Atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus

PURPOSE OF REVIEW: Our aim was to review recent studies that address the increased risk of atherosclerosis and coronary heart disease in patients with rheumatoid arthritis and systemic lupus erythematosus. We examine the strength of this association, how inflammation mediates this increased risk and what impact therapies may have. RECENT FINDINGS: Atherosclerosis is more prevalent and accelerated in both conditions. Indeed the process may actually precede the onset of clinical inflammatory disease. Metabolic alterations include insulin resistance and the generation of proinflammatory HDL. In addition, inflammatory mechanisms central to both rheumatoid arthritis and systemic lupus erythematosus such as macrophage activation, interferon-1 and complement deficiency may contribute to atherogenesis. There is still no consensus as to the value of primary preventive strategies in these conditions. However, drugs such as hydroxychloroquine seem to modify coronary heart disease risk and may improve survival. The recently developed antitumour necrosis factor drugs may also reduce coronary heart disease risk but biomarker studies to date have been inconclusive. SUMMARY: There is an urgent need for clinical trials to examine both the lipid-lowering and inflammatory hypotheses of atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Novel targeted therapies in development may also have a major impact on future coronary heart disease risk in these conditions.     

Vasculitis: mechanisms involved and clinical manifestations

Systemic vasculitis, an inflammatory necrotizing disease of the blood vessel walls, can occur secondary to autoimmune diseases, including connective tissue diseases. Various pathogenic mechanisms have been implicated in the induction of vasculitis, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. This inflammatory activity is believed to contribute to accelerated atherosclerosis, and also leads to increased risk for cardiovascular events in patients with rheumatoid arthritis and systemic lupus erythematosus. Endothelial cell activation is a common pathogenic pathway in the systemic vasculitis associated with rheumatoid arthritis and systemic lupus erythematosus, with elevated levels of endothelin-1 potentially inducing vascular dysregulation.     

Structure activity studies of a novel cytotoxic benzodiazepine

Analogues of Bz-423, a pro-apoptotic 1,4-benzodiazepine with potent activity in animal models of systemic lupus erythematosus and rheumatoid arthritis, have been designed, synthesized, and evaluated in cell-culture assays. The results of these experiments have defined the structural elements of this new cytotoxic agent required for activity.     

Use of complement inhibitors in tissue injury

A great deal of information has accumulated implicating the complement system in several human disease processes. Although some of this information is circumstantial, protein inhibitors of the complement system have been developed and applied successfully to experimental disease models in animals. Two inhibitors, soluble complement receptor 1 (sCR1) and anti-C5 monoclonal antibody, are now being investigated in a variety of clinical conditions such as systemic lupus erythematosus and rheumatoid arthritis (RA), diseases for which current therapy has changed little and remains unsatisfactory. Preliminary successes in Phase II clinical trials of RA have provided optimism that complement inhibition might prove useful in these diseases and become part of standard medical therapy.     

Lymphocyte transformation to connective tissue antigens in adult and juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and a nonarthritic control population

Transformation of peripheral blood lymphocytes after exposure to connective tissue antigens was measured in patients with adult (n = 35) and juvenile rheumatoid arthritis (n = 34), osteoarthritis (n = 21), ankylosing spondylitis (n = 15), and systemic lupus erythematosus (n = 26) and in control subjects (n = 36). The connective tissue antigens included homologous cartilage-type proteoglycan, cyanogen bromide-derived peptides of type I, II, and III collagens, and type I and II helical collagens. Lymphocyte transformation was not detected in the osteoarthritic and control groups, with one exception. Sensitization to at least one connective tissue antigen was detected in approximately one-third of the rheumatoid arthritic and lupus patients and in one-quarter of the juvenile rheumatoid patients. In ankylosing spondylitis, positive responses occurred to proteoglycan in 20% of patients tested but never to collagens or peptides. Sensitivity to proteoglycan was detected only in ankylosing spondylitis except for one patient with juvenile rheumatoid arthritis. In patients with systemic lupus erythematosus and both forms of rheumatoid arthritis, lymphocyte transformation was usually more frequently detected to peptides than to the helical collagens. In adult rheumatoid arthritis, type II peptides elicited an elevated number of responses (14%) as did type I (9%) and III (8%) peptides to lesser degrees. Responses to type I (4%) and II (4%) helical collagens were infrequent. Rheumatoid arthritic patients usually exhibited sensitivity to only one antigen and lymphocyte transformation was often detected when the arthritis was improving. In juvenile rheumatoid arthritis, lymphocyte transformation was detected to peptides of type I (16%), II (9%), and III (29%) collagens and to helical type I (12%) and II (8%) collagens. In systemic lupus erythematosus, sensitization was detected to peptides of type I (13%), II (20%), and III (14%) collagens and to helical type I collagen (18%) but not type II collagen. Simultaneous sensitivity to several antigens often occurred in both systemic lupus erythematosus and juvenile rheumatoid arthritis. Examination of individual patients in all three rheumatic disease groups revealed that immune sensitivity developed to collagen peptides rather than to the helical molecules, particularly in the case of type II collagen. Thus, some patients with inflammatory arthritis exhibit immune responses to connective tissue components which are, as a group, characteristic for each type of arthritis. These responses, which were not obviously associated with disease activity, may develop as a result of inflammation or trauma which destroys connective tissue and exposes molecules, in either a native or degraded state, to cells of the immune system. Expression of sensitivity to these tissue antigens may contribute to the chronicity of the inflammatory arthritides.     

Connective tissue antigens stimulate collagenase production in arthritic diseases

Peripheral blood mononuclear cells from patients with rheumatoid arthritis (n = 27), systemic lupus erythematosus (n = 24), juvenile rheumatoid arthritis (n = 30), osteoarthritis (n = 20), apparently healthy adults (n = 12), and nonarthritic children (n = 8) were exposed to several putative connective tissue antigens to determine if the monokine, mononuclear cell factor, was released. Release of this factor was detected by bioassay in which enhancement of collagenase production from human synovial cells or dermal fibroblasts was measured. The antigens, all of homologous tissue origin, included cyanogen bromide-derived peptides of type I, II, and III collagens, type I and II helical collagens, and cartilage proteoglycan. Of the subjects examined, 44% of the rheumatoid group, 42% of the systemic lupus group, 33% of the juvenile rheumatoid group but only 10% of the osteoarthritic group and 5% of the control group released monokine after exposure of peripheral blood mononuclear cells to at least one of these connective tissue antigens. Patients with rheumatoid arthritis most frequently responded to type II peptides (but not to type II helical collagen) although the frequencies of responses to type I peptides, type I helical collagen and proteoglycan were also elevated over levels observed in the control population. Positive responses in these patients typically occurred to only one antigen, were transient, often occurred close to the onset of arthritis, and appeared to be unrelated to disease activity. The profiles of responses in patients with juvenile rheumatoid arthritis and systemic lupus shared many features in common and were distinct from those of adult rheumatoid arthritis. Patients with systemic lupus or juvenile rheumatoid arthritis responded to all of the antigens tested. Positive responses often occurred simultaneously to several antigens. Responses to type II helical collagen were most common while sensitization to type II peptides was infrequently detected. Positive responses were transient, unrelated to overall disease activity, type of juvenile arthritis, or duration of disease in lupus patients. Stimulation of mononuclear cell factor release by connective tissue molecules and their degradation products may make an important contribution to the chronic inflammation commonly seen in these diseases.     

Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies

Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.     

益生菌对自身免疫病的作用及机制研究现状

自身免疫病是机体免疫功能紊乱而导致组织器官受损的一类疾病,包括类风湿关节炎、系统性红斑狼疮、多发性硬化症、自身免疫性肝炎等。糖皮质激素及免疫抑制剂是治疗自身免疫病的常用药物,但长期使用会产生代谢紊乱、免疫低下、继发感染等副作用。随着肠道菌群与自身免疫病相关研究的进展,益生菌干预自身免疫病成为一大研究热点。研究证实,益生菌缓解自身免疫病安全有效,有望成为辅助疗法甚至替代疗法。本文就益生菌缓解类风湿关节炎、系统性红斑狼疮、多发性硬化症、自身免疫性肝炎等的作用及相关机制进行综述。     

Ocular and systemic manifestations of the acquired connective tissue diseases: Part I

The connective tissue diseases are musculoskeletal disorders which have multisystemic involvement, frequently have associated ocular manifestations, and although the specific etiologies are unknown, they all demonstrate abnormalities of the immune system. In part 1 of this 2 part series, an overview of the immune system will be presented followed by a discussion of the systemic and ocular findings in those acquired connective tissue diseases which are most common or are most likely to have associated ocular involvement, including rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome.     

Antibodies to anticoagulants in rheumatic autoimmune diseases]

The systemic lupus erythematosus (SLE) and the rheumatoid arthritis (RA) as the classic autoimmune diseases exhibit a great number of autoantibodies. Some of them are anticoagulants. Besides inactivating inhibitors against single coagulation factors interfering anticoagulants are known, belonging to the group of anti-phospholipid antibodies and detected as the lupus anticoagulants or anticardiolipin antibodies. Anti-phospholipid antibodies 184 patients with SLE or RA had been checked for. An enzyme immuno assay was used for detection of the anti-cardiolipin antibodies. The relations between occurrence of the anti-cardiolipin antibodies and vascular processes as well as other immunologic parameters had been tested for clinical relevancy.     

Studies on precipitating and hemagglutinating antibodies in systemic lupus erythematosus

We studied the precipitating and hemagglutinating autoantibodies in the sera of patients with various connective tissue diseases in general and lupus in particular. Saline soluble extract of goat thymus had adequate antigenic materials as compared to other organs. Twenty per cent of patients with systemic lupus erythematosus were positive for precipitating autoantibodies by immunodiffusion and 44% by counterimmunoelectrophoresis. Normal human subjects, nonrheumatic disease patients and patients with rheumatoid arthritis and progressive systemic sclerosis were all negative. Forty seven per cent of positive systemic lupus erythematosus sera showed two precipitin systems. Enzyme sensitivities were used as the basis of identification of most of the antigenic specificities. Passive hemagglutination was carried out to identify antibodies to non-histone nuclear protein and nuclear ribonucleo-protein antigens. Thirty eight % of systemic lupus erythematosus patients were positive by this technique. Passive hemagglutination although a highly sensitive technique could not detect antibodies against antigenic systems other than non-histone nuclear protein and nuclear ribonucleoprotein.     

Systemic lupus erythematosus.

Systemic lupus erythematosus is a polysystemic disease with a high incidence of associated glomerulonephritis. Patients with sle rarely have the destructive arthritis so characteristic of rheumatoid arthritis. An unusual case is presented in which both glomerulonephritis and destructive arthritis occurred simultaneously, justifying the diagnosis of both systemic lupus erythematosus and rheumatoid arthritis.Immunohistochemical studies in lupus glomerulonephritis suggest that the pathogenetic mechanisms involve the deposition of immune complexes containing “nuclear” antigens and antinuclear antibodies in the lesions. The detection of mixed cryoglobulins in the sera of patients with sle suggests that a portion of the circulating immune complexes may precipitate at reduced temperatures and be detected as mixed cryoglobulins. The therapy of lupus glomerulonephritis with combinations of corticosteroids and azathioprine, though still in an investigative state, holds great promise. Similar abnormalities in diseases of minks and mice and in sle suggest similar pathogenetic mechanisms in the three species involved. Since the diseases in the lower animals have been associated with persistent viral infection, the investigation of the role of persistent infection in sle seems warranted.     

5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases

The percentage of 5-methylcytosine (m⁵Cyt) has been determined in peripheral blood, synovial mononuclear cells and synovial tissue from patients affected by various rheumatic autoimmune diseases. The determination was performed by reversed-phase high-performance liquid chromatography. Fifteen controls were compared to twenty-one patients affected by rheumatoid arthritis and to nine patients affected by systemic lupus erythematosus. The mean percentage of m⁵Cyt in normal individuals was significantly higher than in the rheumatoid arthritis and systemic lupus erythematosus patients. In addition, patients with active disease showed lower values than patients in remission. This finding is in agreement with the hypothesis that DNA hypomethylation may play a role in the pathogenesis of the autoimmune diseases, resulting in altered oncogen expression. Therapy with cyclosporin A led to a decrease in the percentage of m⁵Cyt in three rheumatoid arthritis patients, but a rebound was observed when the cyclosporin A was suspended. The percentage of m⁵Cyt in the DNA of synovial tissue from four rheumatoid arthritis patients and five patients with osteoarthritis was similar; this observation confirms that, in addition to disease-specific and disease activity-specific variations, the percentage of m⁵Cyt may also show tissue-specific variations.     

靶定IL-17 治疗类风湿关节炎研究进展

IL-17作为前炎症因子参与类风湿关节炎,系统性红斑狼疮等自身免疫性疾病的病理过程。它主要由CD4+T细胞的一个亚群--Th17细胞分泌释放。目前,IL-17在类风湿关节炎的病理过程中的作用引起了医学界广泛的关注,抗IL-17A抗体已经生产并进入临床实验,用于治疗类风湿关节炎、银屑病关节炎等疾病。但其在类风湿关节炎病理过程中的作用尚需进一步研究,其有效性亦尚需进一步探讨。本文主要针对IL-17家族的各个亚型的表达、调控、生物学作用及与类风湿关节炎发病的关系进行阐述,为类风湿关节炎的治疗提供新的思路。     

Clinical relevance of autoantibodies in systemic rheumatic diseases

Autoantibodies directed to intracellular antigens are serological hallmarks of systemic rheumatic diseases. Identification of circulating autoantibodies is helpful in establishing the correct diagnosis, indicating the prognosis and providing a guide to treatment and follow-up. Some autoantibodies are included in diagnostic and classification criteria for diseases such as anti-Sm antigen and anti-double-stranded DNA antibodies in systemic lupus erythematosus, anti-U1 nuclear ribonucleoprotein antibodies in mixed connective tissue disease, and anti-SS-A/Ro and anti-SS-B/La antibodies in Sjögren's syndrome. Over the past 30 years, the identification of new autoantibody systems was advanced by the initiation or adaptation of novel techniques such as double immunodiffusion to detect antibodies to saline-soluble nuclear antigens, extraction-reconstitution and ELISA techniques to detect histone and chromatin antibodies, immunoblotting and immunoprecipitation to detect a wide range of antibodies directed against naturally occurring and recombinant proteins. These techniques have been made possible by advances in cellular and molecular biology and in turn, the sera from index patients have been important reagents to identify novel intracellular macromolecules. This paper will focus on the clinical relevance of several autoantibody systems described by Tan and his colleagues over the past 30 years.Abbreviations ANA antinuclear antibody - CENPs centromere proteins - CTD connective tissue disease - DIA drug-induced autoimmunity - DIL drug-induced lupus - HIV human immunodeficiency virus - IIF indirect immunofluorescence - JCA juvenile chronic arthritis - MCTD mixed connective tissue disease - MSA mitotic spindle apparatus - NOR nucleolar organizer - NuMA nuclear mitosis antigen - PBC primary biliary cirrhosis - PCNA proliferating cell nuclear antigen - PM polymyositis - RA rheumatoid arthritis - RNP ribonucleoprotein - SLE systemic lupus erythematosus - SS Sjögren's syndrome - SSc systemic sclerosis - UCTD undifferentiated connective tissue disease     

Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases

Introduction  

We compared the odds of vitamin D deficiency in three chronic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 2 diabetes (T2DM), adjusting for medications, demographics, and laboratory parameters, common to all three diseases. We also designed multivariate models to determine whether different factors are associated with vitamin D deficiency in different racial/ethnic groups.     

Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis

In this review, the authors discuss the formation and structure of high-density lipoproteins (HDLs) and how those particles are altered in inflammatory or stress states to lose their capacity for reverse cholesterol transport and for antioxidant activity. In addition, abnormal HDLs can become proinflammatory (piHDLs) and actually contribute to oxidative damage. The assay by which piHDLs are identified involves studying the ability of test HDLs to prevent oxidation of low-density lipoproteins. Finally, the authors discuss the potential role of piHDLs (found in some 45% of patients with systemic lupus erythematosus and 20% of patients with rheumatoid arthritis) in the accelerated atherosclerosis associated with some chronic rheumatic diseases.     

Role of neutrophils in systemic autoimmune diseases

Neutrophils have emerged as important regulators of innate and adaptive immune responses. Recent evidence indicates that neutrophils display marked abnormalities in phenotype and function in various systemic autoimmune diseases, and may play a central role in initiation and perpetuation of aberrant immune responses and organ damage in these conditions. This review discusses the putative roles that neutrophils and aberrant neutrophil cell death play in the pathogenesis of various systemic autoimmune diseases, including systemic lupus erythematosus, small vessel vasculitis and rheumatoid arthritis.     

Systemic lupus erythematosus and its ABCs (APRIL/BLyS complexes)

BLyS and APRIL are closely related members of the TNF ligand superfamily. These cytokines individually may contribute importantly to the development and maintenance of systemic lupus erythematosus (SLE). Dillon and colleagues demonstrate that in contrast to most members of the TNF ligand superfamily, which form only homotrimers, BLyS and APRIL can complex as heterotrimers. These complexes have in vitro biological activity, and circulating levels of BLyS/APRIL heterotrimers are frequently elevated in SLE, but not rheumatoid arthritis, patients. Although the mechanism and regulation of heterotrimer formation, the interconversion (if any) between homotrimers and heterotrimers, and, indeed, the normal physiologic role for such heterotrimers remain unknown, their preferential overexpression in SLE, but not in rheumatoid arthritis, raises the possibility that such heterotrimers may be playing a contributory role in SLE.