臺灣博碩士論文加值系統

背景與目的：溶血性貧血是紅血球從正常的生命週期中被破壞所導致的一種貧血。造成溶血性貧血的成因很多，不同的原因也會導致發生紅血球破壞的位置不同，如自體免疫溶血性貧血 (autoimmune hemolytic anemia, AIHA) 即是發生在較大的血管，肇因於病人自己體內的抗體直接攻擊紅血球所致，其分類是以最適合使不同抗體連接到紅血球的溫度來做區別。而微小血管內溶血性貧血 (microangiopathic hemolytic anemia, MAHA) 則是發生在較小的血管中，MAHA為一種非免疫性的溶血狀態，其中最主要與其相關的疾病就是血栓性血小板減少性紫斑症 (thrombotic thrombocytopenic purpura, TTP) 以及溶血性尿毒症候群 (hemolytic-uremic syndrome, HUS)。AIHA的治療主要是給予類固醇或是支持性藥物，而MAHA則需要血漿置換及類固醇。Rituximab (RTX) 是一種抗B細胞的單株抗體，主要用於治療B細胞淋巴瘤。RTX目前可自費用於AIHA及MAHA治療，當作後線使用，不過當前這樣使用的證據仍未充足且尚無適應症。因此本研究以系統性文獻回顧與統合分析的方法，探討RTX用於AIHA及MAHA的療效與安全性。
方法：從PubMed、Cochrane及Embase三個資料庫進行系統性的文獻搜尋，收錄2018年10月15日之前所發表的文獻，並從Google Scholar找尋其他相關文獻。納入含有評估rituximab用於AIHA或MAHA的臨床試驗或觀察性研究。療效以整體反應率 (overall response rate, ORR)、完全反應率 (complete response rate, CRR) 以及復發率評估。至於安全性則由納入的文獻中摘錄不良反應的發生。統合分析以隨機效應模式進行，計算出所有文獻的加權平均，以及在有比較組的文獻中計算出相對效果。
結果：經過文獻評讀之後，總共將37篇文獻中所含的1057位病人納入本研究。平均整體反應率為0.84 (95% CI, 0.80-0.88)，完全反應率為0.61 (95% CI, 0.49-0.73)。次族群分析中，AIHA組別整體反應率為0.79 (95% CI, 0.73-0.84)，完全反應率為0.44 (95% CI, 0.33-0.55)，MAHA組別的反應率則為0.93 (95% CI, 0.89-0.97)。從統合回歸的分析中發現年齡愈小者其反應率愈高 (ORR: p=0.0103; CRR: p<0.0001)。復發率為0.21 (95% CI, 0.15-0.26)，次族群分析中AIHA病人的復發率為0.28 (95% CI, 0.20-0.36)，MAHA病人的復發率為0.09 (95% CI, 0.05-0.13)。平均不良反應率為0.13 (95% CI, 0.10-0.17)，其中血液毒性相關反應為40件、感染34件、輸注相關反應33件。相對整體反應率為1.18 (95% CI, 1.02-1.36)，而相對完全反應率為1.17 (95% CI, 0.98-1.39)。以敏感性分析移除差異較大的文獻所得相對整體反應率為1.09 (95% CI, 1.00-1.09)，相對完全反應率為1.24 (95% CI, 1.03-1.49)。相對復發率為0.93 (95% CI, 0.56-1.55)，以敏感性分析移除差異較大的文獻所得相對復發率為1.09 (95% CI, 0.74-1.60)。相對不良反應率為0.77 (95% CI, 0.36-1.63)。
結論：RTX治療AIHA與MAHA的整體療效顯著，其中微小血管內溶血性貧血呈現更高反應率。在與其他治療比較時，RTX亦顯示出更好的效果，復發率則是沒有差異。此外，RTX呈現安全且耐受性良好，僅少數不良反應發生且不良反應多屬輕微，與其他治療不良反應率相似。
關鍵詞：Rituximab、自體免疫溶血性貧血、微小血管內溶血性貧血

Background: Hemolytic anemia (HA) is a kind of anemia due to the destruction of red blood cells (RBC) from the circulation before their normal life span. Location of RBC destruction occurs varied, such as in larger vessels (eg. autoimmune hemolytic anemia, AIHA) or smaller vessels (eg. microangiopathic hemolytic anemia, MAHA). AIHA is a rare disease caused by autoantibodies directed against erythrocyte self-antigens, and its thermal-based classification is based on the optimal autoantibody-RBC reactivity temperature. MAHA is non-immune hemolysis resulting from intravascular RBC fragmentation, of which main associated diseases are thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). Main treatment options are corticosteroids or supportive care for AIHA, and plasma exchange (plasmapheresis) in conjunction with corticosteroids for MAHA. Rituximab (RTX) is a B cell depleting monoclonal antibody, which is primary used in the treatment of B-cell lymphoma. It has become an alternative therapeutic option for AIHA and MAHA. However, the evidence of efficacy and safety of rituximab in AIHA and MAHA are not yet clear. To further understand the efficacy and safety of RTX in AIHA and MAHA, we conducted the present systematic review and meta-analysis.
Method: Studies were collected from PubMed, Cochrane, and Embase from inception to Oct 15, 2018, and additional studies from Google Scholar. We included clinical trials or observational studies, which assessed the efficacy and safety of RTX in AIHA or MAHA. Efficacy was assessed by overall response rate (ORR) and complete response rate (CRR). Regarding the safety, adverse events (AE) and relapse rate (RR) were extracted from the studies included if available. A meta-analysis was carried out with a random-effects model, estimating mean proportion in all studies, and relative rate in comparative studies.
Result: After quality assessment, a total of 37 studies encompassing 1057 patients were eligible. Pooled mean proportion of ORR was 0.84 (95% CI, 0.80-0.88), and CRR was 0.61 (95% CI, 0.49-0.73). In subgroup analysis, ORR of AIHA was 0.79 (95% CI, 0.73-0.84), and CRR was 0.44 (95% CI, 0.33-0.55). As for MAHA, the response rate was 0.93 (95% CI, 0.89-0.97). Younger patients were significantly associated with better response to RTX in meta-regression (ORR: p=0.0103; CRR: p<0.0001). RR was 0.21 (95% CI, 0.15-0.26). In a further subgroup analysis, RR was 0.28 (95% CI, 0.20-0.36) in AIHA and 9% (95% CI, 0.05-0.13) in MAHA. Mean AE rate was 0.13 (95% CI, 0.10-0.17). Among them, 40 events were hematologic abnormalities, 34 events were infections, and 33 events were infusion-related reactions. Relative ORR was 1.18 (95% CI, 1.02-1.36), and relative CRR was 1.17 (95% CI, 0.98-1.39). After leaving the most different studies out in sensitivity analysis, coming to ORR of 1.09 (95% CI, 1.00-1.19) and CRR of 1.24 (95% CI, 1.03-1.49). Relative RR was 0.93 (95% CI, 0.56-1.55). Regarding the sensitivity analysis, leaving the most different study out coming to 1.09 (95% CI, 0.74-1.60). Relative AE rate was 0.77 (95% CI, 0.36-1.63).
Conclusion:
RTX showed high ORR and CRR in AIHA and MAHA, and a higher response in MAHA subgroup. Comparing to other treatments, RTX showed a better effect. Relapse rate of treatments with RTX was similar to other treatments. RTX was safe and well-tolerated. AE rate of treatment with RTX was low and mostly mild. AE rate of treatments with rituximab was similar to other treatments.
Key words: Rituximab (RTX), autoimmune hemolytic anemia (AIHA), microangiopathic hemolytic anemia (MAHA)

目錄
誌謝………………………………………………………………………………i
中文摘要………………………….…………………………………………..…ii
英文摘要………………….………………………………….…………………iv
目錄………………………………………………………........………….…..vi
圖目錄…………………………………………………………...…………..viii
表目錄…………………………………………...……………………………...ix
縮寫表…………………………………….……………….……...……….…….x
第一章 緒論…………………………………………………………………….1
第一節 研究背景與動機………………….……………………………......1
第二節 研究目的……………………………………………..………...…16
第二章 文獻探討………………………………………………..………….....17
第一節 Rituximab用於自體免疫溶血性貧血的治療.……………….….17
第二節 Rituximab用於微小血管內溶血性貧血的治療…………...……19
第三章 研究方法和設計…………..…………………………..………...…....20
第一節 研究項目與研究假設…...…………………….………………….20
第二節 研究設計與研究工具………………..………..………………….21
第三節 資料處理與分析...…….………………………………………….31
第四章 研究結果....……….…….......…………………………..……..……...33
第一節 納入研究基本資料…...………….……………………………….33
第二節 Rituximab療效分析結果…………………………….....………..36
第三節 Rituximab安全性分析結果…………………..…..……………...51
第四節 Rituximab與其他治療的療效比較……………………………...53
第五節 Rituximab與其他治療的安全性比較………………….…..……63
第五章 討論…………………………………………………………..…….....65
第一節 Rituximab的療效分析討論……………………………….……..65
第二節 Rituximab的安全性分析討論……….…………………….…….69
第三節 Rituximab與其他治療的療效比較討論…….…..………...…….70
第四節 Rituximab與其他治療的安全性比較討論……………………...73
第五節 研究限制….……………..……………..…………………………75
第六章 結論與建議..………………..…...….…………………………...…....76
第一節 結論…………………………………………………………...…..76
第二節 建議……………………………………………………………….77
第七章 參考文獻……………….………………………………….…….....78
附錄…………………………………………………………………………….88

圖目錄
圖3-2-1 資料處理流程………………………………...……....................30
圖4-2-1 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的整體反應率………………………………………………...……39
圖4-2-2 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的整體反應率漏斗圖……………………………….………..……40
圖4-2-3 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的完全反應率……………………………………..……….………41
圖4-2-4 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的完全反應率漏斗圖………………………………………...……42
圖4-2-5 整體反應率與病人平均年齡的統合回歸………………….......45
圖4-2-6 完全反應率與病人平均年齡的統合回歸………………..….…46
圖4-2-7 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的復發率………………………………………………..….………47
圖4-2-8 Rituximab治療自體免疫血性貧血與微小血管內溶血性貧血的復發率漏斗圖………………………………………………...…48
圖4-4-1 Rituximab與其他治療的相對整體反應率…………..…………55
圖4-4-2 Rituximab與其他治療的相對整體反應率漏斗圖.………….…56
圖4-4-3 Rituximab與其他治療的相對完全反應率…………..…………57
圖4-4-4 Rituximab與其他治療的相對完全反應率漏斗圖.………….…58
圖4-4-5 Rituximab與其他治療的相對復發率………………..…………60
圖4-4-6 Rituximab與其他治療的相對復發率漏斗圖………..…………61

表目錄
表1-1-1 自體免疫溶血性貧血分類………………………......................4
表1-1-2 血栓性血小板減少性紫斑症及溶血性尿毒症候群..................7
表1-1-3 自體免疫溶血性貧血的治療…………......................................9
表1-1-4 微小血管內溶血性貧血的治療…………................................10
表1-1-5 Rituximab………………...……..………………......................14
表3-2-1 文獻評讀工具…………………………..………......................26
表4-1-1 納入分析的研究……………………………..………………..33
表4-1-2 有比較組的文獻…………………………………..………......34
表4-2-1 整體反應率與完全反應率的次族群分析…………..………..42
表4-2-2 整體反應率與完全反應率的統合回歸………………..……..43
表4-2-3 復發率的次族群分析……………………………………..…..48
表4-2-4 復發率的統合回歸…………………………………..………..49
表4-3-1 不良反應事件…………………………………………………51
表4-4-1 Rituximab與其他治療的療效比較的敏感性分析…….....….59
表4-4-2 Rituximab與其他治療的復發率比較的敏感性分析….....….62
表4-5-1 使用rituximab與比較組的不良反應………….…….…….....64
附表3-2-1 PubMed檢索歷史……………..……………………………....88
附表3-2-2 Cochrane檢索歷史……………………………………..……..90
附表3-2-3 Embase檢索歷史……………………...…………………..…..91
附表3-2-4 文獻資訊………………………………………..……………..93
附表3-2-5 療效定義……………………………………………..………103
附表3-2-6 療效與安全性……………………………………..…………109
附表3-2-7 文獻評讀結果…………………………………..……………112

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