was consistent with the order of improvement rate in each group.3. During the observation period of3months, all groups have varying degrees of adverse reactions. The incidence of adverse reactions was highest in the glucocorticoid group. Of30patients in glucocorticoid group, one (3.3percent) patient had mild menstrual abnormalities and transaminase abnormalities, one (3.3percent) patient had dacial acne and mild transaminase abnormalities,3(10percent) patients got stomach discomfort, and6(20percent) patients gained body weight during the treatment, with the manifestations of Cushing’s face, one of them felt limb muscle stiffness after the treatment lasting for one month. After reduction of the drug dose, all the adverse reactions reduced, and there was no significant change of the blood sugar for all patients in the glucocorticoid group.45patients in TⅡ group,4(8.9percent) patients had mild menstrual abnormalities,3(6.7percent) patients got stomach discomfort, one (2.2percent) patient had transaminase abnormalities, and another one (2.2percent) patient got liver discomfort, but her liver function is normal. Among40patients in mycophenolate mofetil group,3(7.5percent) patients had mild transaminase abnormalities.CONCLUSION:The new immunosuppressants MMF may be more effective than T n and glucocorticoid in the treatment of GO, and the side effects were fewer. There is a good prospect for MMF as the treatment of GO; Low doses of TⅡ may be more effective and perhaps have a better tolerability than glucocorticoid in the treatment of GO, the side effects may also be fewer, so it can be used as a replacement when corticosteroids are contraindicated for the treatment of GO. |
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