【作者】 梁善皓；

【导师】 李义凯；

【作者基本信息】 南方医科大学 ， 中西结合临床， 2013， 博士

【摘要】 背景强直性脊柱炎(ankylosing spondylitis,AS)是一种原因不明的慢性炎性疾病,主要侵犯中轴骨,以骶髂关节炎和附着病为其特征。本病多发生于青少年,发病年龄通常在13～31岁,高峰为20～30岁,40岁以后及8岁以前发病者少见。本病发展隐匿,病程长,晚期脊柱强直、关节畸形等致残率极高,且病情不可逆转。早期诊断、综合治疗是改善预后的必要条件。强直性脊柱炎目前尚未有根治的药物。强直性脊柱炎患者治疗目标为缓解脊柱或全身疼痛、晨僵等症状,最大程度地恢复和保持患者活动功能,防止脊柱和关节畸形,提高社会活动能力和工作能力,提高患者生活质量。在治疗方面,采用非药物与药物结合的综合治疗方式。在非药物治疗方面主要采用物理治疗,运动治疗及健康管理等,保持和促进关节活动功能。在治疗方面,NSAIDs是ASAS/EULAR推荐作为治疗AS患者疼痛和晨僵的一线药物疗法,比传统DMARDs较快的减轻关节肿胀、疼痛及增加活动范围。临床常用的传统抗风湿药(disease-modifying antirheumatic drugs, DMARDs)为柳氮磺吡啶(salazosulfapdine,SASP)、甲氨蝶呤(Methotrexate,MTX)、来氟米特(Leflunomide)以及用于难治性强直性脊柱炎的反应停(Thalidomide,沙利度胺),上述药物起效较慢,可缓解临床症状,一定程度上控制病情发展,长期用药的同时需要经常检测生化功能,防止肝肾功能损害。但因为服药时间较长,同时存在较多的副作用,往往降低患者的依赖性。近年来生物制剂(如依那西普、单克隆英夫利西单抗等)的应用给AS的治疗带来里程碑式的革命,疗效快,同时因价格贵也限制其广泛的应用。长期的治疗给患者及其家庭带来巨大的精神和经济压力。中医药在长期治疗AS的实践中,积累了大量的经验和有效方药,治疗方法多样,疗效肯定,且能根据患者个体差异辨证施治,具有巨大的优势。现在药理表明雷公藤多甙、正清风痛宁具有抗炎、抗变态反应作用。目前较多的文献报道了应用雷公藤多甙或正清风痛宁单用,或者联用西药治疗强直性脊柱炎取得了较好的疗效。在缺少大规模临床随机对照研究的情况下,循证医学的发展为临床争议问题的解决提供了良好的途径,通过系统、全面地收集全世界所有已发表和未发表的临床研究结果,采用临床流行病学严格评价文献的原则和方法,筛选出符合质量标准的文献,进行定性或定量合成,得出综合可靠的结论。循证医学Meta分析的相关研究已经在治疗、预防、病因、危害、预后、诊断、经济学分析等多个领域内开展运用,因系统综述或Meta分析的可靠性最高,位于美国纽约州立大学Downstate Medical Center推出“证据金字塔”的顶端。近年来,越来越多临床研究应用随机对照的方法观察、研究和比较了中成药治疗AS的临床效果,并发表了大量的文献,但目前评价治疗性文献的系统评价甚少。本研究的目的在于应用系统评价方法,评价雷公藤多甙、正清风痛宁治疗强直性脊柱炎的疗效,同时对30多年中药种类进行分析,为中医药应用于治疗强直性脊柱炎提供参考。目的通过对中医药治疗强直性脊柱炎的文献进行研究,以求达到以下目的：①系统评价雷公藤多甙治疗强直性脊柱炎疗效及安全性；②系统评价正清风痛宁治疗强直性脊柱炎临床疗效与安全性；③对30多年中药治疗AS的随机或半随机、及临床报道病例数大于20例的治疗文献进行整理,建立数据库,为该病的临床辩证施治及中药用药规律提供参考。方法第一部分：评价雷公藤多甙治疗强直性脊柱炎的疗效及安全性。制定文献的纳入标准为以AS患者为研究对象的随机对照研究,无论其是否采用盲法进行处理,所有文章限定为中文或英文发表。干预用药为雷公藤多甙(苷)为主的口服制剂,不包括以雷公藤液(包括酊剂、酒剂、糖浆等)、雷公藤为组分的中药复方汤剂、复方胶囊或者中成药、外敷膏剂或熏蒸洗剂等。对照干预包括中成药、中药复方汤剂或西药口服。雷公藤多甙(苷)联用其他主要治疗AS药物与该药物比较的试验也纳入。排除标准为：无明确诊断；原始文献试验设计不严谨、统计方法不恰当、样本资料交待不清(不全)或同一人群资料的重复研究结果；缺乏较规范的疗效评价标准；以比较雷公藤的不同入药部位、不同剂量、不同产地、不同的制取方法及剂型的临床疗效为目的的临床试验。电子检索数据库：PUBMED、EMBASE-ASP、Cochrane Library、OVID、Springer-link;中文数据库：中国知识资源总库(CNKI)、万方学术期刊数据库、维普中文期刊数据库(VIP)、中国生物医学文献服务系统(CBM)等作为资料来源,检索时间均从建库至2012年12月。检索词为强直性脊柱炎”、“脊柱炎,强直性”、AS、ankylosing spondilyties为主题词,并与“雷公藤”、“雷公藤片”、“雷公藤多甙(苷)”、Tripterygium wilfordii Hook.f, Tripterygium wilfordii, triptolide,TP, TriPterygium wilfordii hook。评价纳入研究的质量,提取数据用Revman5.1软件进行Meta分析。第二部分：评价正清风痛宁治疗强直性脊柱炎的疗效及安全性。制定文献纳入标准为：符合AS诊断标准,以AS患者为研究对象的随机对照研究,无论其是否采用盲法进行处理,所有文章限定为中文或英文发表。试验治疗用药为正清风痛宁片、正清风痛宁注射液为干预措施,不包括以青风藤制剂(包括酊剂、酒剂、糖浆等)、青风藤为组分的中药复方汤剂、复方胶囊或者外敷膏剂或熏蒸洗剂等。对照干预包括西药、安慰剂、中成药或者空白对照。正清风痛宁联用其他西药治疗AS与该西药比较的临床试验也纳入。排除标准为：无明确诊断；原始文献试验设计不严谨、统计方法不恰当、样本资料交待不清(不全)或同一时间段同一人群资料的重复研究结果,以及样本量少于30例的临床试验研究；缺乏较规范的疗效评价标准；以比较青风藤的不同入药部位、不同剂量、不同产地、不同的制取方法及剂型的临床疗效为目的的临床试验。检索词以“强直性脊柱炎”、“脊柱炎,强直性”、AS、ankylosing spondilyties为主题词,并与“青风藤”、“正清风痛宁片”、“正清风痛宁注射液”、“盐酸青藤碱”、Zhengqing Fengtongning、Zhengqingfengtongning Injection、sinomenine等关键词进行布尔逻辑搭配检。其余方法及步骤同第一部分。第三部分：对30多年来国内中医药治疗强直性脊柱炎用药进行分析。制定文献的纳入标准、排除标准,电子检索数据库：中国知识资源总库(CNKI)、万方学术期刊数据库、维普中文期刊数据库(VIP)等作为资料来源,检索时间均从建库至2012年1月。检索词：以“强直性脊柱炎”、“脊柱炎、强直性”为主题词,并与“中医”、“中药”、“中西医结合”等关键词进行布尔逻辑搭配检索。建立数据库并进行分析。结果第一部分：雷公藤多甙治疗强直性脊柱炎的疗效及安全性的系统评价：(1)共纳入8个随机对照试验,576例患者。所纳入的试验质量普遍较低。(2) Meta分析采用M-H法分析显示,雷公藤多甙在改善枕墙距[MD=1.07,95%CI(-0.71,2.85)]、胸廓活动度[MD=0.13,95%CI(-0.21,0.47)]、指地距[MD=3.43,95%CI(-7.78,14.63)]及降低C反应蛋白[MD=-7.44,95%CI(-7.76,1.21)]方面与中药复方组相当,但后者在总有效率[OR=3.88,95%CI(2.15,7.00)],改善晨僵时间[MD=32.44,95%CI(12.63,52.25)]、Schober试验[MD=-0.67,95%CI(-0.97,-0.38)]及降低血沉[MD=7.44,95%CI(5.38,9.49)]要优于雷公藤多甙。(3)雷公藤多甙可发生的不良事件主要为月经推迟[RD=0.23,95%CI (0.14,0.31)]、胃肠道不适、肝功能异常等,临床中应谨慎使用。第二部分：正清风痛宁治疗强直性脊柱炎临床疗效与安全性的系统评价：共纳入12个随机对照试验,1112例患者。Meta分析采用M-H法分析显示,服用正清风痛宁可提高总有效率[MD=3.07,95%CI(1.88,5.02)]、改善全身痛[MD=-0.43,95%CI(-0.61,-0.24)]、脊柱痛[MD=-0.31,95%CI(-0.44,-0.19)]。局部注射正清风痛宁可提高总有效率[OR=4.10,95%CI(1.73,9.71)]、VAS疼痛评分[MD=-2.84,95%CI(-3.68,-2.00)]。局部注射正清风痛宁的皮肤过敏发生率较高。第三部分：在30多年的强直性脊柱炎的中药治疗中,用量最多的药物种类依次为补虚药、祛风湿药、活血化瘀药、解表药、清热药、渗水利湿药、息风止痉药等。用量最多的药物依次为白芍、威灵仙、牛膝、川乌、当归、独活、杜仲、桂枝、甘草、续断、附子、熟地等。从用药量及用药种类来看,强直性脊柱炎的中医药治疗以补益肝肾、活血通络、祛风湿强筋骨为主,配以其他药物,辩证论治,随证加减,体现了中医学的精髓。结论1、辩证施用的中药复方以及正清风痛宁对治疗AS具有一定的优势,而雷公藤多甙对于AS总有效的疗效稍劣于前两者。中药复方及雷公藤多甙均可改善AS患者中轴功能及降低急性反应物指标(ESR,CRP),受纳入临床结局评价指标及文献数量及质量的限制,因此雷公藤多甙对强直性脊柱炎的疗效与安全性的优势也需更多的临床试验来验证。2、正清风痛宁治疗强直性脊柱炎具有一定的优势,提高临床总有效率及缓解疼痛,支持其应用于强直性脊柱炎治疗,更多高质量的临床试验将有益于验证其临床疗效与安全性。3、强直性脊柱炎的中医药治疗以补益肝肾、活血通络、祛风湿强筋骨为主,配以其他药物,辩证论治,随证加减,体现了中医学的精髓。更多还原

【Abstract】 BackgroundAnkylosing spondylitis (AS) is characterized by the inflammation in the spine and sacroiliac joints causing initial bone and joint erosion, and ultimately ankylosis and fibrosis. The disease mostly occurs in young people, the age of onset is13-31years old, and the peak of age is20-30years old, after the age of40and onset before the age of8are rare. The onset appear insidiously, and has a high disability rates. Early diagnosis and comprehensive treatment is a necessary condition to improve the prognosis.The disease cannot be cured at present. The treatment target is to relieve the pain, to improve morning stiffness, restore the functional activity,prevention of spinal and joint deformities,jimprove social skills and the ability to work.An integrated treatment of non-drug and drug combination.the physical therapy, movement therapy and health care management are used to treated for AS. such as nonsteroidal antiinflammatorydrugs (NSAIDs) and slow-acting drugs (e.g., Methotrexate, Sulfasalazine, Leflunomide,thalidomide, and Thalidomide) are used to treated for AS too. In recent years the emergence of biological agents applied to the treatment of AS brought a landmark revolution, and represents a better therapeutic regimen for short term. The long-term efficacy and the possible adverse events still require large-scale studies to verify. Many patients with AS are unable to pay for biological agents, which are so expensive. The long-term treatment leads to the great spiritual and pressure on patients and their families.The traditional Chinese medicine(TCM) was effective for AS, and Dialectical treatment had great advantages for the treatment. Pharmacological showed that the TWP and zhengqing fengtongning with anti-inflammatory and anti-allergic effects, which have the effect of treatment of ankylosing spondylitis.Even though lack of large-scale clinical randomized controlled trials, the development of evidence-based medicine provides a good way for clinical dispute resolution. The system review is a new method for comprehensive evaluation of the literatures, collecting all the world’s published and unpublished results of clinical studies, using the clinical epidemiology of strict principles and methods to evaluation the literatures, filtering out literatures those meet quality standards, meta-analysis is conducted with software, and then get the conclusion of comprehensive and reliable. The methods of meta-analysis has been using on medical prevention and treatment, causes of disease, risk of disease, prognosis, diagnosis, and economic analysis widely, which are at the top of the " evidence of the pyramid " launched by the in the Downstate Medical Center of State University of New York, United States.In recent years, there are more and more clinical studies on treatment of ankylosing spondylitis with TriPterygium wilfordii hook and Zhengqingfengtongning, most of which are randomized controlled trials. But there are fewer systematic reviews of them for AS. The purpose of this study is to give an objective evaluation on the overall efficacy and safety of TriPterygium wilfordii hook or Zhengqingfengtongning.ObjectiveTo research the Literature of traditional Chinese medicine in treatment of ankylosing spondylitis, the authors aimed to achieve the following goals:①To systematically evaluate the differences of efficacy and safety of TriPterygium wilfordii hook or Zhengqingfengtongning for ankylosing spondylitis;②Search the random and semi-random treatment studies of Traditional Chinese medicine in30years in domestic:establish the databases of the drugs, and explore the drug characteristics of the disease by frequency analysis.MethodPart One:To evaluate the effects and safety of Tripterygium for ankylosing spondylitis. Having devised the criteria for literature inclusion, exclusion, search strategies, retrieve standard. Such database as PUBMED, EMBASE-ASP,Cochrane Library, OVID, Springer-link, CNKI, VIP, Wanfang and CBM, ect, were searched from the date of their establishment to December2012. Key words for search: AS,ankylosing spondilyties, Tripterygium wilfordii Hook.f, Tripterygium wilfordii, triptolide,TP, TriPterygium wilfordii hook.The quality of included studies was evaluated, and meta-analysis was conducted with RevMan5.1software.Part Two:To evaluate the effects and safety of Zhengqingfengtongning for ankylosing spondylitis. Key words for search:AS,ankylosing spondilyties, Zhengqing Fengtongning、Zhengqingfengtongning Injection、sinomenine. The method and process are the same of part one.Part Three:Search the random and semi-random treatment studies of Traditional Chinese medicine in30years in domestic:establish the databases of the drugs, and explore the drug characteristics of the disease by frequency analysis. Such database asCNKI, VIP, Wanfang and CBM, ect, were searched from the date of their establishment to January2012.ResultsPart One:a Systematic reviews of efficacy and safety of Tripterygium for ankylosing spondylitis. A total of8RCTs involving576patients were included. Meta-analysis showed that there were no significant differences between the Tripterygium and Chinese Herbal Compound groups in the effect on improving the chest movement, the Occiput-Wall distance,the Finger-Ground distance and C-reactive protein. The Chinese Herbal Compound showed more effects in improving the total effective rate, the duration of morning stiffness,the Schober test and reducing C-reactive protein.The Tripterygium may cause to postpone to menstrual period,gastrointestinal adverse reactions,liver dysfunction,and so on.Part Two:a Systematic reviews of Efficacy and safety of Zhengqing fengtongning for ankylosing spondylitis. A total of12RCTs involving1112patients were included. Meta-analysis showed that there were significant differences between the Zhengqingfengtongning and western medicines groups in the effect on improving the total effective[MD=3.07,95%CI(1.88,5.02)],total body pain [MD=-0.43,95%CI(-0.61,-0.24)],spinal pain[MD=-0.31,95%CI(-0.44,-0.19)]。Zhengqing fengtongning Injection would improved the total effective [OR=4.10,95%CI(1.73,9.71)], VAS score [MD=-2.84,95%CI(-3.68,-2.00)]. Zhengqingfeng tongning Injection caused a higher incidence of allergic skin.Part Three:In More than30years, the high frequency of Charaeteristies of drug therapy are, in order, tonics, dispelling rheumatism drugs, dredging blood circulation drugs, tranquilizers and antipyretics, eliminating phlegm drugs, and so on.the high frequency of the single herb for AS are, in order, Paceonia lactiflora Pall, Clematis chinensis Osbeck, Cyathula officinalis Kuan, Aconitum carmichaeli Debx, Aaugellica sinensis(Oliv) Diels, Angelica pubescens Maxim. f. biserrata Shan et Yuan, Eucommia ulmoides Oliv, Cinnamomum cassia Presl, Glycyrrhiza uralensis Fisch, Dipsacus aspercides C.Y.Cheng et T.MAi, Aconitum carmichaeli Debx, Rehmannia glutinosa (Gdertn) Iibosch, and so on.The treatment principles include nourishing kidney essence, warming kidney-yang mainly, expelling wind, cold(heat) and dampness, and dredging channels at the same time, together with dredging blood and alleviating pain.ConclusionThe meta-analysis showed that the traditional Chinese medicine and Zhengqingfengtongning had a higher effective for AS than Tripterygium. the traditional Chinese medicine and Tripterygium showed improvements in the axis functions, ESR, CPR, Use high quality clinical trials to further prove the clinical effects and safety of Tripterygium for AS is necessary promptly.There was some sufficient evidence to support the clinical application of the Zhengqingfengtongning in patients with ankylosing spondylitis currently.Use high quality clinical trials to further prove the clinical effects and safety of Tripterygium for AS is necessary promptly.The treatment principles include nourishing Nourishing Liver and Kidney, Blood-Activating and Collateral-Unblocking,mainly, expelling wind, cold(heat) and dampness, at the same time. Dialectical treatment is the essence of traditional Chinese medicine on the treatment.更多还原