镇心安神方治疗特应性皮炎的随访疗效分析及免疫调节作用研究
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摘要
在此论文中研究主要分为相互关联的三个部分,分别为特应性皮炎中医药研究的文献评析、镇心安神方治疗特应性皮炎的随访疗效分析及镇心安神方治疗特应性皮炎的免疫调节作用研究。
1特应性皮炎中医药研究的文献评析
目的：特应性皮炎中医药研究众多,但却相对混乱,缺乏系统总结。本论文通过对中医古籍及近23年国内外发表文献的评价、分析,以期发现并总结特应性皮炎的中医药证治规律,为临床及科研的决策提供证据。
方法：计算机检索PubMed、中国期刊全文数据库、中国生物医学文献数据库、维普、万方数据库,手工检索中医古籍,查找关于特应性皮炎的中医药研究文献,提取相关数据进行描述性分析；并采用Cochrane Handbook5.1.0推荐的随机对照试验方法学质量评估标准对其中随机对照试验文献质量进行评价。
结果：
(1)传统中医古籍对现代特应性皮炎的认识以“四弯风”、“血风疮”、“奶癣”、“胎(?)疮”最具有参考价值；
(2)对近23年发表的特应性皮炎中医药研究文献分析发现：中医证型以脾虚及其相兼证、湿热蕴结证、血虚风燥证三种证型最为常见；治疗上形成了以自拟方、传统方剂化裁、中成药为主,针灸、药浴、穴位注射、推拿等多种措施并用的治疗体系；药物运用上以补气药、清热燥湿药、补血药、利水消肿药、清热凉血药、发散风寒药、清热解毒药等较为常见；常用方剂有消风散、消风导赤散、当归饮子、麻黄连翘赤小豆汤、地黄饮子等；
(3)中医药治疗特应性皮炎的临床试验文献方法学质量较低,需要设计严格的大样本、双盲、随机对照试验支持,以保证研究结论的真实可靠。
结论：目前特应性皮炎的中医药研究缺乏统一的辨证分型标准、疗效评价标准及合理设计并且质控严格的临床试验。
2镇心安神方治疗特应性皮炎的随访疗效分析
目的：评价镇心安神方治疗特应性皮炎的远期疗效及安全性。
方法：采用多中心、计算机随机、阳性药物对照设计,对符合纳入标准、不符合排除标准的特应性皮炎患者按照入组顺序,根据网络随机中心生成的申请序号和组别发放药物,试验药物：镇心安神方1号方或镇心安神方2号方,口服：150ml/次,2次/日,外用：冷湿敷患处,20min/次,2次/日；对照药物：氯雷他定片口服,1次/日,0.1%丁酸氢化可的松乳膏外用,2次/日；疗程均为8周。临床试验结束时对痊愈及显效患者随访24周。
结果：以临床试验结束之日为随访起始点,分别于第4周±7天、12周±7天、24周±7天为访视点,对临床试验中痊愈及显效患者64例进行随访,试验组31例,对照组33例；最终完成24周随访的患者共45例,试验组26例,对照组19例。主要疗效指标为欧洲特应性皮炎研究组(ETFAD)提出SCORAD评分标准,包括客观体征皮肤病变范围、皮损严重程度和主观症状瘙痒和影响睡眠程度；次要测量指标包括皮肤病学生活质量指数(DLQI)量表或儿童皮肤病学生活质量指数(CDLQI)及中医证候积分,安全性指标包括不良事件及相关实验室检查。
(1)试验药物的治疗效果
试验组31例患者治疗前后各项症状积分比较中,SCORAD评分、皮损范围、皮损严重程度、瘙痒程度及睡眠状况积分比较均有显著性差异(P<0.01),治疗前后皮损严重程度单项症状比较中,红斑、丘疹或水肿、渗出或结痂、表皮剥脱、苔藓化及皮肤干燥积分比较均有显著性差异(P<0.01)；DLQI/CDLQI治疗前后比较各年龄段均有显著性差异(P<0.01)；试验组31例患者中治疗前辨证属风湿蕴肤证者13例,辨证属血虚风燥者18例；风湿蕴肤证相关各项证候积分治疗前后比较均有显著性差异(P<0.01)；血虚风燥证相关各项证候积分中,治疗后皮肤干燥、瘙痒程度及口干不欲饮症状积分较治疗前有显著性差异(P<0.01),皮肤色暗及皮肤肥厚证候积分较治疗前无显著性差异(P>0.05)。
对照组33例患者治疗前后各项症状积分比较中,SCORAD评分、皮损范围、皮损严重程度、瘙痒程度及睡眠状况积分比较均有显著性差异(P<0.01)；治疗前后皮损严重程度单项症状比较中,红斑、丘疹或水肿、渗出或结痂、表皮剥脱、苔藓化及皮肤干燥积分比较均有显著性差异(P<0.01)；DLQI/CDLQI治疗前后比较各年龄段均有显著性差异(P<0.01)；对照组33例患者中治疗前辨证属风湿蕴肤证者6例,辨证属血虚风燥者27例；风湿蕴肤证相关各项证候积分中,皮肤潮红、糜烂流滋、丘疹水疱及瘙痒程度积分较治疗前均有有显著性差异(P<0.05),神倦便溏与治疗前比较无显著性差异(P>0.05)；血虚风燥证相关各项证候积分中,皮肤干燥、皮肤肥厚、瘙痒程度及口干不欲饮症状积分较治疗前有显著性差异(P<0.01),皮肤色暗证候积分较治疗前无显著性差异(P>0.05)。
(2)随访疗效分析
主要测量指标：随时间变化试验组停药后各项症状积分变化趋于稳定,对照组停药后各项症状存在不同程度复发；随访结束时两组在皮肤病变面积(试验组：5.04±4.27,对照组：11.53±6.98)、皮损严重程度(试验组：1.81±1.23,对照组：3.68±2.08)、瘙痒及影响睡眠程度(试验组：2.04±1.97,对照组：4.63±3.23)、SCORAD评分(试验组：9.37±6.76,对照组：19.83±11.26)的比较均有显著性差异(P0.05),对照组部分访视点瘙痒及影响睡眠程度及SCORAD评分的组内比较有显著性差异(P<0.05)；皮损严重程度的单项症状比较中,两组患者红斑、丘疹或水肿、渗出或结痂的积分比较差异有统计学意义(P<0.01),苔藓化及皮肤干燥症状变化不明显(P>0.05)；两组部分访视点单项症状组内比较差异有统计学意义(P<0.05)。
次要测量指标：随时间变化两组7-12岁患者DLQI/CDLQI比较有显著性差异(P<0.01),>12岁患者DLQI/CDLQI比较无显著性差异(P>0.05)；试验组26例随访患者中治疗前辨证属风湿蕴肤证者13例,血虚风燥证者13例,对照组19例随访患者中治疗前辨证属风湿蕴肤证者5例,血虚风燥证者14例,随访前后两组风湿蕴肤证相关各项中医证候比较除皮肤潮红外,其他证候积分比较均差异无统计学意义(P>0.05)；对照组瘙痒积分组内比较随访前后有显著性差异(P<0.05)；两组血虚风燥证相关各项中医证候比较中,皮肤干燥、瘙痒及总分差异有统计学意义(P (3)安全性检查
未发现与研究药物相关的严重不良事件及实验室检查异常。结论：镇心安神方治疗特应性皮炎可明显控制复发,远期疗效优于对照药物,安全性好；随访研究仅对临床试验中痊愈及显效患者进行观察,样本量尚小,仍需扩大样本量进一步研究。
3镇心安神方治疗特应性皮炎的免疫调节作用研究
目的：对特应性皮炎患者血清多项细胞因子指标进行检测,以期揭示镇心安神方治疗特应性皮炎的免疫调节作用机制。
方法：分别抽取临床试验中试验组20例特应性皮炎患者治疗前、后及20例健康志愿者空腹外周静脉血5m1待检；采用酶联免疫分析法对60份血清样本中IL-4、IL-12、MDC、Eotaxin-2、IL-17A、IL-21及p-EP浓度进行检测和计算。
结果：
(1)治疗前试验组患者血清细胞因子IL-4、IL-17A、趋化因子MDC水平高于健康对照组(P<0.05)；血清趋化因子Eotaxin-2水平低于健康对照组,差异有统计学意义(P<0.05),血清细胞因子IL-12、IL-21及神经肽β-EP水平比较略有差异,但差异无统计学意义(P>0.05)；
(2)风湿蕴肤证患者血清IL-4、IL-17A水平高于血虚风燥证患者,差异有统计学意义(P<0.05)；风湿蕴肤证患者血清IL-12、MDC水平低于血虚风燥证患者,差异有统计学意义(P<0.05)；血清Eotaxin-2、IL-21及β-EP水平两证型比较略有差异,但差异均无统计学意义(P>0.05)。
(3)治疗前血清IL-4、IL-12、MDC及IL-17A水平与SCORAD评分具有直线相关关系(P<0.05),其中血清IL-4、MDC及IL-17A水平与SCORAD评分呈正相关,血清IL-12水平与SCORAD评分呈负相关,均可作为提示病情严重程度的指标；血清Eotaxin-2、IL-21及p-EP水平与SCORAD评分不存在直线相关关系(P>0.05)。
(4)经镇心安神方治疗后血清IL-12水平较前升高(P<0.05),其变化与SCORAD评分变化呈直线相关(负相关);血清MDC水平较前下降(P<0.05),其变化与SCORAD评分变化呈直线相关(正相关)；血清β-EP水平较前升高(P<0.05),其变化与SCORAD评分变化呈直线相关(正相关)；治疗后血清IL-12、MDC、p-EP水平与健康人群差异不明显；
(5)镇心安神方治疗前后血清IL-4、Eotaxin-2、IL-17A、IL-21变化不明显(P>0.05)；治疗后血清IL-4、IL-17A、IL-21水平仍高于健康人群(P<0.05)；治疗后Eotaxin-2水平与健康人群差异不明显(P>0.05)。
结论：镇心安神方治疗特应性皮炎具有双向免疫调节作用,发挥抑制作用的免疫学靶点仅有MDC(治疗后下降),发挥促进作用的免疫学靶点有IL-12、Eotaxin-2、 IL-21、β-EP (治疗后升高),同时也发现镇心安神方对细胞因子的纠正作用较弱,治疗后血清IL-4及IL-17A表达仍呈亢进状态,其机制仍需进一步探讨。
In the dissertation, the main content includes three relevant parts:the literature review of Traditional Chinese Medicine (TCM) study on Atopic Dermatitis (AD), the follow-up study and immunomodulatory effects research of Formulation for Tranquilizing Heart and Mind (FTHM) in treating AD.
1Literature review of TCM study on AD
Objective In TCM study of AD, there are plenty of researches, however, lack of system reviewing. In this dissertation, the recent23years scientific papers and ancient books of TCM study on AD have been reviewed, analyzed and evaluated. The aim of this study is getting the common rules of TCM treatment on AD, which will provide available evidence to help the future clinical and research.
Methods Relevant publications and writings about TCM study on AD were systematically gathered from databases such as PubMed, CNKI, CBM, VIP, Wanfang data and TCM ancient books, then analyzed. The quality of the publications was evaluated by randomized controlled trials according to the Cochrane handbook.
Results1. In TCM ancient books, the feature of "the wind of four fossae","anemogenous sore" and "infantile eczema" is similar to AD.2. In recent23years publications, the syndrome of spleen deficiency and its related syndromes, the syndrome of accumulated dampness-heat and syndrome of wind and dryness due to blood deficiency are the most common clinical syndromes. The treatment of AD is composed of self-modified formulation, plused or reduced medicine form traditional formulation, TCM patent prescription, acupuncture, medicated bath, acupoint-injection, massage and combination of above methods. Commonly used drugs and formulations include that qi-supplementing drug, blood-supplementing drug, heart-clearing and dampness-drying drug, inducing dieresis for removing edema drug, xiaofeng powder, xiaofengdaochi powder, angelica yin zi, et al.
3. Clinical researches of TCM in treating AD are at low methodological quality. The stricter designed, double-blind, randomized controlled, large sample trials are required to support and ensure the efficacy and safety of TCM.
Conclusions TCM studies on AD are lack of unified standard syndrome, evaluation standard, reasonable designed and strict quality controlled clinical trials.
2The follow-up study of FTHM in treating AD
Objective Evaluate the efficacy and safety of FTHM with the follow-up study on patients who had AD.
Methods We designed and carried out a multicenter, randomized, controlled clinical trial. Patients with AD were randomized received an8week treatment twice-daily dosing of FTHM or loratadine tablets and0.1%hydrocortisone butyrate cream. After the trial,64patients with significantly improved were recruited to a24weeks follow-up study.45patients finished the whole24weeks follow-up study. The results of SCORAD score, lesion area of skin score, severity of lesion-skin score, pruritus degree score, Dermatology Life Quality Index (DLQI)/Children Dermatology Life Quality Index (CDLQI), and TCM syndrome score were assessed during the treatment and week4,12and24in the follow-up study. Adverse events, tolerability, haematological and biochemical parameters were monitored during the study.
Results
1. The effect of trial drug
64patients were recruited for the follow-up study. For over8weeks, the mean SCORAD score decrease from40.03to11.33in treatment group (n=31, P=0.0001), and from37.83to10.18in control group (n=33, P=0.0001). However, the results have no significant difference between two groups at the corresponding time. Lesion area of skin score, severity of lesion-skin score, pruritus degree score and DLQI/CDLQI were all improved after the treatment. There was no significant difference in these results too. No serious adverse effects were observed in both the groups. In treatment group,13patients were diagnosed as the syndrome of wind-damp stagnating in skin and18patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. In control group,6patients were diagnosed as the syndrome of wind-damp stagnating in skin and27patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. In TCM syndromes, only hyperpigmentation and dermatauxe were not improved heavily.
2. The follow-up study
Over24weeks'follow-up study,45patients accomplished the whole trial which including26from treatment group and19from control group. SCORAD score, lsion area of skin score, severity of lesion-skin score, pruritus degree score and DLQI/CDLQI, and TCM syndrome score were stable in treatment group. However, SCORAD score increased from12.59to19.83in control group, which indicates some patients have a recurrence of AD. There were significant differences of erythema score, papule score and effusion score between two groups. There were also significant differences DLQI/CDLQI between patients'age below12in two groups. In treatment group,13patients were diagnosed as the syndrome of wind-damp stagnating in skin and13patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. Erythema score of some patients was higher than at the beginning of the follow-up study. In control group,5patients were diagnosed as the syndrome of wind-damp stagnating in skin and14patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. Dry skin score, pruritus score and total score were higher than at beginning of the follow-up study. Adverse events, tolerability, haematological and biochemical parameters were monitored during follow-up study.
Conclusions FTHM is efficacious in improving clinical symptoms, the quality of life and reducing recurrence in patients with AD. The formulation was safe and well tolerated, but more research of FTHM still needed to reinforce this conclusion.
3Research of immunomodulatory effects of FTHM in treating AD.
Objective To study various of cytokines and chemokines in the peripheral blood of patients with AD and explore the immunomodulatory effects of FTHM in AD patients.
Methods The serum level of IL-4, IL-12, MDC, Eotaxin-2, IL-17A, IL-21and β-EP were detected by enzyme-linked immunosorbent assay (ELISA) before and after treatment by FTHM.20patients and20healthy volunteers were recruited.
Results
1. The serum level of IL-4, IL-17A and MDC in AD patients was significant higher than controls. The serum level of Eotaxin-2in AD patients was significant lower than controls. There was no significant difference in the serum level of IL-12, IL-21and P-EP between AD patients and controls.
2. The serum level of IL-4and IL-17A in patients with the syndrome of wind-damp stagnating in skin was significant higher than patients with the syndrome of wind and dryness due to blood deficiency. The serum level of IL-12and MDC in patients with the syndrome of wind-damp stagnating in skin was significant lower than patients with the syndrome of wind and dryness due to blood deficiency. There was no significant difference in the serum level of Eotaxin-2, IL-21and β-EP between the two TCM syndromes.
3. Relevant analysis indicated that the serum level of IL-4, MDC and IL-17A was positively related to the SCORAD scores, and the serum level of IL-12was negatively related to the SCORAD scores. There was no linear relationship between the serum level of Eotaxin-2, IL-21and p-EP and SCORAD scores.
4. After the treatment of FTHM, the serum level of IL-12and p-EP rose up and the serum level of MDC fell down. There was no significant difference in the serum level of IL-12, MDC and P-EP between AD patients and controls.
5. The influence of FTHM on the serum level of IL-4, Eotaxin-2, IL-17A and IL-21was not significant. After treatment, the serum level of IL-4, IL-17A and IL-21was still higher than controls. There was no significant difference between AD patients and controls at the serum level of Eotaxin-2.
Conclusions FTHM plays a bidirectional immunomodulatory effects in treating patients with AD. MDC is the suppressive target. IL-12, Eotaxin-2, IL-21and P-EP are the promoting targets.
1特应性皮炎中医药研究的文献评析
目的：特应性皮炎中医药研究众多,但却相对混乱,缺乏系统总结。本论文通过对中医古籍及近23年国内外发表文献的评价、分析,以期发现并总结特应性皮炎的中医药证治规律,为临床及科研的决策提供证据。
方法：计算机检索PubMed、中国期刊全文数据库、中国生物医学文献数据库、维普、万方数据库,手工检索中医古籍,查找关于特应性皮炎的中医药研究文献,提取相关数据进行描述性分析；并采用Cochrane Handbook5.1.0推荐的随机对照试验方法学质量评估标准对其中随机对照试验文献质量进行评价。
结果：
(1)传统中医古籍对现代特应性皮炎的认识以“四弯风”、“血风疮”、“奶癣”、“胎(?)疮”最具有参考价值；
(2)对近23年发表的特应性皮炎中医药研究文献分析发现：中医证型以脾虚及其相兼证、湿热蕴结证、血虚风燥证三种证型最为常见；治疗上形成了以自拟方、传统方剂化裁、中成药为主,针灸、药浴、穴位注射、推拿等多种措施并用的治疗体系；药物运用上以补气药、清热燥湿药、补血药、利水消肿药、清热凉血药、发散风寒药、清热解毒药等较为常见；常用方剂有消风散、消风导赤散、当归饮子、麻黄连翘赤小豆汤、地黄饮子等；
(3)中医药治疗特应性皮炎的临床试验文献方法学质量较低,需要设计严格的大样本、双盲、随机对照试验支持,以保证研究结论的真实可靠。
结论：目前特应性皮炎的中医药研究缺乏统一的辨证分型标准、疗效评价标准及合理设计并且质控严格的临床试验。
2镇心安神方治疗特应性皮炎的随访疗效分析
目的：评价镇心安神方治疗特应性皮炎的远期疗效及安全性。
方法：采用多中心、计算机随机、阳性药物对照设计,对符合纳入标准、不符合排除标准的特应性皮炎患者按照入组顺序,根据网络随机中心生成的申请序号和组别发放药物,试验药物：镇心安神方1号方或镇心安神方2号方,口服：150ml/次,2次/日,外用：冷湿敷患处,20min/次,2次/日；对照药物：氯雷他定片口服,1次/日,0.1%丁酸氢化可的松乳膏外用,2次/日；疗程均为8周。临床试验结束时对痊愈及显效患者随访24周。
结果：以临床试验结束之日为随访起始点,分别于第4周±7天、12周±7天、24周±7天为访视点,对临床试验中痊愈及显效患者64例进行随访,试验组31例,对照组33例；最终完成24周随访的患者共45例,试验组26例,对照组19例。主要疗效指标为欧洲特应性皮炎研究组(ETFAD)提出SCORAD评分标准,包括客观体征皮肤病变范围、皮损严重程度和主观症状瘙痒和影响睡眠程度；次要测量指标包括皮肤病学生活质量指数(DLQI)量表或儿童皮肤病学生活质量指数(CDLQI)及中医证候积分,安全性指标包括不良事件及相关实验室检查。
(1)试验药物的治疗效果
试验组31例患者治疗前后各项症状积分比较中,SCORAD评分、皮损范围、皮损严重程度、瘙痒程度及睡眠状况积分比较均有显著性差异(P<0.01),治疗前后皮损严重程度单项症状比较中,红斑、丘疹或水肿、渗出或结痂、表皮剥脱、苔藓化及皮肤干燥积分比较均有显著性差异(P<0.01)；DLQI/CDLQI治疗前后比较各年龄段均有显著性差异(P<0.01)；试验组31例患者中治疗前辨证属风湿蕴肤证者13例,辨证属血虚风燥者18例；风湿蕴肤证相关各项证候积分治疗前后比较均有显著性差异(P<0.01)；血虚风燥证相关各项证候积分中,治疗后皮肤干燥、瘙痒程度及口干不欲饮症状积分较治疗前有显著性差异(P<0.01),皮肤色暗及皮肤肥厚证候积分较治疗前无显著性差异(P>0.05)。
对照组33例患者治疗前后各项症状积分比较中,SCORAD评分、皮损范围、皮损严重程度、瘙痒程度及睡眠状况积分比较均有显著性差异(P<0.01)；治疗前后皮损严重程度单项症状比较中,红斑、丘疹或水肿、渗出或结痂、表皮剥脱、苔藓化及皮肤干燥积分比较均有显著性差异(P<0.01)；DLQI/CDLQI治疗前后比较各年龄段均有显著性差异(P<0.01)；对照组33例患者中治疗前辨证属风湿蕴肤证者6例,辨证属血虚风燥者27例；风湿蕴肤证相关各项证候积分中,皮肤潮红、糜烂流滋、丘疹水疱及瘙痒程度积分较治疗前均有有显著性差异(P<0.05),神倦便溏与治疗前比较无显著性差异(P>0.05)；血虚风燥证相关各项证候积分中,皮肤干燥、皮肤肥厚、瘙痒程度及口干不欲饮症状积分较治疗前有显著性差异(P<0.01),皮肤色暗证候积分较治疗前无显著性差异(P>0.05)。
(2)随访疗效分析
主要测量指标：随时间变化试验组停药后各项症状积分变化趋于稳定,对照组停药后各项症状存在不同程度复发；随访结束时两组在皮肤病变面积(试验组：5.04±4.27,对照组：11.53±6.98)、皮损严重程度(试验组：1.81±1.23,对照组：3.68±2.08)、瘙痒及影响睡眠程度(试验组：2.04±1.97,对照组：4.63±3.23)、SCORAD评分(试验组：9.37±6.76,对照组：19.83±11.26)的比较均有显著性差异(P
次要测量指标：随时间变化两组7-12岁患者DLQI/CDLQI比较有显著性差异(P<0.01),>12岁患者DLQI/CDLQI比较无显著性差异(P>0.05)；试验组26例随访患者中治疗前辨证属风湿蕴肤证者13例,血虚风燥证者13例,对照组19例随访患者中治疗前辨证属风湿蕴肤证者5例,血虚风燥证者14例,随访前后两组风湿蕴肤证相关各项中医证候比较除皮肤潮红外,其他证候积分比较均差异无统计学意义(P>0.05)；对照组瘙痒积分组内比较随访前后有显著性差异(P<0.05)；两组血虚风燥证相关各项中医证候比较中,皮肤干燥、瘙痒及总分差异有统计学意义(P
未发现与研究药物相关的严重不良事件及实验室检查异常。结论：镇心安神方治疗特应性皮炎可明显控制复发,远期疗效优于对照药物,安全性好；随访研究仅对临床试验中痊愈及显效患者进行观察,样本量尚小,仍需扩大样本量进一步研究。
3镇心安神方治疗特应性皮炎的免疫调节作用研究
目的：对特应性皮炎患者血清多项细胞因子指标进行检测,以期揭示镇心安神方治疗特应性皮炎的免疫调节作用机制。
方法：分别抽取临床试验中试验组20例特应性皮炎患者治疗前、后及20例健康志愿者空腹外周静脉血5m1待检；采用酶联免疫分析法对60份血清样本中IL-4、IL-12、MDC、Eotaxin-2、IL-17A、IL-21及p-EP浓度进行检测和计算。
结果：
(1)治疗前试验组患者血清细胞因子IL-4、IL-17A、趋化因子MDC水平高于健康对照组(P<0.05)；血清趋化因子Eotaxin-2水平低于健康对照组,差异有统计学意义(P<0.05),血清细胞因子IL-12、IL-21及神经肽β-EP水平比较略有差异,但差异无统计学意义(P>0.05)；
(2)风湿蕴肤证患者血清IL-4、IL-17A水平高于血虚风燥证患者,差异有统计学意义(P<0.05)；风湿蕴肤证患者血清IL-12、MDC水平低于血虚风燥证患者,差异有统计学意义(P<0.05)；血清Eotaxin-2、IL-21及β-EP水平两证型比较略有差异,但差异均无统计学意义(P>0.05)。
(3)治疗前血清IL-4、IL-12、MDC及IL-17A水平与SCORAD评分具有直线相关关系(P<0.05),其中血清IL-4、MDC及IL-17A水平与SCORAD评分呈正相关,血清IL-12水平与SCORAD评分呈负相关,均可作为提示病情严重程度的指标；血清Eotaxin-2、IL-21及p-EP水平与SCORAD评分不存在直线相关关系(P>0.05)。
(4)经镇心安神方治疗后血清IL-12水平较前升高(P<0.05),其变化与SCORAD评分变化呈直线相关(负相关);血清MDC水平较前下降(P<0.05),其变化与SCORAD评分变化呈直线相关(正相关)；血清β-EP水平较前升高(P<0.05),其变化与SCORAD评分变化呈直线相关(正相关)；治疗后血清IL-12、MDC、p-EP水平与健康人群差异不明显；
(5)镇心安神方治疗前后血清IL-4、Eotaxin-2、IL-17A、IL-21变化不明显(P>0.05)；治疗后血清IL-4、IL-17A、IL-21水平仍高于健康人群(P<0.05)；治疗后Eotaxin-2水平与健康人群差异不明显(P>0.05)。
结论：镇心安神方治疗特应性皮炎具有双向免疫调节作用,发挥抑制作用的免疫学靶点仅有MDC(治疗后下降),发挥促进作用的免疫学靶点有IL-12、Eotaxin-2、 IL-21、β-EP (治疗后升高),同时也发现镇心安神方对细胞因子的纠正作用较弱,治疗后血清IL-4及IL-17A表达仍呈亢进状态,其机制仍需进一步探讨。
In the dissertation, the main content includes three relevant parts:the literature review of Traditional Chinese Medicine (TCM) study on Atopic Dermatitis (AD), the follow-up study and immunomodulatory effects research of Formulation for Tranquilizing Heart and Mind (FTHM) in treating AD.
1Literature review of TCM study on AD
Objective In TCM study of AD, there are plenty of researches, however, lack of system reviewing. In this dissertation, the recent23years scientific papers and ancient books of TCM study on AD have been reviewed, analyzed and evaluated. The aim of this study is getting the common rules of TCM treatment on AD, which will provide available evidence to help the future clinical and research.
Methods Relevant publications and writings about TCM study on AD were systematically gathered from databases such as PubMed, CNKI, CBM, VIP, Wanfang data and TCM ancient books, then analyzed. The quality of the publications was evaluated by randomized controlled trials according to the Cochrane handbook.
Results1. In TCM ancient books, the feature of "the wind of four fossae","anemogenous sore" and "infantile eczema" is similar to AD.2. In recent23years publications, the syndrome of spleen deficiency and its related syndromes, the syndrome of accumulated dampness-heat and syndrome of wind and dryness due to blood deficiency are the most common clinical syndromes. The treatment of AD is composed of self-modified formulation, plused or reduced medicine form traditional formulation, TCM patent prescription, acupuncture, medicated bath, acupoint-injection, massage and combination of above methods. Commonly used drugs and formulations include that qi-supplementing drug, blood-supplementing drug, heart-clearing and dampness-drying drug, inducing dieresis for removing edema drug, xiaofeng powder, xiaofengdaochi powder, angelica yin zi, et al.
3. Clinical researches of TCM in treating AD are at low methodological quality. The stricter designed, double-blind, randomized controlled, large sample trials are required to support and ensure the efficacy and safety of TCM.
Conclusions TCM studies on AD are lack of unified standard syndrome, evaluation standard, reasonable designed and strict quality controlled clinical trials.
2The follow-up study of FTHM in treating AD
Objective Evaluate the efficacy and safety of FTHM with the follow-up study on patients who had AD.
Methods We designed and carried out a multicenter, randomized, controlled clinical trial. Patients with AD were randomized received an8week treatment twice-daily dosing of FTHM or loratadine tablets and0.1%hydrocortisone butyrate cream. After the trial,64patients with significantly improved were recruited to a24weeks follow-up study.45patients finished the whole24weeks follow-up study. The results of SCORAD score, lesion area of skin score, severity of lesion-skin score, pruritus degree score, Dermatology Life Quality Index (DLQI)/Children Dermatology Life Quality Index (CDLQI), and TCM syndrome score were assessed during the treatment and week4,12and24in the follow-up study. Adverse events, tolerability, haematological and biochemical parameters were monitored during the study.
Results
1. The effect of trial drug
64patients were recruited for the follow-up study. For over8weeks, the mean SCORAD score decrease from40.03to11.33in treatment group (n=31, P=0.0001), and from37.83to10.18in control group (n=33, P=0.0001). However, the results have no significant difference between two groups at the corresponding time. Lesion area of skin score, severity of lesion-skin score, pruritus degree score and DLQI/CDLQI were all improved after the treatment. There was no significant difference in these results too. No serious adverse effects were observed in both the groups. In treatment group,13patients were diagnosed as the syndrome of wind-damp stagnating in skin and18patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. In control group,6patients were diagnosed as the syndrome of wind-damp stagnating in skin and27patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. In TCM syndromes, only hyperpigmentation and dermatauxe were not improved heavily.
2. The follow-up study
Over24weeks'follow-up study,45patients accomplished the whole trial which including26from treatment group and19from control group. SCORAD score, lsion area of skin score, severity of lesion-skin score, pruritus degree score and DLQI/CDLQI, and TCM syndrome score were stable in treatment group. However, SCORAD score increased from12.59to19.83in control group, which indicates some patients have a recurrence of AD. There were significant differences of erythema score, papule score and effusion score between two groups. There were also significant differences DLQI/CDLQI between patients'age below12in two groups. In treatment group,13patients were diagnosed as the syndrome of wind-damp stagnating in skin and13patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. Erythema score of some patients was higher than at the beginning of the follow-up study. In control group,5patients were diagnosed as the syndrome of wind-damp stagnating in skin and14patients were diagnosed as the syndrome of wind and dryness due to blood deficiency. Dry skin score, pruritus score and total score were higher than at beginning of the follow-up study. Adverse events, tolerability, haematological and biochemical parameters were monitored during follow-up study.
Conclusions FTHM is efficacious in improving clinical symptoms, the quality of life and reducing recurrence in patients with AD. The formulation was safe and well tolerated, but more research of FTHM still needed to reinforce this conclusion.
3Research of immunomodulatory effects of FTHM in treating AD.
Objective To study various of cytokines and chemokines in the peripheral blood of patients with AD and explore the immunomodulatory effects of FTHM in AD patients.
Methods The serum level of IL-4, IL-12, MDC, Eotaxin-2, IL-17A, IL-21and β-EP were detected by enzyme-linked immunosorbent assay (ELISA) before and after treatment by FTHM.20patients and20healthy volunteers were recruited.
Results
1. The serum level of IL-4, IL-17A and MDC in AD patients was significant higher than controls. The serum level of Eotaxin-2in AD patients was significant lower than controls. There was no significant difference in the serum level of IL-12, IL-21and P-EP between AD patients and controls.
2. The serum level of IL-4and IL-17A in patients with the syndrome of wind-damp stagnating in skin was significant higher than patients with the syndrome of wind and dryness due to blood deficiency. The serum level of IL-12and MDC in patients with the syndrome of wind-damp stagnating in skin was significant lower than patients with the syndrome of wind and dryness due to blood deficiency. There was no significant difference in the serum level of Eotaxin-2, IL-21and β-EP between the two TCM syndromes.
3. Relevant analysis indicated that the serum level of IL-4, MDC and IL-17A was positively related to the SCORAD scores, and the serum level of IL-12was negatively related to the SCORAD scores. There was no linear relationship between the serum level of Eotaxin-2, IL-21and p-EP and SCORAD scores.
4. After the treatment of FTHM, the serum level of IL-12and p-EP rose up and the serum level of MDC fell down. There was no significant difference in the serum level of IL-12, MDC and P-EP between AD patients and controls.
5. The influence of FTHM on the serum level of IL-4, Eotaxin-2, IL-17A and IL-21was not significant. After treatment, the serum level of IL-4, IL-17A and IL-21was still higher than controls. There was no significant difference between AD patients and controls at the serum level of Eotaxin-2.
Conclusions FTHM plays a bidirectional immunomodulatory effects in treating patients with AD. MDC is the suppressive target. IL-12, Eotaxin-2, IL-21and P-EP are the promoting targets.
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