Cardiovascular involvement in primary systemic vasculitis

Best Practice & Research Clinical Rheumatology 23 (2009) 419–428

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Cardiovascular involvement in primary systemic vasculitis Chetan Mukhtyar, MBBS, MRCP (UK), EULAR Research Fellow a, Paul Brogan, BSc(Hon), MBChB(Hon), MRCPCH, MSc, PhD, Senior Lecturer in Paediatric Vasculitis b, Raashid Luqmani, DM, FRCP, FRCPE, Senior Lecturer in Rheumatology a, * a b

Rheumatology Department, University of Oxford, Oxford, UK Paediatric Rheumatology Department, Institute of Child Health and Great Ormond Street Hospital, London, UK

Keywords: vasculitis cardiovascular disease mortality

The primary systemic vasculitides are a group of autoimmune conditions characterised by occlusion, stenosis or aneurysmal dilatation of blood vessels secondary to intra-mural inflammation. Current therapy has converted the outlook of these diseases from death or severe morbidity to a remitting–relapsing condition in most instances. Longer survival, relapsing course of disease and chronic glucocorticoid therapy probably contribute to an increase in cardiovascular events and morbidity. This article reviews the available data for effect of primary systemic vasculitis on cardiovascular end points like coronary artery disease, congestive cardiac failure, hypertension and aortic aneurysm in all age groups. We examine the interplay between the activated endothelium, autoimmune mechanisms and treatment factors to produce a direct insult or increased atherogenic potential of primary systemic vasculitis. Recommendations to deal with cardiovascular end points are made. Ó 2009 Elsevier Ltd. All rights reserved.

The primary systemic vasculitides (PSVs) are a group of autoimmune conditions characterised by occlusion, stenosis or aneurysmal dilatation of blood vessels secondary to intra-mural inflammation. There have been several proposals to classify and name distinct vasculitic syndromes for the purpose of clinical studies [1–4]. Although each classification system has its limitations, it is agreed broadly that the PSVs can

* Corresponding author. Rheumatology Department, Biomedical Research Unit in Musculoskeletal Science, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK. E-mail address: [email protected] (R. Luqmani). 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.02.002

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be divided into small-, medium- and large-vessel vasculitides [2,5,6]. Amongst them, Wegener’s Granulomatosis (WG), microscopic polyangiitis (MPA), and Churg–Strauss syndrome (CSS) have a strong association with the presence of anti-neutrophil cytoplasm antibodies (ANCAs) [7]. Together, the three syndromes are termed the ANCA-associated vasculitides (AAV). However, these three syndromes behave differently and have different long-term outcomes [8]. The annual incidence of PSVs in northern Europe is 40–54 patients/million [9]. The exact incidence of each form of vasculitis can vary depending on age, sex, ethnicity, geography, time of the year and other environmental factors [10]. The classification system used also has a bearing on the incidence of a specific vasculitic syndrome [11]. PSVs can be life-threatening or organ-threatening. Current therapy has converted the outlook of these diseases from death or severe morbidity to a remitting–relapsing condition in most instances. Longer survival, relapsing course of disease and chronic glucocorticoid therapy probably contribute to an increase in cardiovascular events and morbidity. There are very few data relating to cardiovascular sequelae associated with vasculitis in the young. Most studies relate to Kawasaki disease (KD), or Henoch–Scho¨nlein purpura (HSP) although limited data are emerging in relation to other childhood vasculitic syndromes. This article reviews the role of disease and treatment factors in increasing the burden of cardiovascular disease in PSVs, and possible strategies to manage or modify the cardiovascular risk. For the purposes of this article, we will concentrate on coronary artery disease, congestive cardiac failure, hypertension and aortic aneurysm in all age groups. Aetiopathology of cardiovascular involvement in PSVs The endothelium Endothelial involvement has long been recognised in vasculitis [12] but the precise mechanism of activation and damage differs in the different syndromes of the disease. There are a variety of mechanisms by which endothelial activation and damage may occur. Complement-dependent cytotoxicity, antibodydependent cytotoxicity, direct effect of adhesion molecules and cytokines have all been implicated. Immune complex-mediated activation of complement has been implicated in polyarteritis nodosa (PAN) [13]. ANCAs are actively involved in the neutrophil–endothelial interaction which results in endothelial activation and damage [14]. Anti-endothelial cell antibodies, a family of different antibodies binding to a variety of endothelial antigens, have been detected in many forms of vasculitis [15] but their exact mechanism of action, if any, is unclear. The endothelium actively interacts with endothelial adhesion molecules, leucocytes and cytokines to produce an amplification of the inflammatory cascade [16]. The impact of chronic inflammatory disease and the atherogenic potential of primary systemic vasculitis Chronic rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are associated with increased cardiovascular disease and mortality [17,18]. It has been suggested that this may be due to secondary vasculitis and endothelial dysfunction [19]. Survival from PSV has greatly improved as a result of immunosuppressive therapy, converting it into a chronic disease with episodes of relapse [20]. The disease is associated with high circulating levels of C-reactive protein (CRP), which has been shown to be independently associated with cardiovascular disease in patients with PSVs and healthy individuals as well [21]. Patients with Takayasu’s arteritis (TAK) have been shown to have accelerated atherosclerosis in their carotid arteries, comparable to patients with systemic lupus erythematosus, and significantly greater than healthy controls [22]. Calcific deposits are reported on computed tomography of the aorta in TAK [23]. The role of PSVs causing accelerated atherosclerosis is demonstrated in long-term studies of patients with KD. Dhillon studied vascular responses to reactive hyperaemia in the brachial artery using high-resolution ultrasound [24]. Flow-mediated dilation (FMD, an endothelial-dependent response) was markedly reduced in KD patients compared with control subjects many years after the illness, even in patients without detectable early coronary artery involvement. In contrast, Ikemoto demonstrated impaired FMD only in patients with persistent coronary artery lesions (CAL) [25]. Additionally, another recent cross-sectional study by McCrindle failed to demonstrate differences in brachial artery reactivity (BAR) following KD, as compared to controls [26]. Issues relating to inherent

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methodological insensitivity and variability of BAR in children and under-powering of studies are likely to have contributed to these conflicting observations. Pilla demonstrated reduced arterial distensibility (a measure of arterial stiffness, an independent risk factor for cardiovascular morbidity and mortality in adults) as assessed by using ultrasound pulse wave velocity in the brachioradial arterial segments of 43 children who had KD a median of 3 years previously [27]. Additionally, diastolic blood pressure was found to be significantly higher in the KD group as compared with 166 healthy age-matched controls. These changes in arterial stiffness were subsequently confirmed by Cheung et al. who also reported on the relationship of high-sensitivity CRP (hs-CRP) and stiffer arteries in KD patients [28,29]. A recent study by Dalla et al. demonstrated subclinical atherosclerosis in 20 children with KD as assessed by increased intimal media thickness [30]. PSVs have a significant hidden element with respect to clinically covert involvement and continuing activity in patients thought to be clinically silent. The involvement of the vascular tree in many patients with PSVs is likely to be more widespread than is clinically apparent. For example, a positron emission tomography study of patients with giant cell arteritis (GCA) demonstrated clinically silent but metabolically active areas in the subclavian arteries, femoral arteries and the aorta in 14 of 22 patients [31]. Endothelial dysfunction, distant from the site of the primary inflammatory disease, has been demonstrated in arteries of patients with AAV [32,33] and is reversible with treatment [33,34]. Imaging and autopsy studies in TAK have demonstrated that the disease remains active in patients who are believed to be in clinical remission. In a prospective study of magnetic resonance imaging in TAK, 24 of 43 studies obtained in patients thought to be in clinical remission demonstrated vessel wall oedema [35]. In an autopsy study of 10 patients with TAK, histological evidence of activity was demonstrated in patients thought to be in the chronic fibrotic stage of the disease [36]. Late endothelial dysfunction, disturbed lipid metabolism and disorders of fibrinolysis have been described in patients with KD long after the acute inflammation has resolved. Thus chronic subclinical vascular inflammation combined with atherogenic lipid and fibrinolytic profiles could contribute to the progression of atherosclerosis. Although the inflammatory response following KD was considered to be transient, worryingly it is now apparent that markers of subclinical inflammation including serum amyloid A (SAA) and hs-CRP remain elevated years after KD, and could directly contribute to accelerated atherosclerosis. Moreover, there is now a theory that calcification inhibitory proteins such as fetuin-A are lowered by chronic inflammation which could contribute to vascular calcification in other inflammatory diseases, but this has not yet been studied in KD [37]. Thus there is an emerging body of data suggesting that KD can progress from an acute vasculitis to a state of chronic subclinical vascular inflammation. An episode of PSVs could set the scene for accelerated atherosclerosis by several mechanisms: (1) widespread direct structural injury to arteries from acute inflammation, (2) chronic vascular inflammation years after the acute injury with arterial intimal-media calcification, (3) secondary proatherogenic changes in lipid and fibrin metabolism and (4) alteration of carotid baroreceptor sensitivity and systemic hypertension. Iatrogenic effect In addition to the biological impact of chronic diseases, most patients with chronic relapsing PSVs are treated with long-term glucocorticoid therapy for 18 months to 2 years [38–40]. The median cumulative dose of prednisolone in patients with GCA prior to discontinuation of therapy is 6.5 g [38]. In AAV, continuation of glucocorticoid therapy is recommended for at least 18 months [39,41]. Chronic glucocorticoid therapy is associated with hypertension, diabetes mellitus and change in the lipid profile, all of which adversely influence the risk of cardiovascular outcomes. However, there is evidence that glucocorticoid therapy may improve the endothelial dysfunction of GCA [34]. Cardiovascular involvement in large vessel vasculitis Giant cell arteritis GCA is a PSV with an affinity to affect the aorta and other medium and large arteries with a welldefined elastic lamina in patients older than 50 years of age. It is the commonest primary systemic

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vasculitis, especially in people of Northern European and Scandinavian descent [42]. The aortic involvement is often subclinical and is associated with development of aneurysm or dissection [43]. Aneurysm formation mainly involves the thoracic aorta but can affect the abdominal aorta as well. An aneurysm of the ascending aorta can produce a functional aortic regurgitation [44]. The disease duration prior to a diagnosis of thoracic aneurysm is over 10 years [43], but thoracic dissections present about one year after diagnosis of GCA [43]. In rare cases, the aneurysm can precede the diagnosis of GCA [44,45]. In two retrospective population cohorts, the incidence of all aortic aneurysms and dissections was 18.7 and 18.9 per 1000 person-years respectively [43,46]. The incidence of thoracic and abdominal aneurysms is 8.2–15.1 and 5.55–10.1 per 1000 person-years (Table 1) [43,45,46]. The standardised morbidity rate (SMR) for thoracic aortic aneurysm in comparison to the general population is 17.3 (95% confidence interval (CI) 7.9, 33), but there is no statistical increase for abdominal aneurysms [47]. The incidence of coronary heart disease in GCA is 8.2–12.6 per 1000 person-years [48,49]. The risk of coronary heart disease is higher in patients with GCA (adjusted hazard ratio 1.9; 95% 1.2–2.7) compared with healthy controls [49]. Coronary artery disease is most commonly a long-term sequelae in GCA, but it is known to occur at disease presentation [50]. Incidence figures for hypertension and congestive cardiac failure have not been adequately reported, but they are expected adverse events secondary to systemic vasculitis and/or its treatment with glucocorticoid therapy. When present, hypertension is a risk factor associated with aortic aneurysm and cerebrovascular accident [46,51]. Takayasu’s arteritis TAK is a granulomatous aortitis which also involves the proximal branches of the aorta with an incidence of 0.4–2/million/year in Northern Europe [9]. The rarity of this condition has precluded adequate documentation of robust clinical outcome data. The onset of TAK is typically during the third decade of life; however, it can and does affect children as well [29]. Park et al. reported that in a series of 108 Korean patients with TAK, only 7% were under 10 years of age, and 19% were 10–20 years old at onset of disease [30] with females affected more often than males. Aortic involvement predominantly results in stenosis, but aneurysm formation occurs in about 10% of the patients [36,52,53]. Most commonly, the aneurysms diffusely affect the entire length of the aorta and its branches (Table 2). When an aneurysm is present in the ascending aorta, it may be associated with functional aortic regurgitation. Coronary arterial involvement in TAK can be divided into three distinct morphological types – stenosis or occlusion of the coronary ostia, diffuse or focal coronary arteritis and coronary aneurysm formation [54,55]. Hypertension in TAK is common (up to 85% in one cohort) and often renovascular in origin [56]. Congestive cardiac failure has been documented in 44% in one cohort [57]. In a series of 19 children with TAK, examination revealed hypertension in 89%, absent pulses in 58% and arterial bruits in 42% [53]. Conventional digital subtraction angiography remains an important tool in the initial evaluation of paediatric TAK. Increasingly, magnetic resonance angiography (MRA) is being used in detection of early signs of large-vessel disease, and has the added advantage of potentially revealing the presence of ongoing large arterial wall inflammation. One caveat, however, is that magnetic resonance may result in false positive diagnoses for TAK based on aortic signs in young children. In our experience, two pre-school children referred to us with the presumptive diagnosis of TAK on the basis of aortic calibre variation observed on MRA turned out to have alternative diagnoses, Table 1 Incidence of aortic aneurysms and dissections in cohorts of giant cell arteritis (All numbers are per thousand person years).

Total aortic aneurysm/dissection Thoracic aortic aneurysms/dissections Thoracic aortic dissections Abdominal aortic aneurysms/dissections Abdominal aortic dissections NA – Not available.

Evans 1994

Nuenninghoff 2003

Gonzalez-Gay 2004

NA 9.99 NA 5.55 NA

18.7 8.2 5.4 10.1 0.6

18.9 15.1 1.9 5.7 1.0

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Table 2 A comparison of the aortic aneurysm distribution in two cohorts of ethnically well defined patients with Takayasu arteritis. Author

Country

N

Type 1

Type 2

Type 3

Type 4

Sharma 1990 Yamada 1992

India Japan

88 84

12 (14%) 19 (23%)

1 (1%) 9 (11%)

24 (27%) 3 (4%)

51 (58%) 53 (63%)

Type 1 ¼ Involvement of aortic arch and its branches only; Type 2 ¼ involvement of the thoracic aorta and its branches only; Type 3 ¼ involvement of the abdominal aorta and its branches only; Type 4 ¼ involvement of the entire length of the aorta and its branches.

and with normal aortic anatomy on subsequent formal digital subtraction arteriography. Late cardiovascular sequelae are common in children and include hypertension due to renal artery stenoses or mid-aortic narrowing. Angioplasty or reconstructive vascular surgery are therapeutic options for children, similar to adults. Cardiovascular involvement in medium- and small-vessel diseases Kawasaki disease KD is associated with the development of systemic vasculitis complicated by coronary and peripheral arterial aneurysms, and myocardial infarction in some patients [58]. It has an incidence of 8 per 100 000 children in the UK, and has superseded rheumatic fever as the commonest cause of acquired heart disease in children in the United Kingdom and USA [58,59]. It is generally accepted that an as yet undefined infectious trigger in a genetically predisposed individual results in the disease. Despite intensive research into the illness the cause remains unknown, and although there have been significant improvements in diagnosis and treatment of children with the disease, there are still a number of important unanswered questions regarding aetiopathogenesis and long-term outlook. Echocardiography and cardiac angiographic data indicate that 20–40% of untreated KD patients develop coronary artery abnormalities [58]. Approximately 50% of these lesions regress within 5 years, and in most patients with mild coronary arterial aneurysms (3–4 mm) regression occurs within 2 years. Giant aneurysms (>8 mm) are unlikely to resolve, and some may develop stenosis with risk of coronary thrombosis, myocardial infarction and death. In 1993, a report from the British Paediatric Surveillance Unit indicated a mortality rate of 3.7% in the UK for KD [60]. Current mortality rates reported from Japan are much lower at 0.14% [61]. The reasons for this difference include improved therapy and better case recognition. In an epidemiological study from Japan looking at long-term outcomes of a cohort of 6576 patients with KD enrolled between 1982 and 1992, the mortality rate for patients without cardiac sequelae in the acute phase of the disease and female patients with sequelae did not differ from the normal population. The mortality rate of males with cardiac sequelae was, however, 2.4 times higher than the normal population [62]. Epidemiological studies from Japan also have demonstrated that late sequelae, especially in patients with large aneurysms, include myocardial ischaemia with a frequency of 30% within 4 years after onset of the disease [59]. ANCA-associated vasculitis and polyarteritis nodosa WG, MPA, CSS and PAN are herein considered as a group as they all affect medium- to small-sized vasculature. AAV causes necrotising vasculitis with few or no immune deposits (pauci-immune) affecting small vessels (capillaries, venules and arterioles). It has an incidence of 11–16/million/year in Northern Europe [9]. PAN has an incidence of 0.4–2/million/year and exclusively involves mediumsized vessels without glomerulonephritis. In childhood, PAN is rare but occurs more commonly than the ANCA-associated vasculitides [63]. Most studies reporting outcomes in these conditions have considered these conditions together without subgroup analysis. The changing definitions also contribute to the ambiguity of disease-specific outcomes [11]. Aortic and coronary involvement has been described in WG and MPA only in case reports and accurate estimate of the incidence remains unknown [64,65]. In one retrospective cohort of 85 patients

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with MPA, hypertension was noted in 34% and congestive cardiac failure in 18% of the patients. Myocardial infarction as a cause of death in WG has been documented in 6 of 26 patients and 13 of 146 in two separate cohorts [66,67]. The presence of cardiac involvement at diagnosis is rare in WG, but when present, it is associated with an increased risk of relapse (hazard ratio 2.87) [68]. In a cohort of 595 patients with PAN, MPA and CSS, 82 patients (14%) had congestive cardiac failure at diagnosis; 20 of those patients died within the first year (of 60 total deaths). However, this was not significantly associated with mortality in multivariate analysis [69]. Four of those 60 patients were thought to have died due to a heart-related condition, but the precise cause of death was not reported. AAV and PAN in children share many of the features of the adult diseases although clearly the consequences of damage have important and different implications for growing children. There is no data on the cardiovascular morbidity in children with AAV. In a study describing the renal changes on selective visceral digital subtraction arteriography in children with PAN, 40% of the children had aneurysms mostly affecting small- and medium-sized arteries and the presence of these was significantly associated with renal impairment and hypertension [70]. Prognosis for children with PAN varies in different series. The most recently published mortality rate for PAN is approximately 10% in children at Great Ormond St Hospital [71]. Although the medium-term prognosis is good, it is not yet clear if survivors of PAN in childhood are prone to premature atherosclerosis later in life; this is an area of ongoing research [72]. Henoch–Scho¨nlein purpura HSP is the most common form of systemic vasculitis in childhood and predominantly affects small vessels [73]. The presence of palpable purpura in the absence of thrombocytopaenia is an essential classification criterion. Although cases among adults have been described, HSP typically affects children between the age of 3 to 10 years, with 50% of the cases occurring at or before the age of 5 [74]. Gardner-Medwin et al. reported an estimated annual incidence of 20.4 per 100 000 children in the UK [75]. Males are most commonly affected, particularly in the autumn and winter, and HSP may follow an intercurrent infection such as an upper respiratory tract infection. Although the cause of HSP is unknown it is likely that immunoglobulin A (IgA) has a pivotal role in the pathogenesis of the disease, a hypothesis supported by the almost-universal deposition of IgA in lesional vascular tissue. A wide variety of infectious agents have been reported as potential triggers of HSP. With regards to host susceptibility, several genetic polymorphisms relating to HSP and in particular severity and/or risk of renal involvement have recently been described [76]. Some instances of hypertension have been reported many years after normalisation of renal function and urinalysis [77]. An increased incidence of pre-eclampsia has also been reported [78]. In view of this, most would advocate monitoring of BP for a minimum of 2 years after normalisation of urinary sediment, although lifelong follow-up (annual BP and urinalysis by GP) has been proposed by some for all children with HSP [77]. In unselected populations of HSP, the overall risk of significant long-term renal impairment is around 2% [77]. Where isolated haematuria is associated with proteinuria, the risk of long-term renal dysfunction is around 5% [79]. Children presenting with the acute nephritic syndrome have a less favourable outcome, with a long-term risk of chronic renal failure CRF of 10–20% [79]. Those with a mixed nephritic–nephrotic presentation have the worst long-term outlook, with up to 33% developing CRF [88]. Those with more aggressive renal biopsy changes are more likely to have a poorer long-term outlook [79]. Data examining the possibility that HSP presenting in young children could predispose to early atherosclerosis are not described. This seems an important area of future research, particularly since there is a well-described association between renal impairment and accelerated atherosclerosis in the young. Strategies to deal with cardiovascular complications of PSVs At diagnosis A diagnosis of PSVs must trigger imaging investigations to determine the extent of the vascular involvement. The choice of the imaging modality will depend on the nature of the PSVs and the

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consequent risk of the specific cardiovascular end point. For example, all patients with large vessel vasculitis may benefit from imaging of their aorta at diagnosis, but patients with PAN may need visceral angiography. Management Medical – High-dose glucocorticoid therapy has a definite role in inducing remission in PSVs, and it is recommended at an initial dose of 1 mg/kg (maximum 60 mg/day for adults) [39,40]. In large-vessel vasculitis, there is evidence that it reverses the endothelial dysfunction [34]. However, due to its longterm complications, tapering of the glucocorticoid dose should start after 1 month, with the aim of reaching a dose of 10–15 mg/day at 3 months [39,40]. In GCA, low-dose methotrexate (10–15 mg/ week) has a modest glucocorticoid-sparing effect and may be appropriate for some patients [80]. Low-dose aspirin should be considered in all patients with GCA to reduce the risk of developing cardiovascular and cerebrovascular events [40]. It is also used in conjunction with immunosuppression and glucocorticoids in children with PAN. Treatment of patients with KD with intravenous immunoglobulin (IVIG) and aspirin reduces the incidence of coronary artery lesions from approximately 20–40% to <5% [58,59], although recently in the UK we and others have reported an alarmingly higher incidence of CAL despite IVIG therapy, probably relating to delayed diagnosis of KD in the UK [81,82]. Surgical – Renovascular hypertension due to TAK is amenable to surgical repair and reconstruction of the vessel [83,84]. This procedure is associated with a small peri-operative mortality [84,85]. Percutaneous renal angioplasty is safer in that respect, but has a greater re-stenosis rate [83,86]. When possible, the surgery should be performed in the quiescent phase of the disease to reduce the risk of re-stenosis [83,87]. Monitoring and follow-up All patients with PSVs may have a higher risk of cardiovascular events than the general population. They should be monitored long-term due to the risk of relapse, cardiovascular events and iatrogenic complications. Patients with large-vessel vasculitis, especially those with hypertension, should be monitored with periodic imaging of the aortic tree due to the increased risk of aortic aneurysm [40]. Blood pressure monitoring is recommended for all patients at each follow-up visit. Hypertension may be iatrogenic due to glucocorticoid therapy or nephrotoxic drugs, or as a result of the disease. In patients with HSP, monitoring of the blood pressure is recommended for a minimum of 2 years after normalisation of urinary sediment, although lifelong follow-up (annual BP and urinalysis by GP) has been proposed by some for all children with HSP. Children with significant renal impairment at presentation, and/or persistent proteinuria should undergo regular assessment of their GFR (e.g., at 1, 3 and 5 years post acute episode of HSP) [79]. Conclusions We have reviewed the cardiovascular morbidity (predominantly aortic and cardiac events) of primary systemic vasculitis. We are learning more about the endothelium as an active organ which interacts with, and actively amplifies the immunological reactions leading to vasculitis. Glucocorticoid therapy assists in reducing the endothelial dysfunction in the short term, but is probably responsible for some of the long-term sequelae in PSVs. Glucocorticoid-sparing therapy may be appropriate for some patients with GCA. Patients with PSVs are now living longer with improvements in therapy. Data from long-term follow-up studies to document cardiovascular events are not available, although these studies are currently underway. The heterogeneity of cohorts, the overlapping definitions in recording of clinical events (e.g., cardiomyopathy, congestive cardiac failure and heart failure) make it difficult to report the exact incidence of specific events. These problems are not insurmountable, and published recommendations for conduct of clinical trials and studies in AAV will address at least part of this problem [88].Patients with chronic rheumatic diseases have a higher risk of developing cardiovascular events. With improving survival, PSVs may not be an exception. Over the past 20 years, there have been four collaborative European clinical trials relating to AAV in adults, which have recruited 554 patients

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[89]. These patients have been followed to study long-term cardiovascular and other outcomes. The European League Against Rheumatism has also published evidence-based recommendations for the management of PSVs, including the cardiovascular outcomes [39,40].

Practice points 1. Cardiovascular events are common in patients with chronic rheumatic diseases. They should be screened for in patients with chronic PSVs. 2. Simple measures such as low-dose aspirin may be helpful in preventing cardiovascular events. 3. Glucocorticoid therapy is helpful in inducing remission and reversing endothelial dysfunction, but should be tapered to 10–15 mg/day at 3 months. 4. The late cardiovascular sequelae of vasculitis in children are best described for KD, with little or no data for other paediatric vasculitides.

Research agenda 1. An appropriately designed longitudinal study to investigate cardiovascular events at diagnosis and in the long-term in PSV, with either homogeneous cohort or subgroup analysis for each outcome of interest. 2. Role of therapeutic agents, for example aspirin, in prevention of coronary events. 3. Establishing regional databases for collating information on these rare conditions. 4. Establishing reliable surrogate markers of vascular injury to be used in routine clinical practice to guide therapy and allow prognostication.

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