Ameliorative Effect of Dabigatran on CFA-Induced Rheumatoid Arthritis via Modulating Kallikrein-Kinin System in Rats

Rheumatoid arthritis is an autoimmune disease that affects joints, leading to swelling, inflammation, and dysfunction in the joints. Recently, research efforts have been focused on finding novel curative approaches for rheumatoid arthritis, as current therapies are associated with adverse effects. Here, we examined the effectiveness of dabigatran, the antithrombotic agent, in treating complete Freund’s adjuvant (CFA)-induced arthritis in rats. Subcutaneous injection of a single 0.3 mL dosage of CFA into the rat’s hind leg planter surface resulted in articular surface deformities, reduced cartilage thickness, loss of intercellular matrix, and inflammatory cell infiltration. There were also increased levels of the Anti-cyclic citrullinated peptide antibody (ACPA), oxidative stress, and tissue Receptor activator of nuclear factor–kappa B ligand (RANKL). Proteins of the kallikrein-kinin system (KKS) were also elevated. The inhibitory effects of dabigatran on thrombin led to a subsequent inhibition of KKS and reduced Toll-like receptor 4 (TLR4) expression. These effects also decreased RANKL levels and showed anti-inflammatory and antioxidant effects. Therefore, dabigatran could be a novel therapeutic strategy for arthritis.     

miRNA-Mediated Epigenetic Regulation of Treatment Response in RA Patients—A Systematic Review

This study aimed to evaluate the role of microRNAs (miRNA) as biomarkers of treatment response in rheumatoid arthritis (RA) patients through a systematic review of the literature. The MEDLINE and Embase databases were searched for studies including RA-diagnosed patients treated with disease-modifying antirheumatic drugs (DMARDs) that identify miRNAs as response predictors. Review inclusion criteria were met by 10 studies. The main outcome of the study was the response to treatment, defined according to EULAR criteria. A total of 839 RA patients and 67 healthy donors were included in the selected studies. RA patients presented seropositivity for the rheumatoid factor of 74.7% and anti-citrullinated C-peptide antibodies of 63.6%. After revision, 15 miRNAs were described as treatment response biomarkers for methotrexate, anti-tumour necrosis factor (TNF), and rituximab. Among treatments, methotrexate presented the highest number of predictor miRNAs: miR-16, miR-22, miR-132, miR-146a and miR-155. The most polyvalent miRNAs were miR-146a, predicting response to methotrexate and anti-TNF, and miR-125b, which predicts response to infliximab and rituximab. Our data support the role of miRNAs as biomarkers of treatment response in RA and point to DMARDs modifying the miRNAs expression. Nevertheless, further studies are needed since a meta-analysis that allows definitive conclusions is not possible due to the lack of studies in this field.     

Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients

Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A₁, A_2A, A_2B and A₃) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A_2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A_2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A_2A- and A_2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.     

Hand radiographs preprocessing, image representation in the finger regions and joint space width measurements for image interpretation

In this paper, the first stage of studies concerning the computer analysis of hand X-ray digital images is described. The images are preprocessed and then skeletization of the fingers is carried out. Then, the interphapangeal and metacarpophalangeal joints are detected and contoured. Joint widths are also measured. The obtained results largely concur with those obtained by other authors—see Beier et al. [Segmentation of medical images combining local, regional, global, and hierarchical distances into a bottom-up region merging scheme, Proc. SPIE 5747 (2005) 546-555], Klooster et al. [Automatic quantification of osteoarthritis in hand radiographs: validation of a new method to measure joint space width, Osteoarthritis and Cartilage 16 (1) (2008) 18-25], Ogiela et al. [Image languages in intelligent radiological palm diagnostics, Pattern Recognition 39 (2006) 2157-2165] and Ogiela and Tadeusiewicz [Picture languages in automatic radiological palm interpretation, Int. J. Appl. Math. Comput. Sci. 15 (2) (2005) 305-312].     

Effect of couple illness perception congruence on psychological adjustment in women with rheumatoid arthritis.

Objective: To characterize similarities and differences in illness perceptions between women with rheumatoid arthritis (RA) and their husbands, and examine whether illness perception congruence predicted wives' subsequent psychological adjustment. Design: Women with RA and their husbands (N = 190 couples) recruited from community and clinical settings completed mailed surveys at baseline and 4-month follow-up. Main Outcome Measures: Data for this investigation included illness perceptions in partners and illness severity, marital variables, and psychological adjustment in wives. Results: In general, wives and husbands had similar views of RA. Couple congruence concerning women's personal control over RA and its cyclic nature predicted better psychological adjustment in women 4 months later. Post hoc tests showed better psychological adjustment in wives from couples with similar optimistic beliefs about personal control, illness coherence, and RA consequences, when compared to those in couples with similar pessimistic beliefs. Furthermore, when partners disagreed about RA's consequences, wives fared better when husbands overestimated rather than underestimated their beliefs. In contrast, couple congruence about the emotions and timeline of RA was unrelated to adjustment. Conclusion: It may be important for husbands to understand wives' views on their control over RA and its cyclic nature. Furthermore, wives may benefit when they share optimistic views with their husbands about RA, and when their husbands avoid underestimating RA's consequences. Developing interventions to enhance partners' illness understanding may be beneficial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

抗环瓜氨酸肽抗体定量检测ELISA试剂盒的制备及其诊断类风湿性关节炎的意义

目的制备抗环瓜氨酸肽(CCP)抗体定量检测ELISA试剂盒,并探讨其诊断类风湿性关节炎(RA)的意义。方法应用作者合成的CCP制备抗CCP抗体定量检测试剂盒,并进行鉴定。应用该试剂盒检测178份RA患者和712份非RA患者及健康人血清,评价其在RA诊断中的价值。结果所制备的定量检测试剂盒cutoff值为25RU/ml;线性良好,R2值大于0.99;试验内变异系数为5.15%~8.25%,试验间变异系数为6.82%~11.23%;平均回收率为99.7%。该试剂盒在4℃保存6个月,稳定性良好。与国外同类试剂盒同时测定80份样本,阳性符合率为95.7%,阴性符合率为97.1%,总体符合率为96.3%。该试剂盒对RA诊断的敏感性为73.0%,特异性为98.2%。结论所制备的试剂盒各项指标均达到相关要求,能够满足临床检测的需要。     

艾拉莫德联合甲氨蝶呤治疗类风湿关节炎有效性和安全性的系统评价和Meta分析

目的: 系统分析艾拉莫德（iguratimod, IGU）联合甲氨蝶呤（methotrexate,MTX）治疗类风湿关节炎（rheumatoid arthritis,RA）的临床疗效和安全性,为IGU在RA治疗中的合理规范应用提供依据。方法: 检索Pubmed、Cochrane Library、Embase、中国知网数据库（CNKI）、重庆维普中文科技期刊数据库（VIP）、中国生物医学文献数据库（CBM）、万方数据库（Wanfang data）和中国科技期刊数据库等电子数据库。检索时间从建库至2017年6月。纳入IGU联合MTX对比MTX治疗RA的临床随机对照试验（RCT）。由2位研究者根据纳入和排除标准独立选择符合标准的RCT并提取相关数据。用Cochrane系统评价手册进行文献质量分析,运用Review Manager 5.3统计软件对各疗效指标进行系统评价与Meta分析。结果: 共纳入6篇RCT,病例数合计553例。6篇文献的整体Meta分析结果显示,IGU联合MTX治疗RA其主要疗效指标ACR20/50/70应答率均优于MTX组（ACR20：RR=1.53,95%CI：1.13～2.06,P=0.006;ACR50：RR=2.15,95%CI：1.64～2.81,P<0.001;ACR70：RR=2.93,95%CI：1.54～3.72,P<0.001）;次要疗效评价指标方面,IGU联合MTX在降低血沉（ESR）、医生评估的疾病总体状况VAS评分（Physician VAS）和DAS28方面效果均显著优于MTX组,但两组出现的不良事件比较无明显差异（RR=1.06,95%CI：0.91～1.24,P=0.46）。系统评价结果显示,IGU联合MTX治疗方案在降低CRP、TJC28、SJC28、Pain VAS、Patient VAS及HAQ效果方面不亚于MTX单用。结论: 对比单纯使用MTX,IGU联合MTX治疗RA在ACR20/50/70达标率、改善ESR、DAS28方面疗效更优,且并不增加治疗期间不良反应的发生概率,有较好的疗效和安全性,值得在RA临床治疗中推广使用。     

Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis

Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O₂, 5% CO₂), hypoxically (2% O₂, 5% CO₂) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation.