| Purpose: To observe the efficacy and safety of Yiqi Yangyin Tongluo Recipe in the treatment of rheumatoid arthritis of Qi and yin deficiency type by carrying out randomized controlled trials;to further evaluate its anti-inflammatory and pro apoptotic effects,and based on PI3K/ Akt/ mTOR signaling pathway to explore the mechanism of this prescription intervention in rats with rheumatoid arthritis by animal experiments;through systematic review and meta-analysis,to evaluate the clinical efficacy and safety of nourishing yin Chinese medicine compound or Chinese medicine compound combined with western medicine in treating RA,in order to provide a systematic evidence-based medical basis for Yin nourishing therapy in the treatment of rheumatoid arthritis.Material and method:1.80 patients with rheumatoid arthritis of deficiency of both qi and Yin who met the inclusion criteria were randomly assigned to the experimental group or the control group with 40 cases in each group using Stratified-block randomization.The experimental group was treated with Yiqi Yangyin Tongluo traditional Chinese medicine combined with methotrexate,and the control group was treated with Yiqi Yangyin Tongluo TCM simulant combined with methotrexate.The treatment cycle was 12 weeks.Observation indexes: ACR20,acr50 and acr70,curative effect of TCM syndrome,single score of TCM syndrome,symptoms and signs related to rheumatoid arthritis,DAS28 score,VAS score of doctors and patients on current disease status,evaluation of physical function of subjects by HAQ table,safety evaluation.2.Animal experiment: 50 SPF female Wistar rats were randomly divided into five groups,including normal group,model group,Yiqi Yangyin Tongluo formula group,methotrexate group,Yiqi Yangyin Tongluo formula + methotrexate group(10 rats in each group)using random number table.Except for normal group,the other groups received CIA model construction.Yiqi Yangyin Tongluo Decoction group,methotrexate group and Yiqi Yangyin Tongluo Decoction plus methotrexate group were given Yiqi Yangyin Tongluo Decoction,methotrexate suspension and Yiqi Yangyin Tongluo Decoction plus methotrexate suspension respectively.The normal group and model group were given sterile water for injection.After8 weeks of continuous administration,the serum and synovial tissue were taken.The arthritis state of rats was evaluated by arthritis index,joint swelling degree,joint pathological section,serum IL-17 and IL-23 levels;the ability of promoting synovial cell apoptosis was evaluated by the qualitative and quantitative expression of PI3 K,Akt,p-Akt,mTOR,Bcl-2 and Bax protein content in synovial tissue,and the ratio of p-Akt / Akt and Bcl-2 / Bax.3.Chinese database and English database were used to retrieve the literatures according to the subject words from the date of establishment to November 9,2020.The literatures were screened according to the criteria,and the data were extracted through Excel app.Then,the literature quality score(Jadad scale)and the literature bias risk assessment(Cochrane Collaboration Network bias risk assessment toolbar)were performed.Revman 5.3.0 software was used for meta analysis and heterogeneity test.The clinical total effective rate,TCM syndrome total effective rate,symptom(joint swelling number,swelling index,joint tenderness number,tenderness index and morning stiffness time),serological indexes(ESR,CRP,RF,IgG,IgM,TNF-α,IL-1)and safety indexes between the experimental group and the control group were evaluated and analyzed.Results:1.Clinical research resultsClinical evaluation of Western Medicine.The results showed that more patients in the experimental group reached the improvement standards of ACR20,acr50 and acr70 than control group,and the difference was statistically consequence(P<0.05).The DAS28 score,VAS score of pain,VAS score of patients,VAS score of doctors and HAQ score of physical function of subjects in the experimental group gradually decreased with time,and the test group score less than the control group in the 12 th week,the difference was statistically consequence(P<0.05).Compared with baseline level,at week 12,the number of joint tenderness,joint swelling and morning stiffness time of the experimental group decreased significantly.And the level of the experimental group at the 12 th weekwas lower than that in the control group,the difference was statistically consequence(P<0.05).The ESR and CRP levels in the experimental group at the 12 th weekwere significantly lower than the baseline level.the ESR and CRP levels of the experimental group at the 12 th week were significantly lower the control group(P<0.05).Efficacy evaluation of TCM Syndrome.The total effective rates of TCM syndromes in the experimental group and the control group at week 12 were 93.94% and 58.82% respectively,and the experimental group was significantly higher than the control group(P<0.05).Compared with the baseline level,the total score of TCM syndromes,joint swelling,shortness of breath,muscle soreness,dry eyes,dry mouth,spontaneous sweating,night sweats,hand foot heart heat,deficiency,fatigue and dreaminess,emaciation and skin tarnish in the experimental group and the control group at the 12 th week were significantly lower(P<0.05).Compared with the control group,the total score of TCM syndromes,joint swelling,shortness of breath,muscle soreness,dry eyes,dry mouth,spontaneous sweating,night sweating,hand foot and heart heat scores in the experimental group at week 12 were lower(P <0.05).Compared with the control group,the score of emaciation,skin dullness,asthenia and dreaminess syndromes of the experimental group was lower,but the difference was not statistically consequence(P>0.05).Clinical safety evaluation.Compared with the control group,the incidence of gastrointestinal adverse reactions,bone marrow suppression,liver and kidney function damage and other adverse reactions in the experimental group was lower,but the difference was not statistically consequence(P<0.05).2.Results of animal experimentsAnti inflammatory effect of Yiqi Yangyin Tongluo Recipe.Compared with the model group,Yiqi Yangyin Tongluo recipe group,methotrexate group and methotrexate +Yiqi Yangyin Tongluo recipe group could reduce ankle swelling,AI index,IL-17 and IL-23levels(P<0.05),and improve the histopathological damage of ankle synovium.There was no significant difference between Yiqi Yangyin Tongluo recipe group and methotrexate group(P> 0.05).Compared with methotrexate group or Yiqi Yangyin Tongluo recipe group,Yiqi Yangyin Tongluo recipe+methotrexate group improved inflammation significantly in reducing ankle swelling,AI index,IL-17 and IL-23 levels,and improving the histopathological damage of ankle synovium(P<0.05).Effect of Yiqi Yangyin Tongluo Recipe on PI3 K / Akt / mTOR signaling pathway.Western blot and immunohistochemistry results showed that: compared with the model group,Yiqi Yangyin Tongluo recipe group,methotrexate group and methotrexate+Yiqi Yangyin Tongluo recipe group could down regulate the expression of PI3 K,mTOR and bcl-2protein,up regulate the expression of Bax,decrease the ratio of p-Akt / Akt and Bcl-2 / Bax,and up regulate the apoptosis rate of synovial cells(P < 0.05).There was no significant difference between Yiqi Yangyin Tongluo recipe group and methotrexate group(P>0.05).Compared with methotrexate group or Yiqi Yangyin Tongluo prescription group,Yiqi Yangyin Tongluo prescription+methotrexate group has a more significant effect in down-regulating PI3 K,mTOR,Bcl-2 protein overexpression,up-regulating Bax expression,reducing p-Akt/Akt and Bcl-2/Bax ratio,and up-regulating apoptosis rate of synovial tissue(P< 0.05)3.Meta analysis resultsAnalysis of total effective rate and symptom.Compared with the western medicine control group,the total effective rate of traditional Chinese medicine or traditional Chinese medicine combined with western medicine based on nourishing yin was higher than that of the control group in the treatment of RA(P < 0.00001);The total effective rate of traditional Chinese medicine or traditional Chinese medicine combined with western medicine based on nourishing yin was higher than that of the control group(P < 0.05);in terms of improving symptoms,Ziyin method in the treatment of RA was better than the conventional western medicine control group in reducing the number of joint swelling,joint swelling index,joint tenderness index,joint tenderness index and morning stiffness time(P<0.05).Serological index analysis.In terms of reducing laboratory indexes,Ziyin method was better than the conventional western medicine control group in reducing ESR,CRP and RF(P<0.01);In the aspect of reducing immunoglobulin level,the effect of nourishing yin method on reducing IgG was not significantly different from that of the control group(P>0.05),and the effect of reducing IgM was significantly better than that of the control group(P<0.05);In terms of reducing serum inflammatory factor levels,the effect of Ziyin method is better than that of the control group in reducing TNF-α(P<0.05),while the effect of reducing IL-1 is not statistically significant compared with the control group(P>0.05).Security analysis.In terms of safety,compared with the control group,the incidence of adverse reactions of nourishing yin intervention in RA is lower,especially in reducing leukopenia and gastrointestinal discomfort,the difference was statistically significant(P <0.05).Conclusion:1.Clinical research conclusion(1)Yiqi Yangyin Tongluo decoction combined with methotrexate has obvious advantages over methotrexate in reducing DAS28,VAS,HAQ score,improving joint symptoms and signs,reducing serum ESR and CRP levels,and improving ACR 20/ 50/70 compliance rate.(2)Yiqi Yangyin Tongluo recipe combined with methotrexate has obvious advantages in improving the total effective rate of TCM syndrome,reducing the total scores and single scores of TCM syndromes.(3)The safety of Yiqi Yangyin Tongluo recipe combined with methotrexate is obviously better than that of methotrexate.2.Conclusion of animal experiment(1)Yiqi Yangyin Tongluo Recipe can improve the arthritis state of CIA rats,and Yiqi Yangyin Tongluo Recipe combined with methotrexate has the most significant effect.(2)Yiqi Yangyin Tongluo Recipe intervenes rheumatoid arthritis through apoptosis mediated by PI3K/Akt/mTOR signaling pathway.3.Conclusion of meta analysisTreatment of RA by nourishing yin has obvious advantages in improving the total effective rate of clinical and TCM syndromes,improving joint symptoms and signs,and reducing serum inflammatory factors.Meanwhile,the incidence of adverse reactions is low and the safety is high. |
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