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研究生(外文):Tsu-Yi Hsieh
論文名稱(外文):Functional and structural improvement, and underlying mechanism of mycophenolate for lupus nephritis
指導教授(外文):Joung-Liang Lan
外文關鍵詞:MycophenolateLupus nephritis
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全身性紅斑狼瘡為國人最主要之全身性自體免疫疾病,亦為健保之重大傷病。狼瘡腎炎至今仍為全身性紅斑狼瘡病人重要之致死及致殘原因。近二十年來,狼瘡腎炎之治療已在以病理變化分類的狼瘡腎炎治療及使用靜脈注射cyclophosphamide (CYC, 癌德星)及高劑量類固醇之併用之引導治療後有所進展,可大幅減少進展至末期腎病及尿毒症之機會,但CYC治療具有增加主要器官感染、生殖腺毒性、骨髓抑制、及長期次發性癌症等眾多副作用,用於以生育年齡年輕女性為主的狼瘡腎炎病患實有必要之惡的無奈及長期安全的顧慮。酶酚酸(Mycophenolate mofetil, MMF)為抑制淋巴球活化之免疫抑制劑,由近十年中多項人體臨床藥物試驗的成功經驗中成為至今唯一可以與CYC療效相當之狼瘡腎炎治療,但至今仍未具足夠研究說明臨床有效的CYC, MMF治療如何改善狼瘡腎炎的病理變化,也沒有足夠研究分別機轉不同但臨床療效近似的CYC, MMF治療是否在病理變化的進步上有所不同。因此,我們以臺中榮總經腎臟切片並接受MMF治療的狼瘡腎炎患者為研究對象,評估MMF對狼瘡腎炎之臨床參數、實驗室檢查及病理參數改善及其與CYC治療患者病理參數改善的不同。

Lupus nephritis remained main threatening of SLE patients for their long term survival and morbidities. Nowadays, the treatment of lupus nephritis could be categorized based on pathological classification of lupus nephritis by renal biopsy. Intravenous cyclophosphamide (CYC) with or without steroid is used mainly to induce remission in patients with severe lupus nephritis. But the risk of increasing severe infection, gonadal toxicities, bone marrow suppression and secondary malignancy risk diminished the clinical benefit. Mycophenolate mofetil (MMF), a potent noncompetitive reversible inhibitor of T & B lymphocyte proliferation via reversible inhibition of the enzyme inosine 5-monophosphate dehydrogenase (IMPDH), is the only immunosuppressant in recent decades showed clinical efficacy similar to CYC treatment in lupus nephritis.
However, there are very few reports providing evidence of structural improvement or changes after clinically effective immunosuppressant therapy. Lack of evidence for structural improvement (i.e. changes in activity/chronicity index and individual parameters after treatment) was noted in both MMF and CYC treatment for lupus nephritis. There is also no data about differences in pathological structural improvements of those two drugs, even with different mechanisms of action between MMF and CYC.
So we initiate a study on lupus nephritis, based on renal biopsies to evaluate serial changes of clinical parameters, laboratory parameters and pathological structures after treatment with MMF. The pathological structural improvement by MMF treatment would be compared with those by CYC treatment to find out the possible underlying differences between these two drugs with different mechanisms but similar efficacy.
Our study revealed MMF therapy is effective for Chinese/Taiwanese with proliferative lupus nephritis and membranous lupus nephritis. The improvement of nephritis is concordant with systemic lupus activity improvement. There are solid structural improvements of nephritis by analyzing serial renal biopsy, based on WHO/ISN criteria for lupus nephritis. Overall activity index, all individual activity parameters revealed improvement after MMF treatment along with mild but statistical significant progression of chronicity score. In comparison with CYC treatment with similar clinical efficacy, MMF treatment group showed similar improvement in overall activity index, but more improvement in leukocyte infiltration score and improvement in interstitial mononuclear cell infiltrations, better in progression of overall chronicity index and less glomerular sclerosis, fibrous crescent and interstitial fibrosis. Adequate adjustment of MMF dose to adequate response should be considered when treatment is less optimal, especially for those with less than MMF 2000mg/day. Through serial 3 renal biopsies, MMF therapy proved to be with persistent effects on clinical, laboratory and structural aspects for patients with lupus nephritis.
The results might be helpful in establishing personalized therapy for different lupus nephritis patients and achieving better therapeutic outcome of lupus nephritis.

縮寫表……………………………………………………………... xi
第一章 Introduction
第一節. Lupus nephritis 1
第二節. Mycophenolate mofetil 6
第二章Background………………………………………………… 16
第三章Materials and Methods…………………………………… 18
第四章 Results 21
第五章 Discussion 27
圖表 32
參考文獻 46

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