【作者】 崔中光；

【导师】 侯明；

【作者基本信息】 山东大学 ， 内科学（专业学位）， 2014， 博士

【摘要】 研究背景原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是一种免疫介导的以血小板减少为主要特征的自身免疫性疾病,是临床最常见的出血性疾病,约占出血性疾病的1/3。其临床特点是外周血中血小板数量减少,广泛皮肤、粘膜甚至内脏出血,严重者可引起致死性的颅内出血。近几年发现部分患者表现为乏力、倦怠、忧郁、精神压力大等,也是ITP患者临床表现之一,西方学者研究发现其生存质量低于癌症患者,严重影响了人们的身心健康。患者实验室检查表现为骨髓巨核细胞发育、成熟障碍；血小板生存时间缩短以及部分患者出现抗血小板自身抗体等。ITP发病机制除了与体液免疫抗体介导引起血小板破坏过多外,还与细胞免疫有关,特别是T细胞功能紊乱直接抑制巨核细胞产生血小板；另有研究巨核细胞本身凋亡异常也与ITP发病机制有关。在过去近五十多年里,口服泼尼松(Prednisone, Pred)一直是本病的首选治疗,开始剂量1.0～1.5mg/kg·d,分次口服至少4周,约70%病例可获得疗效,患者血小板计数升高或回复正常后逐渐减量,到血小板数在安全水平以上时用最低量给予维持治疗,但只有30%左右的患者会长期持续缓解,而其余70%左右ITP患者在糖皮质激素逐渐减量或停药时复发。并且长期应用糖皮质激素过程中,几乎每位患者均出现不同程度的副反应,如Cushing症、高血压、糖尿病、骨质疏松、消化性溃疡、体液潴留、激素性精神病、免疫力低下造成严重感染等。值得注意的是几乎每位女性患者均出现库欣综合征,使之谈激素“色变”因此,学者们在不断探索新的更为安全有效的治疗方案,为避免长期应用糖皮质激素造成各系统的并发症,有研究者尝试给予短周期大剂量地塞米松(high-dose dexamethasone, HD-DXM)冲击治疗ITP,即给予地塞米松40mg/d,分2次口服,连用4d,以后不再维持用药。尤其近年来,短周期大剂量地塞米松冲击作为初诊成人原发免疫性血小板减少症的一线治疗,其有效率高、安全性好、价格低廉等在国外有不少报道。然而,也有报道ITP患者给予单个疗程HD-DXM冲击治疗,尽管短期有效率高,副作用少,但停药后存在不同程度地复发,三个月后其复发率与传统泼尼松方案大致相同,而多个疗程HD-DXM冲击治疗,治疗周期长,患者依从性差,糖皮质激素副作用又会增加。到目前为止,就有关ITP患者HD-DXM冲击治疗,冲击几个疗程,间隔多长时间再次冲击或是否给予维持治疗尚没有统一的意见,应用短周期大剂量地塞米松冲击治疗ITP的研究在我国也比较少,本研究我们优化了HD-DXM治疗方案,采用连续2个周期大剂量地塞米治疗新诊断成人ITP患者,试图既能提高ITP患者疗效,又能降低远期复发率,且安全性好,患者能耐受。目的1)观察优化方案连续2个周期大剂量地塞米松冲击治疗成人新诊断原发免疫性血小板减少症(ITP)患者的近、远期疗效,并与传统常规剂量泼尼松治疗进行比较。2)两种治疗方案安全性比较。方法73例新诊断的ITP患者随机分为两组,地塞米松组37例,给予地塞米松40mg/d,分2次口服,连用4d。间隔7d后再重复一个周期,以后不再进行维持治疗；泼尼松治疗组36例,给予泼尼松1.0～1.5mg/kg-d分3次口服,连用4周后逐渐减量。治疗前有活动性出血的患者酌情给予输注血小板。观察二组间的近、远期疗效和安全性。治疗期间无效的病人,采用其它方案,包括rhTPO、脾切除、CsA、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上。另外,检测地塞米松组患者第一周期治疗结束后第一天血象(即冲击治疗第5天),检测血小板数。结果近期疗效：治疗后第1、2周末地塞米松组有效率明显高于泼尼松组(67.6%比36.1%,78.4%比55.6%,P值均<0.05),治疗后第3周末有效率仍高于泼尼松组,但差异无统计学意义(86.5%比75.0%,P>0.05)。远期疗效：随访3个月,除第1个月末地塞米松组复发率与泼尼松组差异无统计学意义(18.7%比22.2%,p>0.05)外,第2、3个月末地塞米松组复发率明显低于泼尼松组(21.9%比48.1%,34.4%比63.0%,P值均<0.05)。地塞米松组冲击治疗(第一周期)第5天血小板数低于100×109者与高于100×109者比较,3月后其复发率明显升高(47.1%比15.0%,P值<0.05)。不良反应：地塞米松组不良反应轻微,少数患者出现一过性高血压及高血糖,无1例并发感染及出现柯兴氏症。所有患者均能耐受,完成治疗方案。而泼尼松组32例出现不同程度柯兴氏症表现,2例病人继发口腔真菌感染,1例女性病人继发真菌性阴道炎,1例老年病人继发带状疱疹,经相应治疗病情控制,完成治疗方案。结论1)连续2个疗程大剂量地塞米松治疗ITP患者的近、远期疗效均优于常规剂量泼尼松；大剂量地塞米松治疗ITP较传统泼尼松治疗起效迅速,能短期内实现血小板快速上升。2)地塞米松组冲击治疗(第一周期)第5天血小板数低于100±109/L的患者与高于100±109/L的患者比较,3月后复发率高,有利于ITP的分层治疗。3)大剂量地塞米松治疗ITP均能耐受,安全性好,副作用少；而泼尼松治疗组副作用明显多于地塞米松组。研究背景原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是血液系统常见出血性疾病,主要由于自身免疫因素,导致血小板破坏过多或巨核细胞生成障碍,使患者血液中血小板数量减少,临床表现以出血为主。糖皮质激素是治疗初诊成人ITP的一线药物,对大部分ITP有效；而约1/3患者糖皮质激素治疗无效或治疗过程中复发,或需要较大剂量的糖皮质激素才能维持疗效从而引起明显的副作用。对这部分患者,目前尚无统一的治疗标准。国外部分学者认为,在所有治疗ITP的方案中,脾切除是获得持续完全反应最有效的手段引,故将经脾切除仍无反应的患者定义为难治性ITP。难治性ITP定义目前尚无统一的标准,根据有关文献,具有下列之一者为难治性ITP：(1)标准剂量糖皮质激素(泼尼松1-2mg/kg/d)治疗4周,血小板计数仍<50×109/L,或者血小板恢复正常,但随激素减量血小板计数随之下降,或需泼尼松>30mg才能维持血小板数目稳定者；(2)脾切除(包括脾栓塞、脾化疗)后血小板计数仍≦50x109/L,或者血小板一度恢复正常又下降,需继续内科治疗者；(3)经糖皮质激素、脾切除、静脉注射免疫球蛋白、免疫抑制剂等多方面治疗无效,血小板计数≦30×109/L；(4)血小板计数≦20x109/L,尤以≦10×109/L有明显出血危及生命的重症患者。也有资料提出了比较完整的难治性ITP的诊断标准：(1)经糖皮质激素和脾切除治疗无效；(2)年龄10岁以上；(3)排除可能导致血小板减少的其他疾病；(4)血小板计数≦20×109/L；(5)ITP病程3个月以上；符合以上5项者为难治性ITP。2013年ITP国内专家共识(修订版),诊断难冶性ITP需满足以下3点：①脾切除后无效或者复发；②仍需要治疗以降低出血的风险；③除外了其它引起血小板减少的原因。由于脾切除对某些经糖皮质激素治疗无效的病人来说难以接受或者无法实施,所以难治性ITP可能还应该包括这部分患者。对于难治性ITP的病人,可以选择脾切除治疗或者应用二线治疗药.脾切除是对糖皮质激素治疗耐药患者的首选,不过仍有1/3患者无效或复发。另外,部分患者由于年龄、基础疾病等因素而无脾切除手术适应症,还有部分患者不愿接受外科脾切除治疗。ITP治疗的二线药物包括免疫抑制剂(环孢素A, Cyclosporin A,CsA)、利妥昔单抗(rituximab, RTX)、促血小板生成素(thrombopietin,TPO)等。利妥昔单抗是人鼠嵌合型单克隆抗CD20抗体,因其能够清除产生自身抗体的B淋巴细胞,且相对安全及较少引起骨髓抑制,现多用于治疗难冶性ITP。项系统性回顾表明利妥昔单抗的完全反应率(血小数>150×109/L)为44%,总体有效率(血小板>50×109/L)为62%,治疗反应从3周到6个月,且价格昂贵。环孢菌素是钙依赖磷酸酶抑制剂,抑制T淋巴细胞增殖,并能调节ITP患者体内失衡的T细胞亚群。其作用特点是作用于淋巴细胞增殖的早期,不抑制造血系统。起效较慢,视病情情况,可以选择环孢菌素。TPO可以增加巨核细胞的数量,刺激血小板增生,实验表明TPO一次注射可使造血功能正常患者的血小板增加约3倍。给药方法是皮下注射hTPO1.Oug/kg,1次/d,疗程14d,总有效率68%,但停药后血小板数量逐渐下降至基线。免疫抑制剂及利妥昔单抗治疗起效时间长,TPO起效快但停药后血小板回落,患者不能获得长期缓解。因此寻找一种既能使难治性ITP患者血小板快速上升,又能获得长期缓解的治疗方案尤为迫切,我们应用rhTPO联合环孢素A双靶点针对ITP不同发病机制,干预难治性ITP。目的观察重组人血小板生成素(recombinant human thrombopoietin,rhTPO)联合环孢素A(CsA)治疗难治性免疫性血小板减少症(R-ITP)的近期、远期疗效及安全性。方法41例难治性ITP患者,随机分为观察组和对照组2组。观察组(21例)皮下注射rhTPO1ug(300U)/kg·d,疗程14d,同时口服环孢素A (CsA)3～4mg/kg·d,分2次,疗程3个月。对照组(20例)皮下注射rhTPO lug(300U)/kg·d,疗程14d后,停药观察。治疗期间无效或复发的病人,采用其它方案,包括脾切除、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上结果近期疗效：第1、2周末观察组与对照组有效率分别为61.9%、55.5%(x2=0.17,P>0.05);90.5%、90.0%(x2=0.22, P>0.05),均无显著性差异。远期疗效：治疗后第1月末观察组与对照组复发率分别为15.8%、44.4%(x2=3.62,P>0.05)无显著性差异。而第2、3个月末2组复发率分别为26.3%、61.1%(x2=5.90, P<0.05);31.6%、83.3%(x2=10.07, P<0.01),均有显著性差异。对照组及观察者所有患者均能耐受治疗,治疗后患者2组白细胞计数、血红蛋白及血凝常规、尿常规、电解质、心电图均无明显异常变化。对照组有1例出现轻度头晕乏力,1例注射部位疼痛均自行缓解。观察组恶心腹胀1例,转氨酶轻度升高2例,经对症处理后消失,均未停用环孢素A。2组患者无一例因副作用而停药。结论TPO联合环孢素A治疗难治性ITP,既能获得显著近期疗效,又能较长时间维持疗效。对照组及观察者所有患者均能耐受治疗,副作用轻微。更多还原

【Abstract】 BackgroundPrimary immune thrombocytopenia (ITP) is an immune-mediated autoimmune disease, characterized by platelet destruction induced by auto antibodies directed against specific glycoproteins of platelet surface, impaired megakaryocyte maturation with reduced platelet production. Accumulating evidence from studies of platelet kinetics also points to the contribution of immune-mediated suppression of megakaryocyte and platelet development in many patients; megakaryocyte apoptosis and suppression of megakaryopoiesis in vitro by ITP plasma or T-cells.ITP is one of the most common clinical bleeding disorders, ITP occurs in approximately one-third of bleeding disorders., its clinical features include petechiae, ecchymoses, mucosa bleeding, menorrhagia,rare visceral hemorrage, even fatal intracranial bleeding. Some patients experience fatigues, apprehension of bleeding, withdraw from important professional activities, and a poor quality of life.Conventional prednisone is the first-line therapy for ITP patients,1.0to1.5mg of prednisone per kilogram of body weight daily for four weeks, approximate70%of ITP patients can achieve response, and only30%of patient can receive sustaining remission. The long-term treatment of prednisone for ITP patients will cause severe side effects, such as Cushing syndrome, hyperglycemia, hypertention, peptic ulcer, infection and mental disorders. Unfortunately, tapering in prednisone dosage or discontinuation causes most ITP patients to relapse. So that it is necessary to develop effective and safe therapeutic regimen for ITP patients, which not only increase platelet count quickly but also achieve a long-term remission and patients could tolerate it.In recent years, treatment of primary immune thrombocytopenia with a short of course of high-dose dexamethasone (HD-DXM) has achieved better therapeutic response. Now HD-DXM regimen has been recommended as the first-line therapy for patients with ITP by west doctors and experts. ITP patients were given a single course of HD-DXM pulse therapy, although the short-term efficacy was very high and less side effects, relapse rate also was high after three months, patients could not receive sustained remission. Multiple courses of HD-DXM pulse therapy were given, treatment cycle is long, patient compliance is poor, glucocorticoid effects will increase again. So far, for the HD pulse therapy, how long interval to administer or whether to give maintenance treatment, there is no unified opinion.The study of this regimen is rare in our country. In our present study, we optimize the regimen, by administering2cycles’high-dose dexamethasone as initial therapy in primary thrombocytopenia and compare with conventional prednisone therapy.Objective:To investigate the efficacy and safety of a schedule of2cycles’ high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP), and compare with conventional dose prednisone therapy.Method:A total of73newly diagnosed ITP patients were divided into2groups randomly. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then failed to maintain. In the remaining36patients (Prednisone group), prednisone was administered orally at1.0～1.5mg·kg-1·d-1for4weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.Results:For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.Conclusion1)HD-DXM possesses an advantage over traditional dose prednisone therapy in efficacy and reduces the recurrence rate. High-dose dexamethasone therapy could result in rapider response than prednisone treatment.2) A platelet count of less than100×109/L on day5was associated with a high risk of relapse.3)HD-DXM is well tolerated and safety. Objective:To investigate the efficacy and safety of a schedule of2cycles of high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP),and compare with conventional dose prednisone therapy.Methods:A total of73patients with newly diagnosed ITP were randomly divided into2groups. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then the patients discontinued treatment. In the remaining36patients (prednisone group), prednisone was administered orally at1.0～1.5mg mg·kg-1·d-1for4consecutive weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.Results:For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.Conclusion(1)HD-DXM possesses an advantage over traditional prednisone therapy in efficacy and reduces the recurrence rate; high-dose dexamethasone pulse could result in rapider response than prednisone.(2) A platelet count of less than100×109/L on day5in patient (Dexamethasone group) was associated with a high risk of relapse at the end of third month of follow-up.(3) HD-DXM is well tolerated and safety. BackgroundPrimary immune thrombocytopenia (ITP), one of the most common bleeding disorders, is an acquired immune-mediated autoimmune disease. The pathogenic mechanism of ITP is complex, and both accelerated platelet destruction in the reticuloendothelial system and impaired megakaryocyte maturation with reduced platelet production have been proven to contribute to thrombocytopenia.1,2The incidence is nearly30new cases per1million per year. Depending on the severity of the thrombocytopenia, the most common manifestations of ITP range from easy bruising and petechiae, to epistaxis and gingival bleeding and, more rarely, anal, gastrointestinal, or intracranial bleeding.Glucocorticoids are the standard first-line therapy for ITP and most patients achieve a durable response. However, approximately one third of the patients with ITP fail to response to glucocorticoid therapy. These patients often need high doses of glucocorticoids to maintain the therapeutic effects, and these usually cause significant adverse effects. Splenectomy or second-line therapies such as immunosuppressive agents, Rituximab, and recombinant human thrombopoietin (rhTPO) can be chosen for patientswith glucocorticoid treatment failure. Treatments with immunosuppressive agents or Rituximab often require a long treatment course to achieve satisfactory responses.4,5Patients can achieve a rapid response with rhTPO treatment but usually the response is not sustained once the regime was withdrawn, making it difficult to achieve a long-term remission for ITP patients. It has become increasingly important to develop effective therapeutic regimens, which not only increase the number of platelets quickly but also achieve a long-term remission for ITP. In the present study, the efficacy of rhTPO combined with cyclosporin A(CsA) for the treatment of refractory ITP was investigated, and results showed that the short-term and long-term responses in the combination treatment group was better than that in the rhTPO control group. This suggests that combined use of rhTPO and CsA might be an effective alternate regimen for the management of refractory ITP patients. ObjectiveThe management of patients with refractory immune thrombocytopenia is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in combination with cyclosporin A (CsA) for the management of refractory ITP patients.MethodsForty-one refractory ITP patients were randomly divided into an observation group and control group. In the observation group, twenty-one patients received subcutaneous injection of rhTPO at a dose of lug/kg (300U/kg) once daily up to day14. Simultaneously they also received oral CsA at a dose of1.5-2mg/kg twice daily for three months. In the control group, rhTPO alone was administered subcutaneously at1ug/kg once daily in the other twenty ITP patients for14consecutive days and then the treatment was withdrawn. If treatment failure occurred or patients relapsed during therapy, other treatment regimens, including splenectomy, Rituximab, or combined application of immunosuppressive therapy, could be chosen.ResultsThere was no significant difference in the response rate at the end of the first week after treatment initiation between the observation group and the control group (61.9%vs.55.5%, x2=0.17, P>0.05), neither was there at the end of the second week(90.5%vs.90.0%, x2=0.22,P>0.05).However, the relapse rate in the observation group was significantly lower than that in control group at the end of the first (15.8%vs.44.4%, x2=3.62, P<0.05), second (26.3%vs.61.1%, x2=5.90, P<0.05) and the third month(31.6%vs.83.3%, x2=10.07, P<0.01). In addition, rhTPO plus CsA were well tolerated and adverse events recorded were mild.Conclusion Combination therapy with rhTPO and CsA was effective in the management of refractory ITP patients, with a relatively short time to response and low recurrence rate, it might be considered as a potential second-line treatment regimen for ITP.更多还原