摘要
类风湿关节炎(rheumatoid arthritis, RA)是一种慢性炎症性自身免疫性疾病,为世界上主要致残性疾病之一,严重影响着患者的身心健康和生活质量。我国患病率约为0.32%-0.36%。本病可造成全身多关节肿胀疼痛,晚期可致关节畸形,功能丧失,患病10年的患者中至少50%不能坚持工作,是世界上主要致残性疾病之一。除此以外,RA造成的家庭、社会的经济负担也不容乐观。一项研究报道,2001年～2003年成都地区仅缓解病情的类风湿关节炎药物的用药金额就高达2907.39万元,平均年增长率11.6%。RA对骨质破坏、健康、生存质量的影响以及造成的经济负担,日益引起国内外风湿病专家的关注。
RA的首要治疗目标是通过控制炎症症状、阻止关节破坏、保持关节功能、维持正常社会活动,最大程度提高患者长期的健康、生活质量。我科室根据活动期RA的病机特点结合多年的临床经验,认为活动期RA的主要病机为湿热毒邪久恋,血凝痹阻经络,病邪深入骨骱,胶着不去,腐蚀筋骨气血,致关节肿痛僵硬,甚导致骨破坏,强调湿热瘀是活动期RA的重要病机关键,清热活血法是活动期RA的基本治疗大法。
本研究在RA清热活血法的指导下,以首都医学发展科研基金北京医学卫生科技联合攻关项目为依托,采用随机多中心平行对照的试验设计,将多家中医院就诊的符合纳入标准的142例辨证属湿热瘀阻证活动期RA患者随机分入中药组71例和中西药组71例,通过24周的临床观察,评价两种治疗方案对RA疾病活动度和病情的控制以及中医证候疗效、生活质量的疗效及安全性。并对我中心随机入组、并完成24周观察期的77例患者进行长期跟踪随访研究,以评价中药降低RA疾病活动度、控制风湿病情、提高患者生活质量的远期疗效。
一、理论研究
1.通过整理RA中医病名、病因病机、转归特点的历代认识和当代名医名家认识,总结中医对RA疾病认识的共识,尤其是湿热痹组、瘀血阻络为活动期RA关键病机的共识。
2.在RA辨证治疗古籍文献梳理的基础上,重点对现代研究成果进行分析归纳,总结病证结合、分期论治RA的诊疗思路：早期多以祛风除湿、温经散寒、通络止痛为法；活动期多以清热除湿、宣痹通络为法；晚期病久伤及气血者以益气养血、活血通脉为法,肝肾虚损、正虚邪恋者以补益肝肾、强壮筋骨为法；瘀血阻络伴见任何证型,均应配合活血化瘀之品。
3.通过整理导师治疗RA的经验,总结出导师祛邪为主,兼顾正气的辨治经验；强调整体辩证,关注患者心理状态,注重从肝论治；重视中西医结合治疗,中药辨证治疗配合NSAIDs、DMARDs以及糖皮质激素治疗RA的经验、观点。
4.通过整理古籍文献有关生活质量的论述和生存质量评价在目前中医药治疗RA疗效评价中应用,提出生存质量评价可以充分反映出中医药在治疗RA中的优势,应作为重要的评价指标引入中医治疗RA的临床研究中。
二、临床研究
目的评价清热活血方药对湿热瘀阻证活动期RA疾病活动度和病情的控制以及中医证候疗效、生活质量的疗效及安全性,并通过远期随访观察其远期疗效。
方法临床试验阶段,分为中药组(清热活血方药组)、中西药组(清热活血方药联合甲氨蝶呤组),进行为期24周的随机多中心平行对照试验研究；开放性随访阶段,对所用中西药种类、剂量进行限定后,仍分为中药组、中西药组,通过制定完善的随访病例,严格规划并确定随访期、随访频率,收集RA疾病活动性以及生活质量相关数据,以期评价中药降低RA疾病活动度、控制风湿病情、提高患者生活质量的远期疗效。
结果本临床研究按计划共随机入组了142例受试者,中药组71例,中西药组71例,两组间的人口学特征均平衡,各项临床特征基线均平衡,患者人群为病情重度活动、病程较短的中年女性RA患者。最终有129例受试者完成了24周的治疗,其中我中心77例。我中心中药组有3例、中西药组有5例在随访各时点均失访,最终中药组和中西药组随访病例数分别为35和34例,基线时,随访两组患者的人口学特征均平衡,各项临床特征基线均平衡,具有可比性。截止至2012年3月,最长随访247周,最短随访144周,中药组平均随访202.17周,中西药组平均随访203.12周,约为4年。结果表明：
1.两组均具有降低RA疾病活动度,并长期维持的作用。治疗12周后,DAS28评分即开始有明显下降；治疗24周后,中药组、中西药组达到疾病缓解患者所占比率分别为22.86%、17.44%,DAS28评分下降的均值分别为1.91、1.97；至目前随访时,两组疾病活动性仍维持24周时水平,达到疾病缓解患者所占比率分别为23.08%、42.86%。
2.两组都可以长期控制RA疾病病情。治疗12周后,中西药组疾病病情即得到明显控制,较之中药组ACR20、50、70达标率分别提高了15.50%、12.60%、1.41%；治疗24周后,这种差异逐渐缩小,ACR20、50、70达标率较之中药组分别提高了2.82%、9.85%、0。至目前随访时,由于所有缺失数据均视为ACR20不达标,导致了目前随访时两组ACR20达标率有所下降,两组ACR20达标率分别为67.7%、64.3%,两组ACR70达标率分别为35.5%、25.0%。
3.两组均能改善患者生活质量及躯体功能,并可保持躯体功能、提高患者长期的生活质量。治疗4周后中药组和中西药组即可开始明显提高穿衣及仪容整理能力、起居能力、餐具使用能力、徒步行走能力、日常活动能力。治疗24周后,两组患者生活质量继续提高,躯体功能明显改善、控制在轻度残障范围内。4年后两组患者生活质量、躯体功能进一步提高,除中西药组的餐具使用能力外,其余两组各维度仍维持在轻度残障范围内。
基线期HAQ总分和病程、疾病活动性、压痛关节数、患者对疼痛的VAS评价、患者对疾病活动的总体评价、医生对疾病活动的总体评价及炎性实验室指标呈正相关；治疗24周后,两组HAQ总分改善率和疾病活动性改善率、肿胀关节数改善率、患者对疼痛的VAS评价改善率、患者对疾病活动的总体评价改善率、医生对疾病活动的总体评价改善率和炎性实验室指标改善率呈正相关；至目前随访时,两组HAQ总分改善率和肿胀关节数改善率、患者对疼痛的VAS评价改善率、患者对疾病活动的总体评价改善率和炎性实验室指标改善率呈正相关。提示我们在治疗RA时,应注重降低疾病活动性(DAS28评分)、减少肿胀关节数、减轻患者的疼痛、降低炎症指标(ESR、CRP),以降低患者对疾病活动的总体评价,最终提高患者长期的生活质量。
4.两组对改善关节功能均有较好的长期疗效。0周时,中药组和中西药组均以Ⅲ级所占比率最高(54.98%、58.82%)。治疗4周后,中西药组关节功能既有明显改善,治疗24周后,以Ⅰ级所占比率最高(55.89%)；而中药组则在治疗12周后才见明显改善,治疗24周后,以Ⅱ级所占比率最高(65.72%)。至目前随访时,两组均以Ⅰ级所占比率最高(73.54%vs67.86%)(P>0.05)。
5.两组均能取得较好的中医证侯疗效。治疗4周后,中药组和中西药组中医证候总有效率分别为29.58%、40.85%；治疗12周后,分别为64.79%、74.65%；治疗24周后,分别为66.06%、78.87%。从具体数值上看,联合西药(MTX)可以提高湿热瘀阻证的中医证候总有效率。
6.降低炎性实验室指标(ESR、CRP)方面：两组在降低CRP方面,中西药组起效较快,治疗4周后即开始下降,明显早于中药组的12周；在降低ESR方面,两组治疗12周后开始有所下降。至目前随访时,从CRP、ESR均值上看,两组均较24周时有所上升,中西药组较中药组指标水平略低,中药组ESR基本维持在30mm/H以下,中西药组维持在40mm/H以下,中药组CRP基本维持在10mg/dl左右,中西药组则波动较大。
7.安全性方面,RCT阶段,中药组不良反应发生率明显低于中西药组(2.82%vs8.45%)；随访过程中,中药组不良反应发生率仍明显低于中西药组(5.71%vs58.82%)。胃肠道刺激问题在长期应用药物,尤其是应用改善病情的抗风湿性药物(Disease-Modifying anti-Rheumatic Drugs, DMARDs)的患者中不容忽视。
8.依从性方面,随访过程中,发现RA患者更换治疗方案原因是多方面的,DMARDs药物的高不良反应发生率所占比率最大。
三、结论
1.理论研究确立了湿热瘀是活动期RA中医病机关键,清热活血为治疗大法。
2.临床研究证实了清热活血方药具有降低RA疾病活动度、控制RA风湿病情、改善患者躯体功能及关节功能、降低炎性实验室指标的作用,坚持应用作用持续,可以提高患者长期的生活质量。
四、特色与创新之处
1.本研究采用目前公认的RA疗效评价标准(DAS28评分、ACR反应标准、生活质量问卷、中医证候疗效)为工具,开展高质量的随机多中心平行对照的临床研究,评价清热活血方药治疗RA的疗效及安全性。
2.本研究对高质量的RCT进行长期跟踪随访,比较4年期的远期影响,为中医药(清热活血方药)治疗RA的远期疾病疗效和长期的生活质量改善提供循证医学证据。
总之,本研究总结出湿热痹阻、瘀血阻络是病情期RA的主要证候,治痹从“辛温”向“辛凉”转变；进而从理论到临床,以国际公认RA病情疗效指标及生活质量评价问卷,评价清热活血法治疗RA的多中心临床研究及远期随访疗效,寻找中医药在治疗慢性病中的优势,为中医药治疗RA的远期疗效提供循证医学证据。
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. As one of the world's major disabling disease, the influence of patients with physical and mental health and quality of life is serious. Prevalence in China is about0.32%-0.36%. The disease can cause multi-joints swelling pain, terminal can cause joint deformities, lost of function, and at least50%patients can't stick to your work sick of10years. In addition, economic burden caused by RA in the family and society is not optimistic. A study reported that in2001-2003in chengdu only ease of rheumatoid arthritis drugs condition, the amount of medicine is as high as29.0739million yuan, the average annual rate of11.6%. RA bone destruction of health, survival, and the influence on the quality of life and the burden of economy increasingly have drawn the attention of rheumatism experts at home and abroad.
The primary goal of RA treatment is control inflammation symptoms, prevent joint destruction, keep joint function, maintain normal social activities and maximize the long-term health of the patients, the quality of life. Our department according to active period of pathogenesis of RA characteristics combined with years of the clinical experience, emphasis on heat and dampness stasis is the important active RA pathogenic mechanism and pathological key of bone damage, Qingrehuoxue therapy is basic treatment method of active period RA.
This project under the guidance of Qingrehuoxue (QRHX) therapy, scientific development in the capital fund Beijing medical medical health technology project. This multicenter randomized controlled parallel trial, enrolled active RA patients were randomized into in Chinese traditional medicine group (CTMG) and Chinese traditional medicine combined Western medicine group (CWMG), which used Qingrehuoxue decoction+Methotrexate(MTX), to assess RA disease activity (DAS28score), improvementof RA disease condition, curative effect of TCM syndrome, the quality of life and safety. And to our center, we carried on long-term follow-up study to observe77patients, which completed24weeks observation period, to evaluate efficacy of Chinese medicine reducing RA disease activities, controlling disease condition, improve the quality of life of the patients.
Therapeutic Study
1. By sorting out the Traditional Chinese Medicine (TCM) historical evolution, know RA related problems and symptoms and, the history of the understanding, combed the RA contemporary etiology and pathogenesis research achievements in TCM, summarized heat, dampness and blood stasis are the key TCM pathogenesis of active RA, and is the key pathogenesis of bone destruction.
2. Through analysed and summarized the differentiating treatment of RA and modern research results, combed the disease and syndrome differentiation with the diagnosis and treatment, staging RA ideas, and sums up the medical treatment of TCM play a role in RA treatment that improve symptoms, control disease condition, enhance the quality of life, the collaborative western medicine, consolidate curative effect.
3. By analyzing and induction of my advisor treatment experience of RA, I summarized his academic thought of dispelling pathogenic factor mainly, consideration to vital qi. At the same time in the syndrome differentiation and treatment based on patients psychological state, he focuses on from treatment through liver differentiation of RA; and focuses on combining traditional Chinese and western medicine treatment of RA. I also summarized his experiences and views on Chinese traditional medicine with NSAIDs, DMARDs and glucocorticoid.
4. Through sorting the TCM literature about the quality of life and application of live quality evaluation in TCM treatment of RA, put forward the quality of life(QOL) evaluation can reflect the advantages of TCM in the treatment of RA, and QOL should be introduced of RA clinical studies as important as the evaluation index into Chinese treatment.
Clinical Study
Objective:to evaluate Qingrehuoxue decoction reduces RA disease activity, improves disease condition and QOL, curative effect of TCM syndrome and safety.
Methods:Clinical trail stage, Enrolled active RA patients were randomized into in CTMG and CWMG. A24weeks of randomized parallel controlled clinic trial was earried out to assess RA disease activity (DAS28score), improvement RA disease condition and by formulating the follow-up list, strict planning to determined the follow-up, a long-term follow-up was carried out to collect related data of RA disease activity and the QOL, so as to evaluate the long-term curative effect of Chinese medicine reduce RA disease activity, control disease condition and improve the QOL.
Results:
We enrolled in this project142patients which were entered in Full Analysis Set (FAS),129patients completed24weeks of treatment. A total of77patients our center completed24weeks of treatment, there were3cases in CTMG,5cases in CWMG were lost at every follow-up points. Eventually, the cases numbers of two groups were35and34cases. At baseline, two groups of patients'demographic characteristics were balance, the clinical features baseline balance too, were comparable. Until March2012, the longest follow-up case was244weeks; the shortest was158weeks, CTMG average follow-up of202.17weeks, the other203.12weeks; the two groups damp-heat and blocking syndrome stasis resistance duration longest were to4years (242weeks vs208weeks), CTMG group average duration98.62±53.88weeks, the other72.63±9.50weeks. The results show that:
1. Both groups RA disease activity were lower, and maintaining the role. After12weeks of treatment, DAS28score started to decreased obviously. After24weeks of treatment, the clinical remission rate of CTMG and CWMG were22.86%,17.44%respectively; the decline of the DAS28scores mean are1.91and1.97of each group. Follow-up to the present, disease activity of two groups remains at24weeks level; the clinical remission rate of CTMG and CWMG were23.08%、42.86%respectively.
2. Two groups can long-term control RA disease condition. After12weeks of treatment, CTMG showed that disease control effect obviously, compared with CTMG ACR20,50,70success rate were increased by15.50%,12.60%,1.41%;24weeks after treatment, and this difference gradually diminishing, the ACR20,50,70success rate compared with CTMG were increased only by2.82%,9.85%,0. Follow-up to the present, because all the missing data was deemed to be not reach ACR20substandard, led to the present ACR20success rate has dropped. Two groups of ACR20success rate were67.7%,64.3%, CTMG ACR50,70success rates were higher than CWMG group with5.2%,10.5%.
3. Both groups could improve the quality of life of the patients physical function, and keep the body function, improve the quality of life of patients with long-term. Both groups could obviously increase HAQ-DI dimensions after four weeks in which represents the Dressing&Grooming, Arising, Eating, Walking, Activities, effect to faster. Treatment for24weeks later, the quality of life and physical function of two groups increased obviously, of each dimension scores mean<1, present that in mild disability range.4years later the quality of life and physical function of two groups has further improved, except Eating ability, the rest dimensions were still maintain the in mild disability range.
At baseline HAQ score was positively correlated with course of the disease, disease activity, tender joints number, the patients evaluation on joint pain VAS, patients evaluation on general health, the doctor evaluation on general health and inflammatory laboratory parameters. Treatment for24weeks later, two groups improvement rate of HAQ score was positively correlated with improvement rate of disease activity, improvement rate of joint swelling number, improvement rate of the patients evaluation on joint pain VAS, improvement rate of patients evaluation on general health, improvement rate of the doctor evaluation on general health and improvement rate of inflammatory laboratory parameters. Follow-up to the present, two groups improvement rate of HAQ score was positively correlated with improvement rate of joint swelling number, improvement rate of the patients evaluation on joint pain VAS, improvement rate of patients evaluation on general health and improvement rate of inflammatory laboratory parameters. Tip us in the treatment of RA, should notice to reduce disease activity (DAS28score), reduce joint swelling number and reduce pain and reduce inflammation index (ESR, CRP), in order to reduce disease activity in patients with the overall evaluation, eventually improve the quality of life of patients with long-term.
4. Both groups have good long-term efficacy to improve joint function.0weeks, both groups are in III level the highest percentage (54.98%,58.82%).4weeks after treatment, CWMG group joint function improved obviously,24weeks after treatment, I level with the highest percentage (55.89%); And the CTMG in the treatment of12weeks to see improved obviously,24weeks after treatment, Ⅱ level with the highest percentage (65.72%). Follow-up to the present, both groups to Ⅰ level percentage was highest (73.54%vs67.86%)(P>0.05).
5. Both groups can make better syndrome curative effect.4weeks after treatment, total effective rate of syndrome of CTMG and CWMG was29.58%,40.85%respectively; After12weeks of treatment, were64.79%,74.65%respectively;24weeks after treatment, were66.06%,78.87%. Concrete on the mean value, the combination of DMARDs (MTX) can enhance the total effective rate of syndrome.
6. Reduce the inflammatory laboratory index (ESR, CRP):in reducing CRP, CWMG worked faster, treatment after4weeks that began to decline, and obviously earlier than CTMG12weeks. In the reducing ESR, two groups were relatively slow, after12weeks treatment to reduce. Two groups of reducing ESR were slower, but CWMG will faster reduce CRP. Follow-up to the present, from CRP, ESR mean on look, both groups has risen, CWMG index level of a slightly lower.
7. Safety, RCT stage, CTMG adverse reaction rate was significantly lower than the CWMG (2.82%vs8.45%); During follow-up stage, CTMG adverse reaction rate is still significantly lower than CWMG group (5.71%vs58.82%). Gastrointestinal stimulation in long-term use drug problems, especially the application of the drug in patients with DMARDs should not be ignored.
8. Compliance, during follow-up stage, found that RA patients' non-compliance reason is various; DMARDs drug adverse reaction rate proportion is the largest.
Conclusion
1. Established the heat, dampness and blood stasis are the key pathogenesis and pathological of active RA, Qingrehuoxue therapy is the basic principle.
2. Clinical study confirms:QRHX decoction with lower RA disease activity, control disease condition, and improve patients with physical function and joint function, adhere to the application works long-term, thus improving the long-term quality of life of patients, and may reduce the inflammatory laboratory index. Add DMARDs drugs can improve total effective rate and shorten the dampness-heat and blood stasis syndrome duration.
Characteristics and innovative points
1. This project uses internationally recognized the European League against-Rheumatism (EULAR) recommended DAS28score, American College of Rheumatology (ACR) recommended ACR Improvement Criteria and RA patients the quality of life (HAQ-D1) questionnaire as the tool, to evaluate the effect of QRHX therapy of RA multicenter randomized controlled parallel trial and follow-up research, is very helpful in the eastern and western medicine talking to each other and using for reference.
2. This high quality of randomized controlled clinical research on long-term follow-up study, compared to the traditional Chinese medicine treatment of RA4-year effect, to provide long-term effect of traditional Chinese medicine treatment of RA provide consultation evidence-based medicine evidence.
All in all, this project summarized dampness-heat and blood stasis syndrome is the main active period RA syndrome, and put to bi treatment from "XinWen" to "Xinliang" change. Further more from the theory to clinical use, uesd international recognized RA curative effect indexes and the Health Assessment Questionnaire, to evaluate Qingrehuoxue therapy of RA multicenter randomized controlled parallel trial and follow-up research, looking for traditional Chinese medicine in the treatment of chronic disease advantages to explore the effect of traditional Chinese medicine to RA provides evidence-based medical evidence.
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