The relation between stress and disease activity in rheumatoid arthritis

This study investigated the relation between stress and current disease activity in rheumatoid arthritis (RA). During a routine clinic appointment, subjects were given ratings of global disease status by their physicians and completed self-report measures of major stress and minor stress. In addition, each subject's erythrocyte sedimentation rate was taken. After controlling for disease severity and major stress, minor stress accounted for a significant amount of the variance in inflammation level. These results suggest that minor stress is associated with current disease activity in RA.     

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Rheumatoid arthritis is characterized by synovial proliferation, neovascularization and leucocyte extravasation leading to joint destruction and functional disability. The blood vessels in the inflamed synovium are highly dysregulated, resulting in poor delivery of oxygen; this, along with the increased metabolic demand of infiltrating immune cells and inflamed resident cells, results in the lack of key nutrients at the site of inflammation. In these adverse conditions synovial cells must adapt to generate sufficient energy to support their proliferation and activation status, and thus switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This alters redox-sensitive signalling pathways and also results in the accumulation of metabolic intermediates which, in turn, can act as signalling molecules that further exacerbate the inflammatory response. The RA synovium is a multi-cellular tissue, and while many cell types interact to promote the inflammatory response, their metabolic requirements differ. Thus, understanding the complex interplay between hypoxia-induced signalling pathways, metabolic pathways and the inflammatory response will provide better insight into the underlying mechanisms of disease pathogenesis.     

Emerging role of leptin in rheumatoid arthritis

Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity‐like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future.     

Angiotensin II in inflammation,immunity and rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. Although classically known for its role in the regulation of circulatory homeostasis, angiotensin II (Ang II) is recognized to act as a powerful proinflammatory mediator. Some research has showed that Ang II plays important roles in autoimmune diseases, including RA, systemic lupus erythematosus and multiple sclerosis. Ang II blockers prove effective in reducing inflammation and autoimmunity in rheumatic diseases and their relative safety, together with their effects for reducing the cardiovascular disease risk, suggest that Ang II blockers may at least act as effective adjunctive therapy for disease control in patients with RA. The present review focuses systematically on the potential impact of Ang II and its receptors on inflammation and immunomodulation in patients with RA.     

Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA)

PTX3 is a secreted molecule which consists of a C-terminal domain similar to classical pentraxins (e.g. C-reactive protein (CRP)) and of an unrelated N-terminal domain. Unlike the classical pentraxins, the long pentraxin PTX3 is expressed in response to IL-1beta and tumour necrosis factor-alpha (TNF-alpha), but not to IL-6, in various cell types. The present study was designed to investigate the expression of PTX3 in RA. Dissociated RA and osteoarthritis (OA) type B synoviocytes were cultured in the presence and in the absence of inflammatory cytokines. PTX3 mRNA expression in synoviocytes was evaluated by Northern analysis. PTX3 protein levels in synovial cell cultures and synovial fluid were estimated by ELISA, and PTX3 distribution in synovial tissues by immunohistochemical techniques. OA synoviocytes were induced to express high levels of PTX3 mRNA by TNF-alpha, but not by other cytokines including IL-1beta and IL-6. RA synoviocytes, unlike OA synoviocytes, constitutively expressed high levels of PTX3 in the absence of deliberate stimulation. The constitutive expression of PTX3 in RA synoviocytes was not modified by anti-TNF-alpha antibodies, IL-1 receptor antagonist or a combination of the two agents. In contrast, interferon-gamma and transforming growth factor-beta inhibited PTX3 constitutive expression in RA synoviocytes. The joint fluid from RA patients contained higher levels of immunoreactive PTX3 than controls and the synovial tissue contained endothelial cells and synoviocytes positive for PTX3 by immunohistochemistry. In conclusion, PTX3 may play a role in inflammatory circuits of RA, and its relevance as a marker of disease activity deserves further study.     

Leflunomide in the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic and highly morbid disease affecting approximately 1% of the world’s population. With the advent of disease-modifying antirheumatic drugs, patients are increasingly able to maintain control of their arthritis and prevent joint destruction. However, not all patients respond adequately to any single disease-modifying antirheumatic drug, and many newer parenteral therapies are cost prohibitive. Leflunomide, an inhibitor of pyrimidine biosynthesis, is the first oral disease-modifying antirheumatic drug to have been approved for rheumatoid arthritis in the USA in the last 15 years, and is now widely used in over 70 countries around the world. Leflunomide is efficacious when used as monotherapy or in combination with methotrexate to treat patients with rheumatoid arthritis, and is generally well tolerated. As clinical use increases, new ways to use leflunomide in order to minimize toxicity and maximize efficacy are being explored.     

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Acute inflammation is a complex and tightly regulated homeostatic process that includes leucocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro‐resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as rheumatoid arthritis (RA), it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive‐feedback regulatory pathways in a variety of cells, including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti‐inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets.     

糖皮质激素对类风湿关节炎炎性因子改变及效果的观察

目的：分析糖皮质激素对类风湿关节炎炎性因子改变及效果。方法：选取我院2014年8月至2015年8月门诊及住院就诊的80例类风湿关节炎患者,依据抽签法分成对照组与观察组,每组40例,对照组采取常规治疗,观察组基于对照组联合糖皮质激素治疗,对比分析两组治疗后炎性因子、RF、ESR、晨僵、关节肿胀数及关节压痛数、DAS评分及VAS评分变化、治疗有效率与不良反应。结果：治疗后,观察组炎性因子TNF-α低于对照组[(31.23±8.74) vs.(36.46±9.12) pg/mL],IL-6低于对照组[(2.62±0.31) vs.(3.67±0.36) pg/L],CRP低于对照组[(15.26±1.03) vs.(17.38±1.10) mg/L],比较有显著差异(P<0.05);观察组RF低于对照组[(15.34±1.21) vs.(20.25±1.24) U/mL],ESR低于对照组[(24.36±1.57) vs.(28.95±1.60) mm/h],晨僵少于对照组[(16.73±1.28) vs.(18.97±1.34)],关节肿胀数低于对照组[(47.28±0.40) vs.(6.73±0.45)],关节压痛数低于对照组[(6.18±0.52) vs.(9.36±1.05) min],比较差异显著(P<0.05);观察组DAS28低于对照组[(1.93±0.20) vs.(2.18±0.26)分],VAS低于对照组[(2.23±0.25) vs.(3.07±0.12)分],比较差异明显(P<0.05);治疗有效率95.00%高于对照组80.00%(P<0.05),观察组总不良反应率25.00%高于对照组20.00%,但无统计学意义(P>0.05)。结论：类风湿关节炎运用糖皮质激素治疗安全性高,可有效降低炎性因子水平,改善患者临床症状,促进身心恢复。     

Calreticulin promotes angiogenesis via activating nitric oxide signalling pathway in rheumatoid arthritis

Calreticulin (CRT) is a multi-functional endoplasmic reticulum protein implicated in the pathogenesis of rheumatoid arthritis (RA). The present study was undertaken to determine whether CRT was involved in angiogenesis via the activating nitric oxide (NO) signalling pathway. We explored the profile of CRT expression in RA (including serum, synovial fluid and synovial tissue). In order to investigate the role of CRT on angiogenesis, human umbilical vein endothelial cells (HUVECs) were isolated and cultured in this study for in-vitro experiments. Our results showed a significantly higher concentration of CRT in serum (5·4 ± 2·2 ng/ml) of RA patients compared to that of osteoarthritis (OA, 3·6 ± 0·9 ng/ml, P < 0·05) and healthy controls (HC, 3·7 ± 0·6 ng/ml, P < 0·05); and significantly higher CRT in synovial fluid (5·8 ± 1·2 ng/ml) of RA versus OA (3·7 ± 0·3 ng/ml, P < 0·05). High levels of CRT are expressed in synovial membrane localized predominantly to inflammatory cells and synovial perivascular areas in both the lining and sublining layers of RA synovial tissue (RAST). Increased nitric oxide (NO) production and phosphorylation level of endothelial nitric oxide synthase (eNOS) were measured in HUVECs following CRT stimulation, while the total eNOS expression was not significantly changed. Furthermore, CRT promoted the proliferation, migration and tube formation of HUVECs, which were significantly inhibited by a specific eNOS inhibitor. These findings suggested that CRT may be involved in angiogenesis events in RA through NO signalling pathways, which may provide a potential therapeutic target in the treatment of RA.     

The type I IFN system in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterized by joint inflammation, immune cell infiltration of the synovia, and cartilage/bone destruction. Despite noteworthy progress in the treatment of RA in recent years, many patients remain refractory to current therapeutic strategies that target either the adaptive immune system or mediators of the innate system. Type I interferons (IFNs) play a significant role in regulation of the innate immune system, originally being discovered as part of intracellular immune defence against viral infection. IFNs are pleiotropic cytokines, mediating both immunostimulatory and immunosuppressive effects. IFN-alpha and beta have been detected in RA synovial fluid and tissue and subsequent therapeutic approaches using type I IFN in murine models of arthritis and in human RA have produced different and controversial results. Great interest has been directed toward principally plasmacytoid dendritic cells (pDCs), although also toward myeloid dendritic cells, as sources of type I IFN. Furthermore, manipulation of DC populations in murine RA models demonstrated that pDCs could suppress the development of arthritis and autoimmunity and may offer an attractive therapy for T-cell-mediated autoimmune diseases. Finally, dendritic cells (DCs) are vehicles for the delivery of therapeutic vaccines, and clinical trials are ongoing in RA with “tolerogenic” DC populations. Further, studies on animal models of RA will elucidate how IFN and DCs contribute to the establishment of autoimmune arthritis and the potential for manipulation of these cell populations and products to re-establish the immune tolerance.     

Prediction of response to methotrexate in rheumatoid arthritis

Introduction: Methotrexate (MTX) is the first-line disease-modifying drug of choice in controlling active inflammation of the synovium that characterises rheumatoid arthritis, a chronic autoimmune inflammatory condition. However, many patients do not respond to treatment with MTX or cannot tolerate the medication. Pre-treatment characteristics that predict response to MTX are, therefore, of particular interest and potential clinical utility.

Areas covered: This narrative review seeks to cover various genotypic and phenotypic characteristics that have been investigated as predictors of treatment response to MTX in RA. Ovid Medline searches (1946 to January 2018) were carried out for ‘methotrexate’ and ‘rheumatoid arthritis’, in combination with relevant terms. All papers identified were English language, with abstracts. Relevant references were also reviewed.

Expert commentary: Despite the introduction of biologic medication and targeted therapies, MTX is likely to remain the mainstay of RA treatment, largely due to its much cheaper cost. Development of a multifactorial predictive algorithm for response to MTX may be of clinical utility, as well as routine MTX drug level testing to improve medication adherence and persistence.     

The role of exercise in the management of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with significant functional impairment and increased risk for cardiovascular disease. Along with pharmacological therapy, exercise seems to be a very promising intervention to improve disease-related outcomes, including functional ability and systemic manifestations, such as the increased cardiovascular risk. In this review, we discuss the physiological mechanisms by which exercise improves inflammation, cardiovascular risk and psychological health in patients with rheumatoid arthritis (RA) and describe in detail how exercise can be incorporated in the management of this disease using real examples from our clinical practice.     

New therapies for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti-tumour necrosis factor-alpha agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti-IL-6 receptor monoclonal antibody and tacrolimus, and newer anti-rheumatic therapies presently in development are summarized.     

The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis

Summary: Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells of synovial joints that have been recognized to play an increasingly important role in the pathogenesis of rheumatoid arthritis (RA). Activation of FLS in the setting of RA leads to the production of a broad array of cell surface and soluble mediators that help to recruit, retain, and activate both cells of the immune system and resident joint cells, leading to the promotion of ongoing inflammation and tissue destruction. The ability of FLS to stimulate both inflammation and tissue damage suggests that this cell type may be a unique target for the treatment of inflammatory arthritis. Greater understanding of how FLS are activated and how they interact with other cells in the RA synovium may provide insights that allow development of novel agents for RA therapy.     

TRIM32 promotes inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes

Rheumatoid arthritis (RA) is a worldwide autoimmune disease. The study of its aetiology and mechanism has always been a focus topic in medicine. This research was designed to investigate the effect of E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) in rheumatoid arthritis (RA). We found in fibroblast-like synoviocytes (FLS) of RA patients, the expression of TRIM32 was significantly increased compared with its expression in osteoarthritis (OA) patients FLS. A widely used pro-inflammatory stimuli tumour necrosis factor-alpha (TNF-α) was found to promote TRIM32 expression in a time-dependent manner. Furthermore, we observed that overexpression of TRIM32 aggravated the production of pro-inflammatory cytokines in FLS, silencing of TRIM32 showed the consistent results. In addition, TRIM32 was found to activate nuclear factor κB (NF-κB) signalling pathway, and TRIM32 could interact with TNF receptor-associated factor 2 (TRAF2) to promote the K63-linked polyubiquitination of TRAF2 in RA-FLS. In conclusion, we suggested that TRIM32 as a positive regulator of inflammatory responses in RA-FLS.     

类风湿性关节炎患者T细胞亚群失衡与炎性粘附分子的关系

目的：探讨类风湿性关节炎（RA）患者细胞免疫调节功能异常与参与介导免疫炎性损伤的细胞粘附分子之间的关系。方法：以ELISA方法检测40例RA患者外周血中IL－2、IL－10、 sICAM-1、sVCAM-1水平。结果：RA患者TH1，细胞因子IL－2水平明显低于健康对照组；TH2细胞因子IL－10及细胞粘附分子sICAM-1/sVCAM-1水平明显高于健康对照组，各组间比较均具有显著性差异（P＜0．01）。结论：RA患者高水平的 IL－10与低水平的IL－2提示TH2细胞功能亢进，进而TH1细胞被抑制，并导致细胞因子谱的偏移；高水平的sICAM-1、sVCAM-1是RA患者慢性炎症损伤的重要介质；异常升高的IL－10与细胞粘附分子的共同作用是导致RA患者病理损伤的重要原因。