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dupilumab治疗糖皮质激素依赖型重度哮喘的疗效和安全性
Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma


Klaus F. Rabe ... 呼吸系统疾病 • 2018.06.28
相关阅读
• 治疗哮喘的另外一种新生物制剂 • dupilumab治疗中至重度未得到控制的哮喘的疗效和安全性 • dupilumab在嗜酸性粒细胞水平升高的持续性哮喘中的应用 • 美泊利单抗在嗜酸性粒细胞哮喘中减少口服糖皮质激素用量的作用

摘要


背景

dupilumab是一种完全人源性抗白细胞介素-4受体α单克隆抗体,它能够阻断白细胞介素-4和白细胞介素-13信号传导。目前尚不清楚在重度哮喘患者中,dupilumab在控制哮喘的情况下减少口服糖皮质激素的效果。

 

方法

我们将210例接受口服糖皮质激素治疗的哮喘患者随机分组,使他们分别接受dupilumab(剂量为300 mg)或安慰剂添加治疗,每2周用药1次,共治疗24周。随机分组之前有一个糖皮质激素剂量调整期,之后从第4~20周,逐渐下调糖皮质激素剂量,然后保持稳定剂量4周。主要终点为第24周时糖皮质激素剂量的降低百分比。关键次要终点为第24周时糖皮质激素剂量降低至少50%的患者比例和糖皮质激素剂量降低至每日<5 mg的患者比例。本研究还对哮喘重度发作率和支气管扩张药使用前的第一秒用力呼气量(FEV1)进行了评估。

 

结果

在dupilumab组和安慰剂组中,糖皮质激素剂量的变化百分比分别为-70.1%和-41.9%(P<0.001);分别有80%和50%的患者剂量降低至少50%,69%和33%的患者剂量降低至每日<5 mg,48%和25%的患者完全停用口服糖皮质激素。尽管dupilumab组的糖皮质激素剂量有所降低,但在整个人群中,dupilumab治疗与安慰剂相比,仍使哮喘重度发作率降低59%(95%置信区间[CI],37~74),使FEV1增加0.22 L(95% CI,0.09~0.34)。dupilumab治疗与安慰剂相比,注射部位反应较常见(9% vs. 4%)。dupilumab组与安慰剂组相比,观察到一过性血嗜酸性粒细胞增多的患者较多(14% vs. 1%)。

 

结论

在糖皮质激素依赖型重度哮喘患者中,dupilumab治疗减少了口服糖皮质激素用药,同时降低了哮喘重度发作率,并增加了FEV1。在约1/7接受dupilumab治疗的患者中观察到一过性嗜酸性粒细胞增多(由赛诺菲和再生元制药[Regeneron Pharmaceuticals]资助;LIBERTY ASTHMA VENTURE在ClinicalTrials.gov注册号为NCT02528214)。





作者信息

Klaus F. Rabe, M.D., Ph.D., Parameswaran Nair, M.D., Ph.D., Guy Brusselle, M.D., Ph.D., Jorge F. Maspero, M.D., Mario Castro, M.D., Lawrence Sher, M.D., Hongjie Zhu, Ph.D., Jennifer D. Hamilton, Ph.D., Brian N. Swanson, Ph.D., Asif Khan, M.B., B.S., M.P.H., Jingdong Chao, Ph.D., Heribert Staudinger, M.D., Ph.D., Gianluca Pirozzi, M.D., Ph.D., Christian Antoni, M.D., Ph.D., Nikhil Amin, M.D., Marcella Ruddy, M.D., Bolanle Akinlade, M.D., Neil M.H. Graham, M.B., B.S., M.D., Neil Stahl, Ph.D., George D. Yancopoulos, M.D., Ph.D., and Ariel Teper, M.D.
From LungenClinic Grosshansdorf, Grosshansdorf, and Christian Albrechts University Kiel, Kiel — both in Germany (K.F.R.); McMaster University and St. Joseph’s Healthcare, Hamilton, ON, Canada (P.N.); Ghent University Hospital, Ghent, Belgium (G.B.); Fundación CIDEA (Centro de Investigación de Enfermedades Alérgicas y Respiratorias), Buenos Aires (J.F.M.); Washington University School of Medicine, St. Louis (M.C.); Peninsula Research Associates, Rolling Hills Estates, CA (L.S.); Sanofi, Bridgewater, NJ (H.Z., B.N.S., H.S., G.P., C.A., A.T.); Regeneron Pharmaceuticals, Tarrytown, NY (J.D.H., J.C., N.A., M.R., B.A., N.M.H.G., N.S., G.D.Y.); and Sanofi, Chilly Mazarin, France (A.K.). Address reprint requests to Dr. Rabe at LungenClinic Grosshansdorf, Wöhrendamm 80, 22927 Grosshansdorf, Germany, or at k.f.rabe@lungenclinic.de. A complete list of investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009;179:19-24.

2. Goleva E, Hauk PJ, Boguniewicz J, Martin RJ, Leung DYM. Airway remodeling and lack of bronchodilator response in steroid-resistant asthma. J Allergy Clin Immunol 2007;120:1065-1072.

3. Shaw DE, Sousa AR, Fowler SJ, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 2015;46:1308-1321.

4. Huscher D, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 2009;68:1119-1124.

5. Ververeli K, Chipps B. Oral corticosteroid-sparing effects of inhaled corticosteroids in the treatment of persistent and acute asthma. Ann Allergy Asthma Immunol 2004;92:512-522.

6. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid–sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-1197.

7. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid–sparing effect of benralizumab in severe asthma. N Engl J Med 2017;376:2448-2458.

8. Robinson D, Humbert M, Buhl R, et al. Revisiting type 2-high and type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy 2017;47:161-175.

9. Macdonald LE, Karow M, Stevens S, et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc Natl Acad Sci U S A 2014;111:5147-5152.

10. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31-44.

11. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013;368:2455-2466.

12. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2015 (http://ginasthma.org/wp-content/uploads/2016/01/GINA_Report_2015_Aug11-1.pdf).

13. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159:179-187.

14. Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115:1265-1270.

15. Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the Asthma Control Questionnaire. Respir Med 2005;99:553-558.

16. Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993.

17. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011;184:602-615.

18. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378:2486-2496.

19. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.

20. Tozawa H, Kanki Y, Suehiro J, et al. Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter. Mol Cell Biol 2011;31:2196-2209.

21. Barthel SR, Johansson MW, McNamee DM, Mosher DF. Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma. J Leukoc Biol 2008;83:1-12.

22. Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 2013;12:117-129.

23. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;389:2287-2303.

24. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375:2335-2348.

25. Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2016;387:40-52.

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