Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression

Introduction

B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E₂ (PGE₂) when activated. In its turn, PGE₂ formed by cyclooxygenase (COX) and microsomal prostaglandin E₂ synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE₂ pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue.

Methods

B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1β and IL-6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis.

Results

Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL-1β in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy.

Conclusions

Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected.     

Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients receiving short-term infliximab therapy

Patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) strategies have an increased susceptibility to infections, especially those caused by intracellular pathogens. In this study we assessed the cytokine production capacity in patients with RA and we further investigated whether anti-TNF therapy modulates the production of pro-inflammatory cytokines involved in the resistance against infections. Whole blood cultures from 10 RA patients and 10 healthy controls were stimulated with heat-killed Candida albicans, Salmonella typhimurium, Staphyloccocus aureus, Aspergillus fumigatus or Mycobacterium tuberculosis and production of interleukin (IL)-1beta, IL-6, IL-10, interferon (IFN)-gamma and TNF-alpha was measured. Before anti-TNF therapy, whole blood cultures from RA patients released significantly less IFN-gamma than healthy controls after stimulation with all tested microorganisms. Short-term anti-TNF therapy did not have an inhibitory effect on the release of the cytokines tested. We conclude that cells of patients with RA have a strongly reduced production capacity of IFN-gamma after bacterial challenge. Although short-term therapy with anti-TNF agents did not further decrease the release of other proinflammatory cytokines, the combination of defective IFN-gamma production in basal conditions and TNF neutralization during anti-TNF therapy is likely to be responsible for the higher susceptibility to infections in patients with RA.     

Plasma Levels of IL-37 and Correlation with TNF-α, IL-17A,and Disease Activity during DMARD Treatment of Rheumatoid Arthritis

The aim of this study was to assess the change of IL-37 concentrations in rheumatoid arthritis (RA) patients under Disease-modifying anti-rheumatic drug (DMARD) therapy, and to establish a correlation between Interleukin-37 and pro-inflammatory cytokines in plasma and disease activity. The plasma level of IL-37 was determined using ELISA in 50 newly diagnosed RA patients and 30 healthy controls (HC). Plasma levels of IL-17A, IL-6 and TNF-α were measured using flow a cytometric bead array assay. We found that the concentrations of IL-37, as well as IL-17A, IL-6 and TNF-α, were higher in plasma of RA patients compared to HCs. Compared to patients who did not respond to DMARD treatment, treatment of patients responsive to DMARDs resulted in down-regulation of IL-17A, IL-6 and TNF-α expression. The plasma level of the anti-inflammatory cytokine IL-37 was also decreased in drug responders after DMARD treatment. The plasma level of IL-37 in RA patients was positively correlated with pro-inflammatory cytokines (IL-17A, TNF-α) and disease activity (CRP, DAS28) in RA patients. IL-37 expression in RA and during DMARD treatment appears to be controlled by the level of pro-inflammatory cytokines. This results in a strong correlation between plasma levels of IL-37 and disease activity in RA patients.     

不同RF型类风湿性关节炎患者Th17相关细胞因子表达研究

目的：探讨类风湿因子阳性与阴性类风湿关节炎（rheumatoid arthritis,RA）患者外周血中辅助T细胞（Th17）及相关细胞因子白介素17（interleukin,IL-17）,白介素6（interleukin,IL-6）表达的差异。方法：收集RA患者51例,根据RF测定分为RF＋、RF-组,健康查体者（对照组）20例,采用流式细胞术检测受检者外周血单个核细胞（PBMC）的Th17细胞的百分率;以酶联免疫吸附法（ELISA）检测受检者血浆中IL-17,IL-6的水平。结果：RA患者CD4＋IL-17＋T细胞,IL-17、IL-6水平均高于对照组,RF因子阳性与阴性RA患者之间CD4＋IL-17＋T细胞,IL-17、IL-6表达水平均存在差异有统计学意义。结论：在RA中不同RF型免疫反应和炎症表达的不同,可能与Th17及相关细胞因子表达差异有关。     

痛敏穴刺血加艾灸疗法治疗类风湿关节炎临床疗效研究

摘要 目的：观察痛敏穴刺血加艾灸疗法治疗类风湿关节炎（RA）患者的临床疗效。方法：选取2019年1月~2022年1月44例类风湿关节炎患者随机分为2组,每组22例。对照组予以来氟米特片和塞来昔布胶囊治疗,观察组在对照组基础上采用痛敏穴刺血加艾灸疗法。两组患者治疗前后采用视觉模拟评分法（VAS）和疾病活动评分（DAS-28）进行评估,并检测类风湿因子(RF)、超敏C反应蛋白（hs-CRP）、血沉(ESR)、类风湿因子（RF）、纤维蛋白原（FIB）、D二聚体水平。结果：两组治疗后VAS评分降低（P<0.05）,而研究组较对照组低（P<0.05）。两组治疗后DAS-28评分降低（P<0.05）,而研究组较对照组低（P<0.05）。两组治疗后RF、hs-CRP、FIB、D二聚体水平均明显下降（P<0.05）,而研究组均明显低于对照组（P<0.05）。观察组总有效率（100.00 %）明显高于对照组（72.73 %）（P<0.05）。结论：痛敏穴刺血加艾灸能够提高RA患者的临床疗效,且能够提高机体的抗炎效应。     

Role of glutathione peroxidase in rheumatoid arthritis: analysis of enzyme activity and DNA polymorphism.

Aberrant expression of the antioxidant enzyme glutathione peroxidase (GPx) could contribute to the etiology of rheumatoid arthritis (RA). However, previous enzyme activity studies examining this relationship were inconclusive. Indirect evidence for this relationship derives from the known efficacy of gold therapy in RA, since gold compounds specifically inhibit GPx. The hypothesis that variants of GPx are associated with RA was examined by two approaches: enzyme activity analysis and restriction fragment length polymorphism (RFLP) association analysis. No significant difference was found in whole blood GPx activity between 28 RA patients and 36 controls. GPx activity appeared to be independent of sex, race, or type of drug treatment. However, a statistically significant difference was found with respect to treatment responsiveness. RA patients classified as good responders to gold therapy, but who were no longer taking gold, had a significantly higher GPx activity compared to both the controls and good responders currently on gold therapy. Aberrantly high GPx activity could contribute to RA by generating excess oxidized glutathione, a potent collagenase activator. Gold therapy would reduce GPx activity to normal levels. The restriction enzyme Pvu II in conjunction with a GPx gene probe identified a useful RFLP (Al, 22 kbp; A2, 15 kbp) with allelic frequencies of A1 and A2 equal to 0.11 and 0.89, respectively, in the control population. No statistically significant association, however, could be demonstrated between this allelic variant of the GPx gene and RA.     

类风湿关节炎与痛风关节炎患者身心健康、炎症状态及免疫功能的比较

目的:比较类风湿关节炎与痛风关节炎患者身心健康、炎症及免疫状态的差异。方法:选择我院2016年5月至2018年8月收治的66例类风湿关节炎患者及63例痛风关节炎患者作为研究对象,并将之分为类风湿关节炎(Rheumatoid arthritis,RA)组及痛风关节炎(Gouty arthritis,GA)组。同时选取60例体检健康人群作为健康组。观察比较三组研究对象身心健康评分、炎症及免疫相关指标水平。结果:RA组及GA组身心健康评分显著低于健康组(P0.05),炎症及免疫相关指标水平显著高于健康组(P0.05)。RA组患者总体健康评分、社会功能评分、红细胞沉降率(ESR)、C反应蛋白(CRP)、免疫球蛋白G(Ig G)、免疫球蛋白A(Ig A)、免疫球蛋白M(Ig M)及补体3(C3)水平显著高于GA组(P0.05),白细胞(WBC)总数明显少于GA组(P0.05),两组患者生理功能、生理职能、身体疼痛、活力、情感职能、心理健康评分及补体4(C4)水平比较差异不显著(P0.05)。结论:相较于健康人群,类风湿关节炎患者及痛风关节炎患者身心健康状况差,易出现炎症、免疫功能紊乱现象,且类风湿关节炎患者炎症程度较深,免疫功能影响更大。     

Decreased suppressive B cell factor (SBF) in rheumatoid arthritis: evidence for a defect in B cell autoregulation

Rheumatoid arthritis (RA) is a disorder characterized by defective immunoregulation. Hypergammaglobulinemia, circulating immune complexes (IC), and autoantibodies such as rheumatoid factor (RF) are common serum abnormalities. To assess IC-mediated feedback suppression in RA, we evaluated the ability of a suppressive B cell factor (SBF) generated by culturing heat-aggregated IgG (HAIgG) with peripheral blood mononuclear leukocytes (PBL) from patients with RA and normal controls to suppress the pokeweed mitogen (PWM)-induced RF plaque-forming cell (PFC) response of normal PBL. RA patients generated less SBF than age-matched controls. Background suppression (supernatants obtained from PBL cultured without HAIgG) was similar in the RA patients and age-matched controls. To determine the effects of nonsteroidal antiinflammatory drug (NSAID) therapy on suppression, RA patients and age-matched controls were studied before and after NSAID therapy. NSAID therapy significantly reduced background suppression in RA patients who were not on immunosuppressive drugs and in age-matched controls, but there was no effect on SBF in RA patients or controls. There was a small increase in background suppression when NSAID were administered to RA patients on immunosuppressives, suggesting an ameliorative effect of NSAID in this group of patients, which tended to increase their level of suppression when compared with RA patients only on NSAID. Spontaneous RF-PFC were measured in normal controls and RA patients and were compared with suppressor activity. There were increased numbers of spontaneous RF-PFC in RA patients. Total suppressor activity was greatest in young adult controls, who also had the least RF-PFC. The percentage of suppression correlated inversely with the number of RF-PFC in patients and controls. Additionally, disease activity in RA as measured by total joint count and erythrocyte sedimentation rate (ESR) was shown to correlate inversely with total suppressor activity. We conclude that the PBL from patients with RA produce decreased SBF after HAIgG stimulation and that loss of suppression is also associated with aging. This study suggests a defect in IC-stimulated B cell suppressor activity in RA leading to decreased ability to suppress antibody and further IC formation. The combination of increased RF-PFC and decreased SBF suggests that there is defective B cell autoregulation in RA, which may be involved in the pathogenesis and chronicity of this disease.     

类风湿关节炎药物治疗的规范化及临床实践探析

目的：在前人研究基础上进一步调查和研究类风湿关节炎（RA）患者药物治疗的规范化状况。方法：对湘潭市中心医院2012年3月至12月门诊就诊的120例风湿关节炎患者进行问卷调查。内容包括患者个人资料、就诊及确诊时间、科室,随诊时间间隔以及改善病情抗风湿药（DMARDs）的应用情况。结果：类风湿关节炎药物治疗不规范,甲氨蝶呤是患者应用最多的DMARDs,占60％,其次为来氟米特（30％）、柳氮磺吡啶（5％）及羟氯喹（5％）。结论：51％以上的RA病人DMARDs治疗不规范,尤其是在县级基层医院。类风湿性疾病的规范治疗需要从早期诊断治疗,优化联合用药,个性化治疗,定期跟踪疗效等方面来规范。     

Multiple imputation procedures allow the rescue of missing data: an application to determine serum tumor necrosis factor (TNF) concentration values during the treatment of rheumatoid arthritis patients with anti-TNF therapy

Longitudinal studies aimed at evaluating patients clinical response to specific therapeutic treatments are frequently summarized in incomplete datasets due to missing data. Multivariate statistical procedures use only complete cases, deleting any case with missing data. MI and MIANALYZE procedures of the SAS software perform multiple imputations based on the Markov Chain Monte Carlo method to replace each missing value with a plausible value and to evaluate the efficiency of such missing data treatment. The objective of this work was to compare the evaluation of differences in the increase of serum TNF concentrations depending on the -308 TNF promoter genotype of rheumatoid arthritis (RA) patients receiving anti-TNF therapy with and without multiple imputations of missing data based on mixed models for repeated measures. Our results indicate that the relative efficiency of our multiple imputation model is greater than 98% and that the related inference was significant (p-value < 0.001). We established that under both approaches serum TNF levels in RA patients bearing the G/A -308 TNF promoter genotype displayed a significantly (p-value < 0.0001) increased ability to produce TNF over time than the G/G patient group, as they received successively doses of anti-TNF therapy.     

Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with rheumatoid arthritis from patients with chronic hepatitis C infection-associated polyarticular involvement

This study was performed to assess the utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies in distinguishing between patients with rheumatoid arthritis (RA) and patients with polyarticular involvement associated with chronic hepatitis C virus (HCV) infection. Serum anti-CCP antibodies and rheumatoid factor (RF) were evaluated in 30 patients with RA, 8 patients with chronic HCV infection and associated articular involvement and 31 patients with chronic HCV infection without any joint involvement. In addition, we retrospectively analysed sera collected at the time of first visit in 10 patients originally presenting with symmetric polyarthritis and HCV and subsequently developing well-established RA. Anti-CCP antibodies and RF were detected by commercial second-generation anti-CCP2 enzyme-linked immunosorbent assay and immunonephelometry respectively. Anti-CCP antibodies were detected in 23 of 30 (76.6%) patients with RA but not in patients with chronic HCV infection irrespective of the presence of articular involvement. Conversely, RF was detected in 27 of 30 (90%) patients with RA, 3 of 8 (37.5%) patients with HCV-related arthropathy and 3 of 31 (9.7%) patients with HCV infection without joint involvement. Finally, anti-CCP antibodies were retrospectively detected in 6 of 10 (60%) patients with RA and HCV. This indicates that anti-CCP antibodies can be useful in discriminating patients with RA from patients with HCV-associated arthropathy.     

Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis

Neutrophils are known to be targets for the biological activity of tumour necrosis factor (TNF)-α in the pathogenensis of rheumatoid arthritis (RA). Therefore, these cells may be among the targets of anti-TNF-α therapy. In this study we evaluated the effect of therapy with adalimumab (a fully human anti-TNF-α mAb; dosage: 40 mg subcutaneously every other week) on certain phenotypic and functional aspects of neutrophils obtained from 10 selected patients with RA and 20 healthy control individuals. Peripheral blood neutrophils were obtained at baseline and during anti-TNF-α therapy (2, 6 and 12 weeks after the first administration of adalimumab). All patients had been receiving a stable regimen of hydroxychloroquine, methotrexate and prednisone for at least 3 months before and during the study. Baseline neutrophil chemotaxis was significantly decreased in RA patients when compared with control individuals (P < 0.001). Two weeks after the first administration of adalimumab, chemotactic activity was completely restored, with no differences noted between patients and control individuals; these normal values were confirmed 6 and 12 weeks after the start of anti-TNF-α therapy. Phagocytic activity and CD11b membrane expression on neutrophils were similar between RA patients and control individuals; no modifications were observed during TNF-α neutralization. The production of reactive oxygen species, both in resting and PMA (phorbol 12-myristate 13-acetate)-stimulated cells, was significantly higher in RA patients at baseline (P < 0.05) and was unmodified by anti-TNF-α mAb. Finally, we showed that the activation antigen CD69, which was absent on control neutrophils, was significantly expressed on neutrophils from RA patients at baseline (P < 0.001, versus control individuals); however, the molecule was barely detectable on cells obtained from RA patients during adalimumab therapy. Because CD69 potentially plays a role in the pathogenesis of arthritis, our findings suggest that neutrophils are among the targets of anti-TNF-α activity in RA and may provide an insight into a new and interesting mechanism of action of anti-TNF-α mAbs in the control of inflammatory arthritis.     

Spontaneous serial fractures of metatarsal bones in female patient with rheumatoid arthritis on long-term steroid therapy

Low-dose oral steroid therapies are very effective in active rheumatoid arthritis (RA), reducing disease activity in acute crisis either while waiting for disease-modifying antirheumatic drugs (DMARDs) to take effect or if it was slow in response to DMARDs. However, long-term steroid therapies are associated with serious side effects, such as osteoporotic reduction of bone mass and frequent fractures. This paper reports a female patient who has suffered RA treated with low-dose oral steroid therapy in a long-term period. Suddenly, she developed severe pain and oedema of forefeet during home distance level walking, with no history of trauma. The diagnosis of spontaneous serial fractures of the 2nd to 4th metatarsal (MT) bone bilaterally was performed by feet radiography. Furthermore, in widening the diagnostic approaches the authors had performed diagnostic musculoskeletal ultrasound to exclude metatarsophalangeal joint effusion and exacerbation of RA. They also made a static analysis of feet on the electronic baropodometer system in order to register biomechanical changes in bipedal standing. One year after, the same diagnostic procedures were done, on which occasion the healing of fractures were verified, with better results in biomechanical static analysis of the feet but without complete regression of static disbalance. This could lead to further disturbances during level walking and daily activities. This paper reports a unique case of the RA patient on long-term low-dose steroid therapy with previously unreported sites of spontaneous metatarsal fractures of feet which causes further static disbalance; consequently the patient might experience problems in every-day life activities.     

Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response

Introduction

In rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.

Methods

The level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.

Results

Plasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.

Conclusions

The plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.     

老年女性类风湿关节炎合并骨质疏松症的代谢特点分析

目的:探讨老年女性类风湿关节炎(RA)合并骨质疏松症的代谢特点。方法:选择老年绝经后女性RA患者共59例,检测患者血生化代谢指标如血糖、血脂、CRP等和骨代谢指标如骨钙素(OC)、β-胶原特殊序列(β-Crosslaps)甲状旁腺素(iPTH)等,并进行统计分析。结果:骨质疏松患者的绝经时间、病程长度、OC、β-Crosslaps、iPTH显著高于骨量正常和骨量减少的患者,25羟基维生素D显著低于骨量正常和骨量减少的患者(P均0.05)。RA患者的骨密度水平与是否使用激素和X线分期情况无关。结论:老年女性RA患者易发生骨质疏松,出现骨质疏松的RA女性患者绝经时间更长,可出现脂代谢紊乱及明显的维生素D缺乏,并具有高转换型骨代谢特点。     

IL-27-producing CD14(+) cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration

Interleukin (IL)-27, a heterodimeric cytokine, has been reported to be involved in the pathogenesis of autoimmune diseases through mediating differentiation of Th1 or Th17 cells and immune cell activity or survival. However, the origin and effects of IL-27 in joints of rheumatoid arthritis (RA) remain unclear. In this study, we investigated the distribution and anti-inflammatory roles of IL-27 in RA synovium. The IL-27 levels in plasma of RA patients, osteoarthritis (OA) patients, or healthy volunteers (n=15 per group) were equivalent and were at most 1 ng/ml, but the IL-27 level in synovial fluid of RA patients (n=15, mean 0.13 ng/ml; range 0.017-0.37 ng/ml) was significantly higher than that in synovial fluid of OA patients (n=15, mean 0.003 ng/ml; range 0-0.033 ng/ml) and potentially lower than in plasma. We analyzed the protein level of IL-27 produced by RA fibroblast-like synoviocytes (FLSs) or mononuclear cells (MNCs) from RA or OA synovial fluid or peripheral blood and showed that IL-27 in RA joints was derived from MNCs but not from FLSs. We also found by flow cytometry that IL-27-producing MNCs were CD14(+), and that these CD14(+)IL-27(+) cells were clearly detected in RA synovium but rarely in OA synovium by immunohistochemistry. Furthermore, we demonstrated that a relatively physiological concentration of IL-27 below 10 ng/ml suppressed the production of IL-6 and CCL20 from RA FLSs induced by proinflammatory cytokines through the IL-27/IL-27R axis. In the synovial fluid of RA, the IL-27 level interestingly had positive correlation with the IFN-γ level (r=0.56, p=0.03), but weak negative correlation with the IL-17A level (r=-0.30, p=0.27), implying that IL-27 in inflammatory joints of RA induces Th1 differentiation and suppresses the development or the migration of Th17 cells. These findings indicate that circulating IL-27-producing CD14(+) cells significantly infiltrate into inflamed regions such as RA synovium and have anti-inflammatory effects in several ways: both directly through the reduction of IL-6 production, and possibly through the induction of Th1 development and the suppression of Th17 development; and indirectly by regulation of recruitment of CCR6(+) cells, such as Th17 cells, through the suppression of CCL20 production. Our results suggest that such a serial negative feedback system could be applied to RA therapy.     

Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis

Although the etiology of early events in rheumatoid arthritis (RA) remains undefined, an anomaly in T cell homeostasis and hyperproliferation of synovial-lining cells are involved in the disease process. Since it has been reported that the ephrin/Eph receptor system plays important signaling roles in inflammation processes, we attempted to examine ephrinB molecules in T cells and synovial cells derived from RA in this study. The expression level of ephrinB1 was significantly high in synovial fibroblasts and CD3-positive exudate lymphocytes in synovial tissues derived from patients with RA compared with those in osteoarthritis (OA). Protein and mRNA levels of ephrinB1 were also higher in peripheral blood lymphocytes (PBLs) prepared from patients with RA than those from normal controls. Similar results were obtained from an animal model of human RA, collagen antibody-induced arthritis mice. Moreover, a recombinant ephrinB1/Fc fusion protein stimulated normal PBLs to exhibit enhanced migration and production of TNF-alpha. EphrinB1/Fc also activated synovial cells established from patients with RA to produce IL-6. Tyrosine phosphorylation of EphB1 was induced in these cells by ephrinB1/Fc. The CpG islands in the 5' upstream regulatory region of the ephrinB1 gene were hypomethylated in RA patients compared with those of normal donors. These results suggest that ephrinB1 and EphB1 receptors play an important role in the inflammatory states of RA, especially by affecting the population and function of T cells. Inhibition of the ephrinB/EphB system might be a novel target for the treatment of RA.     

抗RA33抗体、RF、CRP、ANA与ENA联合检测在类风湿性关节炎患者诊断、治疗及预后中的作用

目的：探讨血清抗RA33抗体、RF、CRP联合检测在类风湿性关节炎患者诊断、治疗及预后中的作用。方法：采用ELISA法对35例类风湿性关节炎患者和30例健康对照者进行抗RA33抗体的检测,间接免疫荧光法检测ANA、免疫印迹法检测ENA,免疫比浊法进行类风湿因子（RF）及CRP的检测。结果：类风湿性关节炎患者组RF水平为：[（104．51±153．88）KIU／L]与健康对照组[（10．89±2．78）KIU／L]比较,差异非常显著（p〈0．01）;类风湿性关节炎组CRP[（11．60±23．24）mg／L]与健康对照组[（2．57±2．18）mg／L]比较,差异显著（p〈0．05）;类风湿性关节炎组抗RA33抗体水平：[（17．81±35．11）U／mL]与健康对照组[（8．10±8．40）U／mL]比较,差异非常显著（p〈0．01）。RF、抗RA33抗体、CRP及ANA诊断类风湿性关节炎的灵敏度分别为：80．00％,34．29％,42．86％,62．86％;RF、抗RA33抗体、CRP及ANA诊断类风湿性关节炎的特异性分别为：93.33％,93.33％,90．00％,96．67％;ENA的检出率均较低。结论：类风湿性关节炎患者抗RA33抗体检出的灵敏度低,但特异性强。对类风湿性关节炎患者进行抗RA33抗体、ANA、RF、CRP、ENA联合检测,对于疾病的进展、病因分析、指导治疗和改善预后均具有重要意义。     

Balance between survivin,a key member of the apoptosis inhibitor family,and its specific antibodies determines erosivity in rheumatoid arthritis

Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.