Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice

Administration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anti-citrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, low-dose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzyme-linked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (T_reg) population by fluorescence activated cell sorter (FACS). ACPA-sIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the T_reg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the T_reg population.     

Early environmental factors and rheumatoid arthritis

The precise cause of autoimmune diseases such as rheumatoid arthritis (RA) remains uncertain. In recent years there has been extensive investment in pursuing genes important in RA. However, estimates suggest that the risk of developing RA is at most 50% determined by genes. There has been limited success defining the environmental factors important in developing RA. We hypothesize that this lack of success may be due to a concentration on the time around disease onset. There is evidence of production of the autoantibodies rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP) and increased levels of C-reactive protein (CRP) years before RA becomes clinically apparent. In addition, early life events including intrauterine growth retardation (IUGR) may have long lasting effects on immune function. We review the evidence that the early environment through effects on growth and infectious exposure may influence the likelihood of developing autoimmune diseases such as RA.     

定量CT在评估类风湿性关节炎相关间质性肺病中的应用

目的:探究胸部CT定量分析对于类风湿性关节炎相关间质性肺病（RA-ILD）患者肺间质改变早期诊断及病情评估的价值。方法:收集临床确诊RA患者105例,同时收集胸部CT无间质改变的非结缔组织病患者对照组80例。测量两组研究对象肺总体积（TLV）,利用定量CT肺部密度直方图计算CT值为-200~-700 HU的肺体积占全肺体积百分比（LAA-200~-700%）、CT值小于-950 HU的肺体积占全肺体积百分比（LAA-950%）、主动脉直径（AD）、肺动脉干直径（PAD）、主肺动脉干比值（AD/PAD）、左肺下叶直径2 mm支气管周围血管数量及面积（视区范围80 mm2）。比较RA患者组与对照组的测量值差异。结果:RA患者组与对照组相比,TLV、LAA-200~-700%、PAD、左肺下叶直径为2 mm的支气管视区范围为80 mm2时肺血管数量及面积均存在差异,其中RA患者组TLV为（4 047.60±1 160.11） mL,小于对照组（4 507.30±1 207.50） mL;LAA-200~-700%为14.42%±8.62%,大于对照组10.40%±3.87%,PAD为（26.39±3.59） mm,大于对照组（25.27±2.57） mm;RA组左肺下叶直径为2 mm支气管层面视区范围为80 mm2时肺血管数量为13.3±6.28,面积为（105.48±59.07） mm2;对照组血管数量为17.06±4.70,血管面积为（164.88±46.02） mm2,差异有统计学意义（P<0.001）。结论:RA-ILD患者肺部与对照组相比有差异,定量CT能有效识别评估RA-ILD早期肺血管改变。     

Towards prevention of autoimmune diseases: The example of rheumatoid arthritis

Prevention is the ultimate aim for clinicians and scientists concerned with severe diseases, like many immune-mediated conditions. Here, we describe recent progress in the understanding of etiology and molecular pathogenesis of rheumatoid arthritis (RA), which make this disease a potential prototype for prevention that may include both public health measures and targeted and personalized approaches that we call “personalized prevention.” Critical components of this knowledge are (i) better understanding of the dynamics of the RA-associated autoimmunity that may begin many years before onset of joint inflammation; (ii) insights into how this immunity may be triggered at mucosal surfaces after distinct environmental challenges; (iii) better understanding of which features of the pre-existing immunity may cause symptoms that precede joint inflammation and predict a high risk for imminent arthritis development; and (iv) how molecular events occurring before onset of inflammation might be targeted by existing or future therapies, ultimately by specific targeting of Major histocompatibility complex (MHC) class II restricted and RA-specific immunity. Our main conclusion is that studies and interventions in the phase of autoimmunity preceding RA offer new opportunities to prevent the disease and thereby also understand the molecular pathogenesis of its different variants.     

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.     

Positive association between serum thymic stromal lymphopoietin and anti-citrullinated peptide antibodies in patients with rheumatoid arthritis

Thymic stromal lymphopoietin (TSLP) has been suggested recently to play an important role in the pathophysiology of rheumatoid arthritis (RA). However, there is little information on serum TSLP concentrations in RA and its clinical significance. The present study investigated whether serum TSLP concentrations were affected in patients with RA. Using an enzyme-linked immunosorbent assay (ELISA), we measured TSLP concentrations in the serum obtained from 100 patients with RA, 60 patients with osteoarthritis (OA) and 34 healthy volunteers. We also investigated the correlation between serum TSLP concentrations and clinical parameters of disease activity in RA [disease activity score using 28 joint counts (DAS28)-C-reactive protein (CRP), DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI]), patient’s/-physician’s Visual Analogue Scale (VAS), swollen joints count, tender joints count, CRP, ESR and matrix metalloproteinase-3 (MMP-3) concentrations]. In addition, we investigated the correlation between serum TSLP concentrations and anti-citrullinated peptide antibody (ACPA) and serum tumour necrosis factor (TNF)-α. Serum TSLP levels in patients with RA were significantly higher than those in patients with OA and in healthy volunteers. Interestingly, serum TSLP concentrations were correlated significantly with ACPA titres, but not with other clinical parameters. There was a significant increase in serum TSLP concentrations in patients with RA, which was correlated positively with serum ACPA titres. These findings suggest that in patients with RA, TSLP may play a role in ACPA production by B cells.     

Comparative analysis of autoantibodies targeting peptidylarginine deiminase type 4, mutated citrullinated vimentin and cyclic citrullinated peptides in rheumatoid arthritis: associations with cytokine profiles,clinical and genetic features

Antibodies against cyclic citrullinated peptides (anti‐CCP) are widely used for diagnosis of rheumatoid arthritis (RA). We performed a comparative analysis of antibodies targeting the citrullinating enzyme peptidylarginine deiminase type 4 (anti‐PAD4) and mutated citrullinated vimentin (anti‐MCV) with anti‐CCP autoantibodies in RA patients and examined their relationships with clinical parameters, cytokine profiles and the PADI4 gene. Autoantibodies were examined by enzyme‐linked immunosorbent assay (ELISA) in sera of 170 RA patients and 103 controls. Cytokine profiles were measured using a multiplex system. PADI4 polymorphisms (89G > A, 90T > C and 92G > C) were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Anti‐PAD4, anti‐MCV and anti‐CCP autoantibodies were detected in 24, 61 and 74% of RA patients, respectively. Positive correlations were observed between anti‐PAD4 and disease duration; anti‐CCP and erythrocyte sedimentation rate (ESR); anti‐MCV and ESR and C‐reactive protein. Anti‐MCV antibodies were associated with high disease activity score 28 (DAS‐28) in early RA. Concentrations of T helper type 1 (Th1) [tumour necrosis factor (TNF)‐α, interleukin (IL)‐12, IL‐2, IL‐1β], Th2 (IL‐4, IL‐6, IL‐10, IL‐13) and Th17 (IL‐17) cytokines were higher in RA than in controls. Th2 and, to a lesser extent, Th1‐related cytokines, showed positive correlations with anti‐MCV and anti‐CCP. The GTG haplotype in PADI4 was associated with anti‐CCP and anti‐MCV, but not anti‐PAD4 antibodies. In conclusion, anti‐PAD4 antibodies are detected mainly in established RA, which is in contrast to the early detection of antibodies against citrullinated peptide/proteins (ACPAs). Among autoantibodies, anti‐MCV appear to perform better as markers of disease activity. Furthermore, anti‐CCP and anti‐MCV are associated genetically with the citrullinating enzyme PAD4 and are related strongly to Th1 and Th2 cytokines, suggesting a feed‐forward loop between cytokines and ACPA production.     

Rheumatoid arthritis with diffuse pulmonary rheumatoid nodules

Rheumatoid nodules in dermal or subcutaneous tissues, while indicative of rheumatoid arthritis, are very rare. It is even less common to identify these rheumatoid nodules by biopsy as well as in autopsy materials from lung tissue. These nodules may be single or multiple, which seldom cause respiratory symptoms. Here, a patient with diffuse pulmonary rheumatoid nodules and interstitial fibrosis throughout both lungs, is described. The patient, with articular symptoms and seropositivity, exhibited a rapid clinical course and died of respiratory failure 3 months after the appearance of dyspnea. Chest radiography indicated interstitial pneumonitis with bilateral diffuse peripheral shadows. At autopsy, numerous rheumatoid nodules and interstitial fibrosis had destroyed both lungs, such that no residual normal pulmonary tissue remained. It is believed that this was an extremely rare case exhibiting large numbers of rheumatoid nodules throughout the lungs. Findings with this patient indicate that, in patients with rheumatoid arthritis, clinical interstitial pneumonitis confirmed radiologically does not exclude the existence of rheumatoid lung nodules.     

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.     

Targeting the chemotactic function of CD147 reduces collagen-induced arthritis

CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147-cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147-cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4(+) T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by >75%. Such findings suggest that CD147-cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues.     

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.     

Cross-reactive rheumatoid factors in rheumatoid arthritis with extra-articular disease.

Rheumatoid factors (RF) have been shown to have considerable heterogeneity and bind with IgG as well as with a variety of substances such as nuclear histone, non-histone nuclear protein, nitrophenyl groups or ssDNA. We describe evidence that polyclonal RF cross-reactive with ssDNA (CRRF) are widely distributed in a variety of rheumatic diseases, and that their serum level is significantly higher in rheumatoid arthritis (RA) with extra-articular disease. Although the mechanism of the cross-reactivity is not clear, the presence of CRRF could be a serological feature of a clinical subset of RA. The high prevalence rate of CRRF in RA with extra-articular disease also suggests its pathogenetic role in the extra-articular manifestation of this disease.     

Lung involvement in connective tissue diseases: A comprehensive review and a focus on rheumatoid arthritis

The lungs are frequently involved in Connective Tissue Diseases (CTDs). Interstitial lung disease (ILD) is one of the most common pleuropulmonary manifestations that affects prognosis significantly. In practice, rheumatologists and other physicians tend to underestimate the impact of CTD-ILDs and diagnose respiratory impairment when it has reached an irreversible fibrotic stage. Early investigation, through clinical evidence, imaging and – in certain cases – lung biopsy, is therefore warranted in order to detect a possible ILD at a reversible initial inflammatory stage. In this review, we focus on lung injury during CTDs, with particular attention to ILDs, and examine their prevalence, clinical manifestations and histological patterns, as well as therapeutic approaches and known complications till date. Although several therapeutic agents have been approved, the best treatment is still not certain and additional trials are required, which demand more knowledge of pulmonary involvement in CTDs.     

Humoral autoreactivity directed against surfactant protein-A (SP-A) in rheumatoid arthritis synovial fluids

SP-A is found principally in the lung, and has been associated with lamellar bodies also found in the synovial joint. Both SP-A and C1q contain collagen-like regions, and SP-A and C1q have some structural similarities, both having a globular head region and a collagen-like tail. Here we are able to show that (i) autoreactivity to SP-A, as expressed by IgG and IgM autoantibodies, is present in synovial fluid (SF) isolated from patients with rheumatoid arthritis (RA); (ii) in absorption experiments only a limited degree of cross-reactivity between autoantibodies reactive with C1q and SP-A is observed; (iii) there is no cross-reactivity between autoantibodies reactive with type II collagen (CII) and those reactive with SP-A or C1q; (iv) autoantibodies react with polymeric (dimers and larger) SP-A, but not with monomeric SP-A subunits, indicating that a degree of quaternary structure is required for antibody binding. Unlike CII, which not accessible in the normal joint, both SP-A and C1q are available within the SF in patients with RA and may therefore provide antigens driving an autoimmune response directed against collagen-like structures.     

Use of prognostic markers in early rheumatoid arthritis to identify patients at risk of destructive disease

As the benefits of early aggressive treatment of rheumatoid arthritis have become clear, and with the availability of newer (and more expensive) therapies, we need to be able to identify which patients are most at risk of destructive disease and poorer outcomes, and therefore, pinpoint which patients are most likely to benefit from intensive intervention at an early stage. A need for reliable prognostic markers is paramount in identifying these patients. Anticyclic citrullinated peptide antibody and serum inflammatory markers can precede the onset of disease by months and aid in both diagnosis and prognosis. Newer imaging modalities are now available and add to information gained from conventional radiography. This article reviews laboratory markers and imaging currently used in recognizing those patients at risk of nonreversible, destructive disease.