凉血活血复方治疗进展期银屑病的随机、双盲对照研究及相关机制探讨
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摘要
背景银屑病是以表皮细胞过度增殖、角化不全等表皮动力学紊乱为特征的慢性炎症性皮肤病，确切病因尚不清楚。目前认为，可能是感染、创伤、药物、遗传因素等内外因素相互作用，通过免疫介导的自身免疫性疾病，主要表现特征为角质形成细胞过度增生,炎症细胞浸润和新生血管形成。
调节性T细胞（T regulatory,Treg）是体内存在的以调节自身T细胞为主要功能的T细胞亚群，是机体以主动方式来维持自身稳定的重要途径，是发挥免疫抑制效应的T细胞。目前研究表明，银屑病患者的外周血及皮损中CD4+CD25+Treg细胞的数量减少，Foxp3的表达降低，均将导致Teff细胞中Th1和Th17的异常活化和增殖，引发或加重银屑病的反应过程。
银屑病皮损中显著的真皮微血管扩张提示了微血管因素可能是启动银屑病病理变化的关键之一，血管内皮细胞生长因子（VEGF，vascular endothelial growthfactor）是重要的促进血管生成因子之一。
我国在中药治疗银屑病方面积累了大量有效方剂，但是“中药疗效是安慰剂效应”的偏见在西医领域仍存在。随着现代医学中临床研究方法的深入发展，采用临床流行病学的设计、测量与评价的方法，使中医的临床研究有了长足的进步，临床研究中对照、随机和双盲原则逐渐被用于中医药的研究中。
凉血活血复方是我科在前人的研究基础上通过拆方分析和动物实验反复筛试得到的具有凉血、活血、清热、养血、祛风功能的中药复方，用于治疗进展期银屑病。前期课题组已经对该复方治疗银屑病进行了相关的临床研究，但缺少循证医学的客观评价。
目的：①通过研究CD4+CD25+Foxp3+Treg细胞在进行期银屑病患者外周血CD4+Treg细胞中的比例及其Foxp3表达水平，探讨Treg细胞在银屑病发病中的作用及其临床意义。②科学地评价凉血活血复方治疗进展期银屑病的疗效与安全性。③探讨凉血活血复方治疗进展期银屑病的可能作用靶点，以明确其作用机制，促进中药的临床应用和开发。
方法：（1）Treg细胞在进行期银屑病的差异表达：采用流式细胞术检测20例进行期斑块型银屑病患者、28例急性点滴型银屑病患者以及20例健康对照者外周血CD4+CD25+Foxp3+/CD4+Treg细胞的比例及反应Foxp3表达水平的平均荧光强度（MFI）。（2）凉血活血复方的疗效及安全性分析：应用随机、双盲、安慰剂对照的实验设计，观察中药凉血活血复方治疗进展期银屑病的临床疗效及安全性，共入组62例，凉血活血复方治疗组35例，安慰剂对照组27例，疗程8周，治疗后通过比较银屑病皮损面积和严重程度指数(PASI)评分、医生对病情的整体评分(PGA)、皮肤病生活质量指数(DLQI)、患者就l0cm目视模拟标尺对病情的整体评分(VAS)和生活质量SF-36等指标，评定其疗效，记录不良反应发生率。（3）凉血活血复方的作用机制探讨：应用凉血活血复方治疗进展期银屑病患者28例，用药8周后，应用流式细胞术，检测其治疗前后的外周血Treg细胞的比例及其Foxp3的表达水平，并与20例正常人对照相比较，评价与PASI评分的相关性；酶联免疫吸附（ELISA）法，检测治疗前后患者血清中血管内皮生长因子（VEGF）含量的，同时对靶皮损进行治疗前后PSI评分及皮肤镜比对，进行相关性分析。
结果：①进行期银屑病患者外周血Treg细胞的比例和Foxp3表达水平均明显低于健康对照者（P＜0.05），急性点滴型低于进行期斑块型。②进行期银屑病患者外周血Treg细胞的比例和Foxp3表达降低水平与PASI评分无相关性。③凉血活血复方治疗进展期银屑病8周时有效率57.6%，明显高于安慰剂对照组的24.0%（P<0.05）。④治疗组的PASI评分、PGA、DLQI、VAS以及SF-36均较对照组有明显改善（P均＜0.05）。⑤凉血活血复方的不良反应率17.14%，主要为稀便和大便次数增多，未见其余毒副作用。⑥凉血活血复方治疗8周后，外周血Treg细胞的比例（1.58±0.87）及Foxp3表达水平（27.94±16.34）均明显上调，分别为2.60±0.88和32.52±14.27（P<0.05）。⑦进展期银屑病患者外周血血清VEGF的含量为80.40±10.75pg/mL，凉血活血复方治疗8周后，VEGF的含量明显下降，为57.68±10.22pg/mL（P<0.05），皮损处微血管密度减少。⑧进展期银屑病患者治疗前血清VEGF的含量与PASI评分呈弱相关（n=28，r=0.383，P=0.045<0.05），而与皮损PSI评分明显正相关（n=28，r=0.932，P=0.000＜0.05）。
结论①急性点滴型和进行期斑块型银屑病患者外周血Treg细胞水平及Foxp3表达水平低下，与PASI评分无相关性，提示Treg细胞在银屑病进展中起重要作用。②本文首次应用随机、双盲、安慰剂对照的方法研究了中药凉血活血复方治疗进展期银屑病的临床疗效及安全性，探索出用于中药汤剂临床疗效评价的科学方法，凉血活血复方治疗进展期银屑病疗效确切，不良反应少，安全性好。③凉血活血复方治疗进展期银屑病后，上调Treg细胞及其表达，降低血清VEGF的含量，可能通过免疫调节及抗血管生成等多靶点作用而起效。
Background：Psoriasis is a common，chronic，inflammatory disease of the skin,whose typical clinical manifestions are increased cellular activity of the epidermis anddilated capillaries of the dermis．The exact mechanism of psoriasis is not clearlyunderstood yet. As we known, psoriasis is an immune-mediated disorder, in which theexcessive proliferations of keratinocytes and the dilated capillaries in the papillaedermis are the consequence of interaction among the infections,environmental factorsand genetic factors.
Regulatory T (TReg) cells, defined by the expression of CD4, CD25and thetranscription factor forkhead box P3(FOXP3), have a central role in protecting anindividual from auto immunity and are considered to be of vital importance formaintaining immunologic self-tolerance and preventing autoimmune diseases. Thedifferential expression of CD4+CD25+Foxp3+regulatory T cells in peripheral blood ofpatients with psoriasis of active stage indicates its clinical significance in thepathogenesis of psoriasis.
Vascular endothelial growth factor (VEGF) plays an important role in thedevelopment angiogenesis.Dermatoscope is now widely used in the diagnosis ofpsoriatic lesions and the evaluation of treatment.
There have been lots of complex prescriptions of traditional Chinese medicine intreatment psoriasis for a long time in our country. Nowdays, to evaluate the efficacy andsafety of traditional Chinese medicin,a randomized, double-blind，placebo controlclinical trial is essencial.
Liangxuehuoxue Complex Prescription followed by the therapeutic principles of cooling blood,activating blood circulation,expelling wind-evil and regulating diuresisshowed perfect effects on psoriasis through the previous animal experiments andclinical studies.
Objective①To explore the differential expression of CD4+CD25+Foxp3+regulatory T cells in peripheral blood of patients with psoriasis of active stage and itsclinical significance in the pathogenesis of psoriasis.②To evaluate the efficacy andsafety of Liangxuehuoxue Complex Prescription on treatment of psoriasis of activestage and To promote the clinical application and development of traditional Chinesemedicine.To explore the possible acting targets of Liangxuehuoxue ComplexPrescription on progressive psoriasis and its mechanisms.
Methods (1)The differential expression of Tregs: CD4+CD25+Foxp3+regulatoryT cells and the expression of Foxp3(mean fluorescence intensity,MFI) were determinedby flow cytometry in peripheral blood of28patients with acute guttate psoriasis,20patients with plaque psoriasis of active stage and20healthy volunteer controls.(2)Efficacy and safety of Liangxuehuoxue Complex Prescription: In this randomized,double-blind，placebo control clinical trial of62patients with progressive psoriasis，35were treated with Liangxuehuoxue Complex Prescription and27were treated withplacebo for8weeks. The therapeutic outcomes was evaluated by PASI score, PGAscore,DLQI,VAS and SF-36. And the adverse effects were analized.(3) Mechanisms ofLiangxuehuoxue Complex Prescription:28patients with progressive psoriasis weretreated with Liangxuehuoxue Complex Prescription for8weeks. CD4+CD25+Foxp3+regulatory T cells and the expression of Foxp3(mean fluorescence intensity, MFI) weredetermined by flow cytometry in peripheral blood of the patients before and after thetreatment and20healthy volunteer controls. The therapeutic outcomes were evaluatedby PASI score. The serum levels of VEGF were detected by enzyme-linkedimmunosobant assays technique and the correlation with PSI score, dermatoscope inlesions were analized.
Results (1) The proportion of CD4+CD25+Foxp3+regulatory T cells in CD4+cells in patients with acute guttate psoriasis and plaque psoriasis of active stage(%)（1.09±0.71and2.09±1.04）were lower than that in control group（4.16±1.48）(p＜0.),the mean fluorescence intensity (MFI) of Foxp3in patients with plaque psoriasis ofactive stage and acute guttate psoriasis （26.84±13.85and21.74±13.81）were lowerthan that in control group（40.47±22.60）(p＜0.05).(2) The proportion of Treg cells andthe expression of Foxp3in psoriasis of active stage had no correlations with PASI scoring.(3) Effective rate of the study group was57.6%after treatment. It wassignificantly higher than that of the control group (24.0%)(p <0.05).(4) PASI score,PGA score,DLQI,VAS and SF-36of the study group were significantly alleviated thanthose of the control group (P <0.05).(5) There were no significant adverse reactions andtoxicity.(6) The proportion of CD4+CD25+Foxp3+regulatory T cells(%)(1.58±0.87)and the mean fluorescence intensity (MFI) of Foxp3(27.94±16.34)wereupregulated(2.60±0.88and32.52±14.27)(p＜0.05).(7) The serum levels of VEGF(80.40±10.75pg/mL) were significantly decreased(57.68±10.22pg/mL)(p＜0.05) andthe microvessel density were decreased.(8) The serum levels of VEGFwere significantlypositively correlated with PSI scorings（r=0.0.932，P=0.000）.
Conclusion (1) The lower proportion of Treg cells and the expression of Foxp3inpatients with acute guttate psoriasis and plaque psoriasis of active stage had nocorrelation with PASI scoring. Regulatory T cells play an important role in thepathogenesis of psoriasis in active stage and maybe a suggestion for disease progressevaluation.(2) Liangxuehuoxue Complex Prescription is effective and safe on treatmentof progressive psoriasis.(3) In the treatment of Liangxuehuoxue Complex Prescriptionon progressive psoriasis, the Tregs were upregulated and the serum levels of VEGFwere decreased. These may be some multiple targets as immunoregulation andantiangiogenesis.
调节性T细胞（T regulatory,Treg）是体内存在的以调节自身T细胞为主要功能的T细胞亚群，是机体以主动方式来维持自身稳定的重要途径，是发挥免疫抑制效应的T细胞。目前研究表明，银屑病患者的外周血及皮损中CD4+CD25+Treg细胞的数量减少，Foxp3的表达降低，均将导致Teff细胞中Th1和Th17的异常活化和增殖，引发或加重银屑病的反应过程。
银屑病皮损中显著的真皮微血管扩张提示了微血管因素可能是启动银屑病病理变化的关键之一，血管内皮细胞生长因子（VEGF，vascular endothelial growthfactor）是重要的促进血管生成因子之一。
我国在中药治疗银屑病方面积累了大量有效方剂，但是“中药疗效是安慰剂效应”的偏见在西医领域仍存在。随着现代医学中临床研究方法的深入发展，采用临床流行病学的设计、测量与评价的方法，使中医的临床研究有了长足的进步，临床研究中对照、随机和双盲原则逐渐被用于中医药的研究中。
凉血活血复方是我科在前人的研究基础上通过拆方分析和动物实验反复筛试得到的具有凉血、活血、清热、养血、祛风功能的中药复方，用于治疗进展期银屑病。前期课题组已经对该复方治疗银屑病进行了相关的临床研究，但缺少循证医学的客观评价。
目的：①通过研究CD4+CD25+Foxp3+Treg细胞在进行期银屑病患者外周血CD4+Treg细胞中的比例及其Foxp3表达水平，探讨Treg细胞在银屑病发病中的作用及其临床意义。②科学地评价凉血活血复方治疗进展期银屑病的疗效与安全性。③探讨凉血活血复方治疗进展期银屑病的可能作用靶点，以明确其作用机制，促进中药的临床应用和开发。
方法：（1）Treg细胞在进行期银屑病的差异表达：采用流式细胞术检测20例进行期斑块型银屑病患者、28例急性点滴型银屑病患者以及20例健康对照者外周血CD4+CD25+Foxp3+/CD4+Treg细胞的比例及反应Foxp3表达水平的平均荧光强度（MFI）。（2）凉血活血复方的疗效及安全性分析：应用随机、双盲、安慰剂对照的实验设计，观察中药凉血活血复方治疗进展期银屑病的临床疗效及安全性，共入组62例，凉血活血复方治疗组35例，安慰剂对照组27例，疗程8周，治疗后通过比较银屑病皮损面积和严重程度指数(PASI)评分、医生对病情的整体评分(PGA)、皮肤病生活质量指数(DLQI)、患者就l0cm目视模拟标尺对病情的整体评分(VAS)和生活质量SF-36等指标，评定其疗效，记录不良反应发生率。（3）凉血活血复方的作用机制探讨：应用凉血活血复方治疗进展期银屑病患者28例，用药8周后，应用流式细胞术，检测其治疗前后的外周血Treg细胞的比例及其Foxp3的表达水平，并与20例正常人对照相比较，评价与PASI评分的相关性；酶联免疫吸附（ELISA）法，检测治疗前后患者血清中血管内皮生长因子（VEGF）含量的，同时对靶皮损进行治疗前后PSI评分及皮肤镜比对，进行相关性分析。
结果：①进行期银屑病患者外周血Treg细胞的比例和Foxp3表达水平均明显低于健康对照者（P＜0.05），急性点滴型低于进行期斑块型。②进行期银屑病患者外周血Treg细胞的比例和Foxp3表达降低水平与PASI评分无相关性。③凉血活血复方治疗进展期银屑病8周时有效率57.6%，明显高于安慰剂对照组的24.0%（P<0.05）。④治疗组的PASI评分、PGA、DLQI、VAS以及SF-36均较对照组有明显改善（P均＜0.05）。⑤凉血活血复方的不良反应率17.14%，主要为稀便和大便次数增多，未见其余毒副作用。⑥凉血活血复方治疗8周后，外周血Treg细胞的比例（1.58±0.87）及Foxp3表达水平（27.94±16.34）均明显上调，分别为2.60±0.88和32.52±14.27（P<0.05）。⑦进展期银屑病患者外周血血清VEGF的含量为80.40±10.75pg/mL，凉血活血复方治疗8周后，VEGF的含量明显下降，为57.68±10.22pg/mL（P<0.05），皮损处微血管密度减少。⑧进展期银屑病患者治疗前血清VEGF的含量与PASI评分呈弱相关（n=28，r=0.383，P=0.045<0.05），而与皮损PSI评分明显正相关（n=28，r=0.932，P=0.000＜0.05）。
结论①急性点滴型和进行期斑块型银屑病患者外周血Treg细胞水平及Foxp3表达水平低下，与PASI评分无相关性，提示Treg细胞在银屑病进展中起重要作用。②本文首次应用随机、双盲、安慰剂对照的方法研究了中药凉血活血复方治疗进展期银屑病的临床疗效及安全性，探索出用于中药汤剂临床疗效评价的科学方法，凉血活血复方治疗进展期银屑病疗效确切，不良反应少，安全性好。③凉血活血复方治疗进展期银屑病后，上调Treg细胞及其表达，降低血清VEGF的含量，可能通过免疫调节及抗血管生成等多靶点作用而起效。
Background：Psoriasis is a common，chronic，inflammatory disease of the skin,whose typical clinical manifestions are increased cellular activity of the epidermis anddilated capillaries of the dermis．The exact mechanism of psoriasis is not clearlyunderstood yet. As we known, psoriasis is an immune-mediated disorder, in which theexcessive proliferations of keratinocytes and the dilated capillaries in the papillaedermis are the consequence of interaction among the infections,environmental factorsand genetic factors.
Regulatory T (TReg) cells, defined by the expression of CD4, CD25and thetranscription factor forkhead box P3(FOXP3), have a central role in protecting anindividual from auto immunity and are considered to be of vital importance formaintaining immunologic self-tolerance and preventing autoimmune diseases. Thedifferential expression of CD4+CD25+Foxp3+regulatory T cells in peripheral blood ofpatients with psoriasis of active stage indicates its clinical significance in thepathogenesis of psoriasis.
Vascular endothelial growth factor (VEGF) plays an important role in thedevelopment angiogenesis.Dermatoscope is now widely used in the diagnosis ofpsoriatic lesions and the evaluation of treatment.
There have been lots of complex prescriptions of traditional Chinese medicine intreatment psoriasis for a long time in our country. Nowdays, to evaluate the efficacy andsafety of traditional Chinese medicin,a randomized, double-blind，placebo controlclinical trial is essencial.
Liangxuehuoxue Complex Prescription followed by the therapeutic principles of cooling blood,activating blood circulation,expelling wind-evil and regulating diuresisshowed perfect effects on psoriasis through the previous animal experiments andclinical studies.
Objective①To explore the differential expression of CD4+CD25+Foxp3+regulatory T cells in peripheral blood of patients with psoriasis of active stage and itsclinical significance in the pathogenesis of psoriasis.②To evaluate the efficacy andsafety of Liangxuehuoxue Complex Prescription on treatment of psoriasis of activestage and To promote the clinical application and development of traditional Chinesemedicine.To explore the possible acting targets of Liangxuehuoxue ComplexPrescription on progressive psoriasis and its mechanisms.
Methods (1)The differential expression of Tregs: CD4+CD25+Foxp3+regulatoryT cells and the expression of Foxp3(mean fluorescence intensity,MFI) were determinedby flow cytometry in peripheral blood of28patients with acute guttate psoriasis,20patients with plaque psoriasis of active stage and20healthy volunteer controls.(2)Efficacy and safety of Liangxuehuoxue Complex Prescription: In this randomized,double-blind，placebo control clinical trial of62patients with progressive psoriasis，35were treated with Liangxuehuoxue Complex Prescription and27were treated withplacebo for8weeks. The therapeutic outcomes was evaluated by PASI score, PGAscore,DLQI,VAS and SF-36. And the adverse effects were analized.(3) Mechanisms ofLiangxuehuoxue Complex Prescription:28patients with progressive psoriasis weretreated with Liangxuehuoxue Complex Prescription for8weeks. CD4+CD25+Foxp3+regulatory T cells and the expression of Foxp3(mean fluorescence intensity, MFI) weredetermined by flow cytometry in peripheral blood of the patients before and after thetreatment and20healthy volunteer controls. The therapeutic outcomes were evaluatedby PASI score. The serum levels of VEGF were detected by enzyme-linkedimmunosobant assays technique and the correlation with PSI score, dermatoscope inlesions were analized.
Results (1) The proportion of CD4+CD25+Foxp3+regulatory T cells in CD4+cells in patients with acute guttate psoriasis and plaque psoriasis of active stage(%)（1.09±0.71and2.09±1.04）were lower than that in control group（4.16±1.48）(p＜0.),the mean fluorescence intensity (MFI) of Foxp3in patients with plaque psoriasis ofactive stage and acute guttate psoriasis （26.84±13.85and21.74±13.81）were lowerthan that in control group（40.47±22.60）(p＜0.05).(2) The proportion of Treg cells andthe expression of Foxp3in psoriasis of active stage had no correlations with PASI scoring.(3) Effective rate of the study group was57.6%after treatment. It wassignificantly higher than that of the control group (24.0%)(p <0.05).(4) PASI score,PGA score,DLQI,VAS and SF-36of the study group were significantly alleviated thanthose of the control group (P <0.05).(5) There were no significant adverse reactions andtoxicity.(6) The proportion of CD4+CD25+Foxp3+regulatory T cells(%)(1.58±0.87)and the mean fluorescence intensity (MFI) of Foxp3(27.94±16.34)wereupregulated(2.60±0.88and32.52±14.27)(p＜0.05).(7) The serum levels of VEGF(80.40±10.75pg/mL) were significantly decreased(57.68±10.22pg/mL)(p＜0.05) andthe microvessel density were decreased.(8) The serum levels of VEGFwere significantlypositively correlated with PSI scorings（r=0.0.932，P=0.000）.
Conclusion (1) The lower proportion of Treg cells and the expression of Foxp3inpatients with acute guttate psoriasis and plaque psoriasis of active stage had nocorrelation with PASI scoring. Regulatory T cells play an important role in thepathogenesis of psoriasis in active stage and maybe a suggestion for disease progressevaluation.(2) Liangxuehuoxue Complex Prescription is effective and safe on treatmentof progressive psoriasis.(3) In the treatment of Liangxuehuoxue Complex Prescriptionon progressive psoriasis, the Tregs were upregulated and the serum levels of VEGFwere decreased. These may be some multiple targets as immunoregulation andantiangiogenesis.
引文
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