阵发性睡眠性血红蛋白尿症的靶向治疗_West China Medical Journal

Authors：

 杨春丽 ,  朱焕玲

四川大学华西医院血液科, 成都, 610041;

Corresponding author：

朱焕玲, Email: zhuhuanling@medmail.com.cn

Keywords：

阵发性睡眠性血红蛋白尿症; 溶血; 重组人源型抗补体蛋白C5单克隆抗体; 靶向治疗

DOI：

10.7507/1002-0179.20140418

Video：

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Abstract Full text Figures/Tables Video References Cited by

阵发性睡眠性血红蛋白尿症（PNH）是一种罕见的造血干细胞克隆性的溶血性疾病，目前治疗困难。重组人源型抗补体蛋白C5单克隆抗体（eculizumab）的出现及临床应用开启了PNH靶向治疗的新篇章。eculizumab通过与补体C5结合，防止C5裂解形成C5b及膜攻击复合物，减少溶血，降低输血需求，提高患者生活质量。2007年，eculizumab分别被美国食品和药物管理局、欧盟委员会通过用于治疗PNH血管内溶血。现对PNH患者使用eculizumab靶向治疗作一综述。

Citation： 杨春丽, 朱焕玲. 阵发性睡眠性血红蛋白尿症的靶向治疗. West China Medical Journal, 2014, 29(7): 1365-1368. doi: 10.7507/1002-0179.20140418 Copy

1.	Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 1995, 333(19):1253-1258.
2.	Rosse WF. Paroxysmal nocturnal hemoglobinuria as a molecular disease[J]. Medicine (Baltimore), 1997, 76(2):63-93.
3.	Luzzatto L. Paroxysmal nocturnal hemoglobinuria:an acquired X-linked genetic disease with somatic-cell mosaicism[J]. Curr Opin Genet Dev, 2006, 16(3):317-322.
4.	Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria[J]. Cell, 1993, 73(4):703-711.
5.	Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene[J]. EMBO J, 1994, 13(1):110-117.
6.	Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria[J]. Lancet, 2009, 373(9665):759-767.
7.	Rother RP, Rollins SA, Mojcik CF, et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria[J]. Nat Biotechnol, 2007, 25(11):1256-1264.
8.	Dmytrijuk A, Robie-Suh K, Cohen MH, et al. FDA report:eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria[J]. Oncologist, 2008, 13(9):993-1000.
9.	Alexion Pharmaceuticals. Inc. Solaris® (eculizumab) prescribing information[EB/OL]. (2012-12-01)[2014-01-01]. http://www.soliris.net/sites/default/files/assets/soliris_pi.pdf.
10.	Hill A, Hillmen P, Richards SJ, et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria[J]. Blood, 2005, 106(7):2559-2565.
11.	Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 2006, 355(12):1233-1243.
12.	Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 2004, 350(6):552-559.
13.	Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria[J]. Blood, 2008, 111(4):1840-1847.
14.	Kanakura Y, Ohyashiki K, Shichishima T, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria:the AEGIS clinical trial[J]. Int J Hematol, 2011, 93(1):36-46.
15.	Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria:long-term follow-up and prognostic factors. French Society of Haematology[J]. Lancet, 1996, 348(927):573-577.
16.	Moyo VM, Mukhina GL, Garrett ES, et al. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays[J]. Br J Haematol, 2004, 126(1):133-138.
17.	Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)[J]. Blood, 2003, 102(10):3587-3591.
18.	Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria[J]. Blood, 2005, 106(12):3699-3709.
19.	Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria[J]. Blood, 2007, 110(12):4123-4128.
20.	Hill A, Rother RP, Wang X, et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria[J]. Br J Haematol, 2010, 149(3):414-425.
21.	Parker CJ. The pathophysiology of paroxysmal nocturnal hemoglobinuria[J]. Exp Hematol, 2007, 35(4):523-533.
22.	Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan[J]. Medicine, 2004, 83(3):193-207.
23.	Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization[J]. Haematologica, 2010, 95(4):567-573.
24.	Parker CJ. Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy[J]. Hematology Am Soc Hematol Educ Program, 2011, 2011(1):21-29.
25.	Tichelli A, Socié G, Marsh J, et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression[J]. Ann Intern Med, 2002, 137(3):164-172.
26.	Kelly R, Arnold L, Richards S, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab[J]. Br J Haematol, 2010, 149(3):446-450.

1. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 1995, 333(19):1253-1258.
2. Rosse WF. Paroxysmal nocturnal hemoglobinuria as a molecular disease[J]. Medicine (Baltimore), 1997, 76(2):63-93.
3. Luzzatto L. Paroxysmal nocturnal hemoglobinuria:an acquired X-linked genetic disease with somatic-cell mosaicism[J]. Curr Opin Genet Dev, 2006, 16(3):317-322.
4. Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria[J]. Cell, 1993, 73(4):703-711.
5. Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene[J]. EMBO J, 1994, 13(1):110-117.
6. Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria[J]. Lancet, 2009, 373(9665):759-767.
7. Rother RP, Rollins SA, Mojcik CF, et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria[J]. Nat Biotechnol, 2007, 25(11):1256-1264.
8. Dmytrijuk A, Robie-Suh K, Cohen MH, et al. FDA report:eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria[J]. Oncologist, 2008, 13(9):993-1000.
9. Alexion Pharmaceuticals. Inc. Solaris® (eculizumab) prescribing information[EB/OL]. (2012-12-01)[2014-01-01]. http://www.soliris.net/sites/default/files/assets/soliris_pi.pdf.
10. Hill A, Hillmen P, Richards SJ, et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria[J]. Blood, 2005, 106(7):2559-2565.
11. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 2006, 355(12):1233-1243.
12. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria[J]. N Engl J Med, 2004, 350(6):552-559.
13. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria[J]. Blood, 2008, 111(4):1840-1847.
14. Kanakura Y, Ohyashiki K, Shichishima T, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria:the AEGIS clinical trial[J]. Int J Hematol, 2011, 93(1):36-46.
15. Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria:long-term follow-up and prognostic factors. French Society of Haematology[J]. Lancet, 1996, 348(927):573-577.
16. Moyo VM, Mukhina GL, Garrett ES, et al. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays[J]. Br J Haematol, 2004, 126(1):133-138.
17. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)[J]. Blood, 2003, 102(10):3587-3591.
18. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria[J]. Blood, 2005, 106(12):3699-3709.
19. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria[J]. Blood, 2007, 110(12):4123-4128.
20. Hill A, Rother RP, Wang X, et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria[J]. Br J Haematol, 2010, 149(3):414-425.
21. Parker CJ. The pathophysiology of paroxysmal nocturnal hemoglobinuria[J]. Exp Hematol, 2007, 35(4):523-533.
22. Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan[J]. Medicine, 2004, 83(3):193-207.
23. Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization[J]. Haematologica, 2010, 95(4):567-573.
24. Parker CJ. Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy[J]. Hematology Am Soc Hematol Educ Program, 2011, 2011(1):21-29.
25. Tichelli A, Socié G, Marsh J, et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression[J]. Ann Intern Med, 2002, 137(3):164-172.
26. Kelly R, Arnold L, Richards S, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab[J]. Br J Haematol, 2010, 149(3):446-450.

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阵发性睡眠性血红蛋白尿症的靶向治疗

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