Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. METHODS: This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. DISCUSSION: If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. TRIAL REGISTRATION: ClinicalTrials. gov NCT05034029 . Registered on 30 Sept 2021.

Validation of new classification criteria of rheumatoid arthritis in an international multicentre study.

OBJECTIVES: Early identification of patients with rheumatoid arthritis (RA) is essential to allow prompt therapy. In this study, we aimed to evaluate the performance of the newly proposed ERA criteria, compared to the 1987 ACR and 2010 ACR/EULAR criteria in an international multicentre study. METHODS: A total of 606 patients with disease duration ≤2 years and age ≥16 years who were diagnosed as RA or non-RA were enrolled from China, Sweden and India. The clinical and laboratory parameters were recorded. We compared the sensitivity, specificity, predictive value, likelihood ratio (LR), and the area under the ROC curve (AUC) of three criteria in these cohorts. Concordance between the three criteria was calculated with the Kappa coefficient. RESULTS: Three hundred and twelve RA and 294 non-RA patients were included. The Early Rheumatoid Arthritis (ERA) criteria had significantly higher specificity compared to the 2010 ACR/ EULAR criteria (83.7% vs. 78.2%, p=0.02) and sensitivity were similar (79.2% vs. 78.5%, p=0.883). In comparison with the 1987 ACR criteria, the ERA criteria had higher sensitivity (79.2% vs. 54.5%, p<0.001) but lower specificity (83.7% vs. 89.1%, p<0.001), and the AUC of the ERA criteria (0.878) was comparable to the 2010 ACR/EULAR criteria (0.849) and higher than the 1987 ACR criteria (0.791, p<0.0001). Patients from the three countries, seronegative and very early arthritis cohorts yielded consistent results. CONCLUSIONS: The ERA criteria demonstrate a better performance across ethnics in early RA diagnosis, and is more feasible in daily practice.

Classification criteria of early rheumatoid arthritis and validation of its performance in a multi-centre cohort.

OBJECTIVES: To develop classification criteria for early rheumatoid arthritis (ERA) based on a large cohort of early inflammatory arthritis patients and to evaluate the performance of these criteria. METHODS: The study population comprised a cohort of early inflammatory arthritis patients with symptom duration less than one year. Classification criteria of ERA were developed by incorporating the most sensitive or specific variables. Performance of the ERA criteria, 1987 ACR and 2010 ACR/EULAR criteria were evaluated. RESULTS: A total of 803 patients were enrolled in this study. By the end of the one year follow-up, 514 patients were diagnosed with RA, 251 with other rheumatic diseases, and 38 patients with undifferentiated arthritis. The ERA criteria are as follows: 1) morning stiffness ≥30 minutes; 2) arthritis of 3 or more joint areas; 3) arthritis of hand joints; 4) positive RF; 5) positive anti-CCP antibody. Rheumatoid arthritis is defined by the presence of 3 or more of the criteria. The sensitivity (84.4%) of the ERA classification criteria was much higher than the 1987 ACR criteria (58.0%). In a validation cohort of early inflammatory arthritis patients, the area under the ROC curves (AUC) showed a better performance for the ERA criteria (0.906, 95%CI 0.866 to 0.945) than the 1987 ACR criteria (0.786, 95%CI 0.725 to 0.848) and the 2010 ACR/EULAR criteria (0.745, 95%CI 0.677 to 0.814). CONCLUSIONS: A set of ERA classification criteria has been developed with good performance for early RA. It is applicable in clinical practice and research.

Effects of thapsigargin on the proliferation and survival of human rheumatoid arthritis synovial cells.

A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 µM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A). The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner. Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 µM treated for 4 days compared to the control. The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times. Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions. Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells. The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.

Causal association of menstrual reproductive factors on the risk of osteoarthritis: A univariate and multivariate Mendelian randomization study.

OBJECTIVE: Several observational studies have revealed a potential relationship between menstrual reproductive factors (MRF) and osteoarthritis (OA). However, the precise causal relationship remains elusive. This study performed Mendelian randomization (MR) to provide deeper insights into this relationship. METHODS: Utilizing summary statistics of genome-wide association studies (GWAS), we conducted univariate MR to estimate 2 menstrual factors (Age at menarche, AAM; Age at menopause, AMP) and 5 reproductive factors (Age at first live birth, AFB; Age at last live birth, ALB; Number of live births, NLB; Age first had sexual intercourse, AFSI; Age started oral contraceptive pill, ASOC) on OA (overall OA, OOA; knee OA, KOA and hip OA, HOA). The sample size of MRF ranged from 123846 to 406457, and the OA sample size range from 393873 to 484598. Inverse variance weighted (IVW) method was used as the primary MR analysis methods, and MR Egger, weighted median was performed as supplements. Sensitivity analysis was employed to test for heterogeneity and horizontal pleiotropy. Finally, multivariable MR was utilized to adjust for the influence of BMI on OA. RESULTS: After conducting multiple tests (P<0.0023) and adjusting for BMI, MR analysis indicated that a lower AFB will increase the risk of OOA (odds ratio [OR] = 0.97, 95% confidence interval [CI]: 0.95-0.99, P = 3.39×10-4) and KOA (OR = 0.60, 95% CI: 0.47-0.78, P = 1.07×10-4). ALB (OR = 0.61, 95% CI: 0.45-0.84, P = 2.06×10-3) and Age AFSI (OR = 0.66, 95% CI: 0.53-0.82, P = 2.42×10-4) were negatively associated with KOA. In addition, our results showed that earlier AMP adversely affected HOA (OR = 1.12, 95% CI: 1.01-1.23, P = 0.033), and earlier ASOC promote the development of OOA (OR = 0.97, 95% CI: 0.95-1.00, P = 0.032) and KOA (OR = 0.58, 95% CI: 0.40-0.84, P = 4.49×10-3). ALB (OR = 0.98, 95% CI: 0.96-1.00, P = 0.030) and AFSI (OR = 0.98, 95% CI: 0.97-0.99, P = 2.66×10-3) also showed a negative association with OOA but they all did not pass multiple tests. The effects of AAM and NLB on OA were insignificant after BMI correction. CONCLUSION: This research Certificates that Early AFB promotes the development of OOA, meanwhile early AFB, ALB, and AFSI are also risk factors of KOA. Reproductive factors, especially those related to birth, may have the greatest impact on KOA. It provides guidance for promoting women's appropriate age fertility and strengthening perinatal care.

Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats.

Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 µg/kg/d × 3 wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT(6w) model group (MCT + saline × 2 wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 µg/kg/d × 2 wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT(4w) model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn't change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT(4w) model rats. Moreover, N(G)-Nitro-l-arginine Methyl Ester (l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated MCT induced rats PAH may through relaxing pulmonary arteries and inhibiting pulmonary vascular remodeling. NO pathway might be one of the mechanisms in urantide induced pulmonary artery dilation. Thus, it is expected that urantide may be a novel therapy for PAH.

Can low-dose methotrexate reduce effusion-synovitis and symptoms in patients with mid- to late-stage knee osteoarthritis? Study protocol for a randomised, double-blind, and placebo-controlled trial.

BACKGROUND: Osteoarthritis (OA) is a common chronic disease in older adults. Currently, there are no effective therapies to reduce disease severity and progression of knee OA (KOA), particularly in mid- to late-stages. This study aims to examine the effect of methotrexate (MTX) on knee effusion-synovitis and pain in symptomatic patients with mid- to late-stage KOA. METHODS/DESIGN: This protocol describes a multicentre randomised placebo-controlled clinical trial aiming to recruit 200 participants with mid- to late-stage symptomatic KOA and with effusion-synovitis grade of ≥ 2. Participants will be randomly allocated to the MTX group (start from 5 mg per week for the first 2 weeks and increase to 10 mg per week for the second 2 weeks and 15 mg per week for the remaining period if tolerated) or the placebo group. Primary outcomes are effusion-synovitis size measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS). Secondary outcomes are signal intensity alteration within infrapatellar fat pad (IPFP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and subscores, and the Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders. Both intention-to-treat and per-protocol analyses will be performed. DISCUSSION: If MTX intervention can relieve symptoms and reduce inflammation in patients with mid- to late-stage KOA, it has the potential for significant clinical and public health impact as this low-cost and commonly used intervention would delay the time to knee replacement, leading to substantial cost savings and improve quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03815448 . Registered on 21 January 2019.

Erratum to development and formulation of the classification criteria for osteoarthritis.

[This corrects the article DOI: 10.21037/atm-20-4673.].

Development and formulation of the classification criteria for osteoarthritis.

BACKGROUND: The classification criteria of osteoarthritis (OA) is lack of the support of relevant research evidence and there is no standardized protocol for detailed steps of the development or clinical verification of classification criteria has yet been established. This study aims to describe the development process of the Categorization of Osteoarthritis CHecklist (COACH), which is designed to choose the precise treatment option for patients with OA. METHODS: A multidisciplinary panel was established to gather opinions. We conducted questionnaire survey and literature review to generate and COACH Panel members were invited to review the drafted classification criteria and optimize classification criteria. The final list of items was discussed and reached the agreement by the core group of the panel. RESULTS: Thirty-six experts participated in COACH Panel including rheumatologist (80.6%; 29/36), orthopedist (13.9%; 5/36), methodologist (2.8%; 1/36) and rehabilitation physician (2.8%; 1/36) for classification factors generating and optimizing. The main body of the final classification criteria consists of six types of OA pathogenesis, eight types of medical findings (which can be grouped into two categories), and six types of the location. The final criteria include load-based type, structure-based type, inflammation-based type, metabolic-based type, systemic factor based type and mixed type. CONCLUSIONS: COACH can better help clinicians quickly classify OA patients and help to choose the best treatment option from the aspects of types, findings and locations. What's more, the classification criteria are also helpful to promote the basic medical research and targeted prevention of OA.

Guidelines for the diagnosis and treatment of osteoarthritis in China (2019 edition).

Osteoarthritis (OA) is a degenerative disease of middle-aged and elderly people, contributed a higher burden of disease in China and the world. In 2017, under the support of the Rheumatology and Immunology Expert Committee of the Cross-Strait Medical and Health Exchange Association. The objective was to develop an evidence-based diagnosis and treatment guideline for OA in China based on emerging new evidence. The guideline was registered at International Practice Guidelines Registry Platform (IPGRP-2018CN028). The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence and the strength of recommendations, and the RIGHT (Reporting Items for Practice Guidelines in Healthcare) checklist was followed to report the guideline. The guideline provides recommendations for the OA diagnosis, disease risks monitoring and evaluate, treatment purpose and physical, medical and surgical interventions. This guideline is intended to serve as a tool for Chinese clinicians for the best decisions-making on diagnosis and treatment of OA.

Testosterone alleviates tumor necrosis factor-alpha-mediated tissue factor pathway inhibitor downregulation via suppression of nuclear factor-kappa B in endothelial cells.

We have observed earlier that testosterone at physiological concentrations can stimulate tissue factor pathway inhibitor (TFPI) gene expression through the androgen receptor in endothelial cells. This study further investigated the impact of testosterone on TFPI levels in response to inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Cultured human umbilical vein endothelial cells were incubated in the presence or absence of testosterone or TNF-alpha. TFPI protein and mRNA levels were assessed by enzyme-linked immunosorbent assay and quantitative real-time reverse transcription polymerase chain reaction. To study the cellular mechanism of testosterone's action, nuclear factor-kappa B (NF-kappaB) translocation was confirmed by electrophoretic mobility shift assays. We found that after NF-kappaB was activated by TNF-alpha, TFPI protein levels declined significantly by 37.3% compared with controls (P < 0.001), and the mRNA levels of TFPI also decreased greatly (P < 0.001). A concentration of 30 nmol L(-1) testosterone increased the secretion of TFPI compared with the TNF-alpha-treated group. NF-kappaB DNA-binding activity was significantly suppressed by testosterone (P < 0.05). This suggests that physiological testosterone concentrations may exert their antithrombotic effects on TFPI expression during inflammation by downregulating NF-kappaB activity.

Urantide improves the structure and function of right ventricle as determined by echocardiography in monocrotaline-induced pulmonary hypertension rat model.

Urotensin II (UII) has been reported to play a key role in pulmonary arterial hypertension (PAH) development. Doppler echocardiography, a noninvasive and simple tool, is recommended for diagnosing PAH. This study was designed to investigate the effect of urantide, a UII receptor antagonist, on the structure and function of the right ventricle in PAH rat models by Doppler echocardiography. A total of 60 male rats were divided into two groups: early- and late-treatment groups. Rats in the urantide and MCT (monocrotaline) subgroups were injected with 10 µg/kg urantide in the urantide group or an equal amount of normal saline in the MCT group 1 week after PAH model construction in the early-treatment group and 4 weeks after the construction in the late-treatment group. Rats in the control group received an equal volume of normal saline solution. PAH-related indexes were measured by echocardiography. PAH rat models exhibited higher right ventricular diastolic diameter and lower time to peak, ejection time, and peak flow velocity of pulmonary artery than controls (P < 0.05). However, compared with the MCT group, all abovementioned indexes were improved in the urantide group (P < 0.05). No significant differences in pulmonary artery diameter and left ventricular ejection fraction were noted among the groups. Compared with the MCT group, systolic pulmonary arterial pressure (SPAP) and mean pulmonary arterial pressure (mPAP) were significantly lower in the urantide group (P < 0.05). SPAP examined by echocardiography was correlated with mPAP by catheterization (P < 0.05). Urantide treatment improved right heart failure parameters in MCT-induced PAH rats, thus providing a potential new strategy for treating PAH.

Combined immunosuppressive treatment (CIST) in lupus nephritis: a multicenter, randomized controlled study.

OBJECTIVES: The standard strategy for treating lupus nephritis comprises glucocorticoids together with either intravenous cyclophosphamide or oral mycophenolate mofetil, but the low remission rate is still a challenge in practice. This study was aimed to seek higher remission rate of lupus nephritis using a combined strategy. METHOD: A 24-week trial was conducted in 17 rheumatology or nephrology centers in China. A total of 191 lupus nephritis patients were randomized to follow a combined immunosuppressive treatment (CIST) with intravenous cyclophosphamide, an oral immunosuppressive agent, namely mycophenolate mofetil, azathioprine or leflunomide, and hydroxychloroquine (n = 95), or receive intravenous cyclophosphamide alone (n = 96) for 24 weeks. Glucocorticoid was given to both groups. The primary end point was a complete remission with a most stringent standard as proteinuria < 150 mg per 24 h, normal urinary sediment, serum albumin, and renal function at 24 weeks. The secondary end point was treatment failure at 24 weeks. RESULTS: At week 24, both the rate of complete remission (39.5%) and total response (87.2%) was higher in the combined group, compared with CYC group (20.8% and 68.8%, p < 0.05). The cumulative probability of complete remission was also higher in the combined group (p = 0.013). In addition, the combined treatment was superior to routine CYC with less treatment failure (12.8% vs.31.2%, p < 0.001). No difference was found between the incidences of severe adverse events in the two arms: 3.2% (3/95 combined group) vs.4.2% (4/96 CYC group). CONCLUSION: Treatment with a combined immunosuppressive agent is superior to routine CYC only therapy in lupus nephritis.

The Chinese version of the SLEQOL is a reliable assessment of health-related quality of life in Han Chinese patients with systemic lupus erythematosus.

To assess the health-related quality of life (HRQOL) of Han Chinese people with systemic lupus erythematosus (SLE) using a Chinese version of the Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL-C) and explore the factors influencing HRQOL of people with SLE. Participants were Han Chinese people with SLE. The SLEQOL-C and 36-item Short Form Health Survey (SF-36) were used to estimate the HRQOL. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Participant factors included age, gender, educational background, disease duration, erythrocyte sedimentation rate (ESR), and complement C3 and C4 levels. The results showed that higher SLEQQL-C scores correlated with lower SF-36 both measures are essential for HRQQL prediction. The SLEQOL-C scores were correlated with educational level,age, FACIT-F score, SLEDAI score, and ESR, which suggests that poor educational background, old-age, and increased fatigue, disease activity, and ESR might represent poor HRQOL. Although disease duration did not significantly correlate with the scores on the SLEQOL-C; those whose disease duration was 12-24 months had higher SLEQOL-C summary scores and physical functioning, symptoms, and treatment subscale scores than did those whose duration was less than 6 months. The FACIT-F score, education level, age, disease duration, SLEDAI score, and ESR contributed to SLEQOL-C scores. The SLEQOL-C is reliable for assessing HRQOL of Han Chinese people with SLE. Fatigue, educational level, age, disease duration, ESR, and disease activity mainly influenced HRQOL of SLE patients.

[High-dose immunosuppression and autologous peripheral blood stem cell transplantation for immunological reconstitution in two patients with primary Sjögren's syndrome].

OBJECTIVES: To assess the safety and efficacy of high-dose immunosuppression and autologous peripheral blood cell transplantation (APBSCT) in severe and refractory primary Sjögren's syndrome (pSS) and to analyze immune reconstitution in pSS. METHODS: Two patients with severe and refractory primary pSS were included in this study. They suffered still with active pSS despite the use of prednisone and immunosuppression agents. A regimen of high-dose immunosuppression and APBSCT was carried out for them. Dynamic T cell subgroup was tested with flow cytometry before and after PBSCT and the diversity of T cell receptor repertoire and CDR3 spectrum with RT-PCR and genescan. RESULTS: Both of the pSS cases underwent PBSCT smoothly. Clinical assessments showed improvement. Immune reconstruction lagged behind hematopoietic reconstitution. The skew of T cell receptor repertoire was somewhat corrected and CDR3 spectrum changed from oligoclonality to poly-clonality. CONCLUSION: High dose chemotherapy (HDC) and APBSCT are feasible and safe and can result in short-term or middle-term improvement of disease in patients with severe pSS which is refractory to conventional treatment. It is observed in this study that immune reconstruction recovered 3 moths after the treatment. Long-term efficacy of HDC + PBSCT in pSS should be studied in large number of cases with follow up of longer time.

Comparison of three classification criteria of rheumatoid arthritis in an inception early arthritis cohort.

The aim of this study is to compare the three classification criteria for rheumatoid arthritis (RA) in a large cohort of early arthritis patients. Patients who had at least one clinically swollen joint with disease duration no more than 1 year and age more than 18 years were enrolled. The clinical and laboratory parameters were recorded. The patients were diagnosed by two experienced rheumatologists. Undiagnosed patients were followed up every 3 months until 1 year. The sensitivity, specificity, and predictive value were compared among the early RA (ERA) criteria, the 1987 ACR criteria, and the 2010 ACR/EULAR criteria in this inception cohort of early arthritis patients. A total of 417 patients with inflammatory arthritis were recruited. By the end of 1 year follow-up, there were 399 patients (95.7 %) with a definitive diagnosis and 18 (4.3 %) patients remained as undifferentiated arthritis. Among the patients with definitive diagnosis, 202 (50.6 %) patients were diagnosed with RA and 197 (49.4 %) with non-RA. The sensitivity of ERA criteria was equal to 2010 ACR/EULAR criteria (both were 72.3 %), but much higher than 1987 ACR criteria (72.3 vs. 39.1 %, P < 0.001); the specificity of ERA criteria was comparable to 2010 ACR/EULAR criteria (87.8 vs. 83.2 %) and slightly lower than 1987 ACR criteria (87.8 vs. 92.4 %, P < 0.001). Unlike the complicated scoring system of 2010 criteria, the ERA criteria were more feasible to use in practice with five criteria only. The ERA criteria have a high sensitivity and more clinically feasibility in daily practice for early RA diagnosis.

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi-center study.

AIM: The aim of this study was to determine the efficacy and safety of a weekly dose of leflunomide (50 mg/week) in early rheumatoid arthritis patients with mild or moderate disease activity. METHODS: The patients of early rheumatoid arthritis (ERA) with mild or moderate disease activity were randomly selected for inclusion in this study and were assigned to either the treatment group (leflunomide 50 mg/week, LEF50) or the control group (leflunomide 10 mg/day, LEF10). All patients were treated for 24 weeks. Clinical efficacy was assessed using the disease activity score in 28 joints (DAS28) - erythrocyte sedimentation rate (ESR) and European League Against Rheumatism (EULAR) response. A Chi-squared test, Fisher's exact-test and paired t-tests were used to analyze the data. RESULTS: A total of 244 patients who met the inclusion criteria and received at least one medicine dose were analyzed. At the baseline, the DAS28 (ESR) of the ERA patients were 4.41 ± 0.69 in LEF 50 group and 4.52 ± 0.64 in LEF 10 group, respectively. At week 24, the DAS28 (ESR) in two groups ( 2.94 ± 1.10 and 3.02 ± 1.14 ) were significant decreased compare with the baseline, respectively (P<0.01). There was no significant difference in DAS28 (ESR) between the LEF50 and LEF10 groups at week 24. (P > 0.05). At weeks 8, 12 and 24, the EULAR response (good responses + moderate responses) were 47.6%, 58.7% and 59.5%, in the LEF50 group and 43.2%, 49.1% and 53.4% in the LEF10 group, respectively. There was no significant different of EULAR response rates in the two groups at week 8, 12, and 24, respectively (P>0.05). There was no serious adverse events during the study. CONCLUSION: A weekly dose of 50 mg leflunomide showed similar benefits to a daily dose of 10 mg leflunomide for the treatment of mild-to-moderate early rheumatoid arthritis.

[The effect of homocysteine on fibrinolytic system in human umbilical vein endothelial cells].

OBJECTIVES: To investigate the relationship between homocysteine (Hcy) and the fibrinolytic system in acute myocardial infarction (AMI) and human umbilical vein endothelial cells (HUVEC). METHODS: Cultured HUVEC was divided into 10 groups (0, 10, 50, 200, 500 micromol/L Hcy with or without 15 micromol/L of folic acid). There were 53 patients of acute myocardial infarction (AMI) and 48 healthy controls. The plasminogen activator inhibitor-1 (PAI-1) and activator of plasminogen (tPA) antigen levels in HUVEC's supernatant and plasma were measured with Elisa kit. Concentration of plasma Hcy was measured by reverse-phase high-performance liquid chromatography with precolumn derivatization and fluorometric detection in the patients and healthy controls. Total RNA was extracted using the guanidinium isothiocyanate method. The semi-quantification of PAI-1 and tPA mRNA in HUVEC was carried out by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: (1) PAI-1 mRNA and secreted protein levels were both significantly enhanced by Hcy at the concentration of 500 micromol/L, compared with the control group (P < 0.05). (2) The tPA mRNA and antigen levels were decreased significantly at concentration of 500 micromol/L of Hcy, compared with that of 10 micromol/L Hcy (P < 0.05), but compared with the control group (0 micromol/L), the tPA mRNA and antigen levels of 10 micromol/L of Hcy were much higher (P < 0.05). (3) The addition of folic acid reduced PAI-1 but increased tPA at both mRNA and protein levels, which were both obvious at concentrations of 500 micromol/L Hcy, compared with only Hcy group (P < 0.05). (4) Hcy, tPA, and PAI-1 antigen levels were increased in AMI group. Hcy is a independent risk factor of AMI (P < 0.05). There weren't significant correlation between Hcy and tPA or Hcy and PAI-1 in both groups (P > 0.05), although the coefficient correlation was higher in patients than in controls. CONCLUSIONS: These results suggested that hyperhomo-cysteinemia increased the incidence of thrombotic disease, which may be caused by decreasing the activity of fibrinolytic system, whereas, folic acid may be protective against the toxic action of Hcy.