【作者】 何羿婷；

【导师】 黄春林；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2005， 博士

【摘要】 一、背景 类风湿性关节炎(RA)是一种以关节的慢性炎症为主要表现的自身免疫性疾病,是临床多发病、疑难病,致残率较高。西医强调尽早使用控制疾病的抗风湿药和联合用药,以控制或延缓病情的发展,防止骨质破坏,但由于至今尚未发现真正的能控制疾病发展的药物,加上西药严重的毒副作用,致使RA的治疗十分棘手。RA属于中医痹病中的旭痹,中医治疗痹病具有疗法众多、疗效肯定、毒副作用少的特点,已显示出一定的优势。但由于中医药治疗RA的临床研究存在着不少问题,导致研究结论的真实性和可重复性受到影响,难以科学、客观地评价中医药治疗RA的疗效,也远不能反映出中医治疗RA的优势。随着中医药临床研究水平的不断提高,以及临床流行病学/DME方法在中医药领域中的广泛应用和我国GCP规范的实施,迫切需要将中医药对RA己显示出较好临床疗效的治疗方案进行更深入的研究,探讨中医药治疗RA的能体现中医优势的优化方案,不仅有利于提高中医药治疗RA的临床水平,使之能被国际医药界所接受,而且对于中医药临床研究水平的提高具有普遍的指导意义。 二、目的 本课题根据尪痹病证特点,采用辨病+辨证相结合的综合治疗方案,通过多中心、随机对照临床试验和盲法评价的方法,与国内外公认的、经典的西医综合治疗方案进行对比,采用国际公认的疗效判断标准(ACR-20),引用HAQ量表进行患者生活质量的评价,结合中医证候疗效评价及骨质变化等指标,对中医综合治疗方案进行观察和评价,为提高类风湿关节炎这一难治性疾病的临床疗效进行了有益的探索,弥补当前类风湿关节炎治疗中的不足,规范类风湿关节炎的中医治疗方案,提高类风湿关节炎的中医治疗水平,以期能在全国推广和应用,并能使国际医药界所接受。 三、方法 本研究为多中心、随机对照的临床试验,来自全国九个研究单位的522例患者被纳入研究,病例分组采用各中心控制的简单随机化方法,研究中采用了单盲与第三者评价的方法。治疗组为中医综合治疗方案,即在使用雷公藤多甙片、益肾蠲痹丸治疗的基础上,根据中医证型的不同分别加用寒湿痹颗粒、湿热痹颗粒、寒热痹颗粒和尫痹颗粒;对照组为西医综合治疗方案,即非甾体抗炎药扶他林缓释片加慢作用药甲氨喋呤、柳氮磺胺吡啶。观察疗程为半年。本研究对方案依从性较好的329例活动期病例进行了有效性观察,对所有接受治疗病例510例(505例+5例)进行了安全性观察。有效性观察包括主要疗效指标:ACR-20、X线改变、中医证候疗效;次要疗效指标:症状/体征、主观指标、实验室指标、生存质量HAQ量表等,并进行了多中心效应分析、分层分析等。安全性观察主要包括不良事件及实验室指标异常的分析。更多还原

【Abstract】 Background:Rheumatoid Arthritis (RA) is one sort of autoimmunity disease manifested as chronic arthral inflammation with high disabled ratio. In order to control aggravation of the disease and avert the damage of bone joints, Western medicine emphasizes the use of anti-rheumatism drugs and the combined use with other drugs. Unfortunately, up to the present, there is no ideal drug to be able to satisfactorily control the development of the disease. And to make things worse, the western medical drugs are full of side effects, so the therapy of RA is very intractability. According to the traditional Chinese Medicine (TCM) RA belongs to the diseases of Wang-bi. Compared with treatment with west medicine, TCM has some advantages in treatment of RA, which are characterized as multiple therapeutics, affirmative curative effects and fewer side effects.Since there exist in the clinical research of the TCM on RA a lot of questions which influences the validity and reliability of the studies and so it is hard to precisely evaluate the curative effect of the TCM and manifest its advantages. With the improvement of clinic research, and the wide-spread apply of Clinical Epidemiology Measure/DME in TCM and GCP normative put in practice in our country, It is urgently needed to have further studies on those TCM treatment prescription which have showed pretty good clinical therapeutic effects, in order to find out the better treatment plans which can manifest the advantages of TCM. So these studies are good not only to improve the treating level of TCM on RA, which would be accepted by the medical world, but also to have the general directing meaning to improve clinical research of TCM.Objective:Based on characteristics of the wangbi, the study, adopting the integration treatment plans of disease oriented and symptom orienteddiagnosis of TCM, and via the means of polycentric and random comparison clinic experimentation and blind evaluate, contrasting with classical and accepted western integration project, using the standard curative effect estimate criterion (ACR-20), quoting HAQ measuring scale to evaluate patient’ s life quality , uniting the guidelines of the evaluation of the curative effect of TCM and osseous change, observed and evaluated the TCM treatment plans, so as to improve the clinic curative effect on RA, which is still a refractory disease. It would also make up the shortage of RA therapy at present, make a norm for TCM treatment plans and improve therapeutic levels of RA. Hopefully the treatment would be nationally spread and applied, and internationally accepted.Method:The study was a clinic test of multi-center and random contrast, 522 patients coming from 9 study units in the country were grouped by simple randomization methods. During the course of study single blind and independence evaluations were adopted. The reatment group was TCM treatment plan, namely based on the use of tripterygium glycosides , YISHENJUANBIWAN, and the treatment varied according to different types of symptom, so there were such different treatment plans as Hanshibi granule, Shirebi granule, hanrebi granule and wangbi granule; contrast group was western medical integration therapy, namely NSAID diclofenac sodium sustained release tablets, DMARD- MTX and SASP. The period of treatment was half a year. The studies observed 329 activity cases that had good compliance with the research project, surveyed the security of 510 cases (505+5) that received therapy. Validity observation included the main index of the curative effect: ACR-20, X-ray, the therapeutic effect on symptom of TCM; the secondary index: symptom/body signs, subjective index, laboratory index, survival quality HAQ measure scale and so on. At the same time multi-center domino effect analysis, delamination analysis and so on were undertaken. Security observations mostly included bad events and analysis of the laboratory abnormal indexes.Result:1. Analysis of the main curative effect index :ACR improvement rate between treatment and contrast groups: by means of PP method the results showed that the difference is not of statistics significance (P>0. 05) between two groups after 12weeks and 24weeks. By ITTmeans the difference had no significance (P>0. 05) after 24weeks.X-ray improvement rate between two groups: compared with before, X-ray grading difference was statistically of significance ( Z=-2. 11, p=0. 04) after 24 weeks , TCM group excelled western medical group in X-ray improvement.The comparison of the curative effect of TCM symptoms: there was not of statistics significance in the availability rate between the two groups after 12 、 24weeks (P >0. 05). There was also not of statistics significance at any time according to inefficacy ,availability, apparent effect, clinic heal (P >0.05) .2. Analysis of the secondary curative effect index:(1) Symptom/sign (rest pain, tenderness count, tenderness index, swollen count, swollen index, morning numb, mean grasp force of two hands and walking time of 20 meters):Every time point after treatment was compared with baseline, the result showed: difference of tenderness count in 2 weeks, mean grasp force of two hands in 2, 4 weeks, walking time of 20 meters in 2, 4 weeks with baseline had no significance(P>0. 05). Other indexes at each time point was better compared with baseline. The difference had statistics significance (P<0. 01 或 P<0. 05) .The two groups were compared after treatment, and the results showed: the difference on rest pain had statistics significance in 2、 16and 24weeks(P<0. 05). The western medical group was superior to TCM group. At other time points, no change of other indexes could be found.(2) Subjective index analysis (evaluation coming from patients, doctors) ① Compared with baseline at the every time point after treatment:both the indexes were improved, the difference of which was of statistics significance (P<0. 01);② The change between two groups between the time points after treatment: the difference had no statistics significance (P>0. 05) .(3) Laboratory index analysis (ESR、 CRP 、 RF 、 IgA 、 IgG 及 IgM)① Compared with baseline: after 12 weeks , ESR、 IgA and IgG had someimprovement in the TCM group, and the difference had statistics significance(P<0.01, P<0. 05); after 24 weeks, ESR、 CRP、 RF 、 IgA 、 IgG and IgM wereall improved, the difference of which were of statistics significance (P<0. 01,P<0. 05); compared with baseline, after 12、 24 weeks, the indexes of the westernmedical group were decreased, and the difference had statistics significance (P<0.01, P<0.05) .(2) Compared with two groups after treatment: for RF after 12 weeks and ESR after 24 weeks, the decrease in the western medical group excelled that of the TCM group, the difference had statistics significance (P<0. 01, P<0. 05), other difference had no statistics significance (P>0. 05) . (4) Living quality HAQ analysis① Comparison between mean HAQ of the two groups with baseline: after 12、 24 weeks, HAQ score was improved, and the difference had statistics significance (P<0.01, P<0. 05) .② HAQ mean value between two groups after therapy: the difference had no statistics significance between each week (P>0.05), which meant similar improvement of HAQ in the two groups. 3. Security analysisIn the respect of security, bad events and the abnormality of laboratory index were analyzed. The results were mainly manifested as followings:(1) With the exception of the similarity in the abnormal reaction frequency of alimentary canal symptonu kidney function and abnormal menstruation among the three groups, the frequency of the blood system , liver damage and other abnormal reactions in the TCM group was lower than that of the western medical group.(2) In the respects of the person—time of abnormal liver function that first set in and the degree of abnormality, the TCM group was lower to the other two groups.(3) Considering the patient number of abnormal menstruation that first set in every week, in 2, 4> 12week the TCM group was slightly lower than the western medical group, while the TCM group was a little higher than the western medical group in other weeks.Concluusion:TCM integration plan could effectively inhibit the inflammation, and the effect was similar to that of generally accepted western medicine therapy, the effects of which were manifested as improving joint functions, reducing the pain and swelling, promoting life quality. And what’ s more, TCM treatment had some potential value in the respect of delaying the development of RA.In the respects of improving and controlling the inflammation, the更多还原