【作者】 刘炽；

【导师】 陈达灿；

【作者基本信息】 广州中医药大学 ， 中西医结合临床， 2009， 博士

【摘要】 自1992年SheeHan等在《柳叶刀》和《英国皮肤病杂志》发表了中医药治疗特应性皮炎可能有效的临床随机对照试验以来,中医药做为一种潜在的有效治疗方法,被越来越多地用于治疗特应性皮炎的临床和实验研究。本文从中医药治疗特应性皮炎的文献研究,序贯试验和较长期的随访观察,以及免疫学角度探讨了清心培土法的疗效和作用机理。第一部分文献研究目的探讨特应性皮炎的基本病因和主导病机。分析中医药治疗特应性皮炎的辨旺论治规律。阐述清心培土法治疗特应性皮炎的心脾制衡策略。方法根据文献分析中医学认识特应性皮炎的历史沿革。根据历代医家的认识,结合特应性皮炎发病特点和临床特征,分析其主导病机和治则治法。全面收集国内外公开发表的中药复方治疗特应性皮炎的文献,运用脏腑辨证结合以方测证的方法分析特应性皮炎中医治疗文献的辨证论治规律。以文献研究结合既往的研究基础阐述清心培土法治疗特应性皮炎的制衡策略。结果特应性皮炎病因主要归于先天禀赋不耐、胎毒遗热,主导病机关乎心火,脾虚,心火耗伤元气,脾虚导致心火,心火脾虚交织互见,虚实错杂。辨证复方治疗特应性皮炎侧重于运用心经药物,辨病复方治疗特应性皮炎侧重于运用肝经药物,日本汉方治疗特应性皮炎侧重于运用肺经药物;三者均将脾经作为最重要的药物治疗靶点。心脾、肝脾、肝肾、脾肺经用药存在显著负相关(P＜0.05,P＜0.01,P＜0.01,P＜0.01)。清心培土法注重心脾动态制衡关系,强调清心法和培土法的共存。它在反映心脾药物消涨使用的同时,又强调泻心与健脾药物相辅相成的作用。结论禀赋不耐是特应性皮炎发病的根本原因,胎毒遗热是发病的主要诱因,心火旺、脾胃虚是其主导病机。中医药治疗特应性皮炎首先重视脾经,并关注脏腑之间的相互制衡关系。清心培土法是在特应性皮炎心脾病机的认识基础上而提出的治法,其蕴含的制衡策略尤其适用于复杂的病例存在心火脾虚交织互见的状况,具有自身的鲜明特色。第二部分临床研究目的评价特应性皮炎积分(SCORing AD,SCORAD)指数在评估特应性皮炎病情严重程度中的可靠性。在以往的研究基础上,开展清心培土法治疗特应性皮炎的近期和远期临床疗效评价。方法SCORAD指数内部相关性分析采用SCORAD指数评估特应性皮炎患者病情严重程度,分析SCORAD指数3个单项之间以及单项与总分之间的相关性。序贯试验以特应性皮炎评分指数(SCORAD)为疗效评价指标,采用序贯试验设计的方法评价清心培土方联合用药治疗特应性皮炎患者1月后的疗效。随访分析采用电话随访2005年2月—2007年10月在本院皮肤科门诊就诊的特应性皮炎临床确诊患者,随访者围绕基本痊愈、好转、无效三级病情详细询问患者或患者家属,总体评价清心培土法治疗特应性皮炎的远期疗效。结果SCORAD指数的皮损面积与皮损强度、SCORAD指数呈显著正相关(r分别为0.541,0.743;P＜0.002,0.000)。皮损面积与主观症状无显著相关(r=0.296,P＞0.05)。皮损强度与主观症状、SCORAD指数呈显著正相关(r分别为0.403,0.881;P＜0.027,0.000)。主观症状与SCORAD指数呈显著正相关(r=0.704;P＜0.000)。序贯试验试验至第7例患者时,试验线触及U界,说明清心培土方联合用药治疗特应性皮炎有效。随访分析共随访了18例患者,停药时间在3月—22月之间。结果基本痊愈5例,好转8例,无效5例,痊愈率27.78%,有效率72.22%。结论SCORAD指数在评估特应性皮炎病情中具有良好的内在一致性和可靠性。本研究运用SCORAD指数评估特应性皮炎病情取得了较好的效果。清心培土法为主,中西医结合治疗特应性皮炎的近期疗效肯定。以清心培土法为主的联合用药方案治疗特应性皮炎具有较好的远期疗效,在缓解病情,减少复发,减少外用激素和抗组胺药物用量方面发挥积极的作用。第三部分实验研究及临床意义分析目的近年来的研究进展认为天然免疫系统和调节性T细胞在特应性皮炎的发病机制中可能扮演重要角色,二者与Th1/Th2失衡存在密切的联系。本研究以血清IL-2/sIL-2R、TNF-α/sTNFR的状况,作为研究特应性皮炎患者CD4+CD25+调节性T细胞和天然免疫系统免疫状态的切入点。对特应性皮炎患者的免疫失调状况及其与?情的相关性进行探讨。还探讨了清心培土法干预后特应性皮炎患者免疫状况和病情的变化。方法采用酶联免疫吸附试验(ELISA)方法检测30例特应性皮炎患者及20例正常人血清中IL-2、sIL-2R、TNF-α、sTNFR水平。采用SCORAD指数评价患者病情严重程度,分析其与血清IL-2、sIL-2R水平、TNF-α、sTNFR的相关性。采用ELISA方法检测9例特应性皮炎患者治疗前后IL-2、sIL-2R、TNF-α及sTNFR的水平以及运用SCORAD指数评价病情的变化,进行自身前后比较,分析免疫指标与病情变化的相关性。结果与正常人对照组相比,特应性皮炎患者血清IL-2、TNF-α水平下降,但无显著差异(P＞0.05),患者血清sIL-2R、sTNFR水平显著高于对照组(P＜0.05,0.001)。患者血清sIL-2R水平的变化分别与皮损面积呈显著正相关(r=0.37,P＜0.05),与患病时间呈显著负相关(r=-0.398,P＜0.05)。患者血清TNF-α、sTNFR水平分别与SCORAD、患病时间无显著相关性(P＜0.05)。9例特应性皮炎患者治疗前后比较,经治疗后IL-2、sIL-2R显著上升(P＜0.05);经治疗后sTNFR、SCORAD积分显著下降(P＜0.05);经治疗后的TNF-α升高,但差异无显著意义(P＞0.05)。治疗后sTNFR与主观症状出现了显著相关性(P＜0.05)。sIL-2R与病情的相关性增强,与皮损面积、主观症状、SCORAD均呈显著相关(P＜0.05)。结论特应性皮炎患者sIL-2R升高与特应性皮炎的皮损面积和患病时间有关。特应性皮炎患者血清增高的sIL-2R可增加其中和IL-2的能力,导致免疫失调,在特应性皮炎病情活动或迁延过程中发挥作用。特应性皮炎患者血清高水平的sTNFR可加强其中和循环中的TNF-α的能力,继而引起TNF-α介导的抗感染和抗炎症反应能力下降,在AD的免疫发病机制中发挥作用。清心培土方联合用药治疗特应性皮炎可促进Th1型细胞因子IL-2增加,降低sTNFR水平,提高TNF-α的活性,缓解病情。更多还原

【Abstract】 Since 1992,Sheehan etc.published a series of clinical randomized controlled trials in "Lancet" and "British Journal of Dermatology"about TCM (Traditional Chinese Medicine) treatments of atopic dermatitis which sugested TCM treatments may be effective on atopic dermatitis.From then on TCM treatments as a potential effective method of treatment was used for the clinical and experimental researchs of atopie dermatitis more and more.The effects and mechanisms of Qing-Xin-Pei-Tu therapy were researched from the points of view including literature studies of TCM treatments of atopic dermatitis,sequential trials and longer-term follow-up observations, as well as the immunological mechanisms in this paper.PartⅠLiterature studiesObjectiveTo explore the basic etiology and pathogenesis of atopic dermatitis. Analysis of the laws of TCM syndrome differentiation of atopic dermatitis. Explanation of Qing-Xin-Pei-Tu therapy which was a TCM treatment strategy of check and balance between Heart and spleen on atopic dermatitis.MethodsAccording to historical literature analysis of the understanding of TCM on atopic dermatitis.According to history of medicine,combined with the characteristics and clinical features of atopic dermatitis,analysis of the leading pathogenesis and therapeutic methods.To collect published treatment literature of atopic dermatitis about Chinese herbal formula.Analysis of the laws on syndrome differentiation of atopic dermatitis by the methods combined with differentiation of Zang and Fu and the predictive diagnosis of syndromes by the effects of herbal prescription treatment.ResultsEtiology of atopic dermatitis was largely attributable to intolerance, ]eft heat and toxins during gestationa]period from Chinese medical viewpoint.The leading pathogenesis was cross-cutting between heart-fire and insufficiency of the spleen.Heart-fire could result in insufficiency of the spleen.Insufficiency of the spleen could result in heart-fire.A mixed situation was made by the cross-cutting between heart-fire and insufficiency of the spleen.Formulas of differentiation of symptoms and signs of atopic dermatitis were focused on the use of drugs for heart channel.Formulas of differentiation of disease were focused on the use of drugs for the liver channel.Formulas of Japanese Kampo treatment were focused on the use of drugs for pulmonary channel.The spleen channel was the most important target for therapy in all Formulas.There were significant negative correlations between heart and spleen,liver and spleen,liver and kidney,spleen and pulmonary separately (P＜0.05,P＜0.01,P＜0.01,P＜0.01).Qing-Xin-Pei-Tu therapy was focused on the relationship of check and balance between heart and spleen and emphasised on co-existence of Qing-Xin therapy and Pei-Tu therapy.At the same time,it also stressed that Jianpi drug and Xiexin drug were complimentary each other.ConclusionsEtiology of atopic dermatitis was largely attributable to intolerance, left heat and toxins during gestational period.The leading pathogenesis was cross-cutting between heart-fire and insufficiency of the spleen.The spleen channel was the most important target for treatment of TCM on atopic dermatitis.Qing-Xin-Pei-Tu therapy was basic Chinese traditional treatment on atopic dermatitis with its own distinct characteristics..It is particularly suited to treat the complex cases accompanied with cross-cutting between heart-fire and insufficiency of the spleen. PaTtⅡClinical studiesObjectiveTo evaluate the reliability of SCORing Atopic Dermatitis index(SCORAD) for atopic dermatitis.To evaluate the short-term and long-term effect of combined therapies of traditional Chinese medicine and Western medicine on patients with atopic dermatitis.MethodsThe internal correlation analysis of SCORAD index:Evaluation of severity of the disease in patients with atopic dermatitis using SCORAD index and the internal correlation analysis of the three individual parts in SCORAD index as well as the correlation between the three individual parts and the total score.Sequential analysis test:The primary efficacy parameter was the SCORAD index.The effect was evaluated by Sequentialanalysis test after the patients had treated by combined therapies of traditional Chinese and Western medicine for one month.Follow-up analysis:Out-patients with atopic dermatitis were followed up by telephone who had visited dermatology department in our hospital during February 2005 to October 2007 period.Patients or patients’ family members were asked about patients’ condition in detail around three topic including basic recovery,improvement and invalid.The long-term effect of Qing-Xin-Pei-Tu therapy used for treatment on atopic dermatitis were evaluated on the whole.ResultsThe internal correlation analysis of SCORAD index:The internal correlations between spread of lesions and intensity of lesions or SCORAD index were significantly(r=0.541,0.743 separately:P＜0.002,0.000 separately). The internal correlations between spread of lesions and sujective symptom was not significantly(r=0.296,P＞0.05).The internal correlations between sujective symptom and SCORAD index was significantly(r=0.704;P＜0.000).Sequential analysis test:After the seventh petient had been treated,the effect of combined therapies of traditional Chinese and Western medicine was affirmed for patients with atopic dermatitis.Follow-up analysis:A total of 18 cases of patients with atopic dermatitis who had stopped treatment from 3 months to 22 months were followed up.As a result,5 cases cured,8 cases improved and 5 cases were invalid.Recovery rate was 27.78%.Effective rate was 72.22%.ConclusionsSCORAD index was used for assessing the condition of atopic dermatitis with good internal consistency and reliability.SCORAD index was used for assessing the condition of atopic dermatitis in this study achieved good results.The short-term effect of combined therapies of traditional Chinese and Western medicine based on Qing-Xin-Pei-Tu therapy were affirmed for patients with atopic dermatitis.The therapeutic schedule had a good long-term effect and could help atopic dermatitis sufferers control their condition,reduce relapse,reduce the usage quantity of topical steroid and antihistamines.PartⅢExperimental study and analysis of clinical significanceObjectiveResearches sugested that natural immune system and regulatory T cells might play an important role in atopic dermatitis pathogenesis in recent years.There were close relationship between Th1/Th2 polarization and natural immune system or regulatory T cells.In this study,serum interleukin-2(IL-2) and soluble interleukin-2 receptors(sIL-2R),tumor necrosis factor(TNF)-αand soluble tumor necrosis factor receptors(sTNFR) were detected as a entry point to study the immune status of CD4+CD25+ regulatory T cells and the natural immune system in patients with atopic dermatitis.The patient’s immune disorders and their correlations with the patient’s condition were discussed.To investigate the effective mechanisms of combined therapies of traditional Chinese and Western medicine on atopic dermatitis,the patients’ conditions and the immune status changes were also discussed after the patients treated by combined therapies of traditional Chinese and Western medicine based on Qing-Xin-Pei-Tu therapy.MethodsSerum IL-2 and slL-2R levels were detected by enzyme-linked immunosorbent assay(ELISA).The disease severity was assessed by SCORAD index.The relationships of IL-2 and slL-2R to SCORAD and course of disease were evaluated.SerumTNFαand sTNFR levels were detected by ELISA.The disease severity was assessed by SCORAD index.The relaLionships of TNF-αand sTNFR to SCORAD and course of disease were evaluated.Patients with atopic dermatitis were enrolled into this study before and after treated by combined therapies of traditional Chinese and Western medicine for one month.Serum IL-2,slL-2R,TNF-α,sTNFR levels were detected by ELISA.The disease severity was assessed by SCORAD index.Results30 patients with atopic dermatitis and 20 normal human controls were enrolled into this study.Before treatment,Serum IL-2 levels were decreased compared with the controls(P＞0.05),while Serum sIL-2R levels were significantly increased in patients with atopic dermatitis(P＜0.05).Serum sIL-2R levels showed a significant positive correlation with the spread of lesions and inverse correlation with course of disease(r=0.37 and -0.398 respectively;all P＜0.05).30 patients with atopic dermatitis and 20 normal human controls were enrolled into this study.Before treatment,serum TNF-αlevels were mildly decreased compared with the controls(P＞0.05),while Serum sTNFR levels were significantly increased in patients with atopic dermatitis(P＜0.001).Serum sTNFR levels did not showed a correlation with the SCORAD and course of disease (all P＞0.05).The state of illness were compared before and after treatment in 9 patients with atopic dermatitis.After treatment for one month,serum IL-2,slL-2R and SCORAD in patients in this study were significantly increased(P＜0.05)and sTNFR levels significantly decreased compared with before treatment.The variable of TNF-αlevels no significantly difference(P＞0.05).Serum sTNFR levels did not showed a correlation with the SCORAD and course of disease(all P＞0.05).ConclusionsThe increased serum levels of sIL-2R in patients with atopic dermatitis had a positive correlation with the spread of lesions and negative correlation with course of disease.Elevated serum sIL-2R in patients with atopic dermatitis might increase the ability of binding IL-2 and lead to immune disorders.This mechanism might play a role in disorder of immune mechanism of atopic dermatitis or persistent activity of patient’s condition.The increased serum levels of sTNFR in patients with atopic dermatitis might enhance the ability of binding TNF-αand reduce anti-infective and anti-inflammatory ability mediated by TNF-α.This mechanism might play a role in the pathogenesis of atopic dermatitis.The levels of Th1 type cytokines and the activity of TNF-αcould be promoted but the levels of sTNFR could be decreased by combined therapies of traditional Chinese and Western medicine based on Qing-Xin-Pei-Tu therapy.The therapeutic schedule was effective for patients with atopic dermatitis.更多还原