[Effect of Juanbi Qianggu Formula on biological behaviors of fibroblast-like synoviocytes in rheumatoid arthritis by regulating FGFR1 signaling pathway based on network pharmacology and cell function experiments].

This study aimed to explore the molecular mechanism of Juanbi Qianggu Formula(JBQGF), an empirical formula formulated by the prestigious doctor in traditional Chinese medicine, in the treatment of rheumatoid arthritis based on network pharmacology and cell function experiments. The main active components and targets of JBQGF were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and Encyclopedia of Traditional Chinese Medicine(ETCM), and the core targets underwent functional enrichment analysis and signaling pathway analysis. Cytoscape 3.6.0 was used to construct a visualized "active component-target-signaling pathway" network of JBQGF. After screening, nine potential pathways of JBQGF were obtained, mainly including G protein-coupled receptor signaling pathway and tyrosine kinase receptor signaling pathway. As previously indicated, the fibroblast growth factor receptor 1(FGFR1) signaling pathway was highly activated in active fibroblast-like synoviocytes(FLS) in rheumatoid arthritis, and cell and animal experiments demonstrated that inhibition of the FGFR1 signaling pathway could significantly reduce joint inflammation and joint destruction in collagen-induced arthritis(CIA) rats. In terms of the tyrosine kinase receptor signal transduction pathway, the analysis of its target genes revealed that FGFR1 might be a potential target of JBQGF for rheumatoid arthritis treatment. The biological effect of JBQGF by inhibiting FGFR1 phosphorylation was preliminarily verified by Western blot, Transwell invasion assay, and pannus erosion assay, thereby inhibiting matrix metalloproteinase 2(MMP2) and receptor activator of nuclear factor-κB ligand(RANKL) and suppressing the invasion of fibroblasts in rheumatoid arthritis and erosive effect of pannus bone. This study provides ideas for searching potential targets of rheumatoid arthritis treatment and TCM drugs through network pharmacology.

The effect of JuanBiQiangGu granules in combination with methotrexate on joint inflammation in rheumatoid arthritis: a randomized controlled trial.

Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1ß, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators (p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32), p < 0.0001), and the median (IQR) ß-CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from 3 (2-4) in the MTX group (p < 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant (p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) (p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) (p < 0.01, p = 0.004); the median (IQR) ALT in the JBQG group was 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) (p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN (p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html; identifier: ChiCTR2100046373.

Multiple intravenous tranexamic acid doses in total knee arthroplasty in patients with rheumatoid arthritis: a randomized controlled study.

BACKGROUND: We aimed to determine the efficacy and safety of multiple doses of intravenous tranexamic acid (IV-TXA) on perioperative blood loss in patients with rheumatoid arthritis (RA) who had undergone primary unilateral total knee arthroplasty (TKA). METHODS: For this single-center, single-blind randomized controlled clinical trial, 10 male and 87 female participants with RA, aged 50-75 years, who underwent unilateral primary TKA were recruited. The patients received one dose of 1 g IV-TXA 10 min before skin incision, followed by articular injection of 1.5 g tranexamic acid after cavity suture during the surgery. The patients were randomly assigned (1:1) into two groups and received an additional single dose of IV-TXA (1 g) for 3 h (group A) or three doses of IV-TXA (1 g) for 3, 6, and 12 h (group B) postoperatively. Primary outcomes were total blood loss (TBL), hidden blood loss (HBL), and maximum hemoglobin (Hb) level decrease. Secondary outcomes were transfusion rate and D-dimer levels. All parameters were measured postoperatively during inpatient hospital stay. RESULTS: The mean TBL, HBL, and maximum Hb level decrease in group B (506.1 ± 227.0 mL, 471.6 ± 224.0 mL, and 17.5 ± 7.7 g/L, respectively) were significantly lower than those in group A (608.8 ± 244.8 mL, P = 0.035; 574.0 ± 242.3 mL, P = 0.033; and 23.42 ± 9.2 g/L, P = 0.001, respectively). No episode of transfusion occurred. The D-dimer level was lower in group B than in group A on postoperative day 1 (P <  0.001), and the incidence of thromboembolic events was similar between the groups (P > 0.05). CONCLUSION: In patients with RA, three doses of postoperative IV-TXA further facilitated HBL and Hb level decrease without increasing the incidence of adverse events in a short period after TKA. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR1900025013 ).

Effect of Multiple Doses of Intravenous Tranexamic Acid on Perioperative Blood Loss in Total Knee Arthroplasty: A Randomized Controlled Study.

OBJECTIVE: To identify the efficacy and safety of multiple doses of intravenous tranexamic acid (IV-TXA) following primary total knee arthroplasty (TKA) with a tourniquet. METHODS: This is a single-blind randomized controlled study that recruited osteoarthritis patients who had undergone primary unilateral TKA from May 2019 to May 2020 at our medical center. A total of 300 patients were randomly divided into three groups to receive: one dose (1 g) of IV-TXA before skin incision combined with one dose (1.5 g) of intra-articular tranexamic acid（IA-TXA) followed by a single dose of IV-TXA (1 g) for 3 h (group A); two doses of IV-TXA (1 g) for 3 and 6 h (group B); or three doses of IV-TXA (1 g) for 3, 6, and 12 h (group C) postoperatively. TKA with a tourniquet was performed by the same surgical team. The primary outcomes were total blood cell loss (TBL), hidden blood loss (HBL), maximum hemoglobin (Hb) drop, and transfusion rate. Secondary outcomes were levels of C-reactive protein (CRP) and D-dimer, and the incidence of postoperative complications. One-way analysis of variance, subgroup analysis, and multivariate correlation analysis were used to calculate the differences among the three groups. RESULTS: The study included 56 male and 244 female patients aged 60-80 years. The mean TBL, the mean HBL, and the maximum Hb drop in group C (471.2 ± 190.6 mL, 428.4 ± 190.3 mL, and 21.2 ± 3.8 g/L, respectively) were significantly lower than those in groups B (563.4 ± 224.6 mL, P = 0.030; 519.9 ± 226.4 mL, P = 0.033; and 23.2 ± 4.1 g/L, P = 0.001, respectively), and A (651.6 ± 254.1 mL, P < 0.001; 607.1 ± 254.3 mL, P < 0.001; and 25.1 ± 4.3 g/L, P < 0.001, respectively). No transfusions were required. The postoperative acute inflammatory reaction was less problematic for patients in Group C, and the incidence of thromboembolic events was similar among the groups (P > 0.05). In addition, there were positive correlations between the HBL and the tourniquet inflation time (r = 0.844, P < 0.001). Similarly, the level of CRP on POD1 (r = 0.393, P < 0.001) and POD3 (r = 0.149, P = 0.010), and the level of D-dimer on POD1 (r = 0.382, P < 0.001) were positively correlated with the HBL. CONCLUSION: Three doses of postoperative IV-TXA decreased blood loss and diminished the postoperative inflammatory and fibrinolytic response more than a single dose or two doses in elderly patients following TKA without increasing the incidence of adverse events.

Multiple-dose tranexamic acid for perioperative blood loss in total knee arthroplasty in patients with rheumatoid arthritis：a single-blinded, randomised, parallel-controlled study protocol in China.

INTRODUCTION: This clinical trial is designed to evaluate the effect of multiple-dose tranexamic acid (TXA) on perioperative blood loss in patients with rheumatoid arthritis (RA). METHODS AND ANALYSIS: A randomised, single-blinded, parallel-controlled study will be designed. Patients with RA (age 50-75 years) undergoing unilateral primary end-stage total knee arthroplasty will be randomly divided into group A or group B. Group A will be treated with one dose of TXA (1 g; intravenous injection 3 hours postsurgery) and group B with three doses (1 g; intravenous injection at 3, 6 and 12 hours postsurgery) after surgery. The primary outcomes will be evaluated with blood loss, maximum haemoglobin drop and transfusion rate. The secondary outcomes will be evaluated with knee function and complications. ETHICS AND DISSEMINATION: The Shanghai Guanghua Hospital of Integrated Traditional Chinese Medicine and Western Medicine Ethics Committee approved in this study in July 2019. Informed consent will be obtained from all participants. Results of the trial will be published in the Dryad and repository in a peer-reviewed journal. Additionally, deidentified data collected and analysed for this study will be available for review from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: ChiCTR1900025013.

[Early efficacies of total knee arthroplasty for knees with severe lateral instability].

OBJECTIVE: To evaluate the outcomes of primary total knee arthroplasty (TKA) in the treatment of knee with severe lateral instability and summarize the essential points of operation and rehabilitation. METHODS: From February 2005 to August 2010, primary TKA was performed in 27 severe lateral unstable knees (25 cases), including 3 males (3 knees) and 22 females (24 knees). Their mean age was 57.8 (37-71) years. And their primary diseases included rheumatoid arthritis (22 knees in 21 cases) and osteoarthritis (5 knees in 4 cases). Thirteen lateral unstable knees were accompanied with 18.08° ± 5.96°(15-35°) varus deformity; in the rest 14 knees, there was medial instability with 20.71° ± 7.03° (15-35°) valgus deformity. Blood loss volume, operative duration and complications were recorded. During the follow-up period, HSS score, knee stability and varus/valgus status were recorded preoperatively, 1, 3, 6, 12 months and then annually postoperatively. RESULTS: AORI type I bone defect was found at the proximal tibia in 18 knees and distal lateral femoral condyle in 10 knees. All defects were reconstructed with cement or autograft. AORI type II bone defects at proximal tibia in 3 knees were reconstructed with metal augmentation. Blood loss during the first 24 hours were (438.9 ± 109.5) (400-700) ml and operative duration (91.1 ± 11.6) (70-110) min. The mean follow-up period was (41.6 ± 10.9) (27-60) months. At the final follow-up, the HSS score increased from (45.8 ± 5.4) to (85.4 ± 4.5) (t = 30.15, P < 0.01) .Five knees in 5 cases had mild postoperative instability. All cases were allowed to walk with knee orthosis for 4-6 weeks. At the end of follow-up, mild lateral instability of 2 knees persisted. One augmented knee had osteolysis beneath metal block. CONCLUSION: TKA for knees with severe lateral instability requires a deep understanding of causes and a rational treatment. Proper handling of bone defects and careful release of lateral soft tissue are two critical points for postoperative knee stability. Wearing knee orthosis during the early postoperative stage may be helpful or residual mild instability.

[Effects of Tuina and Chinese patent drug Shuxuetong injection on deep venous thrombosis and functional rehabilitation after total knee arthroplasty].

OBJECTIVE: To evaluate the efficacy of Tuina and Chinese patent drug Shuxuetong injection in preventing patients undergoing total knee arthroplasty from deep venous thrombosis and in functional rehabilitation. METHODS: A total of 120 patients with diagnosed rheumatoid arthritis in the Department of Orthopaedic Surgery, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine in China were enrolled for this study. The patients underwent total knee arthroplasty and were divided into treatment group (n=60) and control group (n=60) after surgery. Patients in the control group received conventional rehabilitation training, including using a continuous passive motion machine and training of muscle contractions of the lower limb. Patients in the treatment group were administered Shuxuetong injection and Tuina based on the conventional rehabilitation training. The course of treatment lasted for 2 weeks. Hospital for Special Surgery (HSS) knee score, rate of deep venous thrombosis and range of motion of the knee joint were evaluated before and after treatment. RESULTS: There was no significant difference in HSS knee score and range of motion as compared before and after treatment in two group (P>0.05). The rate of deep venous thrombosis of the treatment group was 13.33%, which was lower than 20% of the control group (P<0.05). CONCLUSION: Tuina combined with Shuxuetong injection treatment can prevent deep venous thrombosis in patients with rheumatoid arthritis after total knee arthroplasty.

[Dynamic level observation of brain-derived neurotrophic factor in patients with first-episode generalized anxiety disorder].

OBJECTIVE: To examine the changing pattern of brain-derived neurotrophic factor (BDNF) in the patients with first-episode generalized anxiety disorder (GAD). METHODS: The levels of plasma BDNF and the Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) scores were measured in 34 patients with first-episode GAD recruited from our hospital between January and December 2007. At baseline and Week 6, they were treated by paroxetine and compared with 31 healthy participants in the control group. RESULTS: The baseline level of BDNF [(80 ± 51) ng/L] in the patients with first-episode GAD was higher than that in the control group and had no significant correlation with HAMA and HAMD scores. But at Week 6, the level of BDNF [(70 ± 49) ng/L] had significant correlations with HAMA and HAMD scores (r = 0.4, P = 0 and r = 0.4, P = 0 respectively). At Week 6, the levels of BDNF in the response group (including remission group) and ineffective group were (60 ± 42) ng/L and (83 ± 55) ng/L respectively. And there was significant difference in the levels of BDNF between the ineffective and control groups. The levels of BDNF in the remission and non-remission groups were (59 ± 52) ng/L and (73 ± 49) ng/L respectively. And there was significant difference in the levels of BDNF between the non-remission and control groups. CONCLUSION: The pre-treatment levels of plasma BDNF in the patients with first-episode GAD are higher than those of healthy counterparts. But normal levels may be restored if the patients are cured.