本文選題：Graves眼病 + 眼眶成纖維細胞��； 參考：《南京大學》2011年碩士論文

【摘要】：[背景]： Graves眼病(Graves'ophthalmopathy, GO)是一種慢性自身免疫相關性疾病,由于眼眶球后組織的炎癥反應和親水性氨基葡聚糖的蓄積,伴或不伴有眼眶脂肪組織和眼外肌的增生,引起眼眶球后組織的容積增加導致一系列臨床表現(xiàn),如眼痛、眼球突出、眶周水腫、眼外肌運動障礙、炎癥及損害視力等。大約有20～25%的甲狀腺機能亢進的病人發(fā)生Graves眼病。Graves眼病發(fā)病的機制至今仍不是十分清楚,臨床治療也有一定困難。 Graves眼病的病程經歷兩個階段：早期為活動期,主要病理表現(xiàn)為眼部淋巴細胞和炎性細胞的浸潤、氨基葡聚糖的沉積與水腫；晚期為穩(wěn)定期,表現(xiàn)為球后組織的纖維化及脂肪的沉積。病程不同時期GO患者采取的治療方法和療效不同,因此正確評判Graves眼病的病情對治療方法的選擇和預后的估計有重要意義。國內外文獻報道,GO患者血清透明質酸(Hyaluronic Acid, HA)和細胞間粘附分子-1(Soluble intercellular adhesion molecule-1, sICAM-1)水平可作為評價眼眶活動度與嚴重程度的重要指標,血清堿性成纖維細胞生長因子(Basic fibroblast growth factor, bFGF)和血管內皮生長因子(Vascular endothelial growth factor, VEGF)水平在活動性GO患者中表達增加。 目前Graves眼病的免疫治療,最基本最常用的是糖皮質激素的應用。大量證據表明,糖皮質激素對中、重度浸潤性突眼的治療尤其有效,中、重度及活動性GO患者靜脈使用糖皮質激素類藥物的有效率可達77%。其他免疫抑制劑包括雷公藤多甙、霉酚酸酯、環(huán)孢菌素等在臨床都有一定的應用,并且收到了較好的治療效果。大量循癥醫(yī)學證據表明雷公藤多甙治療甲亢突眼有效,對細胞免疫及體液免疫均有較強的抑制作用,抑制了眼球后組織自身抗體形成,減輕突眼癥狀。我們前期的研究發(fā)現(xiàn)霉酚酸酯和雷公藤治療GO的療效較環(huán)孢素好,且不良反應少,在臨床上可能有較好的應用前景。 [目的]： 通過檢測GO患者血清中VEGF、HA、bFGF、sICAM-1四種標記物的水平,尋找能夠評價GO患者病情活動性的客觀指標,從而更好地評價患者的病情以指導臨床治療。比較GO患者在使用糖皮質激素、雷公藤多甙和霉芬酸脂治療前后四種因子水平變化,尋求更為有效的治療藥物,并為臨床治療推廣提供新的選擇。 [方法]： 1、采用ELISA方法檢測50例GO患者和31例單純Graves病無眼征的患者血清中bFGF、HA、sICAM-1、VEGF因子的表達水平,比較兩組間四種因子水平的變化,并對GO組患者血清四種因子水平、臨床活動性評分及其他指標進行相關性分析。根據臨床評分系統(tǒng)將GO患者分為活動組與穩(wěn)定組,并比較兩組間四種因子水平的變化。 2、采用ELISA方法檢測12例GO患者血清HA、bFGF、sICAM-1、VEGF因子水平,并對GO患者進行臨床活動性評分,分析比較這些因子水平和臨床活動性評分在免疫抑制治療前后的變化,12例患者中口服雷公藤多甙者4例(20mg,3次/d),霉酚酸酯者4例(0.5g,2次/d),強的松者4例(40mg/d×4w,20mg/d×4w, 10mg/d×4w),療程12周。 3、應用SPSS16.0統(tǒng)計學軟件分析,計量資料使用均數(shù)±標準差(x±s)表示,并對數(shù)據進行正態(tài)性檢驗及方差分析。組間比較采用兩獨立樣本t檢驗；GO患者治療前后兩組間的比較采用配對t檢驗；相關性分析采用Spearman相關性分析,P0.05為差異有統(tǒng)計學意義。 [結果]： 1)GO患者血清VEGF、HA、sICAM-1和bFGF水平較Graves病患者明顯升高,有統(tǒng)計學差異(p0.05)。GO患者血清四種因子水平與臨床積分顯著相關(p0.05),與年齡和病程不相關(p0.05)。 2)活動組GO患者血清sICAM-1較穩(wěn)定組明顯升高,有統(tǒng)計學差異(p0.05),而HA和VEGF及bFGF水平較穩(wěn)定組雖有升高,但無統(tǒng)計學差異(p0.05)。 3)GO患者血清HA、VEGF、bFGF三種因子之間呈顯著正相關性(p0.05),而sICAM-1水平與VEGF、bFGF和HA水平均無明顯相關性(p0.05)。 4)治療12周后,各組患者均無眼病惡化情況。GO組經免疫抑制治療后的血清HA、sICAM-1、bFGF、VEGF水平與治療前相比均顯著降低,且臨床活動性評分也顯著降低,差異有統(tǒng)計學意義(p0.05),并且83.33%(10/12)的患者在使用免疫抑制劑治療后臨床活動性分值降低3分以上,口服霉酚酸酯和雷公藤各1例患者臨床積分降低2分。強的松組4例患者中2例出現(xiàn)高血糖反應和胃腸道反應。MMF和TⅡ組與強的松組相比,無明顯的藥物不良反應。 [結論]： 1)HA、sICAM-1、VEGF和bFGF在Graves眼病的發(fā)病過程中可能相互作用,共同參與GO的發(fā)生發(fā)展,其血清中的水平與GO病情的活動性密切相關,可作為評價Graves眼病病情活動性的指標。 2)實驗結果顯示GO患者經免疫抑制藥物治療后血清VEGF、HA、bFGF、sICAM-1水平明顯下降,這四種標記物可以作為監(jiān)測GO病情和調整GO治療方法的有用指標。
[Abstract]:[background]:
Graves (Graves'ophthalmopathy, GO) is a chronic autoimmune related disease, due to the inflammatory reaction of the orbital tissue and the accumulation of hydrophilic glucan, with or without the proliferation of orbital adipose tissue and extraocular muscles. The increase in the volume of posterior orbital tissue leads to a series of clinical manifestations, such as eye pain, and the eyeball process. Edema, dyskinesia of the extraocular muscles, inflammation and impairment of vision, about 20 to 25% of the hyperthyroidism patients with Graves eye disease.Graves eye disease pathogenesis is still not very clear, and clinical treatment is also difficult.
The course of Graves's ophthalmopathy experienced two stages: early stage of activity, the main pathological manifestations were infiltration of ocular lymphocytes and inflammatory cells, deposition and edema of glucan; late stable period, manifested as the fibrosis of the tissue and the deposition of fat. The treatment and effect of GO patients in the course of the disease were different because of different therapeutic methods and effects. It is important to correctly judge the condition of Graves eye disease for the choice of treatment and the estimation of prognosis. The domestic and foreign literature reports that the level of serum hyaluronic acid (Hyaluronic Acid, HA) and intercellular adhesion molecule -1 (Soluble intercellular adhesion molecule-1, sICAM-1) in GO patients can be used as the evaluation of orbital activity and severity. The levels of serum basic fibroblast growth factor (Basic fibroblast growth factor, bFGF) and vascular endothelial growth factor (Vascular endothelial growth factor, VEGF) were increased in active GO patients.
At present, the most basic and most commonly used immunotherapy for Graves eye diseases is the use of glucocorticoids. A large number of evidence suggests that glucocorticoid is especially effective in the treatment of severe invasive exophthalmos, and the effective rate of intravenous glucocorticoids in the moderate, severe and active GO patients can reach 77%. other immunosuppressants including Tripterygium wilfordii, Mycophenolate mofetil and cyclosporin have been used in clinical practice and have received good therapeutic effects. A large number of evidence-based medical evidence shows that Tripterygium wilfordii polysaccharide is effective in the treatment of hyperthyroidism and has strong inhibitory effect on cellular immunity and humoral immunity. It inhibits the formation of autoantibodies in the post eyeball group and alleviated the symptoms of exophthalmos. The study found that the efficacy of mycophenolate mofetil and Tripterygium Wilfordii in the treatment of GO is better than cyclosporine, and has fewer adverse reactions.
[Objective]:
By detecting the level of four markers of VEGF, HA, bFGF, and sICAM-1 in the serum of GO patients, the objective indicators that can evaluate the activity of the patients with GO are searched for better evaluation of the patient's condition to guide the clinical treatment. The changes of the levels of the GO patients before and after the use of glucocorticoid, Tripterygium Wilfordii and mycophenopinic acid are compared. Seek more effective treatment drugs, and provide new options for clinical treatment and promotion.
[method]:
1, the serum levels of bFGF, HA, sICAM-1, VEGF in the serum of 50 patients with GO and 31 cases of simple Graves disease were detected by ELISA, and the levels of four factors between the two groups were compared, and the levels of four serum factors, clinical activity scores and other indexes were analyzed. The clinical scoring system was based on the clinical scoring system. GO patients were divided into active group and stable group, and the levels of four factors were compared between the two groups.
2, the serum levels of HA, bFGF, sICAM-1 and VEGF were detected by ELISA in 12 patients with GO, and the clinical activity score of patients with GO was evaluated. The changes of these factors and clinical activity scores before and after the immunosuppressive therapy were compared. 4 cases (20mg, 3 /d), 4 cases of mycophenolate mofetil (0.5g, 2 /d) were taken in 12 patients with the changes of these factors and clinical activity scores before and after the immunosuppressive therapy. Prednisone was found in 4 patients (40mg/d x 4W, 20mg/d x 4W, 10mg/d x 4W) for 12 weeks.
3, using SPSS16.0 statistical software analysis, the measurement data were expressed with mean standard deviation (x + s) and normal test and variance analysis of the data. Two independent sample t tests were used in the group. The comparison of the two groups before and after the treatment of GO was compared with the paired t test; the correlation analysis adopted the Spearman correlation analysis and the P0.05 was the difference. There is a statistical significance.
[results]:
1) the levels of serum VEGF, HA, sICAM-1 and bFGF in patients with GO were significantly higher than those of Graves patients. There was a statistically significant difference (P0.05) the level of four factors in serum of.GO patients was significantly related to clinical integration (P0.05), not related to age and course of disease (P0.05).
2) the serum sICAM-1 of GO patients in the active group was significantly higher than that in the stable group (P0.05), while the levels of HA and VEGF and bFGF were higher than those in the stable group, but there was no statistical difference (P0.05).
3) there was a significant positive correlation between the three factors of serum HA, VEGF and bFGF in GO patients (P0.05), while sICAM-1 level had no significant correlation with VEGF, bFGF and HA levels (P0.05).
4) after 12 weeks of treatment, the patients in each group had no worsening of eye disease. The serum HA, sICAM-1, bFGF, and VEGF levels in the.GO group were significantly lower than those before the treatment, and the clinical activity score was significantly lower, and the difference was statistically significant (P0.05), and 83.33% (10/12) patients were used in clinical activities after the use of immunosuppressive therapy. The score of sex score was reduced by more than 3, and the clinical integral of 1 patients with oral mycophenolate mofetil and Tripterygium wilfordii was reduced by 2. 2 of the 4 patients in the prednisone group had hyperglycemia and gastrointestinal reaction.MMF and T II, and there was no obvious adverse drug reaction compared with the prednisone group.
[Conclusion]:
1) HA, sICAM-1, VEGF and bFGF may interact in the pathogenesis of Graves ophthalmopathy, and participate in the development of GO. The level of serum is closely related to the activity of GO, and can be used as an index to evaluate the activity of Graves eye disease.
2) the experimental results showed that the levels of serum VEGF, HA, bFGF and sICAM-1 decreased significantly after the treatment of immunosuppressive drugs in GO patients. These four markers could be used as a useful indicator to monitor the condition of GO and to adjust the treatment of GO.
【學位授予單位】：南京大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：R581;R771.3

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