Chinese herbal medicine Xinfeng Capsule in treatment of rheumatoid arthritis:study protocol of a multicenter randomized controlled trial

BACKGROUND： Rheumatoid arthritis （RA）, as a common systemic inflammatory autoimmune disease, affects approximately 1 in 100 individuals. Effective treatment for RA is not yet available because current research does not have a clear understanding of the etiology and pathogenesis of RA. Xinfeng Capsule, a patent Chinese herbal medicine, has been used in the treatment of RA in recent years. Despite its reported clinical efficacy, there are no large-sample, multicenter, randomized trials that support the use of Xinfeng Capsule for RA. Therefore, we designed a randomized, double-blind, multicenter, placebo-controlled trial to assess the efficacy and safety of Xinfeng Capsule in the treatment of RA. METHODS AND DESIGN： This is a 12-week, randomized, placebo-controlled, double-blind, multicenter trial on the treatment of RA. The participants will be randomly assigned to the experimental group and the control group at a ratio of 1：1. Participants in the experimental group will receive Xinfeng Capsule and a pharmaceutical placebo （imitation leflunomide）. The control group will receive leflunomide and an herbal placebo （imitation Xinfeng Capsule）. The American College of Rheumatology （ACR） Criteria for RA will be used to measure the efficacy of the Xinfeng Capsule. The primary outcome measure will be the percentage of study participants who achieve an ACR 20% response rate （ACR20）, which will be measured every 4 weeks after randomization. Secondary outcomes will include the ACR50 and ACR70 responses, the side effects of the medications, the Disease Activity Score 28, RA biomarkers, quality of life, and X-rays of the hands and wrists. The first four of the secondary outcomes will be measured every 4 weeks and the others will be measured at baseline and after 12 weeks of treatment. DISCUSSION： The result of this trial will help to evaluate whether Xinfeng Capsule is effective and safe in the treatment of RA. TRIAL REGISTRATION： This trial has been registered in ClinicalTrials.gov. The identifier is N CT01774877.

Effect of Xifeng Capsule on blood stasis in patients with rheumatoid arthritis by regulating miR-126-VEGF/PI3K/AKT signaling pathway

Objective:From the perspective of miR-126-vascular endothelial cytokine(VEGF)/phosphatidylinositol 3-kinase(PI3K)/ser-threonine protein kinase(AKT)signaling pathway,Xinfeng Capsule(XFC)can improve rheumatoid arthritis(RA))The mechanism of the patient's blood stasis state.Methods:Sixty RA patients meeting the diagnostic criteria were selected and divided into XFC treatment group 30 cases and Leflunomide(LEF)control group 30 cases according to the random number table method.The treatment group took Xinfeng Capsules(3 capsules each time,3 times/d),and the control group took Leflunomide(1 capsule each time,1 times/d).Observe the blood stasis symptom scores of RA patients,and detect the laboratory indicators erythrocyte sedimentation rate(ESR),c-reactive protein(CRP),rheumatoid factor(RF),anti-cyclic citrullinated peptide antibody(CCP),thrombin time(TT),part prothrombin time(APTT),prothrombin time(PT),D dimer(DD),fibrinogen(FBG),platelets(PLT),mean platelet volume(MPV),platelet distribution width(PDW)levels.Real-time fluorescent quantitative PCR method was used to detect the level of miR-126,and the ELISA method was used to detect the levels of tumor necrosis factor(TNF-α),interleukin-6(IL-6),IL-35,VEGF,PI3K,and AKT.Spearman method was used to analyze the correlation between the total score of blood stasis symptoms,blood stasis-related indicators and disease activity indicators,cytokines,miR-126,VEGF,PI3K,and AKT in RA patients.Results:Comparing the two groups after treatment,the XFC group improved blood stasis symptoms,disease activity indicators,decreased miR-126,VEGF,PI3K,AKT,TNF-α,IL-6,D-D,FBG,PLT,and increased IL-35 The level was significantly better than the LEF group,with statistical significance(P<0.05,P<0.01).Correlation analysis showed that there was a certain correlation between the total score of blood stasis symptoms,blood stasis related indicators and disease activity indicators,cytokines,miR-126,VEGF,PI3K,and AKT in RA patients.Conclusion:There is blood stasis in RA patients.XFC may improve the cytokine network disorder of patients through miR-126-VEGF/PI3K/AKT signaling pathway,thereby improving the blood stasis status of RA patients.

Effect of Xinfeng Capsule(新风胶囊) on the Cardiac Function in Patients with Rheumatoid Arthritis

Objective： To study the changes in cardiac function of rheumatoid arthritis （RA） patients and to observe the effect of Xinfeng Capsule （新风胶囊 XFC） on them. Methods： Sixty-eight RA patients were randomly assigned to two groups by a lottery： 38 patients in the treatment group treated orally with XFC, 3 capsules, thrice a day, and 30 in the control group treated with Fengshi Gutong Capsule （风湿骨痛胶囊, FSGTC）, 4 capsules, twice a day, 30 days as one course of treatment, and two courses were given for both groups. A normal control （NC） group including 20 healthy subjects was set up. The clinical efficacy was compared between the two treated groups. The changes in cardiac function, including early diastolic peak flow velocity （E）, late diastolic peak flow velocity （A）, left ventricular fraction shortening （FS）, and E/ A, as well as uric acid （UA）, erythrocyte sedimentation rate （ESR）, α-acid glycoprotein （α-AGP）, and hypersensitive C-reaction protein （hs-CRP）, were observed. The regulation T cell was determined with flow cytometry. Results： （1） The total effective rate in the treatment group and the control group was 92.1% （35/38） and 70.0% （21/30）, respectively. Significant difference was shown between them （P〈0.05）. （2） Compared with those of the NC group, E peak, E/A ratio, and FS of RA patients were lower （P〈0.01）, while A peak was higher （P〈0.01）. Moreover, A peak of the treatment group after treatment was significantly lower （P〈0.05） and E/A ratio was significantly higher （P〈0.05） as compared with those of the control group. （3） The improvement in the treatment group in reducing UA and hs-CRP was superior to those of the control group （P〈0.05）. In addition, the improvement in α-AGP, CD4＋CD25＋ Treg, and CD4＋CD25＋CD12T Treg of the treatment group was obvious as compared with the control group, although the difference was not statistically significant. （Conclusions： The descendent of cardiac function exists in RA patients. XFC could improve cardiac function of RA patients, which is superior to FSGTC. Its mechanism may be related to its effect on raising CD4＋CD25＋Treg and CD4＋CD25＋CD127- Treg cells, decreasing UA, α-AGP, and hs-CRP levels, reducing immune inflammation, adjusting the overall balance of immune response, and thus improving the cardiac function of RA patients.

Xinfeng Capsule(新风胶囊)for the Treatment of Rheumatoid Arthritis Patients with Decreased Pulmonary Function—A Randomized Controlled Clinical Trial

Objective： To determine the effectiveness and safety of Xinfeng Capsules （新风胶囊, XFC） for the treatment of rheumatoid arthritis （RA） patients with decreased pulmonary function. Methods： This was a randomized controlled clinical trial of 80 RA patients. Participants were assigned to the tdal group （40 cases） and the control group （40 cases） by block randomization. The trial group was treated with XFC, three pills each time three times daily for 2 months. The control group was treated with tripterygium glycoside （TPT）, two pills each time three times daily for 2 months. Both groups were followed up after 2 months. The clinical effects, changes in joint and pulmonary function, and quality of life before and after treatment were observed; safety indices were also evaluated. Results： Pain, swelling, tenderness, and duration of morning stiffness of joints were obviously decreased after treatment in both the trial and the control groups compared with baseline （P〈0.01）. Compared with before treatment, hand grip strength increased significantly after treatment in the trial group （P=0.0000）; pulmonary function parameters such as forced expiratory volume in the first second of expiration/forced vital capacity （FEV1/FVC）, 50% of the expiratory flow of forced vital capacity （FEFso）, carbon monoxide diffusing capacity （DLco） were increased （P〈0.01 or P〈0.05）; measures of quality of life such as role-physical, body pain, vitality and mental health were also improved after treatment in the trial group （all P〈0.05）. Joint swelling in the trial group decreased compared with the control group （P=0.0043）, while hand grip strength was increased after treatment （P=0.0000）. The increase in FEFs0, DLco, and the dimensions of quality of life such as vitality and mental health were all significantly greater in the trial group than the control group （P〈0.05 or P〈0.01）. Conclusions： XFC not only relieved joint pain in RA patients, but also significantly improved the ventilation and diffusion function of the lungs. Therefore, XFC could improve the whole body function and enhance the quality of life of RA patients.

Effects of Xinfeng Capsule(新风胶囊) on the Expression of Platelet Derived Growth Factor in Synovium of Adjuvant Arthritis Rats

Objective： To observe the effects of Xinfeng Capsule （新风胶囊, XFC） on platelet parameters in peripheral blood and expression of platelet derived growth factor （PDGF） in synovium of adjuvant arthritis （AA） rats. Methods： A total of 40 male Sprague-Dawley （SD） rats were randomized into 5 groups： normal control （NC）, AA model control （MC）, methotrexate （MTX） treatment, Tripterygium wilfordii polycoride tablet （TPT） treatment, and XFC treatment. Excluding the NC group, the AA model was induced by intracutaneous injection of 0.1 mL Freund＇s complete adjuvant in the right hind limb. Induction of AA and the effects of drug treatments were assessed by voix pedis swelling, arthritis index （AL） body mass, and the pathological changes of joints and cartilage with a light microscopy. Platelet parameters in peripheral blood were detected with an automated hematology analyzer. PDGF in synovium was detected with immunohistochemical methods and PDGF mRNA expression in synovium was detected with reverse transcription polymerase chain reaction. Results： Compared with the NC group, the MC group had significantly increased voix pedis swelling, AI, platelet （PLT） and plateletcrit （PCT） in peripheral blood and PDGF as well as PDGF mRNA in synovium （all P〈0.01） and the joint cartilage was also highly degenerated. Compared with the MC group, the 3 treated groups had significantly decreased voix pedis swelling, AI, PLT, PCT, PDGF, and PDGF mRNA （P〈0.01）. The body mass in the XFC group was significantly higher than those in MTX and TPT groups （P〈0.05）. The levels of PLT, PCT, PDGF, and PDGF mRNA in the XFC group showed a decreasing tendency with no significant difference compared with the M＇IX and TPT groups （P〉0,05）. PDGF and PDGF mRNA of AA rats were positively correlated with voix pedis swelling, AI, PLT, and PCT （P〈0.05 or P〈0.01）. Conclusions： The expression and biosynthesis of PDGF increase in the synovium of AA rats and correlate with voix pedis swelling, AI, PLT, and PCT. XFC can decrease the levels of PDGF, PDGF mRNA, PLT, and PCT, thereby mitigating inflammation induced by platelet activation and reducing voix pedis swelling and the AI in AA rats.

Efficacy and safety of Xinfeng capsule in the treatment of osteoarthritis:a multicenter, randomized, double-blinded, controlled trial

OBJECTIVE: To evaluate the efficacy and safety of Xinfeng capsule(XFC) in patients with osteoarthritis(OA).METHODS: This was a multicenter, double-blinded,randomized, controlled, clinical trial. Patients with OA were assigned to the XFC group [treated with XFC and a glucosamine(GS) placebo, n = 129] or the GS group(treated with GS and an XFC placebo,n = 126). Both groups were treated for 4 weeks. The primary endpoint was the difference between the two groups in the Western Ontario and Mc Master Universities OA(WOMAC) index total score at 4 th week. The secondary endpoints were the visual analogue scale for pain, Lequesne index, function influence index rating, quality of life as assessed by the Short Form-36, erythrocyte sedimentation rate,and C-reactive protein concentration at baseline and at second week and 4 th week. Bone mineral density were checked by X ray absorptiometry at baseline and 4 th week.RESULTS: After 4 weeks of treatment, all patients in both groups showed similar significant improvements compared with baseline. There were no significant differences between groups regarding pain relief, bilateral femoral bone mineral density, and laboratory indices such as erythrocyte sedimentation rate and C-reactive protein concentration.Both groups had a significantly lower function influence index rating score and curative effect for each sign/symptom in week 4 than in week 0, and these changes did not significantly differ between groups. XFC was superior to GS in improving the WOMAC index total score, WOMAC scores for function and stiffness, integrated symptoms, physiological function, energy, emotional function, mental health, and health changes. Fourteen adverse reactions were reported, and the incidence of adverse reactions did not significantly differ between groups. The most common adverse reactions were hepatic impairment, kidney functional damage,gastrectasia, and facial skin allergy. The types of adverse reactions did not differ between groups.CONCLUSION: XFC is effective and safe in the treatment of OA. XFC was superior to GS in improving the WOMAC index total score, WOMAC scores for pain, stiffness, and function, visual analogue scale for pain, Lequesne index, and Short Form-36 quality of life.

Mechanism studies of Xinfeng capsule on improving cardiovascular function though toll-like receptor 4/nuclear factor kappa B pathway in a rat model of adjuvant arthritis

OBJECTIVE: To observe the impact of Xinfeng capsule(XFC) on cardiovascular function in adjuvant arthritis(AA) model rats and investigate the mechanism though toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB) signaling pathway.METHODS: Seventy rats were randomly divided into seven groups: normal control(NC), model control(MC), tripterygium glycosides tablet(TPT),methotrexate(MTX), high, moderate and low dose XFC group. The administration began from day 19 after modeling for 30 day. Paw swelling, arthritic in-dex(AI), cardiac function indexes and myocardial pathological pattern were detected. The expression of TLR4, myeloid differentiation factor(My D) 88, interleukin-1 receptor-associated kinase(IRAK) 1, tumor necrosis factor receptor associated factor(TRAF) 6, NF-κB, tumor necrosis factor-alpha(TNF-α) proteins in myocardial tissue were determined by western blot method.RESULTS: Paw swelling and AI in MC group increased in MC group(P < 0.01), and decreased in high and moderate dose XFC groups(P < 0.01 or P > 0.05). Left ventricular systolic pressure(LVSP),left ventricular end-diastolic pressure(LVEDP),heart rate(HR) were elevated in MC group(P <0.01), and ± dp/dtmax and CI were reduced(P <0.01); while LVSP, LVEDP and HR declined and ±dp/dtmax, CI improved in high dose XFC group(P <0.05 or P < 0.01). LVSP in high dose XFC group were reduced more than other treatment groups(P <0.05 or P < 0.01). The improvements on LVEDP, dp/dt-max were superior to MTX and low dose XFC group, and the improvement on CI was better than low dose XFC group(P < 0.05 or P < 0.01). Myocardial fibers arranged irregular in MC group with intracellular edema and mitochondria damage. The modifications on myocardial structural were shown in each treatment group, but more prominent in TPT, high and moderate dose XFC group. The proteins of TLR4, My D88, IRAK1, TRAF6, NF-κB, TNF-αwere highly expressed in MC group, and those proteins declined in high and moderate dose XFC group(P < 0.05 or P < 0.01). High dose XFC group was superior to MTX and low dose XFC group on reducing TLR4, NF-κB, TNF-α(P < 0.05).CONCLUSION: XFC can not only inhibit the excessive activation of TLR4/NF-κB signaling pathway and the increased inflammatory mediators, but also reduce the damage of myocardial tissue and cells.

The Potential Role of Chinese Medicine in Ameliorating Extra-articular Manifestations of Rheumatoid Arthritis

Rheumatoid arthritis （RA） is a chronic systemic autoimmune disease chiefly affecting synovial membranes of multiple joints. The clinical manifestations are highly variable. Besides joint affection, extra-articular manifestations always occur in RA patients, such as lung, blood vessel, heart, endocrine glands, hematological system, and nervous system affections. In addition to Western medicine therapy, Chinese medicine also plays a significant role in the treatment of RA with good efficacy and less adverse reactions. This paper summarizes the effects of Xinfeng Capsule （新风胶囊）, a Chinese medicine, and the mechanisms of its action in ameliorating the extra-articular manifestations based on a series of clinical and experimental researches.