温阳散寒除湿法治疗类风湿关节炎的临床疗效及作用机制研究
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摘要
目的探讨温阳散寒除湿法(蠲痹颗粒)治疗类风湿关节炎(RA)的临床疗效、作用机制及其安全性,为温阳散寒除湿法治疗RA提供依据,丰富中医药防治RA理论。
方法①引用国际公认的DAS28. CDAI、SDAI疾病活动指数疗效评价方法,将102例寒湿痹阻型RA患者,随机分为治疗组68例和对照组34例,分别采用蠲痹颗粒(45g/d)、正清风痛宁缓释片(120mg/d)治疗8周后,考察其临床疗效和安全性。②建立角叉菜胶致大鼠急性足跖肿胀炎症模型和棉球异物植入诱导大鼠肉芽组织增生慢性炎症模型,随机分为模型组、阳性药组(DEX)、蠲痹颗粒低中、高剂量组。药物干预后,检测蠲痹颗粒灌胃给药对急、慢性炎症反应的影响。③建立CIA大鼠模型,随机分为空白对照组、模型组、阳性药组(MTX)及蠲痹颗粒低、中、高剂量组。药物干预后,关节炎指数(AI)评分法评价关节炎发病程度,石蜡切片HE染色观测踝关节滑膜组织炎症,ELISA法检测血清IL-1p水平。④建立CIA小鼠模型,按临床评分平均分为模型组,阳性药组(MTX),蠲痹颗粒组。药物干预后,关节炎临床评分法评价关节炎发病严重程度,X线钼靶摄片、石蜡切片HE染色分别观测小鼠足爪关节和关节炎病理损伤程度,3H-thymidine掺入法检测CIA小鼠胶原特异性免疫应答水平,流式微珠阵列法(CBA)、ELISA法分别检测胶原诱导的脾淋巴细胞IL-6、TNF-α、IL-17A及IFN-γ,IL-10产生水平,流式细胞术(FACs)检测脾淋巴细胞表面(CD4、CD8、B220比例)及胞内细胞因子(IFN-γ、IL-17A)的表达。
结果①临床观察结果显示,治疗组在总体疗效,证候积分、CRP、ESR及DAS28、 CDAI、SDAI评分等改善方面优于对照组(P<0.01,P<0.05),且安全性良好。②温阳散寒除湿法对大鼠角叉菜胶所致足跖肿胀和棉球异物植入引起的大鼠慢性炎症性肉芽组织增生均有显著抑制作用(P<0.05)。③能改善CIA大鼠关节炎AI评分(P<0.05)及关节滑膜炎症评分(P<0.01),抑制大鼠关节滑膜组织炎细胞浸润、组织细胞增生,降低大鼠血清IL-1p水平(P<0.01)。④能改善CIA小鼠关节炎临床评分(P<0.01),减轻关节炎细胞浸润及骨质损伤,抑制小鼠胶原特异性免疫反应(P<0.01),下调胶原诱导的脾淋巴细胞胞内、胞外IL-17A水平,上调脾淋巴细胞IL-10产生水平(P<0.01),一定程度促进Treg细胞的表达,而对IFN-γ、TNF-α、IL-6及淋巴细胞亚群(CD4、CD8、B220比例)无明显影响。
结论①温阳散寒除湿法是临床治疗RA安全有效的方法。②温阳散寒除湿法具有显著的抗炎作用。③对CIA大鼠、CIA小鼠关节炎具有防治作用。④调控Th17细胞/Treg平衡,下调IL-17A表达,诱导IL-10释放,可能是温阳散寒除湿法治疗RA的作用机制之一。
Objective To study the clinical effects, efficacy mechanism and security of WenYangSanH-anChuShi method(Juan Bi particle) on the treatment of rheumatoid arthritis(RA), to provide theoretical basises for WenYangSanHanChuShi method in RA and enrich theories of treating RA with traditional Chinese medicine.
Methods①Clinical studies cited internationally recognized DAS28, CDAI, SDAI disease activity index to evaluating the curative effect.There are totally102cases of RA patients with cold-dampness syndrome in this study, which are randomly divided into treatment group of68cases and control group of34cases. Treatment group use Juanbi particle(45g/d),and the control group use Zhengqing Fengtongning Retard tablets(120mg/d). Each group take a8weeks treatment, after that,observing the clinical efficacy and safety.②The models of carrageenan-induced edema of rat plantar and formation of cotton ball granulom in rats were adopted to investigate anti-inflammatory of WenYangSanHanChuShi method. Rats were divided into five groups, including the model group, the positive control group(DEX) and Juanbi particle groups(low, medium and high dose group). After drug intervention, effects on acute and chronic inflammation was evaluated.③Type ⅡII bovine collagen(CII)-induced arthritis (CIA) in rats were established for investigating the anti-synovitis of WenYangSanHanChuShi method. Rats were divided into six groups, including the blank control group, model group, the positive control group(MTX) and Juanbi particle groups(low, medium and high dose group).After drug intervention, arthritis disease degree was evaluated by arthritis index (AI) score method. The histological damage of synovial tissues was assessed by histological examination (H&E).Serum level of IL-1β was detected by enzyme-linked immunosorbent assay(ELISA).④Type Ⅱ bovine collagen(CII) induced arthritis (CIA) in mice were established for evaluating the inhibitory effect and mechanism of WenYangSanHanChuShi method. Mice were divided into three groups, including the model group, the positive control group(MTX) and Juanbi particle groups by the clinical score method. After drug intervention, arthritis disease degree was evaluated by the clinical score. The histological damage of arthrosis was assessed by histological examination (H&E) and X-ray mammography radiography. Lymphocyte proliferative ability in CIA mouse was detected by3H-thymidine incorporation assay. The inflammatory cytokine production level of IL-6,IL-17A and TNF-a in collagen(CII)-induced splenic lymphocytes was detected by Cytometric Bead Array (CBA) and IFN-y, IL-10was detected by ELISA. Surface marks of spleen lymphocyte(CD4, CD8, B220ratio) and the level of IFN-y, IL-17A in spleen lymphocytes was detected by fluorescence activated cell sorter(FACs).
Results①Clinical observation results show that the syndrome curative effect of treatment group was better than control group. About improvement of TCM syndrome integral, CRP, ESR, DAS28, CDAI, and SDAI, it was better than the control group (P<0.01, P<0.05),and did not appear obvious side effects and adverse reactions.②WenYangSanHanChuShi method has significant inhibitory effect on swelling of paw and the formation of cotton ball granuloma(P<0.05).③Improving arthritis AI score(P<0.05), joint synovial inflammation (P<0.01), synovial tissue inflammatory cells infiltration and tissue hyperplasia and reducing levels of serum IL-1β(P<0.01) in CIA rats.④Improving clinical scores(P<0.01), reducing arthritis cell infiltration and bone injury, inhibiting immune response collagen induced(P<0.01), reducing the level of IL-17A in intrace-extracellular spleen lymphocytes collagen induced, raising IL-10in collagen induced splenic lymphocytes(P<0.01) and Promoting Treg cell expression in some degree. But there is no obvious influence on the level of IFN-y, TNF-a, IL-6and lymphocyte subgroups(CD4, CD8, B220ratio) in CIA mice.
Conclusion①WenYangSanHanChuShi method is an effective measure in treatment of RA.②WenYangSanHanChuShi method has an obvious anti-inflammatory effect.③It has a therapeutic effect on CIA rats and CIA mice.④The upregulation of expression of IL-10and the downturn of expression of IL-17A in collagen(CII)-induced splenic lymphocytes may be one of the mechanisms in treatment of RA with WenYangSanHanChuShi method.
方法①引用国际公认的DAS28. CDAI、SDAI疾病活动指数疗效评价方法,将102例寒湿痹阻型RA患者,随机分为治疗组68例和对照组34例,分别采用蠲痹颗粒(45g/d)、正清风痛宁缓释片(120mg/d)治疗8周后,考察其临床疗效和安全性。②建立角叉菜胶致大鼠急性足跖肿胀炎症模型和棉球异物植入诱导大鼠肉芽组织增生慢性炎症模型,随机分为模型组、阳性药组(DEX)、蠲痹颗粒低中、高剂量组。药物干预后,检测蠲痹颗粒灌胃给药对急、慢性炎症反应的影响。③建立CIA大鼠模型,随机分为空白对照组、模型组、阳性药组(MTX)及蠲痹颗粒低、中、高剂量组。药物干预后,关节炎指数(AI)评分法评价关节炎发病程度,石蜡切片HE染色观测踝关节滑膜组织炎症,ELISA法检测血清IL-1p水平。④建立CIA小鼠模型,按临床评分平均分为模型组,阳性药组(MTX),蠲痹颗粒组。药物干预后,关节炎临床评分法评价关节炎发病严重程度,X线钼靶摄片、石蜡切片HE染色分别观测小鼠足爪关节和关节炎病理损伤程度,3H-thymidine掺入法检测CIA小鼠胶原特异性免疫应答水平,流式微珠阵列法(CBA)、ELISA法分别检测胶原诱导的脾淋巴细胞IL-6、TNF-α、IL-17A及IFN-γ,IL-10产生水平,流式细胞术(FACs)检测脾淋巴细胞表面(CD4、CD8、B220比例)及胞内细胞因子(IFN-γ、IL-17A)的表达。
结果①临床观察结果显示,治疗组在总体疗效,证候积分、CRP、ESR及DAS28、 CDAI、SDAI评分等改善方面优于对照组(P<0.01,P<0.05),且安全性良好。②温阳散寒除湿法对大鼠角叉菜胶所致足跖肿胀和棉球异物植入引起的大鼠慢性炎症性肉芽组织增生均有显著抑制作用(P<0.05)。③能改善CIA大鼠关节炎AI评分(P<0.05)及关节滑膜炎症评分(P<0.01),抑制大鼠关节滑膜组织炎细胞浸润、组织细胞增生,降低大鼠血清IL-1p水平(P<0.01)。④能改善CIA小鼠关节炎临床评分(P<0.01),减轻关节炎细胞浸润及骨质损伤,抑制小鼠胶原特异性免疫反应(P<0.01),下调胶原诱导的脾淋巴细胞胞内、胞外IL-17A水平,上调脾淋巴细胞IL-10产生水平(P<0.01),一定程度促进Treg细胞的表达,而对IFN-γ、TNF-α、IL-6及淋巴细胞亚群(CD4、CD8、B220比例)无明显影响。
结论①温阳散寒除湿法是临床治疗RA安全有效的方法。②温阳散寒除湿法具有显著的抗炎作用。③对CIA大鼠、CIA小鼠关节炎具有防治作用。④调控Th17细胞/Treg平衡,下调IL-17A表达,诱导IL-10释放,可能是温阳散寒除湿法治疗RA的作用机制之一。
Objective To study the clinical effects, efficacy mechanism and security of WenYangSanH-anChuShi method(Juan Bi particle) on the treatment of rheumatoid arthritis(RA), to provide theoretical basises for WenYangSanHanChuShi method in RA and enrich theories of treating RA with traditional Chinese medicine.
Methods①Clinical studies cited internationally recognized DAS28, CDAI, SDAI disease activity index to evaluating the curative effect.There are totally102cases of RA patients with cold-dampness syndrome in this study, which are randomly divided into treatment group of68cases and control group of34cases. Treatment group use Juanbi particle(45g/d),and the control group use Zhengqing Fengtongning Retard tablets(120mg/d). Each group take a8weeks treatment, after that,observing the clinical efficacy and safety.②The models of carrageenan-induced edema of rat plantar and formation of cotton ball granulom in rats were adopted to investigate anti-inflammatory of WenYangSanHanChuShi method. Rats were divided into five groups, including the model group, the positive control group(DEX) and Juanbi particle groups(low, medium and high dose group). After drug intervention, effects on acute and chronic inflammation was evaluated.③Type ⅡII bovine collagen(CII)-induced arthritis (CIA) in rats were established for investigating the anti-synovitis of WenYangSanHanChuShi method. Rats were divided into six groups, including the blank control group, model group, the positive control group(MTX) and Juanbi particle groups(low, medium and high dose group).After drug intervention, arthritis disease degree was evaluated by arthritis index (AI) score method. The histological damage of synovial tissues was assessed by histological examination (H&E).Serum level of IL-1β was detected by enzyme-linked immunosorbent assay(ELISA).④Type Ⅱ bovine collagen(CII) induced arthritis (CIA) in mice were established for evaluating the inhibitory effect and mechanism of WenYangSanHanChuShi method. Mice were divided into three groups, including the model group, the positive control group(MTX) and Juanbi particle groups by the clinical score method. After drug intervention, arthritis disease degree was evaluated by the clinical score. The histological damage of arthrosis was assessed by histological examination (H&E) and X-ray mammography radiography. Lymphocyte proliferative ability in CIA mouse was detected by3H-thymidine incorporation assay. The inflammatory cytokine production level of IL-6,IL-17A and TNF-a in collagen(CII)-induced splenic lymphocytes was detected by Cytometric Bead Array (CBA) and IFN-y, IL-10was detected by ELISA. Surface marks of spleen lymphocyte(CD4, CD8, B220ratio) and the level of IFN-y, IL-17A in spleen lymphocytes was detected by fluorescence activated cell sorter(FACs).
Results①Clinical observation results show that the syndrome curative effect of treatment group was better than control group. About improvement of TCM syndrome integral, CRP, ESR, DAS28, CDAI, and SDAI, it was better than the control group (P<0.01, P<0.05),and did not appear obvious side effects and adverse reactions.②WenYangSanHanChuShi method has significant inhibitory effect on swelling of paw and the formation of cotton ball granuloma(P<0.05).③Improving arthritis AI score(P<0.05), joint synovial inflammation (P<0.01), synovial tissue inflammatory cells infiltration and tissue hyperplasia and reducing levels of serum IL-1β(P<0.01) in CIA rats.④Improving clinical scores(P<0.01), reducing arthritis cell infiltration and bone injury, inhibiting immune response collagen induced(P<0.01), reducing the level of IL-17A in intrace-extracellular spleen lymphocytes collagen induced, raising IL-10in collagen induced splenic lymphocytes(P<0.01) and Promoting Treg cell expression in some degree. But there is no obvious influence on the level of IFN-y, TNF-a, IL-6and lymphocyte subgroups(CD4, CD8, B220ratio) in CIA mice.
Conclusion①WenYangSanHanChuShi method is an effective measure in treatment of RA.②WenYangSanHanChuShi method has an obvious anti-inflammatory effect.③It has a therapeutic effect on CIA rats and CIA mice.④The upregulation of expression of IL-10and the downturn of expression of IL-17A in collagen(CII)-induced splenic lymphocytes may be one of the mechanisms in treatment of RA with WenYangSanHanChuShi method.
引文
[1]Yunjie Liu,Lingling Zhang,Yingqi W,et al.Therapeutic effects of TACI-Ig on collagenind-uced arthritis by regulating T and B lymphocytes function in DBA/1 mice [J].European Journal of Pharmacology,2011,654:304-314.
[2]中华医学会风湿病学分会.类风湿关节炎诊断及治疗指南[J].中华风湿病学杂志,2010,14(4)：265-270.
[3]Li-Fei Hou,Shi-Jun He,Jun-Xia Wang,et al.SM934,a water-soluble derivative of art eminisin,exerts immunosuppressive functions in vitro and in vivo[J].International Immunopha-rmacology.2009,9:1509-1517.
[4]王晓丽,李小峰,温鸿雁.植物药治疗类风湿关节炎的研究现状[J].山西医药杂志,2007,36(7)：542-546.
[5]彭江云,狄朋桃,李兆福,等.类风湿关节炎发病学初探[J].世界中西医结合杂志,2012,7(10)：34-36.
[6]彭江云,狄朋桃,李兆福,等.云南地区类风湿关节炎中医证候学研究[J].中国中医药信息杂志,2012,19(7)：15-17.
[7]彭江云,李兆福,刘维超,等.蠲痹颗粒抗炎镇痛作用的实验研究[J].中国中医骨伤杂志,2009,17(11)：52-53.
[8]万春平,李兆福,彭江云,等.蠲痹颗粒主要药效学及安全性评价研究[J].风湿病与关节炎,2012,1(5)：16-18.
[9]彭江云,李兆福,刘维超,等.蠲痹颗粒治疗类风湿关节炎40例临床疗效观察[J].云南中医中药杂志,2009,30(12)：12-14.
[10]Vander graaff WL,Pnins AP. Prognostic value of Thl/Th2 ratio in rheumatoid arthritis[J]. Lancet,1998,351(6):1931-1937.
[11]Dan R.Littman, Alexander Y,Rudensky.Th17 and Regulatory T Cells in Mediating and Restraining Inflammation[J]. Cell,2010,140:845-858.
[12]Estelle Bettelli,Yijun Carrier,Wenda Gao.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J].nature,2006,441:235-238.
[13]徐雪,吕玲.Th17与Treg在系统性红斑狼疮发病机制中的作用[J].现代免疫学,2010,30(3)：257-261.
[14]Smolen JS, Breedveld FC, Schiff MH,et al.A simplified disease activity index for rheumatoid arthritis for use in clinical practice[J].Rheumatology(Oxford),2003,42:244-257.
[15]Pincus T,Yazici Y, Bergman M,et al.A proposed continuous quality improvement approach to assessment and management of patients with rheumatoid arthritis without formal joint counts,based on quantitative routine assessment of patient index data (RAPID) scores on a multidimensional health assessment questionnaire (MDHAQ)[J].Best Practice & Research Clinical Rheumatology,2007,21:789-804.
[16]Hochberg MC,Chang RW, Dwosh I,et al.The American College of Rheumatology 1991 revise criteria for classification of global functional status in rheumatoid arthritis[J].Rthritis Rheum,1992,35:498-502.
[17]吴军,张卓莉,李振彪,等.重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白联合甲氨蝶呤治疗活动性类风湿关节炎的疗效和骨代谢的影响[J].中华医学杂志,2010,90：2481-2485.
[18]国家中医药管理局.中医病证诊断疗效标准[S].南京：南京大学出版社,1994：30-31.
[19]国家药品监督管理局.中药新药临床研究指导原则[S].北京：中国医药科技出版社,2002,115-119.
[20]Aletaha D,Ward MM, Machold KP,et al.Remission and active disease in rheumatoid arthritis:defining criteria for disease activity states[J].Arthritis Rheum,2005,52(9):2625-2636.
[21]Aletaha D,Smolen JS. Remission of rheumatoid arthritis:should we care about definitionns?[J]. Clin Exp Rheumatol,2006,24:S45-51.
[22]朱建华.虫类药在RA中的应用[J].中国临床医生,2000,28(4)：12-13.
[23]何羿婷,陈伟,焦树德.应用焦树德教授学术思想临证体会[J].中国中医基础医学杂志,2004,10(4)：59-61.
[24]宋利梅,冯修高.治疗寒湿痹阻型类风湿关节炎的复方中单味药相关药理研究近况[J].现代中西医结合杂志,2009,18(6)：712-713.
[25]刘素苗,张莉芸,马丹.临床疾病活动指数和简化疾病活动指数在类风湿关节炎疾病活动性评估中的比较研究[J].中华风湿病学杂志,2012,16(9)：601-605.
[26]刘栩,路晓燕,赵岩,等.类风湿关节炎诊断和缓解标准及其进展[J].中华内科杂志,2010,49(4)：354-356.
[27]张毅,王旭光,何惠娟,等.木犀草素体内抗炎作用机制研究[J].广东医学院学报, 2009,27(6)：606.
[28]陈孟平,乔为平,赵云华,等.黔产棘茎梅木抗炎作用及部分机制研究[J].中国实验方剂学杂志,2012,18(8)：156.
[29]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：742.
[30]JX Wang,W Tang, R Zhou,et al. The new water-soluble artemisinin derivative SM905 ameliorates collagen-induced arthritis by suppression of inflammatory and Th17 responses [J]. BJP,2008,153:1303-1310.
[31]Drosos AA. Epidemiology of rheumatoid arthritis[J].Autoimmun Rev.2004,3(suppl): S20-22.
[32]张乃峥,曾庆馀,张凤山,等.中国风湿性疾病流行情况的调查研究[J].中华风湿病学杂志,1997,1(1)：31-35.
[33]肖长虹.试论类风湿性关节炎中医研究的思路与方法[J].新中医,1997,29(11)：2.
[34]Skapenko A,Kalden JR. Treatment of rheumatoid arthritis in the third millennium [J].Scand J Rheumatol.2001,30(5):249-254.
[35]Cvetkovic JT,Wallberg-jonsson S,Stegmayr B,et al.Susceptibility for and clinical manifestations of RA are associated with polymorphisms of the TNF-α,IL-1β and IL-1α gene[J]. Rheumatol,2002,29(2):212-219.
[36]King C,Tangye SG, Mackay CR.T follicular helper (TFH) cells in normal and dysregulated immune responses[J]. Annu Rev Immunol,2008,26:741-766.
[37]Kristine Kikly,Ling Liu,Songqing Na,et al.The IL-23/Th17 axis:therapeutic targets for autoimmune inflammation[J].Current Opinion in Immunology,2006,18:670-675.
[38]Kelchtermans H, De Klerck B,Mitera T,et al.Defective CD4+CD25+regulatory T cell function in collagen-induced arthritis:an important factor in pathogenesis,counter-regulated by endogenous IFN-gamma[J]. Arthritis Res Ther,2005,7:R402-415.
[39]Ru Zhou a,Fan Zhang b,Pei-Lan He.etal.(5R)-5-hydroxytriptolide (LLDT-8),a novel triptolide analogmediates immunosuppressive effects in vitro and in vivo.International Immunopharmacology.2005,5:1895-1903.
[40]王绪辉,朱显华,闵熙敬.实验性小鼠内伤痹证模型的建立[J].中国医药学报,1990,5(6)：64-65.
[41]李宝丽,唐方,庞晓东.II型胶原诱导关节炎大鼠模型制备[J].中国免疫学杂志,2006,22(4)：350-352.
[42]李景怡,吴玉章,陈永文,等.盐酸青藤碱抑制小鼠胶原性关节炎的实验研究[J].免疫学杂志,2005,21(4)：313-316.
[43]Maini RN,Taylor PC. Anti-cytokine therapy for rheumatoid arthritis [J].Annu Rev Med,2000,51:207-229.
[44]周茹,杨以阜,左建平.II型胶原诱导的小鼠关节炎动物模型的建立及影响因素[J].中国药理学通报,2006,22(12)：1532.
[45]Estelle Bettelli, Thomas korn,Mohamed Oukka,Vijay K. Kuchroo.Induction and effector functions of TH17 cells[J]. Nature,2008,53(19):1051.
[46]H Kelchtermans,L Geboes,T Mitera,et al.Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis[J]. Ann Rheum Dis,2009,68: 744-750.
[1]周仲瑛.中医内科学[M].北京：中国中医药出版社,2007：464.
[2]祝谌予,翟济生,施如瑜,等.施今墨临床经验集[M].北京：人民卫生出版社,2005：127.
[3]何羿婷,陈伟,焦树德.应用焦树德教授学术思想临证体会[J].中国中医基础医学杂志,2004,10(4)：59-61.
[4]娄高峰,娄玉钤.娄多峰治疗风湿病经验撷菁[J].辽宁中医杂志,2006,33(2)：147-148.
[5]谢海洲.谢海洲论医集[M].上海：上海辞书出版社,1993：158.
[6]肖泓,吴永昕,吴生元.吴生元辨治类风湿性关节炎的经验[J].云南中医中药杂志,2009,30(4)：1-2.
[7]曾升海,田惠民.朱良春治疗痹病的用药经验介绍[J].陕西中医,2001,22(7)：409-450.
[8]商阿萍,路洁.路志正教授治疗类风湿关节炎经验[J].河北中医,2008,30(4)：341-343.
[9]路志正,焦树德.实用中医风湿病学[M].北京：人民卫生出版社,1996：459-460.
[10]范伏元,金朝晖.通痹汤治疗活动期类风湿性关节炎的临床研究[J].中国中医药科技,2006,13(1)：3-4.
[11]赵语华,周艳伟.羌威蠲痹合剂治疗类风湿关节炎活动期的临床研究[J].河北中医,2008,20(9)：907-909.
[12]戴小娟,李武军.桂枝汤加味治疗缓解期类风湿关节炎疗效观察[J].河北中医,2012,34(9)：1348-1349.
[13]考希良,宋绍亮,王诗源.清痹扶正汤防治类风湿关节炎复发临床研究[J].山东中医杂志,2006,25(11)：735-737.
[14]刘喜德,万力生主编.类风湿性关节炎的诊断与治疗[M].北京：人民军医出版社,2006：307-309.
[15]李满意,娄玉钤,杨林江.娄多峰教授治疗类风湿关节炎经验总结[J].风湿病与关节 炎,2013,2(7)：45-50.
[16]吴泳昕,肖泓,吴生元.吴生元辨治类风湿关节炎的经验[J].中国中医药信息杂志,2004,11(10)：920-921.
[17]王智明.张延昌治类风湿性关节炎学术探讨[J].中医药通报,2009,8(1):15-17.
[18]林昌松,关彤,刘晓玲.陈纪藩治疗类风湿关节炎临证经验述要[J].中医药学刊,2004,22(2)：214-216.
[19]王振全,潘贵超.蠲痹通络饮治疗类风湿性关节炎的临床观察[J].吉林中医药,2011,31(8)：772-773.
[20]郭荣胜,李鑫元.自拟方治疗类风湿性关节炎48例疗效观察[J].黑龙江医药,2011,24(3)：476-477.
[21]王来群.蛇蝎散加味治疗类风湿性关节炎138例临床观察[J].中外健康文摘,2010,7(18)：350-351.
[22]王勇.补气温阳祛湿活血法治疗类风湿性关节炎60例[J].中国中医药现代远程教育,2010,8(10)：152-153.
[23]林德土.补精健骨搜风汤治疗类风湿性关节炎66例临床观察[J].中国社区医师,2009,11(23)：143-144.
[24]郝瑞雪,都瑞梅.中药内外合治治疗类风湿性关节炎135例[J].中国民间疗法,2009,17(4)：44-45.
[25]唐加兰,王淑芝,王英丽,等.中药自拟方口服及外洗治疗类风湿性关节炎40例临床疗效观察[J].当代医学,2009,15(15)：142-143.
[26]谭立明.火针治疗类风湿性关节炎45例[J].中医药导报,2010,16(4)：68-69.
[27]龚福英.隔药饼灸治疗类风湿性关节炎33例[J].针灸临床杂志,2007,23(5)：42.
[28]刘秀凤,宁秀兰,陈国清.中药蜡疗膏治疗活动期类风湿关节炎的临床观察及护理[J].中华护理杂志,2012,47(8)：726-728.
[29]周志祥,王汉雄,黄泽彦,等.雷公藤药酒治疗活动期类风湿关节炎48例[J].陕西中医,2011,32(12)：1596-1598.
[30]张俊莉,刘英纯,商风楼.脊里药针治疗类风湿性关节炎108例[J].陕西中医,2004,25(1)：62-63.
[31]Stastny P.Mixed lymphocyte cultures in rheumatoid arthritis[J].J Clin Invest,1976,57(5): 1148-57.
[32]Hameed K, Gibson T. A compar is on of the prevalence of rheumatoid arthritis and other rthumatie diseases amongst Pakistan is living in England and Pakistan [J]. British Journal of Rheumatology,1997,26:781-3.
[33]Silman AJ,Hennessy E,Oilier B,et al.Incidence of rheumatoid arthritis in a genetically predisposed population[J].Br J R heumatol 1992,31 (6):365-8.
[34]古洁若,余步云,周俊宜,等.广东汉族类风湿关节炎某些易感基因研究[J].中华医学遗传学杂志,1997,14(1)：13-14.
[35]朱乃硕,王福庆,陈诗书,等.中国人群HLA-DR4等位基因结构及其与类风湿关节炎相关性研究[J].中华医学杂志,1994,74：428-30.
[36]张胜利,叶德富,郑玲,等.福建籍汉族人群HLA-DR4等位基因与类风湿关节炎相关性研究[J].福建医药杂志,2004,25(1)：75-76.
[37]苏茵,栗占国,贾汝琳.HLA-DRβ1*04亚型的氨基酸序列与类风湿关节炎易感相关性分析[J].中华风湿病学杂志,2004,8(4)：215-219.
[38]潘正论,张源潮.中国内地人群类风湿关节炎与HLA-DRB1共同表位基因关联性的Mate分析[J].中华风湿医学杂志,2004,8(11)：662-668.
[39]郑瑞芝,李蓉,张素华.PTPN22基因多态性与自身免疫性内分泌疾病[J].国际内分泌代谢杂志,2007,27(2)：89-91.
[40]Remmers E F,Plenge R M,Lee A T,et al.STAT4 and risk of rheumatoid arthritis and systemic lupus erythematosus[J].N Engl J Med,2007,357(10):977-986.
[41]庞红梅,舒荣,崔刘福,等.信号转导和转录激活因子4基因多态性与类风湿关节炎发病的相关性[J].苏州大学学报,2010,30(3)：548-550.
[42]许泼实,邵凤民,孙长义.PADI4单核苷酸多态性与类风湿关节炎相关性的Meta分析[J].检验医学,2012,27(9)：707-712.
[43]张强,刘秀梅.sICAM-1和Th1/Th2型细胞因子在类风湿关节炎发病中的作用[J].中国现代医生,2011,49(3)：17-19.
[44]李妍.Th细胞及趋化因子受体CCR4、CCR6与类风湿性关节炎的相关性研究[J].中国误诊学杂志,2010,10(19)：4540-4542.
[45]王娟,刘瑞洪,肖红波.类风湿关节炎大鼠血清Th1/Th2水平及意义[J].现代生物医学 进展,20I0,10(2)：246-247.
[46]李景怡,方勇飞,邹丽云.Thl/Th2细胞因子谱在类风湿关节炎患者外周血和关节积液中的表达及意义[J].第三军医大学学报,2010,32(18)：1921-1924.
[47]Kelchtermans H,De Klerck B,Mitera T,Van Balen M,Bullens D,Billiau A,Leclercq G,Matthys P.Defective CD4+CD25+regulatory T cell function in collagen-induced arthritisran important factor in pathogenesis,counter-regulated by endogenous IFN-gamma[J].Arthritis Res Ther,2005,7:R402-415.
[48]Jang E, Cho M L,Oh H J,et al. Deficiency of Foxp3+ regulatory T cells exacerbates autoimmune arthritis by altering the synovial proportions of CD4+ T Cells and dendritic cells[J].Immune Netw,2011,11(5):299-306.
[49]张蓉,刘秀梅.CD4+CD25+Treg细胞表面CTLA-4及血清IL-10、TGF-β1在类风湿关节炎中的表达及意义[J].中国现代医生,2010,48(9)：1-5.
[50]Fletcher J M,Lonergan R,Costelloe L,et al.CD39+ Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis[J].J Immunol,2009,183(11):7602-7610.
[51]Tsuji F,Yoshimi Miwa,Katsuta O,et al.Point mutation of tyrosine 759 of the IL-6 family cytokine receptor,gp130,augments collagen-induced arthritis in DBA/1J mice[J].BMC Musculoskelet Disord 2009,10:23.
[52]李盛村,鲍捷,王国祥.IL-6与OPG/RANKL/RANK信号通路在风湿性关节炎发病机制中的作用[J].现代预防医学,2013,40(5)：933-935.
[53]Estelle Bettelli,Thomas korn,Mohamed Oukka,Vijay K.Kuchroo.Induction and effector functions of TH17 cells[J].Nature,2008,453(19):1051.
[54]王小超,陆翔,陆玉敏,等.类风湿性关节炎早期患者IL-17水平与骨关节损害的相关性研究[J].山东医药,2011,51(1)：102-103.
[55]马田瑞,韩捷,陈海燕.Th17细胞在类风湿性关节炎发病机制中的作用[J].同济大学学报,2010,31(4)：121-124.
[56]李霞,陈旭赛,马子程.白细胞介素17在胶原性关节炎大鼠血清中的表达及其意义[J].中国组织工程研究与临床康复,2009,13(24)：4721-4724.
[57]谢庆云,魏萌,张波,等.外周血炎性细胞因子与类风湿关节炎[J].中国组织工程研 究,2012,16(45)：7945-7950.
[58]钱红艳,赵文明.TNF-α和RANKL与类风湿关节炎的研究进展[J].微生物学免疫学进展,2013,41(5)：51-55.
[59]Feldmann M,Steinman L.Design of effective immunotherapy for human autoimmunity[J] .Nature,2005,435(7042):612-619.
[60]张春访,蔡辉.滑液及血清TNF-α检测在类风湿性关节炎诊治中的意义[J].实验与检验医学,2008,26(1)：72-73.
[61]刘晓华,汤建平,郑肇巽.类风湿关节炎滑膜组织PDGF与TGF-β1的表达与意义[J].山东医药,2002,42(18)：6-7.
[62]王豫萍,肖林生,周艳,等.类风湿性关节炎与转化生长因子β1基因多态性[J].中国公共卫生,2007,23(11)：1405-1406.
[63]王豫萍,周艳,肖林生,等.TGF-β1-509C/T基因多态性与类风湿性关节炎相关性研究[J].临床检验杂志,2008,26,(1)：31-32.
[64]蒋真,李向培,钱龙,等.HIA-DRB1等位基因分型与类风湿关节炎相关性研究[J].安徽医药,2010,14(11)：1299-1302.
[65]Koval A,Katanaev V L.Wnt3a stimulation elicits G-protein-coupled receptor properties of mammalian Frizzled proteins[J].Biochem J,2011.433:435-440.
[66]肖光华,何青青,何东仪,等.Wnt信号通路与类风湿关节炎关系的研究[J].陕西医药杂志,2012,41(12)：129-1222.
[67]周振华,徐卫东.Wnt信号通路与类风湿关节炎发生研究进展[J].中华风湿病学杂志,2008,12(6)：421-425.
[68]Baron M,Saito H,Gori F.Bone Cells Crosstalk:Noncanonical Roring in the Wnt[J].Cell Metabolism,2012,15(4):415-4.17.
[69]Burridge K,Wennerberg K.Rho and Rac take center stage[J].Cell,2004,116:167-179.
[70]梁柳琴,肖游君,付迪,等.RhoA/ROCK信号通路对TLR-2配体诱导的类风湿关节炎患者成纤维滑膜细胞分泌趋化因子的调控作用[J].中华医学杂志,2011,91(11)：742-745.
[71]Kasperkovitz PV,Verbeet NL,Smeets TJ,et al.Activation of the STAT1 pathway in rheumatoid arthritis[J].Ann Rheum Dis,2004,63(3):233-239.
[72]高薇,张榕,赵丽娟,等JAK/STAT信号通路在大鼠类风湿关节炎模型发病过程中的表 达[J].中华风湿病学杂志,2007,11(4)：229-233.
[73]孙晓云,苏茵,任丽敏,等.甲氨蝶呤对类风湿关节炎患者的治疗作用及对相关细胞因子的影响[J].北京大学学报,2006,38(4)：356-359.
[742]朱剑,黄烽,张江林,等.来氟米特对类风湿关节炎患者外周血Th1/Th2平衡和关节功能的影响[J].中国临床康复,2004,8(20)：4023-4025.
[75]高洁生,谢希,吴轰,等.甲氨蝶呤和来氟米特联合治疗重症类风湿关节炎15月的临床疗效[J].中国新药与临床杂志,2006,25(10)：766-768.
[76]郑红梅,邓紫玉.甲氨蝶呤、柳氮磺吡啶、硫酸羟氯喹联合治疗类风湿关节炎对血脂的影响[J].昆明医科大学学报,2013,34(8)：63-66.
[77]田静,高洁生,吴轰,等.甲氨蝶呤、柳氮磺吡啶、硫酸羟氯喹联合治疗类风湿关节炎疗效及安全性研究[J].中国医师进修杂志,2007,30(10)：52-54.
[78]刘潇潇,杨南萍.IL-1受体拮抗剂联合甲氨蝶呤对类风湿关节炎患者血清趋化因子CCL5的影响及疗效初步评定[J].四川大学学报,2009,40(5)：966-968.
[79]张清,岳涛,周凌,等.人重组白细胞介素-1受体拮抗剂在类风湿关节炎治疗中的继发性失效[J].中华风湿病学杂志,2012,16(5)：335-338.
[80]高晓珺,解骏,肖涟波,等.TNF-α拮抗剂对胶原诱导大鼠类风湿关节炎骨破坏治疗作用的实验研究[J].中国骨质疏松杂志,2013,19(5)：458-464.
[81]陈学曼,刘杨,李振英.雷公藤多甙治疗佐剂关节炎大鼠对TH1/TH2细胞平衡的影响[J].黑龙江医药科学,2009,32(2)：95-86.
[82]曹红,杨明辉,魏锦.雷公藤多苷对类风湿关节炎患者表达趋化因子的影响[J].四川中医,2006,24(10)：21-22.
[83]姚茹冰,高佩芳,赵智明.三七总皂苷对类风湿关节炎环瓜氨酸肽抗原特异性T细胞分泌IFN-γ及IL--4的影响[J].医学研究生学报,2010,23(11)：1148-1150.
[84]刘淑清,陈湘君.益气补肾活血方对佐剂关节炎大鼠IL-10和IL-17的影响[J].风湿病与关节炎,2013,2(12)：26-29.
[85]张琦,吴轰,江泳,等.桂枝芍药知母汤对转基因小鼠胶原诱导性关节炎CRP、IL-2的影响[J].中医杂志,2005,46(11)：854-856.
[86]朱江,谢文利,晋玉章,等.栀子对类风湿性关节炎大鼠血清IL-1β和TNF-α的影响[J].中成药,2005,27(7)：801-803.
[87]刘喜德,张金禄,叶丽红,等.温化蠲痹方对类风湿关节炎患者外周血TNF-a及IL-1p的影响[J].中国中西医结合杂志,2009,29(9)：787-790.
[88]高忠恩,陈宇,王建义,等.中药芪龙风湿丸对类风湿关节炎患者外周血细胞因子IL-1,IL-6,TNF-α的影响[J].蛇志,2007,19(4)：265-267.
[89]刘健,万磊,黄传兵,等.健脾化湿通络中药新风胶囊对老年类风湿关节炎患者肺功能及调节性T细胞的影响[J].中国中西医结合急救杂志,2013,20(1)：5-8.
[90]全世明,曾耀英,陈纪藩,等.通痹灵对多克隆刺激剂作用下小鼠T细胞CD69表达影响的血清免疫药理评价[J].中国免疫学杂志,2002,18(5)：330-333.
[91]常志遂,王义军,胡荫奇.风湿安冲剂对实验性类风湿性关节炎大鼠免疫功能影响的观察[J].中国中医基础医学杂志,2000,6(3)：29-31.
[92]欧晓燃,王幸栓.蚁附蠲痹颗粒对佐剂性关节炎大鼠滑膜组织中Caspase-3表达的影响[J].云南中医中药杂志,2006,27(2)：41-43.
[93]王明艳,许冬青.清络通痹冲剂对佐剂性关节炎大鼠的影响[J].辽宁中医杂志,2002,23(8)：501-502.
[94]金秀娟,沈鹰,陆继娣.风湿痹痛胶囊抗炎消肿及镇痛作用的实验研究[J].贵阳中医学院学报,2007,29(3)：65-67.
[95]王宪英,杨劫,李雪靖.骨痹宁胶囊的药效学研究[J].医药导报,2010,29(4)：436-438.
[96]姚志凌,李明辉,冯欣煜,等.风湿定胶囊的药效学研究[J].时珍国医国药,2005,16(8)：754-755.
[97]张永华,欧晓燃.蚁附蠲痹颗粒镇痛抗炎作用的实验研究[J].成都中医药大学学报,2005,28(3)：24-28.
[98]周丕琪,沈霖,杨艳萍,等.补肾法对类风湿性关节炎患者血液流变学的影响[J].中国骨伤,2002,15(7)：409-410.
[99]吴启富,接红宇,丁朝霞,等.痹祺胶囊对类风湿关节炎患者血压及血液流变学影响的临床研究[J].中医药导报,2011,17(6)：15-17.
[100]李军,刘强,颉旺军.身痛逐瘀汤加味对类风湿关节炎患者血液流变学与微循环的影响[J].中医药学报,2010,38(3)：100-103.
[2]中华医学会风湿病学分会.类风湿关节炎诊断及治疗指南[J].中华风湿病学杂志,2010,14(4)：265-270.
[3]Li-Fei Hou,Shi-Jun He,Jun-Xia Wang,et al.SM934,a water-soluble derivative of art eminisin,exerts immunosuppressive functions in vitro and in vivo[J].International Immunopha-rmacology.2009,9:1509-1517.
[4]王晓丽,李小峰,温鸿雁.植物药治疗类风湿关节炎的研究现状[J].山西医药杂志,2007,36(7)：542-546.
[5]彭江云,狄朋桃,李兆福,等.类风湿关节炎发病学初探[J].世界中西医结合杂志,2012,7(10)：34-36.
[6]彭江云,狄朋桃,李兆福,等.云南地区类风湿关节炎中医证候学研究[J].中国中医药信息杂志,2012,19(7)：15-17.
[7]彭江云,李兆福,刘维超,等.蠲痹颗粒抗炎镇痛作用的实验研究[J].中国中医骨伤杂志,2009,17(11)：52-53.
[8]万春平,李兆福,彭江云,等.蠲痹颗粒主要药效学及安全性评价研究[J].风湿病与关节炎,2012,1(5)：16-18.
[9]彭江云,李兆福,刘维超,等.蠲痹颗粒治疗类风湿关节炎40例临床疗效观察[J].云南中医中药杂志,2009,30(12)：12-14.
[10]Vander graaff WL,Pnins AP. Prognostic value of Thl/Th2 ratio in rheumatoid arthritis[J]. Lancet,1998,351(6):1931-1937.
[11]Dan R.Littman, Alexander Y,Rudensky.Th17 and Regulatory T Cells in Mediating and Restraining Inflammation[J]. Cell,2010,140:845-858.
[12]Estelle Bettelli,Yijun Carrier,Wenda Gao.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J].nature,2006,441:235-238.
[13]徐雪,吕玲.Th17与Treg在系统性红斑狼疮发病机制中的作用[J].现代免疫学,2010,30(3)：257-261.
[14]Smolen JS, Breedveld FC, Schiff MH,et al.A simplified disease activity index for rheumatoid arthritis for use in clinical practice[J].Rheumatology(Oxford),2003,42:244-257.
[15]Pincus T,Yazici Y, Bergman M,et al.A proposed continuous quality improvement approach to assessment and management of patients with rheumatoid arthritis without formal joint counts,based on quantitative routine assessment of patient index data (RAPID) scores on a multidimensional health assessment questionnaire (MDHAQ)[J].Best Practice & Research Clinical Rheumatology,2007,21:789-804.
[16]Hochberg MC,Chang RW, Dwosh I,et al.The American College of Rheumatology 1991 revise criteria for classification of global functional status in rheumatoid arthritis[J].Rthritis Rheum,1992,35:498-502.
[17]吴军,张卓莉,李振彪,等.重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白联合甲氨蝶呤治疗活动性类风湿关节炎的疗效和骨代谢的影响[J].中华医学杂志,2010,90：2481-2485.
[18]国家中医药管理局.中医病证诊断疗效标准[S].南京：南京大学出版社,1994：30-31.
[19]国家药品监督管理局.中药新药临床研究指导原则[S].北京：中国医药科技出版社,2002,115-119.
[20]Aletaha D,Ward MM, Machold KP,et al.Remission and active disease in rheumatoid arthritis:defining criteria for disease activity states[J].Arthritis Rheum,2005,52(9):2625-2636.
[21]Aletaha D,Smolen JS. Remission of rheumatoid arthritis:should we care about definitionns?[J]. Clin Exp Rheumatol,2006,24:S45-51.
[22]朱建华.虫类药在RA中的应用[J].中国临床医生,2000,28(4)：12-13.
[23]何羿婷,陈伟,焦树德.应用焦树德教授学术思想临证体会[J].中国中医基础医学杂志,2004,10(4)：59-61.
[24]宋利梅,冯修高.治疗寒湿痹阻型类风湿关节炎的复方中单味药相关药理研究近况[J].现代中西医结合杂志,2009,18(6)：712-713.
[25]刘素苗,张莉芸,马丹.临床疾病活动指数和简化疾病活动指数在类风湿关节炎疾病活动性评估中的比较研究[J].中华风湿病学杂志,2012,16(9)：601-605.
[26]刘栩,路晓燕,赵岩,等.类风湿关节炎诊断和缓解标准及其进展[J].中华内科杂志,2010,49(4)：354-356.
[27]张毅,王旭光,何惠娟,等.木犀草素体内抗炎作用机制研究[J].广东医学院学报, 2009,27(6)：606.
[28]陈孟平,乔为平,赵云华,等.黔产棘茎梅木抗炎作用及部分机制研究[J].中国实验方剂学杂志,2012,18(8)：156.
[29]魏伟,吴希美,李元建.药理实验方法学[M].北京：人民卫生出版社,2010：742.
[30]JX Wang,W Tang, R Zhou,et al. The new water-soluble artemisinin derivative SM905 ameliorates collagen-induced arthritis by suppression of inflammatory and Th17 responses [J]. BJP,2008,153:1303-1310.
[31]Drosos AA. Epidemiology of rheumatoid arthritis[J].Autoimmun Rev.2004,3(suppl): S20-22.
[32]张乃峥,曾庆馀,张凤山,等.中国风湿性疾病流行情况的调查研究[J].中华风湿病学杂志,1997,1(1)：31-35.
[33]肖长虹.试论类风湿性关节炎中医研究的思路与方法[J].新中医,1997,29(11)：2.
[34]Skapenko A,Kalden JR. Treatment of rheumatoid arthritis in the third millennium [J].Scand J Rheumatol.2001,30(5):249-254.
[35]Cvetkovic JT,Wallberg-jonsson S,Stegmayr B,et al.Susceptibility for and clinical manifestations of RA are associated with polymorphisms of the TNF-α,IL-1β and IL-1α gene[J]. Rheumatol,2002,29(2):212-219.
[36]King C,Tangye SG, Mackay CR.T follicular helper (TFH) cells in normal and dysregulated immune responses[J]. Annu Rev Immunol,2008,26:741-766.
[37]Kristine Kikly,Ling Liu,Songqing Na,et al.The IL-23/Th17 axis:therapeutic targets for autoimmune inflammation[J].Current Opinion in Immunology,2006,18:670-675.
[38]Kelchtermans H, De Klerck B,Mitera T,et al.Defective CD4+CD25+regulatory T cell function in collagen-induced arthritis:an important factor in pathogenesis,counter-regulated by endogenous IFN-gamma[J]. Arthritis Res Ther,2005,7:R402-415.
[39]Ru Zhou a,Fan Zhang b,Pei-Lan He.etal.(5R)-5-hydroxytriptolide (LLDT-8),a novel triptolide analogmediates immunosuppressive effects in vitro and in vivo.International Immunopharmacology.2005,5:1895-1903.
[40]王绪辉,朱显华,闵熙敬.实验性小鼠内伤痹证模型的建立[J].中国医药学报,1990,5(6)：64-65.
[41]李宝丽,唐方,庞晓东.II型胶原诱导关节炎大鼠模型制备[J].中国免疫学杂志,2006,22(4)：350-352.
[42]李景怡,吴玉章,陈永文,等.盐酸青藤碱抑制小鼠胶原性关节炎的实验研究[J].免疫学杂志,2005,21(4)：313-316.
[43]Maini RN,Taylor PC. Anti-cytokine therapy for rheumatoid arthritis [J].Annu Rev Med,2000,51:207-229.
[44]周茹,杨以阜,左建平.II型胶原诱导的小鼠关节炎动物模型的建立及影响因素[J].中国药理学通报,2006,22(12)：1532.
[45]Estelle Bettelli, Thomas korn,Mohamed Oukka,Vijay K. Kuchroo.Induction and effector functions of TH17 cells[J]. Nature,2008,53(19):1051.
[46]H Kelchtermans,L Geboes,T Mitera,et al.Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis[J]. Ann Rheum Dis,2009,68: 744-750.
[1]周仲瑛.中医内科学[M].北京：中国中医药出版社,2007：464.
[2]祝谌予,翟济生,施如瑜,等.施今墨临床经验集[M].北京：人民卫生出版社,2005：127.
[3]何羿婷,陈伟,焦树德.应用焦树德教授学术思想临证体会[J].中国中医基础医学杂志,2004,10(4)：59-61.
[4]娄高峰,娄玉钤.娄多峰治疗风湿病经验撷菁[J].辽宁中医杂志,2006,33(2)：147-148.
[5]谢海洲.谢海洲论医集[M].上海：上海辞书出版社,1993：158.
[6]肖泓,吴永昕,吴生元.吴生元辨治类风湿性关节炎的经验[J].云南中医中药杂志,2009,30(4)：1-2.
[7]曾升海,田惠民.朱良春治疗痹病的用药经验介绍[J].陕西中医,2001,22(7)：409-450.
[8]商阿萍,路洁.路志正教授治疗类风湿关节炎经验[J].河北中医,2008,30(4)：341-343.
[9]路志正,焦树德.实用中医风湿病学[M].北京：人民卫生出版社,1996：459-460.
[10]范伏元,金朝晖.通痹汤治疗活动期类风湿性关节炎的临床研究[J].中国中医药科技,2006,13(1)：3-4.
[11]赵语华,周艳伟.羌威蠲痹合剂治疗类风湿关节炎活动期的临床研究[J].河北中医,2008,20(9)：907-909.
[12]戴小娟,李武军.桂枝汤加味治疗缓解期类风湿关节炎疗效观察[J].河北中医,2012,34(9)：1348-1349.
[13]考希良,宋绍亮,王诗源.清痹扶正汤防治类风湿关节炎复发临床研究[J].山东中医杂志,2006,25(11)：735-737.
[14]刘喜德,万力生主编.类风湿性关节炎的诊断与治疗[M].北京：人民军医出版社,2006：307-309.
[15]李满意,娄玉钤,杨林江.娄多峰教授治疗类风湿关节炎经验总结[J].风湿病与关节 炎,2013,2(7)：45-50.
[16]吴泳昕,肖泓,吴生元.吴生元辨治类风湿关节炎的经验[J].中国中医药信息杂志,2004,11(10)：920-921.
[17]王智明.张延昌治类风湿性关节炎学术探讨[J].中医药通报,2009,8(1):15-17.
[18]林昌松,关彤,刘晓玲.陈纪藩治疗类风湿关节炎临证经验述要[J].中医药学刊,2004,22(2)：214-216.
[19]王振全,潘贵超.蠲痹通络饮治疗类风湿性关节炎的临床观察[J].吉林中医药,2011,31(8)：772-773.
[20]郭荣胜,李鑫元.自拟方治疗类风湿性关节炎48例疗效观察[J].黑龙江医药,2011,24(3)：476-477.
[21]王来群.蛇蝎散加味治疗类风湿性关节炎138例临床观察[J].中外健康文摘,2010,7(18)：350-351.
[22]王勇.补气温阳祛湿活血法治疗类风湿性关节炎60例[J].中国中医药现代远程教育,2010,8(10)：152-153.
[23]林德土.补精健骨搜风汤治疗类风湿性关节炎66例临床观察[J].中国社区医师,2009,11(23)：143-144.
[24]郝瑞雪,都瑞梅.中药内外合治治疗类风湿性关节炎135例[J].中国民间疗法,2009,17(4)：44-45.
[25]唐加兰,王淑芝,王英丽,等.中药自拟方口服及外洗治疗类风湿性关节炎40例临床疗效观察[J].当代医学,2009,15(15)：142-143.
[26]谭立明.火针治疗类风湿性关节炎45例[J].中医药导报,2010,16(4)：68-69.
[27]龚福英.隔药饼灸治疗类风湿性关节炎33例[J].针灸临床杂志,2007,23(5)：42.
[28]刘秀凤,宁秀兰,陈国清.中药蜡疗膏治疗活动期类风湿关节炎的临床观察及护理[J].中华护理杂志,2012,47(8)：726-728.
[29]周志祥,王汉雄,黄泽彦,等.雷公藤药酒治疗活动期类风湿关节炎48例[J].陕西中医,2011,32(12)：1596-1598.
[30]张俊莉,刘英纯,商风楼.脊里药针治疗类风湿性关节炎108例[J].陕西中医,2004,25(1)：62-63.
[31]Stastny P.Mixed lymphocyte cultures in rheumatoid arthritis[J].J Clin Invest,1976,57(5): 1148-57.
[32]Hameed K, Gibson T. A compar is on of the prevalence of rheumatoid arthritis and other rthumatie diseases amongst Pakistan is living in England and Pakistan [J]. British Journal of Rheumatology,1997,26:781-3.
[33]Silman AJ,Hennessy E,Oilier B,et al.Incidence of rheumatoid arthritis in a genetically predisposed population[J].Br J R heumatol 1992,31 (6):365-8.
[34]古洁若,余步云,周俊宜,等.广东汉族类风湿关节炎某些易感基因研究[J].中华医学遗传学杂志,1997,14(1)：13-14.
[35]朱乃硕,王福庆,陈诗书,等.中国人群HLA-DR4等位基因结构及其与类风湿关节炎相关性研究[J].中华医学杂志,1994,74：428-30.
[36]张胜利,叶德富,郑玲,等.福建籍汉族人群HLA-DR4等位基因与类风湿关节炎相关性研究[J].福建医药杂志,2004,25(1)：75-76.
[37]苏茵,栗占国,贾汝琳.HLA-DRβ1*04亚型的氨基酸序列与类风湿关节炎易感相关性分析[J].中华风湿病学杂志,2004,8(4)：215-219.
[38]潘正论,张源潮.中国内地人群类风湿关节炎与HLA-DRB1共同表位基因关联性的Mate分析[J].中华风湿医学杂志,2004,8(11)：662-668.
[39]郑瑞芝,李蓉,张素华.PTPN22基因多态性与自身免疫性内分泌疾病[J].国际内分泌代谢杂志,2007,27(2)：89-91.
[40]Remmers E F,Plenge R M,Lee A T,et al.STAT4 and risk of rheumatoid arthritis and systemic lupus erythematosus[J].N Engl J Med,2007,357(10):977-986.
[41]庞红梅,舒荣,崔刘福,等.信号转导和转录激活因子4基因多态性与类风湿关节炎发病的相关性[J].苏州大学学报,2010,30(3)：548-550.
[42]许泼实,邵凤民,孙长义.PADI4单核苷酸多态性与类风湿关节炎相关性的Meta分析[J].检验医学,2012,27(9)：707-712.
[43]张强,刘秀梅.sICAM-1和Th1/Th2型细胞因子在类风湿关节炎发病中的作用[J].中国现代医生,2011,49(3)：17-19.
[44]李妍.Th细胞及趋化因子受体CCR4、CCR6与类风湿性关节炎的相关性研究[J].中国误诊学杂志,2010,10(19)：4540-4542.
[45]王娟,刘瑞洪,肖红波.类风湿关节炎大鼠血清Th1/Th2水平及意义[J].现代生物医学 进展,20I0,10(2)：246-247.
[46]李景怡,方勇飞,邹丽云.Thl/Th2细胞因子谱在类风湿关节炎患者外周血和关节积液中的表达及意义[J].第三军医大学学报,2010,32(18)：1921-1924.
[47]Kelchtermans H,De Klerck B,Mitera T,Van Balen M,Bullens D,Billiau A,Leclercq G,Matthys P.Defective CD4+CD25+regulatory T cell function in collagen-induced arthritisran important factor in pathogenesis,counter-regulated by endogenous IFN-gamma[J].Arthritis Res Ther,2005,7:R402-415.
[48]Jang E, Cho M L,Oh H J,et al. Deficiency of Foxp3+ regulatory T cells exacerbates autoimmune arthritis by altering the synovial proportions of CD4+ T Cells and dendritic cells[J].Immune Netw,2011,11(5):299-306.
[49]张蓉,刘秀梅.CD4+CD25+Treg细胞表面CTLA-4及血清IL-10、TGF-β1在类风湿关节炎中的表达及意义[J].中国现代医生,2010,48(9)：1-5.
[50]Fletcher J M,Lonergan R,Costelloe L,et al.CD39+ Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis[J].J Immunol,2009,183(11):7602-7610.
[51]Tsuji F,Yoshimi Miwa,Katsuta O,et al.Point mutation of tyrosine 759 of the IL-6 family cytokine receptor,gp130,augments collagen-induced arthritis in DBA/1J mice[J].BMC Musculoskelet Disord 2009,10:23.
[52]李盛村,鲍捷,王国祥.IL-6与OPG/RANKL/RANK信号通路在风湿性关节炎发病机制中的作用[J].现代预防医学,2013,40(5)：933-935.
[53]Estelle Bettelli,Thomas korn,Mohamed Oukka,Vijay K.Kuchroo.Induction and effector functions of TH17 cells[J].Nature,2008,453(19):1051.
[54]王小超,陆翔,陆玉敏,等.类风湿性关节炎早期患者IL-17水平与骨关节损害的相关性研究[J].山东医药,2011,51(1)：102-103.
[55]马田瑞,韩捷,陈海燕.Th17细胞在类风湿性关节炎发病机制中的作用[J].同济大学学报,2010,31(4)：121-124.
[56]李霞,陈旭赛,马子程.白细胞介素17在胶原性关节炎大鼠血清中的表达及其意义[J].中国组织工程研究与临床康复,2009,13(24)：4721-4724.
[57]谢庆云,魏萌,张波,等.外周血炎性细胞因子与类风湿关节炎[J].中国组织工程研 究,2012,16(45)：7945-7950.
[58]钱红艳,赵文明.TNF-α和RANKL与类风湿关节炎的研究进展[J].微生物学免疫学进展,2013,41(5)：51-55.
[59]Feldmann M,Steinman L.Design of effective immunotherapy for human autoimmunity[J] .Nature,2005,435(7042):612-619.
[60]张春访,蔡辉.滑液及血清TNF-α检测在类风湿性关节炎诊治中的意义[J].实验与检验医学,2008,26(1)：72-73.
[61]刘晓华,汤建平,郑肇巽.类风湿关节炎滑膜组织PDGF与TGF-β1的表达与意义[J].山东医药,2002,42(18)：6-7.
[62]王豫萍,肖林生,周艳,等.类风湿性关节炎与转化生长因子β1基因多态性[J].中国公共卫生,2007,23(11)：1405-1406.
[63]王豫萍,周艳,肖林生,等.TGF-β1-509C/T基因多态性与类风湿性关节炎相关性研究[J].临床检验杂志,2008,26,(1)：31-32.
[64]蒋真,李向培,钱龙,等.HIA-DRB1等位基因分型与类风湿关节炎相关性研究[J].安徽医药,2010,14(11)：1299-1302.
[65]Koval A,Katanaev V L.Wnt3a stimulation elicits G-protein-coupled receptor properties of mammalian Frizzled proteins[J].Biochem J,2011.433:435-440.
[66]肖光华,何青青,何东仪,等.Wnt信号通路与类风湿关节炎关系的研究[J].陕西医药杂志,2012,41(12)：129-1222.
[67]周振华,徐卫东.Wnt信号通路与类风湿关节炎发生研究进展[J].中华风湿病学杂志,2008,12(6)：421-425.
[68]Baron M,Saito H,Gori F.Bone Cells Crosstalk:Noncanonical Roring in the Wnt[J].Cell Metabolism,2012,15(4):415-4.17.
[69]Burridge K,Wennerberg K.Rho and Rac take center stage[J].Cell,2004,116:167-179.
[70]梁柳琴,肖游君,付迪,等.RhoA/ROCK信号通路对TLR-2配体诱导的类风湿关节炎患者成纤维滑膜细胞分泌趋化因子的调控作用[J].中华医学杂志,2011,91(11)：742-745.
[71]Kasperkovitz PV,Verbeet NL,Smeets TJ,et al.Activation of the STAT1 pathway in rheumatoid arthritis[J].Ann Rheum Dis,2004,63(3):233-239.
[72]高薇,张榕,赵丽娟,等JAK/STAT信号通路在大鼠类风湿关节炎模型发病过程中的表 达[J].中华风湿病学杂志,2007,11(4)：229-233.
[73]孙晓云,苏茵,任丽敏,等.甲氨蝶呤对类风湿关节炎患者的治疗作用及对相关细胞因子的影响[J].北京大学学报,2006,38(4)：356-359.
[742]朱剑,黄烽,张江林,等.来氟米特对类风湿关节炎患者外周血Th1/Th2平衡和关节功能的影响[J].中国临床康复,2004,8(20)：4023-4025.
[75]高洁生,谢希,吴轰,等.甲氨蝶呤和来氟米特联合治疗重症类风湿关节炎15月的临床疗效[J].中国新药与临床杂志,2006,25(10)：766-768.
[76]郑红梅,邓紫玉.甲氨蝶呤、柳氮磺吡啶、硫酸羟氯喹联合治疗类风湿关节炎对血脂的影响[J].昆明医科大学学报,2013,34(8)：63-66.
[77]田静,高洁生,吴轰,等.甲氨蝶呤、柳氮磺吡啶、硫酸羟氯喹联合治疗类风湿关节炎疗效及安全性研究[J].中国医师进修杂志,2007,30(10)：52-54.
[78]刘潇潇,杨南萍.IL-1受体拮抗剂联合甲氨蝶呤对类风湿关节炎患者血清趋化因子CCL5的影响及疗效初步评定[J].四川大学学报,2009,40(5)：966-968.
[79]张清,岳涛,周凌,等.人重组白细胞介素-1受体拮抗剂在类风湿关节炎治疗中的继发性失效[J].中华风湿病学杂志,2012,16(5)：335-338.
[80]高晓珺,解骏,肖涟波,等.TNF-α拮抗剂对胶原诱导大鼠类风湿关节炎骨破坏治疗作用的实验研究[J].中国骨质疏松杂志,2013,19(5)：458-464.
[81]陈学曼,刘杨,李振英.雷公藤多甙治疗佐剂关节炎大鼠对TH1/TH2细胞平衡的影响[J].黑龙江医药科学,2009,32(2)：95-86.
[82]曹红,杨明辉,魏锦.雷公藤多苷对类风湿关节炎患者表达趋化因子的影响[J].四川中医,2006,24(10)：21-22.
[83]姚茹冰,高佩芳,赵智明.三七总皂苷对类风湿关节炎环瓜氨酸肽抗原特异性T细胞分泌IFN-γ及IL--4的影响[J].医学研究生学报,2010,23(11)：1148-1150.
[84]刘淑清,陈湘君.益气补肾活血方对佐剂关节炎大鼠IL-10和IL-17的影响[J].风湿病与关节炎,2013,2(12)：26-29.
[85]张琦,吴轰,江泳,等.桂枝芍药知母汤对转基因小鼠胶原诱导性关节炎CRP、IL-2的影响[J].中医杂志,2005,46(11)：854-856.
[86]朱江,谢文利,晋玉章,等.栀子对类风湿性关节炎大鼠血清IL-1β和TNF-α的影响[J].中成药,2005,27(7)：801-803.
[87]刘喜德,张金禄,叶丽红,等.温化蠲痹方对类风湿关节炎患者外周血TNF-a及IL-1p的影响[J].中国中西医结合杂志,2009,29(9)：787-790.
[88]高忠恩,陈宇,王建义,等.中药芪龙风湿丸对类风湿关节炎患者外周血细胞因子IL-1,IL-6,TNF-α的影响[J].蛇志,2007,19(4)：265-267.
[89]刘健,万磊,黄传兵,等.健脾化湿通络中药新风胶囊对老年类风湿关节炎患者肺功能及调节性T细胞的影响[J].中国中西医结合急救杂志,2013,20(1)：5-8.
[90]全世明,曾耀英,陈纪藩,等.通痹灵对多克隆刺激剂作用下小鼠T细胞CD69表达影响的血清免疫药理评价[J].中国免疫学杂志,2002,18(5)：330-333.
[91]常志遂,王义军,胡荫奇.风湿安冲剂对实验性类风湿性关节炎大鼠免疫功能影响的观察[J].中国中医基础医学杂志,2000,6(3)：29-31.
[92]欧晓燃,王幸栓.蚁附蠲痹颗粒对佐剂性关节炎大鼠滑膜组织中Caspase-3表达的影响[J].云南中医中药杂志,2006,27(2)：41-43.
[93]王明艳,许冬青.清络通痹冲剂对佐剂性关节炎大鼠的影响[J].辽宁中医杂志,2002,23(8)：501-502.
[94]金秀娟,沈鹰,陆继娣.风湿痹痛胶囊抗炎消肿及镇痛作用的实验研究[J].贵阳中医学院学报,2007,29(3)：65-67.
[95]王宪英,杨劫,李雪靖.骨痹宁胶囊的药效学研究[J].医药导报,2010,29(4)：436-438.
[96]姚志凌,李明辉,冯欣煜,等.风湿定胶囊的药效学研究[J].时珍国医国药,2005,16(8)：754-755.
[97]张永华,欧晓燃.蚁附蠲痹颗粒镇痛抗炎作用的实验研究[J].成都中医药大学学报,2005,28(3)：24-28.
[98]周丕琪,沈霖,杨艳萍,等.补肾法对类风湿性关节炎患者血液流变学的影响[J].中国骨伤,2002,15(7)：409-410.
[99]吴启富,接红宇,丁朝霞,等.痹祺胶囊对类风湿关节炎患者血压及血液流变学影响的临床研究[J].中医药导报,2011,17(6)：15-17.
[100]李军,刘强,颉旺军.身痛逐瘀汤加味对类风湿关节炎患者血液流变学与微循环的影响[J].中医药学报,2010,38(3)：100-103.