The term 'systemic vasculitis' describes a heterogeneous group of rare diseases, the systemic vasculitides, characterized by inflammation and fibrinoid necrosis of blood vessel walls. Vasculitis may be primary in origin (with no identifiable cause) or it may be secondary to infection, malignancy, or autoimmune disease. Although rare, there is evidence to suggest that vasculitis accelerating atherosclerosis is a complicating feature of most, possibly all, autoimmune diseases. This includes connective tissue diseases (CTDs) such as rheumatoid arthritis (RA), scleroderma, sarcoidosis and systemic lupus erythematosus (SLE).

In this review, which focuses on vasculitis associated with CTDs, we look at the progress that has been made in classifying the systemic vasculitides and discuss the pathogenesis of systemic vasculitides in CTDs and their adverse clinical sequelae, giving particular attention to RA and SLE. The standardized treatment for vasculitis is effective in the majority of patients, but some relapse and need other therapeutic approaches. In evaluating new treatment strategies for the management of systemic vasculitis, we explore the role of endothelin (ET)-1 in systemic vasculitides and discuss the therapeutic potential of endothelin receptor blockade in these entities.

Early attempts to classify systemic vasculitis into discrete categories were based primarily on blood vessel size, and indeed that approach still underpins more recent classification schemes. These schemes include those of the American College of Rheumatology 1 and of the international consensus conference held in Chapel Hill, North Carolina, USA that gave rise to the Chapel Hill nomenclature 2. Today, most physicians use the Chapel Hill nomenclature, which is based on clinical and histopathological features of vasculitis (Figure 1).

In essence, classification schemes, including the Chapel Hill nomenclature, recognize two major groups of systemic vasculitides 2: large vessel vasculitis, which consists of giant cell arteritis (GCA) and Takayasu arteritis, both of which involve the aorta and its major branches; and necrotizing vasculitis, which encompasses the rest of the vasculitides. The necrotizing systemic vasculitides include polyarteritis nodosa and Kawaski disease, which affect medium-sized arteries, and a large group of disorders in which the vasculitis affects arterioles, capillaries and venules (Figure 1). Within this latter group there are four disorders, namely Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis, which are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCAs). Other types of small vessel vasculitis include Henoch-Schönlein purpura, which is characterized by IgA-dominant immune deposits in the small blood vessels, and essential cryoglobulinaemic vasculitis, in which cryoglobulin immune deposits are responsible for small blood vessel vasculitis (Figure 1).

The vasculitides that occur in autoimmune diseases usually affect small-sized vessels, as is the case in SLE, systemic sclerosis and Sjögren's syndrome. Where vasculitis occurs during the course of RA, the small arteries are involved in most patients but medium-sized arteries can also be affected, mimicking polyarteritis nodosa. A comprehensive overview of the classification of systemic vasculitides was recently reported by Sunderkötter and Sindrilaru 3.

Progress in the classification of the systemic vasculitides has facilitated better understanding of the pathogenesis underlying these inflammatory conditions, which can involve cell-mediated inflammation, immune complex (IC)-mediated inflammation, and ANCA-mediated inflammation. Of central importance is that many data have accumulated demonstrating that various inflammatory pathways lead to endothelial cell activation, which may induce complications such as vessel occlusion and tissue destruction in a predisposed host, and longstanding disease. Investigations into ANCA vasculitides have pioneered the field and expanded our understanding of the pathogenesis of vessel inflammation. Comprehensive overviews of the pathogenic mechanisms that underlie the vasculitides and the distinction between primary and secondary vasculitis were published elsewhere 34.

In GCA, for example, vasculitis is essentially a T-cell driven process that is triggered by exposure to antigens, most probably infectious agents. Dendritic cells present in the adventitia and media of the blood vessel wall are potent antigen-presenting cells that can prime naïve T cells. In patients with GCA they are responsible for activating CD4⁺ T cells, which orchestrate vascular injury by recruiting macrophages and monocytes to the vessel walls 5. These cells induce systemic inflammation via the release of cytokines, such as interleukin-1 and interleukin-6. Tissue resident T cells also release interferon-γ, which is a key proinflammatory cytokine that has been implicated in the pathogenesis of GCA. Sustained inflammation mediated by T cells, macrophages and the proinflammatory cytokines released by these cells leads to extensive intimal thickening and vessel occlusion (Figure 2). Platelet-derived growth factor and vascular endothelial growth factor play key roles in the subsequent development of the lumen-occlusive arteritis that characterizes GCA.

In contrast to GCA, which appears to be an antigen-driven disease with local T cell and macrophage activation in the vessel wall, IC formation is usually considered to be the major pathological event in polyarteritis nodosa, cryoglobulinaemia and Henoch-Schönlein purpura. In polyarteritis nodosa, for example, antibody-mediated IC deposition can lead to renal infarction. Micro-aneurisms are another manifestation that can occur as a consequence of IC formation in the medium-sized necrotizing systemic vasculitides, which can also lead to blood vessel occlusion. However, this is mediated to a large extent by circulating antibodies in blood and antibody-dependent effector mechanisms rather than as a result of cell-mediated inflammation. With regard to IC-mediated vascular damage, it has been demonstrated in CD18^-/- mice that ICs induce damage from the luminal side but not from perivascular areas. Therefore, in this entity it has been suggested that the interaction of ICs, Fcγ receptors and adhesion molecules leads to disturbances in transmigration and activation of polymorphonuclear neutrophils, with consequent vessel damage 6.

Autoantibodies play a central role in the ANCA-related vasculitis that is characteristic of Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis and necrotizing glomerulonephritis. These antibodies are directed against enzymes that are contained in the granules of neutrophils and monocytes. In Wegener's granulomatosis they primarily target proteinase 3, which is a neutral serine protease, and – in microscopic polyangiitis and Churg-Strauss syndrome – they target myeloperoxidase, which is an enzyme that is involved in the generation of reactive oxygen species. Both proteinase 3-ANCA and myeloperoxidase-ANCA can contribute to vasculitis in the small blood vessels, causing adverse clinical sequelae such as pauci-immune glomerulonephritis and pulmonary haemorrhage, as demonstrated in animal models (myeloperoxidase) 7. An enhancing effect of ANCAs on leucocyte diapedesis caused by their interaction with the endothelium was recently demonstrated in a study involving passive transfer of immunoglobulin 8; this procedure resulted in microvascular haemorrhage.

Vasculitis may occur in many autoimmune diseases, including RA and SLE (which are the focus of this review), Sjögren's syndrome, scleroderma and sarcoidosis. Primary Sjögren's syndrome is associated with enhanced risk for B-cell lymphoma 9, in which the presence of purpura or vasculitis are clinical risk indicators for future non-Hodgkin's lymphoma development, as has been identified in a number of studies primarily based on epidemiological data 10. In association with SLE, for example, distinctive characteristics of coexistent vasculitis include the presence of anti-Ro-SSA, HLA and DR3 antibodies, as well as (more rarely) anti-DNA, anti-Sm and anti-RNP antibodies. Clinical presentation can include purpura, peripheral neuropathy of the lower limbs, and hypergammaglobulinaemia. Many patients will also exhibit evidence of rheumatoid factor activity, cryoglobulinaemia due to monoclonal IgM (kappa) paraprotein, and low complement levels. Pulmonary involvement is uncommon in vasculitis associated with Sjögren's syndrome, although patients may develop interstitial lung disease, pulmonary hypertension, or lymphocytic interstitial pneumonia. Mesenteric vasculitis and biliary cirrhosis are seen in cases with gastrointestinal tract involvement, whereas cognitive dysfunction, infarcts and neuropsychiatric symptoms may indicate central nervous system involvement. Renal involvement is less common in vasculitis related to Sjögren's syndrome, but when it does occur it usually manifests as interstitial nephritis. Vasculitis is extremely rare in scleroderma. If present, it is usually seen in the small blood vessels, sometimes in association with ANCA-related vasculitis. Vasculitis is also rare in sarcoidosis. It may affect the skin as leucocytoclastic granulomatosis often in association with sarcoid necrotizing granulomatosis 11. It may also occur as synovial vasculitis. Very rarely, the aorta, pulmonary artery and mesenteric arteries are affected, giving rise to a very severe form of large-vessel vasculitis that mimics Takayasu arteritis. Patients with this form of vasculitis develop aortitis with stenoses, aneurisms and dissection, and have a poor prognosis.

Atherosclerosis appears to be accelerated in patients with vasculitis, although it is difficult to discern its contributing impact on subsequent vascular occlusion. Moreover, corticosteroids, which are required for the treatment of inflammatory diseases such as RA, chronic obstructive pulmonary disease and inflammatory bowel disease, may also enhance risk for cardiovascular complications, as was recently demonstrated 12.

Vasculitis is a known complication of RA, often occurring several years after the initial onset of disease. Observational studies have shown that, independent of sex, patients with RA have reduced life expectancy in comparison with the non-RA population 13. Rheumatoid vasculitis is characterized by the occurrence of mononeuritis multiplex, purpura and visceral involvement, with the latter sometimes being severe. This vasculitis is severe and, in its systemic form, should usually be treated with corticosteroids and cyclophosphamide. Despite such treatment, the outcome is worse than with the majority of vasculitides 14.

In addition to this severe inflammatory disease, patients with RA appear to be at significantly increased risk from coronary events in comparison with healthy individuals 15. Observational studies have shown that, compared with healthy normal individuals, patients with RA are at double the risk for developing coronary artery disease 1617, as reflected by unrecognized myocardial infarction, as well as congestive heart failure 18 and sudden cardiac death 16 (Figure 3). A recent study that sought to identify demographic and cardiovascular risk factors in RA patients with and without atherosclerotic plaque in the carotid arteries 19 demonstrated that age, hypertension (especially raised systolic blood pressure), raised cholesterol, raised low-density lipoprotein levels and (to a lesser extent) homocysteinaemia were the factors that differed most significantly between the two patient populations.

As data from these and other observational studies have illustrated, RA patients are at significantly increased risk for developing cardiovascular disease relative to the normal population. Studies have also shown that inflammation is a key link between RA and accelerated atherosclerosis. Correlations have been demonstrated between intima-media thickness (a surrogate marker for cardiovascular disease) and measures of inflammation such as erythrocyte sedimentation rate and C-reactive protein 20. It has also been suggested that corticosteroids may facilitate atherosclerosis 21.

The picture in SLE is similar to that in RA, except that patients with SLE exhibit an even greater incidence of atherosclerotic plaque in carotid arteries 2223, a higher rate of calcification in the coronary arteries 24, and a correspondingly higher frequency of myocardial infarction and stroke when compared with the normal population. It should be noted that patients with SLE and antiphospholipid syndrome, but also those with subacute cutaneous lupus erythematosus, frequently present with a livedo vasculopathy. This is of particular interest because it reflects a certain type of small-vessel vasculitis. However, in patients with antiphospholipid syndrome that is independent of any underlying disease, livedo may be present in the absence of other signs or findings of vasculitis.

Although risk factors for atherosclerosis in SLE patients are similar to those in patients with RA, there are additional SLE-related risk factors (Figure 4). These include the development of autoantibodies to endothelium, high-density lipoprotein and phospholipids, as well as dyslipidaemia 22. The enhanced frequency of circulating ICs, activated complement products and nephritis are additional SLE-related risk factors 25. These additional risk factors may explain why SLE patients are at greatly increased cardiovascular risk, even relative to that in patients with RA. Certainly, SLE carries a risk for accelerated atherosclerosis that is greater than the net sum of classical risk factors 26. Whether accelerated atherosclerosis in SLE is uniquely related to inflammatory activity or to additional factors, or both, remains uncertain. By unravelling the pathogenic mechanisms that are responsible for the vasculitis that occurs in RA and SLE, as well as the interaction of inflammation and procoagulatory mechanisms, we may develop a greater understanding of the contribution of vasculitis to adverse cardiovascular outcomes in these and other CTDs.

Systemic vasculitis is characterized by multiple phenotypes that reflect the different pathogenic mechanisms that are responsible for inducing inflammation in the large, medium and small blood vessels (arterioles, venules and capillaries) of the body's tissues and organs. Although cell-mediated inflammation is characteristic of GCA, a systemic vasculitis of the large blood vessels, IC-mediated inflammation and ANCA-mediated inflammation are seen in the necrotizing vasculitides that affect medium-sized and small blood vessels.

Systemic vasculitis, a rare complication of autoimmune disorders, can nevertheless occur in most if not all CTDs. Evidence suggests that inflammation is a key link between vasculitis and accelerated atherosclerosis in these patients. Certainly, patients with RA and SLE are at significantly increased risk for cardiovascular morbidity and mortality in comparison with the normal population. Although preliminary data point to effects of immunosuppression on cardiovascular complications, this must be substantiated. There is a clear need for prevention studies (lipid and blood pressure control) in conjunction with control of disease activity, which requires delineation of the factors that drive vasculitis and endothelial cell activation.

Endothelial cell activation via autoantibody or IC binding is a common pathogenic pathway in systemic vasculitis associated with RA and SLE, superimposing on 'baseline risks' (blood pressure, Toll-like receptor ligands, enhanced low-density lipoproteins and smoking), leading among other things to enhanced release of ET-1. There is evidence, albeit limited, suggesting that ET-1 plays a role in some clinical manifestations of vasculitis. Potentially, endothelin receptor antagonism may have a place in the treatment of specific vascular manifestations of vasculitis as an adjunct to standard therapy with corticosteroids and immunosuppressant agents. Effective ET-1 blockade has been demonstrated in SLE patients with pulmonary arterial hypertension.

AECA = anti-endothelial cell antibody; ANCA = anti-neutrophil cytoplasmic antibody; CTD = connective tissue disease; ET = endothelin; GCA = giant cell arteritis; IC = immune complex; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.

The authors have received speaker fees and reimbursement for travel expenses from Actelion Pharmaceuticals Ltd.