| Research Background:Rheumatoid Arthritis(RA)is an unknown etiology autoimmune diseases.Due to the complexity of the participation factor and regulatory mechanism,RA pathogenesis have failed to fully elucidated.Early growth response protein-2(Egr-2)and Egr3 coordinated control and regulate inflammation antigen induced proliferation of T and B cell activation.Studies have shown that Egr2/Egr3 can directly control suppressor of cytokine signaling1(SOCS1)and SOCS3.SOCS family can inhibit signal transducer and activator of transcription 1(STAT1)/STAT3,final performance for control the proliferation and differentiation of helper T cells(help T cell 1,Th1)1 and Th17 cell.RA belongs to the category of "bi disease" of traditional Chinese medicine.The type of "han si bi zu" is common around RA patients."Wen Jing Tong Luo" is one of the effective treatment for RA,JAK/STAT signaling pathways may be involved in the intervention mechanism.Besides this biological mechanisms of "Wen Jing Tong Luo" may be related to the upstream of the Egr.But there is no related reports.Objective:Combined with the research hypothesis of RA that Egr2/Egr3-SOCS1/SOCS 3-STAT1/STAT3 inflammatory pathways as the research basis,to explore the molecular biology mechanism of "Wen Jing Tong Luo" to treat RA "han si bizu",then find the evidence of Egr2/Egr3 in RA.Method:72 cases with conforming RA patients,randomly divided into treatment group and control group.Control group to use methotrexate(MTX)or/and use leflunomide(LEF),and the treatment group use methotrexate(MTX)or/and use leflunomide(LEF)plus the SGFZ soup,treatment for 12 weeks.(1)Through clinical observation of curative effect,defined "Wen Jing Tong Luo" in the treatment of RA clinical crative effect of the specific content includes:General signs and safety indicators;related to the physical and chemical indicators evaluation(including erythrocyte sedimentation rate(ESR),c-reactive protein,rheumatoid factor);DAS28 score,ACR(20/5070),TCM syndrome score,MSUS evaluation.(2)Reasearch the way that "Wen Jing Tong Luo" intervene the inflammatory pathways by Egr2/Egr3,specific methods are as follows:RT-qPCR to Egr2/Egr3,SCOS1/SOCS3 and STAT1/STAT3mRNA expression in CD4+T cells;Flow cytometry instrument measuring to the change of CD4+IFN-γ+(Th1)cells and CD4+IL17A+(Th 17);ELISA to the expression of IL-17A,IFN-γ,TGF-β and IL-6.Results:Select 72 cases of patients with RA of "han si bi zu" which is in active syndrome,including 12 cases off cases,6 cases of treatment group and control group in 6 cases.Total effective cases of 60 cases,each group had 30 cases.Two groups of patients before treatment no obvious differences in demographic characteristics and clinical features.1.Clinical curative effect evaluation of "Wen Jing Tong Luo" to the type of "han si bi zu"of RA patientsClinical symptoms:The group comparison before and after the treatment,the treatment group and control group in the morning stiffness duration,number of joint pain,number of joint swelling,VAS score were decreased(P<0.05).Comparison between before and after treatment groups,the number and duration of morning stiffness,joint swelling,VAS scores,the treatment group is better than that of control group(P<0.05).MSUS evaluation:In hand joints,MCPJ joints involvement condition were higher than PIPJ joint.Number of MCPJ joints involved in the two groups after treatment,and also the previous classification rate less synovitis(P<0.05).There is no significant difference between two groups(P>0.05).Two groups of blood flow signals not seen obvious abnormity,no statistical significance(P>0.05).TCM syndrome integral:The total integration of the two groups after treatment significantly lower than before treatment(P<0.01),the trend of the treatment group was obviously better than the control group.In the comparison of the overall efficient.the treatment group with 96.67%of the total effective rate is significantly higher than 66.67%in the control group.In TCM syndrome score of each dimension analysis show that the treatment group is better than that the control group in the morning stiffness,joint swelling.joint pain.joint tenderness and fear evil cold temperature(P<0.05).Disease activity evaluation:The treatment group and control group is improved DAS28 score(P<0.05),although there is no obvious difference between two groups(P>0.05),but the treatment group in the overall efficiency is better than that of control group(P<0.05).ACR(20/50/70):The treatment group of ACR70 has 4 cases,ACR50 has 14 cases;ACR20 has 5 cases,ACR20 falls below has 7 cases,the total effective rate is 76.67%;The control group of ACR70 has 0 case,ACR50 has 15 cases,ACR20 has 5 cases,ACR20 falls below has 10 cases,the total effective rate is 66.67%.Do not have statistically significant between two groups(P>0.05).HAQ scores:Compared the two groups after treatment,both of HAQ scores significantly is lower than before treatment(P<0.01),after treatment the HAQ scores of two groups have no significant difference(P>0.05).2 Reasearch the way that "Wen Jing Tong Luo" intervene the inflammatory pathways by Egr2/Egr3Inflammatory cytokines:The two groups of IFN-y significantly decreased after treatment(P<0.01),the two groups before treatment IFN-y difference was statistically significant,so the two groups are not comparable(P>0.05).The two groups after treatment of IL-6,IL17A TGF-β level significantly decreased(P<0.01),the comparison between the two groups have no obvious difference(P>0.05).mRNA results:The two groups of Egr2/Egr3 mRNA,SCOS1/SOCS3mRNA relative expression were significantly increased after treatment(P<0.05);The STAT1 and STAT3 mRNA expression of relative amount were significantly decreased after treatment(P<0.05),there was no statistically significant difference between groups compared after treatment(P>0.05).Thl/TH17 cell percentage:Within the group comparison,the treatment group of Th1 cells(CD4+IFN-γ+),Th17 cells(CD4+IL-17A+)in CD4+T cells and the proportion of no significant difference before and after therapy(P>0.05).The control group of Thl cells(CD4+IFN-γ+)and Th17 cells(CD4+IL-17A+)ratio of all higher(P<0.05).Compared to two groups of Thlcells(CD4+IFN-γ+)and Th17 cells(CD4+IL-17A+)in CD4+T cell percentage of change,there is no statistically significant difference(P>0.05).Conclusion:1."Wen Jing Tong Luo" combined with traditional DMARDs medicine is one of the effective treatment for RA.It is not only improved RA cold syndrome in patients with joint pain,swelling,and chills all over the body such as the cold symptoms and physical signs,reduce blood sedimentation,but also improved DAS28,TCM syndrome integral etc,and no significant liver and kidney damage.2.Egr2/Egr3-SOCS1/SOCS3-STAT1/STAT3 inflammatory pathways involved in the pathogenesis of RA of "hansibizu"."Wen Jing Tong Luo" combined with traditional DMARDs medicine can regulate the expression of Egr2/Egr3mRNA,then raised the expression of SOCS1/SOCS3mRNA,reduce STAT1/STAT3mRNA,in the end influence the proliferation/differentiation of Th1,Th17 cells,so as influence the expression of IFN-γ,IL-17A,IL-6 and TGF-β,thus suppressing inflammatory reaction in patients with RA. |
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