Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease?

BACKGROUND: Chronic inflammatory rheumatic disorders are associated with excess cardiovascular mortality. This may result from arteriosclerosis following inflammatory damage to the vessel wall by vasculitis. Our hypothesis that vasculitis results in arteriosclerosis by causing vascular endothelial dysfunction was tested in patients with primary systemic necrotizing vasculitis (SNV). METHODS AND RESULTS: Endothelial function was assessed in cross-sectional and longitudinal studies of patients with primary SNV by measuring flow-mediated, endothelium-dependent brachial artery vasodilatation. These patients exhibited marked endothelial dysfunction compared with controls. Remission induction in patients with active primary SNV restored endothelial function. CONCLUSIONS: Endothelial function is significantly impaired in adults with primary SNV, supporting the hypothesis that premature arteriosclerosis in chronic inflammatory rheumatic disorders results from endothelial dysfunction secondary to vasculitis. Normalization of endothelial function after the treatment of primary SNV suggests that early suppression of disease activity in chronic inflammatory rheumatic disorders may reduce long-term vascular damage. The role of inflammation in atheroma formation is increasingly appreciated; this work raises questions regarding the potential for anti-inflammatory therapy in atherosclerosis itself.

Cardiovascular risk and COX-2 inhibition in rheumatological practice.

The use of specific COX-2 inhibitors in place of standard nonsteroidals for the treatment of arthritis appears to reduce the risk of serious gastrointestinal toxicity in this group of patients. However, the role played by these inhibitors in the generation or exacerbation of ischaemic cardiovascular disease is less clear. Clinical studies demonstrate that hypertension can be induced or aggravated by COX-2 inhibitors to a degree similar to that which occurs with standard nonsteroidals. Endothelial dysfunction, an indicator of cardiac ischaemia, may also be exacerbated by specific COX-2 inhibition and there is much debate as to whether these changes lead to an absolute increase in ischaemic cardiac events. These effects on cardiovascular risk factors appear all the more important in patients with rheumatoid arthritis where there is an increase in the incidence of ischaemic heart disease. Here we review the available data on COX-2 inhibition and cardiovascular disease and conclude that all patients who started these agents should have a careful assessment and modification of any cardiovascular risk factors.

Accelerated atherogenesis in autoimmune rheumatic diseases.

The observation that systemic inflammatory rheumatic diseases such as rheumatoid arthritis (RA) are associated with a significantly increased rate of cardiovascular disease, which often occurs at a younger age than in the normal population, is particularly important given the increasing interest in the role of inflammation in atherogenesis in the general population. This review examines the accumulating evidence for accelerated atherogenesis of RA and updates the hypothesis that vasculitis plays a major role in this. Endothelial dysfunction (ECD), widely regarded as initial lesion in atherogenesis, has been shown to occur commonly in primary vasculitis. This ECD is a diffuse event, demonstrable in more than one vascular bed. It is not simply due to scarring in the vessel wall, related to the focal inflammation of the underlying vasculitis, since it may be reversed by suppression of the immune inflammation. However, the mechanisms for this ECD differ from that of the primary vasculitis. Preliminary evidence suggests that inflammatory mediators such as CRP, TNF, or sphingolipids may be involved. The diffuse ECD of vasculitis may have important consequences for both the progression of the primary disease and for cardiovascular events. A model for the role of vasculitis-induced ECD in the accelerated atherogenesis of rheumatic diseases is presented. These concepts are discussed together with the messages they suggest for 'idiopathic' atherosclerosis in the general population.

Epidemiology of systemic vasculitis: changing incidence or definition?

The epidemiology of the systemic vasculitides is poorly documented. Many studies have been conducted from tertiary referral centers, with resulting problems of referral bias and uncertainty of denominator population, or have involved small populations. We have estimated the incidence of the major forms of systemic vasculitis in a stable, ethnically homogeneous population of 414,000 adults from 1988 to 1994. The overall annual incidence of systemic vasculitis (excluding giant cell arteritis) is 39/million (95% confidence intervals; ranging from 31 to 47). The annual incidence of Wegener's granulomatosis is 8.5/million (range, 5.2 to 12.9), Churg-Strauss syndrome 2.4/million (0.9 to 5.3), microscopic polyangiitis 2.4/million (0.9 to 5.3), adult Henoch-Schonlein purpura 1.2/million (0.3 to 3.5), and systemic rheumatoid vasculitis 12.5/million (8.5 to 17.7). These data suggest that the overall incidence of systemic vasculitis is greater than previously thought (10/million) with Wegener's granulomatosis and systemic rheumatoid vasculitis being the most common. Whether this represents a genuine increase in incidence or increased physician awareness is uncertain.

Vasculitis associated with connective tissue disorders.

This article focuses on the important association of vasculitis with the connective tissue diseases. The immunopathologic mechanisms in these secondary vasculitides, with complement and immune-complex involvement, differ from those involved in primary systemic necrotizing vasculitis even though histologically the lesions may appear identical. Any size of vessel may be involved, so biopsy evidence of small vessel disease does not exclude arterial lesions elsewhere. The clinical manifestations are equally wide ranging and vary from one connective tissue disease to another. Treatment of vasculitis is generally with immunosuppressive agents but is dependent on the degree and severity of the vasculitis. There is an important need to make a distinction between vasculopathy, where there is no evidence of underlying inflammation, and true vasculitis because the former requires anticlotting therapy rather than immunosuppression.

Damage occurs early in systemic vasculitis and is an index of outcome.

Because death after acute systemic vasculitis is now uncommon, alternative measures of outcome are required. A significant component of patient morbidity is disease-related damage, which can be quantified by the Vasculitis Damage Index (64 items in 11 organ-based systems). We investigated serially the time-course of damage in 120 patients with systemic vasculitis, to determine the earliest indicators of outcome. High damage scores at 2 years after presentation were characteristic of fatal disease (OR 8.1-12.4). Significant damage occurred within 6 months of presentation, and was a feature of fatal disease. More damage occurred after presentation than after relapse. Lung and multi-system damage were early indicators of poor outcome in severe non-fatal disease. Damage occurs early in systemic vasculitis, and is an indicator of poor outcome. This novel observation, together with evidence of persistent subclinical disease activity and the high frequency of relapse, suggests a need for new treatment strategies. Analogy with the management of acute leukaemia suggests a strategy of early diagnosis and intensive induction of remission, with early escalation of treatment for resistant disease.

Planes, kangaroos, and the CAPD manual.

The Western Australian (WA) Remote Area Dialysis Programme was developed in 1988 due to the cultural need to dialyze an increasing number of aboriginal patients in their own communities, rather than relocating them up to 3000 km away in Perth. The success of the program relies on remote area health services (RAHS), which have no prior experience in continuous ambulatory peritoneal dialysis (CAPD), providing consistent routine and emergency medical care to the patients. Our aim was to standardize the care of all CAPD patients in remote WA by providing the RAHS with an easy-to-follow manual. Although the RAHS received treatment protocols, and in-service education, consistent care was not always provided. We confirmed this by: (1) examining the existing quality assurance tools, peritonitis and hospital admission rates, (2) discussion with remote area staff regarding patients, and (3) informal assessment of remote area staff receptiveness to in-service education by a CAPD nurse. We identified the causes of the inconsistent care to be: (1) high remote area staff turnover (six months average for a registered nurse), (2) the protocols were difficult to follow, and (3) confusion for the RAHS as to the appropriate contact person at our hospital. In 1994, the situation was exacerbated by the dramatic increase in the number of patients and RAHS involved (14 new patients, bringing the total to 20 patients in 12 centers) plus the introduction of a second treating hospital (with differing protocols). A team of two CAPD nurses and two nephrologists was established, to collaborate with two remote area hospitals and the second treating hospital to produce the "Remote Area CAPD Manual." The manual is an easy-to-follow, step-by-step guide for the management of CAPD by non-dialysis personnel. It has led to improved management of CAPD, improvement in communication with RAHS, and the increased confidence of remote area staff in the management of CAPD patients. In conclusion, RAHS can give consistent care if provided with clear, concise guidelines.

Delay in presentation to primary care physicians is the main reason why patients with rheumatoid arthritis are seen late by rheumatologists.

OBJECTIVES: To study the delay from the time of symptom onset to assessment by a Rheumatologist in patients with rheumatoid arthritis (RA) and to determine the contributions of patient and physician dependent factors to this delay. METHODS: Data were collected from 169 consecutive patients with RA at the time of assessment by Rheumatologists working in hospitals serving an inner city population in Birmingham, UK. Dates were recorded for: (i) onset of inflammatory joint symptoms; (ii) initial assessment in primary care; and (iii) referral from primary to secondary care. (iv) initial assessment by a rheumatologist in secondary care. RESULTS: The median delay from the onset of symptoms to a patient being assessed in secondary care was 23 weeks (IQR 12-54 weeks). The median delay before the patient was assessed in primary care was 12 weeks (IQR 4-28 weeks). For 96 patients (57%) more than half of the overall delay in assessment in secondary care was accounted for by a delay in assessment in primary care. CONCLUSIONS: Patient dependent factors, leading to a delay in consulting primary care physicians, are the principal reasons for the delay in patients with RA being seen by Rheumatologists in our population. A considerable body of evidence demonstrates that the earlier that therapy is introduced the better the clinical outcome. Consequently it is important to understand why some patients with RA delay in seeking medical advice, in order to allow effective interventions to reduce this delay.

Infliximab leads to a rapid but transient improvement in endothelial function in patients with primary systemic vasculitis.

OBJECTIVE: To assess the immediate effects of tumour necrosis factor alpha (TNFalpha) blockade on endothelial function in systemic vasculitis. METHODS: Endothelial function was assessed by laser Doppler flowmetry in patients with active vasculitis after 10 infusions of infliximab. For comparison endothelial responses were assessed after five infusions of cyclophosphamide plus methylprednisolone. RESULTS: Endothelial dependent vasodilatation (EDV) improved significantly within 24 hours of infliximab infusion. The median change in red blood cell flux (interquartile range) was 5.7 (4.3-8.2) before infusion v 8.4 (7.5-10.9) at 24 hours; p=0.027. This was not maintained at day 14. No improvement was seen in EDV after cyclophosphamide plus methylprednisolone infusion. CONCLUSION: The rapid but transient improvement in EDV after TNFalpha inhibition suggests that TNFalpha may have a direct role in the impairment of endothelial function.

Development of an interactive learning tool for teaching rheumatology--a simulated clinical case studies program.

OBJECTIVES: To promote independent self-study involving problem solving and decision analysis in the undergraduate medical curriculum, we have developed a series of interactive web-based clinical case studies. METHODS: An initial needs assessment was performed to determine students' attitudes to e-learning. From these results we designed a series of 30 interactive case studies for delivery from a web-server. RESULTS: A survey of 59 undergraduate students believed that online teaching resources were a useful supplement to existing teaching and they could see a positive use for e-learning. The interactive case studies program was well received by a broad range of respondents (n = 84) of different abilities and backgrounds who felt that the program was realistic and clearly presented in an intuitive manner. CONCLUSIONS: The recent increases in numbers of medical undergraduates, the trend towards student-centred learning and the emphasis on patient-related teaching means a great pressure on teachers and resources in medical schools. The case studies program we have developed was effective and well received by both biomedical and medical students. This approach may provide a way to increase the exposure of students to clinical cases involving interactive diagnostic and treatment procedures, that mimic real-world scenarios, but with fewer resource implications.

Arterial blood gas analysis or oxygen saturation in the assessment of acute asthma?

BACKGROUND: A study was undertaken to determine if arterial blood gas estimation is always necessary in the assessment of patients presenting to hospital with acute severe asthma, or whether oxygen saturation as measured by pulse oximetry is a reliable screening test for predicting those in respiratory failure. METHODS: A prospective study was conducted in a specialist respiratory medical unit. Arterial blood gas tensions and pulse oximetry were measured in 89 consecutive patients admitted with acute severe asthma. Respiratory failure was defined as PaO2 < 8.0 kPa or PaCO2 > 6 kPa. RESULTS: When oxygen saturation was 92% or higher (72 patients) respiratory failure was found in three (4.2%) cases. In the 82 patients with a saturation of 90% or higher six patients (7.3%) had respiratory failure. CONCLUSIONS: In the initial assessment of acute severe asthma an oxygen saturation of > 92% suggests that respiratory failure is unlikely and therefore arterial blood gas measurement is unnecessary. This study is only relevant to the assessment of asthmatic patients at presentation. Other parameters of severity must be continually assessed in all asthmatic patients admitted to hospital irrespective of the initial SaO2, and blood gases measured when clinically indicated.

Churg-Strauss syndrome as an unusual cause of spontaneous atraumatic intra-pericardial thrombosis.

Intra-pericardial thrombosis is usually due to haemorrhage into the pericardial space or after traumatic pericardiocentesis. An unusual case of spontaneous atraumatic intra-pericardial thrombosis due to Churg-Strauss syndrome, which responded well to immunosuppressive therapy, is presented.

Isolated nail fold vasculitis in rheumatoid arthritis.

OBJECTIVES: To establish the clinical significance of isolated nail fold vasculitis in patients with rheumatoid arthritis (RA). METHODS: Patients attending hospital with established RA were assessed by a single observer using unaided vision. Isolated nail fold vasculitis (NFV) was diagnosed as small nail edge or nail fold lesions without any evidence of other extra-articular or systemic vasculitis. Patients were followed prospectively. RESULTS: Thirty patients with isolated NFV were identified and followed for a median interval of 22 months. Three patients died within three months of diagnosis and six developed complications possibly indicative of extra-articular disease: xerostomia (three), pericarditis (one), pleural effusion and empyaema (one), pulmonary fibrosis (one). No patient developed systemic vasculitis. CONCLUSION: Isolated NFV has a favourable prognosis compared with systemic vasculitis. There is a low risk of developing systemic or extra-articular disease.

Wegener's granulomatosis--increased incidence or increased recognition?

We aimed to calculate the annual incidence of Wegener's granulomatosis (WG) in Norfolk (UK) and to compare the clinical spectrum of disease to that seen in tertiary centres in both the UK and USA. We also aimed to examine the seasonal onset of symptoms. This was a prospective study of all patients presenting with WG to a district hospital with a well-defined stable population (515,000) during the period 1988-1993. The annual incidence for WG in the adult population is 8.5/million (95% CI 5.2-12.9). These are the first incidence figures for a well-defined population and are higher than previously published. The clinical spectrum of disease in Norfolk was similar to that seen in tertiary centres and there is supportive evidence for a seasonal variation in the onset of symptoms (highest in winter).

The incidence of rheumatoid vasculitis in the Norwich Health Authority.

Systemic rheumatoid vasculitis (SRV) is an uncommon but potentially serious complication of RA. The incidence of SRV is unknown. The aim of this study was to estimate the incidence of SRV in the UK. Over a 6-yr period vigorous attempts were made to identify all patients with newly diagnosed SRV living within the Norwich Health Authority (NHA). The overall annual incidence of SRV is 12.5/million (95% CI: 8.5-17.7). The annual incidence rate for men was 15.8/million (95% CI: 9.5-24.7) and 9.4/million (95% CI: 4.8-16.4) for women. The incidence of SRV in this study is higher than previous estimates.

Dysregulated intracellular Ca2+ stores and Ca2+ signaling in synovial fluid T lymphocytes from patients with chronic inflammatory arthritis.

OBJECTIVE: Peripheral blood (PB) T cells from rheumatoid arthritis (RA) patients proliferate poorly to mitogen, a change that is related to decreased intracellular Ca2+ ([Ca2+]i) signaling after T cell receptor (TCR) stimulation. We hypothesized that this was, in part, due to the effect of mediators of inflammation and predicted that greater changes in [Ca2+]i signaling would be seen in synovial fluid (SF) T cells. We also examined the mechanisms underlying the altered [Ca2+]i signals. METHODS: Paired PB and SF T cells from patients with chronic inflammatory arthritis were stimulated with mitogen to assess the magnitude of the [Ca2+]i signal in cell populations by fluorometry, the pattern of the [Ca2+]i signal in individual cells in a single-cell ion-imaging system, and the spatial distribution of Ca2+ within intracellular organelles. RESULTS: There was a significantly smaller [Ca2+]i signal after phytohemagglutinin protein stimulation of SF T cells (peak rise in [Ca2+]i signal PB versus SF 200 nM versus 180 nM; P < 0.05). In single SF T cells, a change in the pattern of the [Ca2+]i signal and a reduction in the number of responding cells was seen. These changes were a magnification of those seen in RA PB compared with control PB T cells. The contribution of Ca2+ release from intracellular stores to the final [Ca2+]i signal in PB and SF T cells was equal, but there was a significant increase in the Ca2+ remaining in the endoplasmic reticulum (ER) in SF T cells after TCR activation (PB versus SF 6 nM versus 19 nM; P < 0.05). Non-ER Ca2+ stores were not similarly affected. CONCLUSION: We found abnormalities in the magnitude, pattern, and spatial distribution of [Ca2+]i signaling in T cells from SF of patients with chronic inflammatory arthritis. A reduction in the number of responding SF T cells may partly explain some of our observations. However, we propose that the observed redistribution of SF Ca2+ stores may underlie the altered [Ca2+]i signaling, thus making these cells hyporesponsive to mitogen. The inflammatory environment of the joint and the late stage of differentiation of SF T cells are both likely to contribute to these changes in [Ca2+]i signaling, resulting in aberrant T cell function and promotion of disease chronicity.

Effect of classification on the incidence of polyarteritis nodosa and microscopic polyangiitis.

OBJECTIVE: Polyarteritis nodosa (PAN) has been used as a generic term for systemic vasculitis. The distinction between classic PAN and microscopic polyangiitis (MPA) has not always been made. The aims of this study were to compare the American College of Rheumatology (ACR) criteria for PAN with the Chapel Hill Consensus Conference (CHCC) definitions of classic PAN and MPA, and to estimate the annual incidence of PAN and MPA. METHODS: The 1990 ACR criteria and CHCC definitions for systemic vasculitis were applied to an unselected cohort of 130 patients with systemic vasculitis attending a single district hospital in the UK between February 1, 1988 and January 31, 1994. RESULTS: Eight patients who met the ACR criteria for PAN and who also met the CHCC definition of MPA but not classic PAN were identified. A further 5 patients met the CHCC definition of MPA but not the ACR criteria for any other type of systemic vasculitis. No patient who met the CHCC definition of classic PAN was identified. The annual incidence of MPA was calculated to be 3.6/million (95% confidence interval 1.7-6.9), and the annual incidence of PAN (ACR criteria) was 2.4/million (95% confidence interval 0.9-5.3). CONCLUSION: Classic PAN as defined by the CHCC is rare, because small vessel involvement is excluded from this definition.

Percutaneous image-guided biopsy of lung nodules in the assessment of disease activity in Wegener's granulomatosis.

OBJECTIVE: In patients with known Wegener's granulomatosis (WG) and persistent chest radiographic abnormalities, assessment for disease activity is often difficult, prompting the need for histological diagnosis to determine appropriate treatment. Here we report the use of automated image-guided core needle biopsy of pulmonary lesions for the assessment of disease activity in WG, rather than for primary diagnosis. METHODS: Image-guided percutaneous core needle biopsy was performed on five occasions in four patients with thoracic WG and persistent radiographic abnormalities of the chest. Clinical features, indication for biopsy, radiographic abnormalities and pathological findings were recorded. RESULTS: Adequate pathological specimens were obtained, allowing exclusion of infection and tumour. Active chronic inflammation with or without vasculitis was demonstrated in each case, indicating the need for further immunosuppressive therapy. A small pneumothorax following biopsy in one case required no treatment. Follow-up chest imaging revealed a reduction in the extent of thoracic disease following therapy in all cases. CONCLUSIONS: The safety and diagnostic accuracy of image-guided core biopsy of thoracic lesions makes it a useful tool in the assessment of disease activity in WG patients with persistent chest radiographic lesions.

Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI).

Assessment of disease severity in systemic vasculitis encompasses mortality, which is now uncommon, and morbidity, which is increasing in significance. Morbidity includes permanent scars or damage, an evolving concept offering a novel perspective which may be particularly valuable in chronic disease. We have developed a method for assessing damage in systemic vasculitis, but the relationship between damage and disease severity was unknown. Therefore, we examined whether the number of items of damage or the pattern of damage varied with the severity of systemic vasculitis. We established the characteristics of severe disease by examining fatal vasculitis as an example of the most severe disease possible. We then showed that more damage occurred in fatal vasculitis, more systems were damaged, and critical damage akin to organ failure was more common in fatal than non-fatal vasculitis. These observations were reproduced in specific diagnostic groups, namely classical Wegener's granulomatosis and systemic rheumatoid vasculitis. Thus, severe disease was characterized by many items of damage, multisystem damage and critical damage. This pattern of damage was also seen in a subgroup of patients with non-fatal vasculitis, who also have severe disease.