中医药治疗系统性红斑狼疮多维疗效评价指标体系构建的研究
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摘要
背景
系统性红斑狼疮(systemic lupus erythematosus, SLE)是一种临床常见的自身免疫性疾病,其病因、发病机制尚未完全阐明,至今还没有一种治疗手段能够根治该病。在激素问世以前52%的患者在2年内死亡,随着激素和免疫抑制剂的临床成熟应用,目前其5年存活率已超过80%,但与此同时,治疗药物尤其是激素的副作用已成为影响SLE预后的重要因素,中医药在SLE的防治方面积累了大量的临床经验,尤其在减少激素用量和维持量、减少激素副作用和并发症、顺利递减激素或免疫抑制剂的用量等方面初现了疗效优势,但由于缺乏科学的疗效评价指标体系,直接影响了临床疗效的衡量、确定和成果推广,因此建立国内外公认的能反映中医药干预疗效优势的疗效评价指标体系成为当务之急。
广东省名中医榻国维教授通过数十年的临床研究,认为阴虚火旺、虚火上炎是贯穿SLE全过程的主要病机,滋肾养阴清热法是SLE基本法则,据此研制了滋阴清热狼疮胶囊(狼疮Ⅱ号胶囊),临床上配合糖皮质类固醇激素治疗阴虚内热型活动性SLE,疗效确切。我们于2003年—2007年获得国家中医药管理局课题资助进行了中药狼疮Ⅱ号对SLE患者SLEDAI活动指数、激素用量及生存质量的影响为期3个月的初步研究,结果初步证明中药狼疮Ⅱ号治疗SLE有效安全,能改善临床症状,减少激素用量,减轻激素副作用,尤其对改善SLE患者近期的中医症候及提高生存质量有较好的作用。
目的
本课题在以往研究的基础上,采用国际疗效ICF体系,建立包括系统性红斑狼疮SLEDAI活动指数、SF—36量表及疲劳程度指数量表FSS、中医证候积分、激素用量计分、激素副作用计分表等在内的多维评价指标体系,运用中药滋阴清热狼疮胶囊治疗活动期SLE的小样本RCT研究进行验证,在多时点、多效点上筛选、优化反映中医药治疗SLE优势和特色的多维疗效评价指标体系。该项研究将积极地发掘和确证中医药干预SLE的优势点,使之在SLE的综合治疗中发挥更大的作用,有可能弥补当前中医药治疗SLE疗效评价方面的不足,并对中医药治疗SLE的临床推广有重要的现实意义。同时本项目通过多维指标的综合分析,探索中医药干预治疗SLE患者指导激素减撤的指标。
方法
1.根据文献研究结果,充分复习国内外SLE的临床试验的设计方案,系统评价目前国际通用的SLE活动指数评价量表的不足和优势,参照ICF分类本研究初步的SLE多维疗效评价体系应包括如下内容：系统性红斑狼疮疾病活动指数(SLEDAI)积分表、激素计分(GCS)表、激素副作用计分(GCSES)表、疲劳程度指数(FSS)量表、SF—36量表、中医症候积分(TCMSS)表。
2.组织前瞻性、多中心、随机对照试验进行中医疗效评价体系的的验证研究,通过72例活动期SLE病例RCT试验研究(中医干预治疗组与西医组按1：1的比例分配,每组各36例)。探讨并确定不同结局评价层次使用的量表及相应的评价时点。患者纳入后,进行了以上各量表的重复测定,具体测定时间分为7个时间点,分别为治疗前、疗后4、8、12、16、20、24周。
3.疗效评价系统的初步构建及验证对RCT试验研究所记录的各种评价量表的数据进行统计分析。根据RCT分析结果,通过开展多维度、多时点疗效评价初步量表的临床研究,对资料进行分析并筛选指标。筛选原则：着重考虑指标的重要性、敏感性、代表性、确定性,兼顾可操作性和可接受性。指标选题的分析方法：采用反应度法、相关系数法、主成分分析、因子分析等,同时结合专业认识。最后根据上述过程,即可确定疗效评价量表的指标,从而形成初步的中医药治疗SLE多维疗效评价指标体系。
结果
本研究运用SLEDAI;TCMSS量表；GCS表;GCSES表;FSS量表、SF—36量表等开展中药滋阴清热狼疮胶囊干预治疗轻中度活动期SLE的多中心临床随机对照试验研究进行疗效评价比较,两组治疗前后各量表于各时点及整体变化疗效比较均无统计学意义(P>0.05),可能与样本含量较少有关。但根据各积分趋势图提示长期服用中药滋阴狼疮胶囊对治疗轻中度活动性SLE患者,在改善中医症候、SLEDAI积分及稳定病情方面较西医组具有更好的趋势；中医干预组在两组激素用量无差异的情况下,具有更好改善激素副作用的趋势。同时本研究提示两组在治疗SLE轻中度活动患者的激素用量方面都基本保持一致,具有规范性。结合临床经验,推断可以激素计分作为临床疗效评价体系研究中反映病情变化的应变量进一步探讨其他评价量表与其的相关性,为评价体系的构建提供依据。
本研究通过组间前后非参数检验进行各量表各观察时点的反应度分析,结果显示中医干预组各量表反应度集中较好的时间点分别是SLEDAI:疗后4-8周；TCMSS:疗后4-12周；SF-36：疗后16-24周；GCS：疗后4-24周,均P值<0.05。本研究发现激素副作用积分仅在疗后4周反应度较好(P值<0.05),FSS量表则仅在疗后24周较好(P值>0.05)。
通过建立多元线性回归分析方程,对各量表各时点与激素计分进行标准化回归系数分析,结果显示中医干预组在各时点与激素计分变化具有相关性的指标为治疗前：SLEDAI及FSS量表；疗后4周：TCMSS:疗后8周：SLEDAI, TCMSS, SEGCS,SF-36:疗后12周：SLEDAI,FSS,SF-36；疗后16周：SLEDAI,FSS,SF-36；疗后20周：SLEDAI, GCSES,SF-36；疗后24周：SLEDAI, TCMSS,SF-36,各标准化回归系数均P值<0.05。以标准化回归系数值作为权重标准,对同一时点各量表的标准化回归系数值之权重进行排序,各时点权重排序相关性由重到轻分别是：疗后4周：TCMSS;疗后8周：GCSES, FSS, TCMSS;疗后12-16周：SLEDAI, SF-36, FSS;疗后20周：SLEDAI, SF-36, GCSES;疗后24周：SLEDAI, SF-36, TCMSS。
通过对各条目与量表总分分别进行Pearson相关分析及探索性因子分析,结果显示各量表中影响积分变化的主成分条目分别是：TCMSS量表：口干咽痛、乏力、腰膝酸软、五心烦热、斑疹、关节疼痛；SLEDAI量表：血尿、蛋白尿、脓尿、低补体血症、白细胞减少；GCSES计分表：多毛、满月脸水牛背、痤疮、高血压、骨质疏松；SF-36量表中影响SF-36总分变化的主要领域：情感角色、活力、躯体角色及躯体功能等四个领域；FSS量表中各条目治疗前及疗后的各时点对总分的构成均有较高的相关性。以上条目与量表总分间均Pearson目关系数>0.4,P值<0.05,具有较高相关性。
结论
1.多维疗效评价体系的初步构建：中医药干预治疗轻中度活动期SLE的临床研究可根据研究目的及时间的不同选择不同的评价指标构建体系。近期疗效评价研究(4～8周)：可选择SLEDAI量表作为观察疾病活动性的疗效评价指标；中医症候积分表可作为中医症候变化的疗效评价指标,同时中医症候积分包括了患者客观的疾病损害和主观的不适症状,以及相应的生理、心理指标,因此轻度活动期SLE在疗后第4周～12周都可以作为综合评价SLE患者疗效的替代指标。第8周可选择激素副作用计分作为观察激素的副作用及临床并发症严重程度的观察指标。中期疗效评价研究(12周～16周)：可选择SLEDAI量表作为观察疾病活动性变化的疗效评价指标；SF-36量表可作为观察患者生存质量的疗效评价指标。远期疗效评价研究(20周～24周)：中度活动期SLE可选择SLEDAI量表作为观察疾病活动性的疗效评价指标；SF-36量表作为观察患者生存质量变化的疗效评价指标；第20周可选择激素副作用计分作为观察激素的副作用的疗效评价指标。第24周可选择疲劳程度指数(FSS)量表作为观察患者疲劳情况的疗效评价指标；轻度活动期SLE仅适宜选择反应生存质量变化的SF-36量表作为疗效评价指标。
2.激素用量调整的依据：轻、中度活动期SLE病例：疗后4-8周均可根据SLEDAI或TCMSS结合GCSES的总分相应调整激素用量；疗后12-24周可根据SF-36量表的总分结合GCSES分值相应调整激素量；中度活动期SLE病例：疗后12～24周内均可根据SLEDAI量表的总分调整相应激素用量,疗后12周也可参考中医症候积分调整激素用量。
3.各量表的主成分分析：结果提示各条目均主要与主观感受及生理感受相关,初步推断中医药干预治疗轻中度活动期SLE的疗效评价体系中,反应患者主观感受及生理感受领域的相关条目是构成反应中医药疗效体系的主要组成成分。同时本课题中影响SLEDAI积分构成及变化的主成分条目包括血尿、蛋白尿、脓尿、低补体血症、白细胞减少,结合中医症候积分变化主要构成条目关节疼痛、斑疹,初步推断在轻中度活动期SLE阴虚内热证中肾脏损害、免疫学、血液系统、皮疹、关节疼痛与疾病活动程度相关,可根据这些条目积分的变化调整激素用量。
Objectives
This project used the international efficiency ICF system to establ-ish a multidimensional assessment system of curative effect in treating SLE with traditional Chinese medicine (TCM) including the SLE diseae activity index (SLEDAI),The MOS 36item short-form health survey (SF-36), fatigue severity scale(FSS), traditional Chinese medical symptom score (TCMSS), glucocrticosteroid dosage score(GCS), glucocrticosteroid side effect score(GCSES). At the same time, this RCT trail using LangchuangⅡCapsule to cure the active lupus selected and optimized the multidimensional assessment system of curarive effect from a multi-time points and multi-effect points which can manifest the characteristic and the advantage of Chinese medicine in treating SLE. This study would verify the advantage of Chinese medicine of curing SLE so that it can play a more important role in the combined treatment of SLE and make up for the inefficiency of evaluating Chinese medicine in treating SLE. Also, this trail has the realistic meaning of popularizing the Chinese medicine in treating SLE. Through the analysis of the multidimensional assessment, the study seeks for the regulation of using Chinese medicine to decrease even cease the use of glucocrticosteroid (GC) and is trying to use GCS to directly evaluate the effect and influence of using combining TCM treatment to decrease the side effect of GC.
Methods
1. according to the results of literature and the review of the design of the clinical trails of SLE all over the world, evaluate the advantage and disadvantage of the worldwide SLE active index scale systematically. The SLE multidimensional assessment system of curative effect should include the following scales:SLEDAI, GCS, GCSES, FSS, SF-36 and TCMSS scale.
2. Through the prospective, multi-center, randomized controlled trails to verify the assessment System of TCM effect, the trail has recruited 66 active SLE patients(Chinese medicine combine GC group had 33patients and the basic treatment group had 33patients) and discuss the scale and the corresponding evaluating time point of different outcome evaluating level. After recruiting, different researchers would evaluate all the above scales repeatedly at different point. There are 7 time points which are before the treatment and 4,8,12,16,20,24 weeks after the treatment.
3. According to the results and through the clinical trail of multi-dimensional, multi-time points Assesssment System for TCM Effect, w e analyzed all the data (All the data has been analyzed by SPSS13.0.) and selected the indexes。The principle of the selection is to pay mo re attention to the importance, sensitivity, representativeness and t he certainty of the indexes and at the same time, we should also cons ider the operability and acceptability. We used the activity analysis, Correlation Coefficient analysis, Principal constituent Analysis and F actor analysis and combined these analysis with the professional know ledge. Finally, we verified the index of the assesssment System of TC M effect and formed the multidimensional assesssment System of TCM ef feet in curing SLE.
Result
This multi-center randomized controlled clinical trail evaluated the effect of "LangchuangⅡCapsule" in curing the mild and moderate active SLE using SLEDAI, TCMSS, GCS, GCSES, FSS, SF-36 scale. The results of all scores of different scale before and after the treatment at the different time point and the overall effect between two groups have no statistical significance (P>0.05), which is probably related to the small specimen. According to the tendency chart, it revealed that long term of taking "LangchuangⅡCapsule" has advance in improving the SLEDAI score, TCMSS score and stabling the patients among the mild and moderate active SLE compared with western medicine group. Under the condition of same dosage of GC in two groups, the TCM group has the tendency to decrease the side effect of GC. At the same time, the trail showed that two groups are accordant in GC dosage of mild or moderate active SLE patients. The change of GC dosage adjusted depending the patients'condition and the decrease of the score revealed the validity of the treatment. Therefore, there is the conclusion that it is necessary to discuss the relationship between other scales and the glucocrti-costeroid score which is the index reflecting the change of disease in the assesssment System and also can provide the evidence of the assesssment System.
The trail did the Responsiveness Analysis with rank test through the subject contrast of two isolated groups at different time points before and after the treatment. The results showed that in the TCM group:①responsiveness of SLEDAI is more sensitive at 4-8 weeks after the treatment;②TCMSS is more sensitive at 4-12weeks after the treatment;③SF-36 is more sensitive at 16-24 weeks after the treatment④GCS has good sensitivity during 4-24 weeks of the treatment；⑤GCSES only has good responsiveness at 4 weeks after the treatment and the responsiveness of FSS is only has good responsiveness at 24 weeks after the treatment (P<0.05).
Through the multiple linear regression and the standardized regret-ssion coefficient analysis of the GCS at different time points, the results showed that the scales relative with the GCS at different time points in the TCM group are:before the treatment is SLEDAI and FSS;4 weeks after the treatment is TCMSS;12 weeks after the treatment:SLEDAI, FSS, SF-36;16 weeks after the treatment is SLEDAI, FSS, SF-36; 20 weeks after the treatment is SLEDAI, GCSES, SF-36; 24 weeks after the treatment is SLEDAI, TCMSS, SF-36(all the standardized regression coeficien are P<0.05). Make the standardized regression coefficient as the weight standard of influence on GCS and sequence the weight standard at the same time point of each scale. The correlativity of all the weight standard of influence on GCS at each time point are sequenced from much to litte:4 weeks after treatment:TCMSS;8 weeks after treatment:SESCT, FSS, TCMSS; 12-16 weeks after treatment;SLEDAI, SF-36, FSS; 20 weeks after treatment: SLEDAI, SF-36, GCSES; 24 weeks after treatment:SLEDAI, SF-36, TCMSS.
Based on the evaluation scale we selected from each time point in the TCM group, we do the further analysis to discuss the important items which influence the change of the TCM treatment in the scale. Through the Pearson correlation analysis and the exploratory factor analysis of all the items and the total score in the scale, we got the following results:among the evaluation scales at each time point before and after the treatment, the main items which influencing the different total scores change in the different scales are TCMSS scale:dry mouth and sore throat, fatigue, limp aching lumbus and knees, vexing heat in the five hearts, macule and arthralgia; SLEDAI scale:hematuria, proteinuria, pyuria, leukocyte-openia and hypocomplementemia; GCSES scale:hairy, Moon face, buffalo back, acne, hypertension and osteoporosis; the main territories of SF-36 scale which influencing the total score of SF-36 are:emotional role, vitality, physical role and physical function; the sensitive time point of each item before and after the treatment in the FSS has great relation-ship with the composition of the total score. The Pearson correlation coefficient between the above items and the total score of the scales is above 0.4(P<0.05) which indicates the great correlativity.
Conclusion:
1. The initial construction of the E assessment system:The clinical trails using TCM to treat the mild and moderate active SLE should choose the different evaluation index system depending on different object and time. At the valuation study about short-term effect(4-8 weeks):we can choose SLEDAI scale as the evaluation index to observe the active change of the clinical symptoms; TCMSS can be the evaluation index to observe the change of the TCM patterns so that it can be the alternative index of the effect at 4-12 weeks after the treatment of the mild active SLE. GCSES can be the evaluation index while observing the side effect and complications of GC on the 8th week. At the Evaluation study about Medium-term effect(12-16 weeks):SLEDAI can be the evaluation index to observe the active change of the clinical symptoms and SF-36 can be the evaluation index of living quality. At the Evaluation study about long-term effect(20-24 weeks):Moderate SLE can choose SLEDAI scale as the evaluation index to observe the active change of the clinical symptoms; SF-36 as the evaluation index to observe the change of the patients'living quality, its emotional role, vitality, physical role and physical function are the important evaluation points. FSS can be the evaluation index to observe the condition of fatigue in the 24th week, the GCSES can be the evaluation index to observe the side effece of the GC in the 20th week. Mild active SLE had better choose SF-36 to be the evaluation index which can reflect the change of living quality.
2. Adjusting the dosage of GC according to the change of total scores of evaluation index of effect:mild and moderate active SLE patients:we should adjust the dosage of GC according to the change of the score of SLEDAI or TCMSS combining the score of GCSES at 4-8 weeks after the treatment, and according to the change of the score of SF-36 combining the GCSES at 12-24 weeks after the treatment, moderate active SLE patients: should adjust the dosage of GC according to the change of total score of SLEDAI, and should adjust the dosage of GC according to the change of total score of TCMSS at 4 weeks after the treatment.
3. Primary Conponent Analysis of each scale:based on Analysis, all the main items of different scales are related with the subjective f eeling and physiological sensation, therefore, we can deduce that in the assesssment System of treating mild and moderate active SLE with TCM, the relative items reflecting the patients'subjective feeling and physiological sensations are the major parts of the assesssment S ystem of TCM effect.
In this trail, the main items influencing the composition and cha nge of the SLEDAI score includes hematuria, proteinuria, pyuria, hypo complementemia and leukocytopenia. Combining the change of TCMSS, th e major items are macule and arthralgia. Therefore, it is deduced tha t in the yin deficiency and inner heat pattern of mild and moderate a ctive SLE patients, kidney damage, immunology, blood system, macule a nd arthralgia are related with the condition of the disease according to whose change of score we can adjust the glucocrticosteroid dosage.
系统性红斑狼疮(systemic lupus erythematosus, SLE)是一种临床常见的自身免疫性疾病,其病因、发病机制尚未完全阐明,至今还没有一种治疗手段能够根治该病。在激素问世以前52%的患者在2年内死亡,随着激素和免疫抑制剂的临床成熟应用,目前其5年存活率已超过80%,但与此同时,治疗药物尤其是激素的副作用已成为影响SLE预后的重要因素,中医药在SLE的防治方面积累了大量的临床经验,尤其在减少激素用量和维持量、减少激素副作用和并发症、顺利递减激素或免疫抑制剂的用量等方面初现了疗效优势,但由于缺乏科学的疗效评价指标体系,直接影响了临床疗效的衡量、确定和成果推广,因此建立国内外公认的能反映中医药干预疗效优势的疗效评价指标体系成为当务之急。
广东省名中医榻国维教授通过数十年的临床研究,认为阴虚火旺、虚火上炎是贯穿SLE全过程的主要病机,滋肾养阴清热法是SLE基本法则,据此研制了滋阴清热狼疮胶囊(狼疮Ⅱ号胶囊),临床上配合糖皮质类固醇激素治疗阴虚内热型活动性SLE,疗效确切。我们于2003年—2007年获得国家中医药管理局课题资助进行了中药狼疮Ⅱ号对SLE患者SLEDAI活动指数、激素用量及生存质量的影响为期3个月的初步研究,结果初步证明中药狼疮Ⅱ号治疗SLE有效安全,能改善临床症状,减少激素用量,减轻激素副作用,尤其对改善SLE患者近期的中医症候及提高生存质量有较好的作用。
目的
本课题在以往研究的基础上,采用国际疗效ICF体系,建立包括系统性红斑狼疮SLEDAI活动指数、SF—36量表及疲劳程度指数量表FSS、中医证候积分、激素用量计分、激素副作用计分表等在内的多维评价指标体系,运用中药滋阴清热狼疮胶囊治疗活动期SLE的小样本RCT研究进行验证,在多时点、多效点上筛选、优化反映中医药治疗SLE优势和特色的多维疗效评价指标体系。该项研究将积极地发掘和确证中医药干预SLE的优势点,使之在SLE的综合治疗中发挥更大的作用,有可能弥补当前中医药治疗SLE疗效评价方面的不足,并对中医药治疗SLE的临床推广有重要的现实意义。同时本项目通过多维指标的综合分析,探索中医药干预治疗SLE患者指导激素减撤的指标。
方法
1.根据文献研究结果,充分复习国内外SLE的临床试验的设计方案,系统评价目前国际通用的SLE活动指数评价量表的不足和优势,参照ICF分类本研究初步的SLE多维疗效评价体系应包括如下内容：系统性红斑狼疮疾病活动指数(SLEDAI)积分表、激素计分(GCS)表、激素副作用计分(GCSES)表、疲劳程度指数(FSS)量表、SF—36量表、中医症候积分(TCMSS)表。
2.组织前瞻性、多中心、随机对照试验进行中医疗效评价体系的的验证研究,通过72例活动期SLE病例RCT试验研究(中医干预治疗组与西医组按1：1的比例分配,每组各36例)。探讨并确定不同结局评价层次使用的量表及相应的评价时点。患者纳入后,进行了以上各量表的重复测定,具体测定时间分为7个时间点,分别为治疗前、疗后4、8、12、16、20、24周。
3.疗效评价系统的初步构建及验证对RCT试验研究所记录的各种评价量表的数据进行统计分析。根据RCT分析结果,通过开展多维度、多时点疗效评价初步量表的临床研究,对资料进行分析并筛选指标。筛选原则：着重考虑指标的重要性、敏感性、代表性、确定性,兼顾可操作性和可接受性。指标选题的分析方法：采用反应度法、相关系数法、主成分分析、因子分析等,同时结合专业认识。最后根据上述过程,即可确定疗效评价量表的指标,从而形成初步的中医药治疗SLE多维疗效评价指标体系。
结果
本研究运用SLEDAI;TCMSS量表；GCS表;GCSES表;FSS量表、SF—36量表等开展中药滋阴清热狼疮胶囊干预治疗轻中度活动期SLE的多中心临床随机对照试验研究进行疗效评价比较,两组治疗前后各量表于各时点及整体变化疗效比较均无统计学意义(P>0.05),可能与样本含量较少有关。但根据各积分趋势图提示长期服用中药滋阴狼疮胶囊对治疗轻中度活动性SLE患者,在改善中医症候、SLEDAI积分及稳定病情方面较西医组具有更好的趋势；中医干预组在两组激素用量无差异的情况下,具有更好改善激素副作用的趋势。同时本研究提示两组在治疗SLE轻中度活动患者的激素用量方面都基本保持一致,具有规范性。结合临床经验,推断可以激素计分作为临床疗效评价体系研究中反映病情变化的应变量进一步探讨其他评价量表与其的相关性,为评价体系的构建提供依据。
本研究通过组间前后非参数检验进行各量表各观察时点的反应度分析,结果显示中医干预组各量表反应度集中较好的时间点分别是SLEDAI:疗后4-8周；TCMSS:疗后4-12周；SF-36：疗后16-24周；GCS：疗后4-24周,均P值<0.05。本研究发现激素副作用积分仅在疗后4周反应度较好(P值<0.05),FSS量表则仅在疗后24周较好(P值>0.05)。
通过建立多元线性回归分析方程,对各量表各时点与激素计分进行标准化回归系数分析,结果显示中医干预组在各时点与激素计分变化具有相关性的指标为治疗前：SLEDAI及FSS量表；疗后4周：TCMSS:疗后8周：SLEDAI, TCMSS, SEGCS,SF-36:疗后12周：SLEDAI,FSS,SF-36；疗后16周：SLEDAI,FSS,SF-36；疗后20周：SLEDAI, GCSES,SF-36；疗后24周：SLEDAI, TCMSS,SF-36,各标准化回归系数均P值<0.05。以标准化回归系数值作为权重标准,对同一时点各量表的标准化回归系数值之权重进行排序,各时点权重排序相关性由重到轻分别是：疗后4周：TCMSS;疗后8周：GCSES, FSS, TCMSS;疗后12-16周：SLEDAI, SF-36, FSS;疗后20周：SLEDAI, SF-36, GCSES;疗后24周：SLEDAI, SF-36, TCMSS。
通过对各条目与量表总分分别进行Pearson相关分析及探索性因子分析,结果显示各量表中影响积分变化的主成分条目分别是：TCMSS量表：口干咽痛、乏力、腰膝酸软、五心烦热、斑疹、关节疼痛；SLEDAI量表：血尿、蛋白尿、脓尿、低补体血症、白细胞减少；GCSES计分表：多毛、满月脸水牛背、痤疮、高血压、骨质疏松；SF-36量表中影响SF-36总分变化的主要领域：情感角色、活力、躯体角色及躯体功能等四个领域；FSS量表中各条目治疗前及疗后的各时点对总分的构成均有较高的相关性。以上条目与量表总分间均Pearson目关系数>0.4,P值<0.05,具有较高相关性。
结论
1.多维疗效评价体系的初步构建：中医药干预治疗轻中度活动期SLE的临床研究可根据研究目的及时间的不同选择不同的评价指标构建体系。近期疗效评价研究(4～8周)：可选择SLEDAI量表作为观察疾病活动性的疗效评价指标；中医症候积分表可作为中医症候变化的疗效评价指标,同时中医症候积分包括了患者客观的疾病损害和主观的不适症状,以及相应的生理、心理指标,因此轻度活动期SLE在疗后第4周～12周都可以作为综合评价SLE患者疗效的替代指标。第8周可选择激素副作用计分作为观察激素的副作用及临床并发症严重程度的观察指标。中期疗效评价研究(12周～16周)：可选择SLEDAI量表作为观察疾病活动性变化的疗效评价指标；SF-36量表可作为观察患者生存质量的疗效评价指标。远期疗效评价研究(20周～24周)：中度活动期SLE可选择SLEDAI量表作为观察疾病活动性的疗效评价指标；SF-36量表作为观察患者生存质量变化的疗效评价指标；第20周可选择激素副作用计分作为观察激素的副作用的疗效评价指标。第24周可选择疲劳程度指数(FSS)量表作为观察患者疲劳情况的疗效评价指标；轻度活动期SLE仅适宜选择反应生存质量变化的SF-36量表作为疗效评价指标。
2.激素用量调整的依据：轻、中度活动期SLE病例：疗后4-8周均可根据SLEDAI或TCMSS结合GCSES的总分相应调整激素用量；疗后12-24周可根据SF-36量表的总分结合GCSES分值相应调整激素量；中度活动期SLE病例：疗后12～24周内均可根据SLEDAI量表的总分调整相应激素用量,疗后12周也可参考中医症候积分调整激素用量。
3.各量表的主成分分析：结果提示各条目均主要与主观感受及生理感受相关,初步推断中医药干预治疗轻中度活动期SLE的疗效评价体系中,反应患者主观感受及生理感受领域的相关条目是构成反应中医药疗效体系的主要组成成分。同时本课题中影响SLEDAI积分构成及变化的主成分条目包括血尿、蛋白尿、脓尿、低补体血症、白细胞减少,结合中医症候积分变化主要构成条目关节疼痛、斑疹,初步推断在轻中度活动期SLE阴虚内热证中肾脏损害、免疫学、血液系统、皮疹、关节疼痛与疾病活动程度相关,可根据这些条目积分的变化调整激素用量。
Objectives
This project used the international efficiency ICF system to establ-ish a multidimensional assessment system of curative effect in treating SLE with traditional Chinese medicine (TCM) including the SLE diseae activity index (SLEDAI),The MOS 36item short-form health survey (SF-36), fatigue severity scale(FSS), traditional Chinese medical symptom score (TCMSS), glucocrticosteroid dosage score(GCS), glucocrticosteroid side effect score(GCSES). At the same time, this RCT trail using LangchuangⅡCapsule to cure the active lupus selected and optimized the multidimensional assessment system of curarive effect from a multi-time points and multi-effect points which can manifest the characteristic and the advantage of Chinese medicine in treating SLE. This study would verify the advantage of Chinese medicine of curing SLE so that it can play a more important role in the combined treatment of SLE and make up for the inefficiency of evaluating Chinese medicine in treating SLE. Also, this trail has the realistic meaning of popularizing the Chinese medicine in treating SLE. Through the analysis of the multidimensional assessment, the study seeks for the regulation of using Chinese medicine to decrease even cease the use of glucocrticosteroid (GC) and is trying to use GCS to directly evaluate the effect and influence of using combining TCM treatment to decrease the side effect of GC.
Methods
1. according to the results of literature and the review of the design of the clinical trails of SLE all over the world, evaluate the advantage and disadvantage of the worldwide SLE active index scale systematically. The SLE multidimensional assessment system of curative effect should include the following scales:SLEDAI, GCS, GCSES, FSS, SF-36 and TCMSS scale.
2. Through the prospective, multi-center, randomized controlled trails to verify the assessment System of TCM effect, the trail has recruited 66 active SLE patients(Chinese medicine combine GC group had 33patients and the basic treatment group had 33patients) and discuss the scale and the corresponding evaluating time point of different outcome evaluating level. After recruiting, different researchers would evaluate all the above scales repeatedly at different point. There are 7 time points which are before the treatment and 4,8,12,16,20,24 weeks after the treatment.
3. According to the results and through the clinical trail of multi-dimensional, multi-time points Assesssment System for TCM Effect, w e analyzed all the data (All the data has been analyzed by SPSS13.0.) and selected the indexes。The principle of the selection is to pay mo re attention to the importance, sensitivity, representativeness and t he certainty of the indexes and at the same time, we should also cons ider the operability and acceptability. We used the activity analysis, Correlation Coefficient analysis, Principal constituent Analysis and F actor analysis and combined these analysis with the professional know ledge. Finally, we verified the index of the assesssment System of TC M effect and formed the multidimensional assesssment System of TCM ef feet in curing SLE.
Result
This multi-center randomized controlled clinical trail evaluated the effect of "LangchuangⅡCapsule" in curing the mild and moderate active SLE using SLEDAI, TCMSS, GCS, GCSES, FSS, SF-36 scale. The results of all scores of different scale before and after the treatment at the different time point and the overall effect between two groups have no statistical significance (P>0.05), which is probably related to the small specimen. According to the tendency chart, it revealed that long term of taking "LangchuangⅡCapsule" has advance in improving the SLEDAI score, TCMSS score and stabling the patients among the mild and moderate active SLE compared with western medicine group. Under the condition of same dosage of GC in two groups, the TCM group has the tendency to decrease the side effect of GC. At the same time, the trail showed that two groups are accordant in GC dosage of mild or moderate active SLE patients. The change of GC dosage adjusted depending the patients'condition and the decrease of the score revealed the validity of the treatment. Therefore, there is the conclusion that it is necessary to discuss the relationship between other scales and the glucocrti-costeroid score which is the index reflecting the change of disease in the assesssment System and also can provide the evidence of the assesssment System.
The trail did the Responsiveness Analysis with rank test through the subject contrast of two isolated groups at different time points before and after the treatment. The results showed that in the TCM group:①responsiveness of SLEDAI is more sensitive at 4-8 weeks after the treatment;②TCMSS is more sensitive at 4-12weeks after the treatment;③SF-36 is more sensitive at 16-24 weeks after the treatment④GCS has good sensitivity during 4-24 weeks of the treatment；⑤GCSES only has good responsiveness at 4 weeks after the treatment and the responsiveness of FSS is only has good responsiveness at 24 weeks after the treatment (P<0.05).
Through the multiple linear regression and the standardized regret-ssion coefficient analysis of the GCS at different time points, the results showed that the scales relative with the GCS at different time points in the TCM group are:before the treatment is SLEDAI and FSS;4 weeks after the treatment is TCMSS;12 weeks after the treatment:SLEDAI, FSS, SF-36;16 weeks after the treatment is SLEDAI, FSS, SF-36; 20 weeks after the treatment is SLEDAI, GCSES, SF-36; 24 weeks after the treatment is SLEDAI, TCMSS, SF-36(all the standardized regression coeficien are P<0.05). Make the standardized regression coefficient as the weight standard of influence on GCS and sequence the weight standard at the same time point of each scale. The correlativity of all the weight standard of influence on GCS at each time point are sequenced from much to litte:4 weeks after treatment:TCMSS;8 weeks after treatment:SESCT, FSS, TCMSS; 12-16 weeks after treatment;SLEDAI, SF-36, FSS; 20 weeks after treatment: SLEDAI, SF-36, GCSES; 24 weeks after treatment:SLEDAI, SF-36, TCMSS.
Based on the evaluation scale we selected from each time point in the TCM group, we do the further analysis to discuss the important items which influence the change of the TCM treatment in the scale. Through the Pearson correlation analysis and the exploratory factor analysis of all the items and the total score in the scale, we got the following results:among the evaluation scales at each time point before and after the treatment, the main items which influencing the different total scores change in the different scales are TCMSS scale:dry mouth and sore throat, fatigue, limp aching lumbus and knees, vexing heat in the five hearts, macule and arthralgia; SLEDAI scale:hematuria, proteinuria, pyuria, leukocyte-openia and hypocomplementemia; GCSES scale:hairy, Moon face, buffalo back, acne, hypertension and osteoporosis; the main territories of SF-36 scale which influencing the total score of SF-36 are:emotional role, vitality, physical role and physical function; the sensitive time point of each item before and after the treatment in the FSS has great relation-ship with the composition of the total score. The Pearson correlation coefficient between the above items and the total score of the scales is above 0.4(P<0.05) which indicates the great correlativity.
Conclusion:
1. The initial construction of the E assessment system:The clinical trails using TCM to treat the mild and moderate active SLE should choose the different evaluation index system depending on different object and time. At the valuation study about short-term effect(4-8 weeks):we can choose SLEDAI scale as the evaluation index to observe the active change of the clinical symptoms; TCMSS can be the evaluation index to observe the change of the TCM patterns so that it can be the alternative index of the effect at 4-12 weeks after the treatment of the mild active SLE. GCSES can be the evaluation index while observing the side effect and complications of GC on the 8th week. At the Evaluation study about Medium-term effect(12-16 weeks):SLEDAI can be the evaluation index to observe the active change of the clinical symptoms and SF-36 can be the evaluation index of living quality. At the Evaluation study about long-term effect(20-24 weeks):Moderate SLE can choose SLEDAI scale as the evaluation index to observe the active change of the clinical symptoms; SF-36 as the evaluation index to observe the change of the patients'living quality, its emotional role, vitality, physical role and physical function are the important evaluation points. FSS can be the evaluation index to observe the condition of fatigue in the 24th week, the GCSES can be the evaluation index to observe the side effece of the GC in the 20th week. Mild active SLE had better choose SF-36 to be the evaluation index which can reflect the change of living quality.
2. Adjusting the dosage of GC according to the change of total scores of evaluation index of effect:mild and moderate active SLE patients:we should adjust the dosage of GC according to the change of the score of SLEDAI or TCMSS combining the score of GCSES at 4-8 weeks after the treatment, and according to the change of the score of SF-36 combining the GCSES at 12-24 weeks after the treatment, moderate active SLE patients: should adjust the dosage of GC according to the change of total score of SLEDAI, and should adjust the dosage of GC according to the change of total score of TCMSS at 4 weeks after the treatment.
3. Primary Conponent Analysis of each scale:based on Analysis, all the main items of different scales are related with the subjective f eeling and physiological sensation, therefore, we can deduce that in the assesssment System of treating mild and moderate active SLE with TCM, the relative items reflecting the patients'subjective feeling and physiological sensations are the major parts of the assesssment S ystem of TCM effect.
In this trail, the main items influencing the composition and cha nge of the SLEDAI score includes hematuria, proteinuria, pyuria, hypo complementemia and leukocytopenia. Combining the change of TCMSS, th e major items are macule and arthralgia. Therefore, it is deduced tha t in the yin deficiency and inner heat pattern of mild and moderate a ctive SLE patients, kidney damage, immunology, blood system, macule a nd arthralgia are related with the condition of the disease according to whose change of score we can adjust the glucocrticosteroid dosage.
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