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.     

The inextricable link between atherosclerosis and prototypical inflammatory diseases rheumatoid arthritis and systemic lupus erythematosus

The increased burden of cardiovascular disease in patients with rheumatoid arthritis and systemic lupus erythematosus has recently become the focus of intense investigation. Proatherogenic risk factors and dysregulated inflammation are the main culprits, leading to enhanced atherosclerosis in subgroups of patients with inflammatory diseases. Common molecular pathways shared by atherosclerosis and inflammatory disease may be involved. In this review we map the key determinants of the increased incidence of cardiovascular disease in patients with inflammatory diseases at each step of the atherogenesis.     

Cardiovascular disease in systemic lupus erythematosus: has the time for action come?

PURPOSE OF REVIEW: The recognition that inflammation is a hallmark of atherosclerotic disease has led to a series of studies reporting accelerated atherogenesis in chronic inflammatory diseases. Indeed, systemic lupus erythematosus is associated with an increased incidence of cardiovascular disease and the etiology thereof deserves closer attention. RECENT FINDINGS: The association between systemic lupus erythematosus and accelerated atherosclerosis has recently been confirmed by surrogate-marker studies for cardiovascular disease in patients with systemic lupus erythematosus. Since the propensity towards cardiovascular disease cannot solely be explained by classical risk factors, disease-specific pathways have been put forward as additional risk factors. SUMMARY: In the present review, we will discuss several of these factors as well as their potential impact for future prevention strategies in systemic lupus erythematosus.     

Cardiovascular co-morbidity in patients with rheumatic diseases

During recent years atherosclerosis, the major cause of cardiovascular disease (CVD), has been recognised as a chronic inflammatory condition in which rupture of atherosclerotic lesions appears to play a major role. The risk of CVD is raised in many rheumatic diseases. This risk is high in systemic lupus erythematosus - as much as a 50-times increase among middle-aged women has been reported. Studies on CVD and atherosclerosis in rheumatic disease could thus provide interesting information about CVD and atherosclerosis in addition to being an important clinical problem. A combination of traditional and nontraditional risk factors accounts for the increased risk of CVD and atherosclerosis in rheumatic disease. One interesting possibility is that atherosclerotic lesions in rheumatic disease are more prone to rupture than normal atherosclerotic lesions. It is also likely that increased risk of thrombosis may play an important role, not least in systemic lupus erythematosus. Further, it is not clear whether an increased risk of CVD is a general feature of rheumatic disease, or whether this only occurs among subgroups of patients. It should be emphasised that there is an apparent lack of treatment studies where CVD in rheumatic disease is the end point. Control of disease activity and of traditional risk factors, however, appears to be well founded in relation to CVD in rheumatic disease. Further studies are needed to determine the exact role of lipid-lowering drugs as statins. Hopefully novel therapies can be developed that target the causes of the inflammation in atherosclerotic lesions both in rheumatic patients and in the general population.     

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.     

The role of Toll-like receptors in chronic inflammation

The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been shown to be present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands during inflammation and consequently the activation of TLR signalling pathways may be one mechanism initiating and driving autoimmune diseases. An increasing body of circumstantial evidence implicates a role of TLR signalling in systemic lupus erythematosus (SLE), atherosclerosis, asthma, type 1 diabetes, multiple sclerosis, bowl inflammation and rheumatoid arthritis (RA). Although at present their involvement is not comprehensively defined. However, future therapies targeting individual TLRs or their signalling transducers may provide a more specific way of treating inflammatory diseases without global suppression of the immune system.     

Endothelial cells are a potential site of interaction between estrogens and glucocorticoids

Estrogens and glucocorticoids have synergistic effects in the micro and macrovasculature of endothelial cells. Whereas in the former they both have pro-inflammatory effects, in the latter they both inhibit the expression of adhesion molecules. Since the molecular basis of this synergy has not been defined, we propose possible mechanisms of interaction. An understanding of the functional interaction between estrogens and glucocorticoids in the endothelial cells of the micro and macrovasculature may contribute to clarifying the role of the endothelial cells of different vascular beds during the inflammatory response and in chronic inflammation. These advances could contribute to the design of more effective therapeutic strategies for the prevention of diseases, such as atherosclerosis, systemic lupus erythematosus and rheumatoid arthritis, in which the inflammatory process plays an important pathogenic role.     

PI3K inhibition in inflammation: Toward tailored therapies for specific diseases

In the past decade, the availability of genetically modified animals has enabled the discovery of interesting roles for phosphatidylinositol 3‐kinase‐γ (PI3Kγ) and ‐δ (PI3Kδ) in different cell types orchestrating innate and adaptive immune responses. Therefore, these PI3K isoforms appear to be attractive drug targets for the treatment of diseases caused by unrestrained immune reactions. Currently, pharmacological targeting of PI3Kγ and/or PI3Kδ represents one of the most promising challenges for companies interested in the development of novel safe treatments for inflammatory diseases. In this review we provide a general outline of PI3Kγ‐ and PI3Kδ‐specific functions in distinct subsets of inflammatory cells. We also discuss the therapeutic impact of novel compounds targeting PI3Kγ, PI3Kδ or both, in mouse models of autoimmune disorders (systemic lupus erythematosus (SLE) and rheumatoid arthritis), respiratory diseases (allergic asthma and chronic obstructive pulmonary disease) and cardiovascular dysfunctions (atherosclerosis and myocardial infarction).     

Inflammation and atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) associates with increased cardiovascular mortality. This appears to be predominantly due to ischaemic causes, such as myocardial infarction and congestive heart failure. The higher prevalence of cardiac ischaemia in RA is thought to be due to the accelerated development of atherosclerosis. There are two main reasons for this, which might be inter-related: the systemic inflammatory load, characteristic of RA; and the accumulation in RA of classical risk factors for coronary heart disease, which is reminiscent of the metabolic syndrome. We describe and discuss in the context of RA the involvement of local and systemic inflammatory processes in the development and rupture of atherosclerotic plaques, as well as the role of individual risk factors for coronary heart disease. We also present the challenges facing the clinical and scientific communities addressing this problem, which is receiving increasing attention.     

Vascular involvement in rheumatic diseases: 'vascular rheumatology'

The vasculature plays a crucial role in inflammation, angiogenesis, and atherosclerosis associated with the pathogenesis of inflammatory rheumatic diseases, hence the term 'vascular rheumatology'. The endothelium lining the blood vessels becomes activated during the inflammatory process, resulting in the production of several mediators, the expression of endothelial adhesion molecules, and increased vascular permeability (leakage). All of this enables the extravasation of inflammatory cells into the interstitial matrix. The endothelial adhesion and transendothelial migration of leukocytes is a well-regulated sequence of events that involves many adhesion molecules and chemokines. Primarily selectins, integrins, and members of the immunoglobulin family of adhesion receptors are involved in leukocyte 'tethering', 'rolling', activation, and transmigration. There is a perpetuation of angiogenesis, the formation of new capillaries from pre-existing vessels, as well as that of vasculogenesis, the generation of new blood vessels in arthritis and connective tissue diseases. Several soluble and cell-bound angiogenic mediators produced mainly by monocytes/macrophages and endothelial cells stimulate neovascularization. On the other hand, endogenous angiogenesis inhibitors and exogenously administered angiostatic compounds may downregulate the process of capillary formation. Rheumatoid arthritis as well as systemic lupus erythematosus, scleroderma, the antiphospholipid syndrome, and systemic vasculitides have been associated with accelerated atherosclerosis and high cardiovascular risk leading to increased mortality. Apart from traditional risk factors such as smoking, obesity, hypertension, dyslipidemia, and diabetes, inflammatory risk factors, including C-reactive protein, homocysteine, folate deficiency, lipoprotein (a), anti-phospholipid antibodies, antibodies to oxidized low-density lipoprotein, and heat shock proteins, are all involved in atherosclerosis underlying inflammatory rheumatic diseases. Targeting of adhesion molecules, chemokines, and angiogenesis by administering nonspecific immunosuppressive drugs as well as monoclonal antibodies or small molecular compounds inhibiting the action of a single mediator may control inflammation and prevent tissue destruction. Vasoprotective agents may help to prevent premature atherosclerosis and cardiovascular disease.     

Risk of subsequent coronary heart disease in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden

Background

Certain immune-mediated diseases (IMDs), such as rheumatoid arthritis and systemic lupus erythematosus, have been linked to cardiovascular disorders. We examined whether there is an association between 32 different IMDs and risk of subsequent hospitalization for coronary heart disease (CHD) related to coronary atherosclerosis in a nationwide follow up study in Sweden.

Methods and Findings

All individuals in Sweden hospitalized with a main diagnosis of an IMD (n = 336,479) without previous or coexisting CHD, between January 1, 1964 and December 31 2008, were followed for first hospitalization for CHD. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for CHD were calculated. Overall risk of CHD during the first year after hospitalization for an IMD was 2.92 (95% CI 2.84–2.99). Twenty-seven of the 32 IMDs studied were associated with an increased risk of CHD during the first year after hospitalization. The overall risk of CHD decreased over time, from 1.75 after 1–5 years (95% CI 1.73–1.78), to 1.43 after 5–10 years (95% CI 1.41–1.46) and 1.28 after 10+ years (95% CI 1.26–1.30). Females generally had higher SIRs than males. The IMDs for which the SIRs of CDH were highest during the first year after hospitalization included chorea minor 6.98 (95% CI 1.32–20.65), systemic lupus erythematosus 4.94 (95% CI 4.15–5.83), rheumatic fever 4.65 (95% CI 3.53–6.01), Hashimoto''s thyroiditis 4.30 (95% CI 3.87–4.75), polymyositis/dermatomyositis 3.81 (95% CI 2.62–5.35), polyarteritis nodosa 3.81 (95% CI 2.72–5.19), rheumatoid arthritis 3.72 (95% CI 3.56–3.88), systemic sclerosis 3.44 (95% CI 2.86–4.09), primary biliary cirrhosis 3.32 (95% CI 2.34–4.58), and autoimmune hemolytic anemia 3.17 (95% CI 2.16–4.47).

Conclusions

Most IMDs are associated with increased risk of CHD in the first year after hospital admission. Our findings suggest that many hospitalized IMDs are tightly linked to coronary atherosclerosis.     

Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis

The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.     

Metabolic syndrome in rheumatic diseases: epidemiology,pathophysiology, and clinical implications

Subjects with metabolic syndrome–a constellation of cardiovascular risk factors of which central obesity and insulin resistance are the most characteristic–are at increased risk for developing diabetes mellitus and cardiovascular disease. In these subjects, abdominal adipose tissue is a source of inflammatory cytokines such as tumor necrosis factor-alpha, known to promote insulin resistance. The presence of inflammatory cytokines together with the well-documented increased risk for cardiovascular diseases in patients with inflammatory arthritides and systemic lupus erythematosus has prompted studies to examine the prevalence of the metabolic syndrome in an effort to identify subjects at risk in addition to that conferred by traditional cardiovascular risk factors. These studies have documented a high prevalence of metabolic syndrome which correlates with disease activity and markers of atherosclerosis. The correlation of inflammatory disease activity with metabolic syndrome provides additional evidence for a link between inflammation and metabolic disturbances/vascular morbidity.     

Past,present and future drug treatment for rheumatoid arthritis and systemic lupus erythematosus

Historically, treatment of complex autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus has aimed to relieve symptoms, and in severe cases, use broad-spectrum immunosuppressive treatments in attempts to induce permanent remission. Recent research into the causes of chronic autoimmune inflammatory activation have not only explored the mechanism of action of known therapies, but also provided a number of new targets for therapy, by identifying the cells, cytokines and signalling pathways activated during autoimmune antibody mediated processes. This review briefly outlines progress in the understanding of the autoimmune nature of rheumatoid diseases and the expansion of treatment options, from broad to specific immunotherapies for these closely related diseases.     

The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus

Patients with systemic lupus erythematosus have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease. Recent advances in the etiology of vascular damage in this disease stress the interplay of lupus-specific inflammatory factors with traditional cardiac risk factors, leading to increased endothelial damage. This review analyzes the putative role that immune dysregulation and lupus-specific factors may play in the pathogenesis of premature vascular damage in this disease. The potential role of various cytokines, in particular type I interferons, in the development of accelerated atherosclerosis is examined. Potential therapeutic targets are discussed.     

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.     

Myocardial dysfunction in rheumatoid arthritis: epidemiology and pathogenesis

Data from population- and clinic-based epidemiologic studies of rheumatoid arthritis patients suggest that individuals with rheumatoid arthritis are at risk for developing clinically evident congestive heart failure. Many established risk factors for congestive heart failure are over-represented in rheumatoid arthritis and likely account for some of the increased risk observed. In particular, data from animal models of cytokine-induced congestive heart failure have implicated the same inflammatory cytokines produced in abundance by rheumatoid synovium as the driving force behind maladaptive processes in the myocardium leading to congestive heart failure. At present, however, the direct effects of inflammatory cytokines (and rheumatoid arthritis therapies) on the myocardia of rheumatoid arthritis patients are incompletely understood.     

Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis

Introduction

Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients.

Methods

Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.

Results

The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category.

Conclusions

Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.     

Human articular chondrocytes express 15-lipoxygenase-1 and -2: potential role in osteoarthritis

Introduction

Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients.

Methods

Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.

Results

The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category.

Conclusions

Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.