艾曲波帕联合硫唑嘌呤治疗难治性特发性血小板减少性紫癜的疗效及其对细胞免疫功能的影响研究
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摘要
背景难治性特发性血小板减少性紫癜(RITP)的治疗一直是临床的一大难题,目前尚无统一的安全有效的治疗方案,且对于部分血小板计数(PLT)极度下降的患者有致死的出血风险。艾曲波帕作为升血小板的新药,为RITP的治疗提供了一个安全有效的治疗方法。目的探究艾曲波帕联合硫唑嘌呤治疗RITP的疗效,并观察其对细胞免疫功能的影响。方法选择2013年1月—2018月1月在绍兴市人民医院血液科住院治疗的46例RITP患者,依据随机数字表法将其分为治疗组和环孢素(CSA)组,各23例。另选取同期在本院进行体检的健康者25例作为对照组。治疗组患者给予艾曲波帕联合硫唑嘌呤治疗;CSA组患者给予环孢素联合达那唑治疗。治疗3个月进行疗效评价。比较治疗组与CSA组临床疗效。收集治疗组和CSA组患者治疗前和治疗3个月外周血Th1细胞因子[白介素(IL)-2、γ干扰素(IFN-γ)]和Th2细胞因子(IL-4、IL-5)、B1淋巴细胞(CD_(19)~+淋巴细胞百分数、CD5+CD_(19)~+淋巴细胞百分数)、PLT,并与对照组比较。记录治疗组和CSA组患者不良反应发生情况。结果治疗组患者总有效率为69.9%(16/23),CSA组患者总有效率为73.9%(17/23);两组患者总有效率比较,差异无统计学意义(χ~2=0.107,P=0.743)。治疗组、CSA组患者治疗前IL-2、IFN-γ、CD_(19)~+淋巴细胞百分数、CD5+CD_(19)~+淋巴细胞百分数高于对照组,IL-4、IL-5、PLT低于对照组(P<0.05);治疗组、CSA组患者治疗3个月IL-2、IFN-γ、CD_(19)~+淋巴细胞百分数、CD5+CD_(19)~+淋巴细胞百分数低于本组治疗前,IL-4、IL-5、PLT高于本组治疗前(P<0.05)。治疗组8例患者发生肝功能损伤,CSA组16例患者发生肝功能损伤;治疗组患者肝功能损伤发生率(34.8%)低于CSA组(69.6%)(χ~2=6.527,P=0.013)。结论艾曲波帕联合硫唑嘌呤治疗RITP,安全有效,患者耐受性好;艾曲波帕联合硫唑嘌呤可能通过调节RITP患者外周血Th淋巴细胞及B1淋巴细胞,进而促进血小板生成,从而发挥治疗作用。
Background The treatment of refractory immune thrombocytopenic purpura(RITP) has always been a major clinical problem.At present,there is no unified safe and effective treatment,and there is a risk of death for some patients with extremely low platelet count.Eltrombopag,as a new drug for increased platelet counts,provides a safe and effective treatment for RITP.Objective To study the efficacy of Eltrombopag combined with Azathioprine in the treatment of RITP and its effect on cellular immune function.Methods A total of 46 patients with RITP who were hospitalized in Hematology Department of Shaoxing People's Hospital from January 2013 to January 2018 were selected.They were randomly divided into treatment group and cyclosporine(CSA) group,each with 23 cases.Another 25 healthy persons who had physical examination in our hospital during the same period were selected as the control group.Patients in the treatment group were treated with Eltrombopag combined with Azathioprine.The CSA group was treated with Cyclosporine combined with Danazol.Therapeutic effect was evaluated after 3 months of treatment.The clinical effects of treatment group and CSA group were compared.Th1 cytokines(IL-2,IFN-γ) and Th2 cytokines(IL-4,IL-5),B1 lymphocyte(percentage of CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte),PLT in peripheral blood of treatment group and CSA group were collected before treatment and 3 months after treatment,and compared with the control group.The adverse reactions in the treatment group and CSA group were recorded.Results The total effective rate was 69.9%(16/23) in the treatment group and 73.9%(17/23) in the CSA group.There was no significant difference in the total effective rate between the two groups(χ~2=0.107,P=0.743).Before treatment,the percentage of IL-2,IFN-γ,CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte in the treatment group and CSA group was higher than that in the control group,while the number of IL-4 and IL-5 and platelet count in the treatment group and CSA group was lower than that in the control group(P<0.05).After 3 months of treatment,the percentage of IL-2,IFN-γ,CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte in the treatment group and CSA group was lower than that before treatment,while the number of IL-4 and IL-5 and platelet count was higher than that before treatment(P<0.05).Eight patients in the treatment group and 16 patients in the CSA group suffered from liver function injury.The incidence of liver function injury in the treatment group(34.8%) was lower than that in the CSA group(69.6%),and the difference was statistically significant(χ~2=6.527,P=0.013).Conclusion Eltrombopag combined with Azathioprine in the treatment of RITP is safe,effective and well tolerated.Eltrombopag combined with Azathioprine may play a therapeutic role by regulating Th lymphocyte and B1 lymphocyte in peripheral blood of patients with RITP,thereby promoting platelet formation.
Background The treatment of refractory immune thrombocytopenic purpura(RITP) has always been a major clinical problem.At present,there is no unified safe and effective treatment,and there is a risk of death for some patients with extremely low platelet count.Eltrombopag,as a new drug for increased platelet counts,provides a safe and effective treatment for RITP.Objective To study the efficacy of Eltrombopag combined with Azathioprine in the treatment of RITP and its effect on cellular immune function.Methods A total of 46 patients with RITP who were hospitalized in Hematology Department of Shaoxing People's Hospital from January 2013 to January 2018 were selected.They were randomly divided into treatment group and cyclosporine(CSA) group,each with 23 cases.Another 25 healthy persons who had physical examination in our hospital during the same period were selected as the control group.Patients in the treatment group were treated with Eltrombopag combined with Azathioprine.The CSA group was treated with Cyclosporine combined with Danazol.Therapeutic effect was evaluated after 3 months of treatment.The clinical effects of treatment group and CSA group were compared.Th1 cytokines(IL-2,IFN-γ) and Th2 cytokines(IL-4,IL-5),B1 lymphocyte(percentage of CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte),PLT in peripheral blood of treatment group and CSA group were collected before treatment and 3 months after treatment,and compared with the control group.The adverse reactions in the treatment group and CSA group were recorded.Results The total effective rate was 69.9%(16/23) in the treatment group and 73.9%(17/23) in the CSA group.There was no significant difference in the total effective rate between the two groups(χ~2=0.107,P=0.743).Before treatment,the percentage of IL-2,IFN-γ,CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte in the treatment group and CSA group was higher than that in the control group,while the number of IL-4 and IL-5 and platelet count in the treatment group and CSA group was lower than that in the control group(P<0.05).After 3 months of treatment,the percentage of IL-2,IFN-γ,CD_(19)~+ lymphocyte and CD5+CD_(19)~+ lymphocyte in the treatment group and CSA group was lower than that before treatment,while the number of IL-4 and IL-5 and platelet count was higher than that before treatment(P<0.05).Eight patients in the treatment group and 16 patients in the CSA group suffered from liver function injury.The incidence of liver function injury in the treatment group(34.8%) was lower than that in the CSA group(69.6%),and the difference was statistically significant(χ~2=6.527,P=0.013).Conclusion Eltrombopag combined with Azathioprine in the treatment of RITP is safe,effective and well tolerated.Eltrombopag combined with Azathioprine may play a therapeutic role by regulating Th lymphocyte and B1 lymphocyte in peripheral blood of patients with RITP,thereby promoting platelet formation.
引文
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[10]张之南,沈梯.血液病诊断及治疗标准[M].3版.北京:科学出版社,2009:172-176.
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[12]张庆国,朱锋,张鲁勤,等.特发性血小板减少性紫癜患者治疗前后Th1/Th2水平变化及其临床意义[J].内科理论与实践,2012,7(3):218-221.DOI:10.3969/j.issn.1673-6087.2012.03.017.ZHANG Q G,ZHU F,ZHANG L Q,et al.Changes of Th1/Th2levels in patients with idiopathic thrombocytopenic purpura before and after treatment and their clinical significance[J].Medical Theory and Practice,2012,7(3):218-221.DOI:10.3969/j.issn.1673-6087.2012.03.017.
[13]吕艳,刘文文,王聪,等.特发性血小板减少性紫癜患者T细胞及B细胞亚群变化的研究[J].国际免疫学杂志,2017,40(1):21-25.DOI:10.3760/cma.j.issn.1673-4394.2017.01.005.LYU Y,LIU W W,WANG C,et al.Changes of T cell and B cell subsets in patients with idiopathic thrombocytopenic purpura[J].International Journal of Immunology 2017,40(1):21-25.DOI:10.3760/cma.j.issn.1673-4394.2017.01.005.
[14]JOHNSEN J.Pathogenesis in immune thrombocytopenia:new insights[J].Hematology Am Soc Hematol Educ Program,2012,306(12):1182.DOI:10.1182/asheducati on-2012.1.306.
[15]周文营,董慧敏,陈洪平.特发性血小板减少性紫癜患者血清白细胞介素-6和肿瘤坏死因子-α的水平及其意义[J].广州医学,2012,33(7):977-978.DOI:10.3969/j.issn.1001-9448.2012.07.040.
[16]马艳茹,黄晓军,莫晓冬,等.艾曲波帕治疗异基因造血干细胞移植后难治性血小板减少的临床研究[J].中华血液学杂志,2016,37(12):1065-1069.DOI:10.3760/cma.j.issn.0253-2727.2016.12.011.MA Y R,HUANG X J,MO X D,et al.Clinical study of Etripalpa in the treatment of refractory thrombocytopenia after allogeneic hematopoietic stem cell transplantation[J].Chinese Journal of Hematology,2016,37(12):1065-1069.DOI:10.3760/cma.j.issn.0253-2727.2016.12.011.
[17]CHENG G,SALEH M N,MARCHER C,et al.Eltrombopag for management of chronic immune thrombocytopenia(RAISE):a 6month,randomised,phase 3 study[J].Lancet,2011,377(9763):393-402.DOI:10.1016/S0140-6736(10)60959-2.SA.
[18]LEH M N,BUSSEL J B,CHENG G,et al.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia:results of the long-term,open-label EXTEND study[J].Blood,2013,121(3):537-545.DOI:10.1182/blood-2012-04-425512.
[19]郭宏岗,王佳佳,岑坚,等.地塞米松联合血小板生成素及环孢素治疗免疫性血小板减少症的疗效观察[J].转化医学杂志,2016,5(5):279-282.DOI:10.3969/j.issn.2095-3097.2016.05.007.
[2]ZHAO H,DU W,WANG D,et al.The expression of IFN-γ,IL-4,Foxp3 and perforin genes are not correlated with DNA methylation status in patients with immune thrombocytopenic purpural[J].Platelets,2012,21(2):137-143.DOI:10.3109/09537100903420277.
[3]罗洪强,林茂芳,谢万灼,等.特发性血小板减少性紫癜患者外周血B1细胞变化与病情及预后的关系[J].中国全科医学,2011,14(30):3524-3526.DOI:10.3969/j.issn.1007-9572.2011.30.036.LUO H Q,LIN M F,XIE W Z,et al.The relationship between peripheral blood B1 cell changes and disease condition and prognosis in patients with idiopathic thrombocytopenic purpura[J].Chinese General Practice,2011,14(30):3524-3526.DOI:10.3969/j.issn.1007-9572.2011.30.036.
[4]KISTANGRI G,MCCRAE K R.Immune thromcytopenia[J].Hematol Oncol Clin North Am,2013,27(3):495-520.DOI:10.1016/j.hoc.2013.03.001.
[5]李守玮,李霞.ITP患者血清IL-2、4、6、10及TNF-α的水平及IFN-γ测定的临床意义分析[J].检验医学,2012,27(7):595-597.DOI:10.3969/j.issn.1673-8640.2012.07.018.
[6]孙善芳,潘怀富.小剂量美罗华治疗难治ITP的临床疗效观察[J].实用临床医药杂志,2010,14(23):105-106.DOI:10.3969/j.issn.1672-2353.2010.23.051.
[7]罗洪强,封蔚莹,钟永根,等.CBA技术检测ITP患者Th1/Th2细胞因子平衡偏移的临床意义[J].中国实验血液学杂志,2016,24(6):1846-1849.DOI:10.7534/j.issn.1009-2137.2016.06.042.LUO H Q,FENG W Y,ZHONG Y G,et al.Clinical significance of the balanceshift of Th1 and Th2 type cytokines in patients with primary immune thrombocytopenic purpura detected by cytometric bead array[J].Chinese Journal of Experimental Hematology,2016,24(6):1846-1849.DOI:10.7534/j.issn.1009-2137.2016.06.042.
[8]BUSSEL J B,CHENG G,SALEH M N,et al.Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura[J].N Engl J Med,2007,357(22):2237-2247.DOI:10.3310/hta15suppl1/03.
[9]BUSSEL J B,PROVAN D,SHAMSI T,et al.Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura:a randomised,double blind,placebo-controlled trial[J].Lancet,2009,373(9664):641-648.DOI:10.1016/S0140-6736(09)60402-5.
[10]张之南,沈梯.血液病诊断及治疗标准[M].3版.北京:科学出版社,2009:172-176.
[11]候明.成人原发免疫性血小板减少症诊断与治疗中国专家共识(2016年版)[J].中华血液学杂志,2016,37(2):89-92.DOI:10.3760/cma.j.issn.0253-2727.2016.02.001.HOU M.Chinese Expert Consensus on Diagnosis and Treatment of Adult Primary Immune Thrombocytopenia(2016 Edition)[J].Chinese Journal of Hematology,2016,37(2):89-92.DOI:10.3760/cma.j.issn.0253-2727.2016.02.001.
[12]张庆国,朱锋,张鲁勤,等.特发性血小板减少性紫癜患者治疗前后Th1/Th2水平变化及其临床意义[J].内科理论与实践,2012,7(3):218-221.DOI:10.3969/j.issn.1673-6087.2012.03.017.ZHANG Q G,ZHU F,ZHANG L Q,et al.Changes of Th1/Th2levels in patients with idiopathic thrombocytopenic purpura before and after treatment and their clinical significance[J].Medical Theory and Practice,2012,7(3):218-221.DOI:10.3969/j.issn.1673-6087.2012.03.017.
[13]吕艳,刘文文,王聪,等.特发性血小板减少性紫癜患者T细胞及B细胞亚群变化的研究[J].国际免疫学杂志,2017,40(1):21-25.DOI:10.3760/cma.j.issn.1673-4394.2017.01.005.LYU Y,LIU W W,WANG C,et al.Changes of T cell and B cell subsets in patients with idiopathic thrombocytopenic purpura[J].International Journal of Immunology 2017,40(1):21-25.DOI:10.3760/cma.j.issn.1673-4394.2017.01.005.
[14]JOHNSEN J.Pathogenesis in immune thrombocytopenia:new insights[J].Hematology Am Soc Hematol Educ Program,2012,306(12):1182.DOI:10.1182/asheducati on-2012.1.306.
[15]周文营,董慧敏,陈洪平.特发性血小板减少性紫癜患者血清白细胞介素-6和肿瘤坏死因子-α的水平及其意义[J].广州医学,2012,33(7):977-978.DOI:10.3969/j.issn.1001-9448.2012.07.040.
[16]马艳茹,黄晓军,莫晓冬,等.艾曲波帕治疗异基因造血干细胞移植后难治性血小板减少的临床研究[J].中华血液学杂志,2016,37(12):1065-1069.DOI:10.3760/cma.j.issn.0253-2727.2016.12.011.MA Y R,HUANG X J,MO X D,et al.Clinical study of Etripalpa in the treatment of refractory thrombocytopenia after allogeneic hematopoietic stem cell transplantation[J].Chinese Journal of Hematology,2016,37(12):1065-1069.DOI:10.3760/cma.j.issn.0253-2727.2016.12.011.
[17]CHENG G,SALEH M N,MARCHER C,et al.Eltrombopag for management of chronic immune thrombocytopenia(RAISE):a 6month,randomised,phase 3 study[J].Lancet,2011,377(9763):393-402.DOI:10.1016/S0140-6736(10)60959-2.SA.
[18]LEH M N,BUSSEL J B,CHENG G,et al.Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia:results of the long-term,open-label EXTEND study[J].Blood,2013,121(3):537-545.DOI:10.1182/blood-2012-04-425512.
[19]郭宏岗,王佳佳,岑坚,等.地塞米松联合血小板生成素及环孢素治疗免疫性血小板减少症的疗效观察[J].转化医学杂志,2016,5(5):279-282.DOI:10.3969/j.issn.2095-3097.2016.05.007.