Diffuse endothelial dysfunction is common to ANCA associated systemic vasculitis and polyarteritis nodosa.

BACKGROUND: Excess cardiovascular mortality complicates systemic rheumatic disease, suggesting an accelerated atheromatous process, which it has been proposed relates to the vascular inflammation common in such diseases. Impaired endothelium dependent vasodilatation is an early marker of atheromatous disease. It has previously been shown that such endothelial cell dysfunction (ECD) occurring in the brachial artery can complicate primary systemic necrotising vasculitis (SNV). OBJECTIVE: To determine if ECD occurs in a wider spectrum of primary SNV, if it is restricted to the major arteries, and whether vasculitis subgroup, ANCA status, or renal involvement influenced the endothelial responses. METHODS: Fifty four patients attending the Birmingham vasculitis clinic, including patients with a range of ANCA and non-ANCA associated primary vasculitides, and a group of age matched controls were recruited. The length of patient follow up and disease activity was variable. Disease activity, damage scores, and cardiovascular risk factors were recorded before assessment of flow mediated brachial artery vasodilatation by high resolution ultrasound. Dermal microvascular responses to acetylcholine were also measured in 32 patients and 21 controls by laser Doppler flowmetry. RESULTS: ECD was demonstrated in all primary SNV subgroups of patients with ANCA associated vasculitis and in polyarteritis nodosa, compared with controls. Significant impairment occurred in both vascular beds, regardless of vessel size targeted in the inflammatory vasculitis, ANCA association and titre, or renal involvement. CONCLUSIONS: Diffuse endothelial dysfunction, a predictor of atherosclerotic disease, is found extensively in primary systemic vasculitis. Involvement of different vascular beds is independent of target vessel size or ANCA association, and is unrelated to local disease expression. It is suggested that this results from a systemic response that may be a consequence of primary vasculitis, but is distinct from the local inflammatory vasculitic process.

Seasonal differences in finger skin temperature and microvascular blood flow in healthy men and women are exaggerated in women with primary Raynaud's phenomenon.

AIMS: Patients with primary Raynaud's phenomenon (PRP) have more severe symptoms in the winter. The aetiology of this is more complex than simply increased vasoconstriction in response to the immediate ambient temperature. The aim of this study was to investigate differences in skin temperature (Tsk), microvascular blood flow and responses to endothelium-dependent and independent vasodilators in healthy controls, and women with PRP under identical environmental temperatures but in different seasons. METHODS: Ten women with PRP were compared with age matched women (10) and men (10). Finger skin responses were recorded immediately on arrival, after stabilizing in a temperature regulated laboratory at 22-24 degrees C, and at matched warm (35 degrees C) and cold (15 degrees C) Tsk in the winter and summer. Baseline red blood cell flux (r.b.c. flux), and the change in flux in response to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) were recorded by laser Doppler fluxmetry at the warm and cold Tsk. RESULTS: Arrival Tsk were significantly cooler for all subjects during the winter (mean seasonal difference -2.6 degrees C, P < 0.0001), and markedly colder in subjects with PRP (mean seasonal difference -3.5 degrees C, P < 0.0005). Statistically significant seasonal differences persisted in all subjects at stable Tsk despite an identical laboratory temperature (mean difference 1.3 degrees C, P < 0.0001). To achieve comparable controlled finger Tsk a significantly colder local environment was required for male controls (mean of -2.1 degrees C, P < 0.0001), and a significantly warmer environment for subjects with PRP (mean of + 2.4 degrees C, P < 0.0001) compared with female controls. This needed to be warmer in the winter, by a mean of 2.4 degrees C, than the summer for all subjects. Vasodilatation in response to ACh, but not SNP, was significantly smaller (P < 0.0001) in the PRP group compared with the female controls for all visits, with most of this difference arising in the winter visits (P < 0.01). CONCLUSIONS: There is a seasonal and persistent influence on finger Tsk, and microvascular blood flow in healthy men and women, which modifies the observed responses to immediate changes in finger Tsk. The seasonal differences are greater in women than men, and are further exaggerated in women with PRP, in whom this is associated with reduced endothelium-dependent vasodilatation.

Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis: a pilot study.

Periarticular osteoporosis around inflammed joints and generalized osteoporosis have been shown to be markers of disease activity and severity in children with juvenile idiopathic arthritis (JIA). Bone mineral density (BMD) in adults can be assessed precisely by dual X-ray absorptiometry (DXA), but this technique has not been used widely in children. Quantitative ultrasound (QUS) may provide an alternative method for assessment of bone status. The aim of this pilot study was to compare QUS to DXA in assessing generalized osteoporosis in a cohort of patients JIA. Twenty-two Caucasian children (15 females, 7 males) with JIA of duration 19-142 months (mean 71 mo) and age 7-17 yr were recruited. Total body and lumbar spine BMD and bone mineral content (BMC) were measured by DXA using standard procedures on a Lunar DPX-L scanner. QUS was performed using Myriad SoundScan 2000. Speed of sound (SOS) was measured at the right midtibia. The DXA results were compared to QUS using linear regression analysis. Spine and total body BMD measured by DXA correlated significantly with tibia SOS (spine: r = 0.57, p < 0.007; total body: r = 0.68, p < 0.001). Spine BMC was similarly related to SOS as BMD (r = 0.58, p < 0.007). Individual patient weight and height were strong predictors of BMD, but only moderate predictors of SOS. The mean spine BMD was lower in the JIA patients compared to the normal ranges (mean Z-score of -1.19). BMD Z-scores were negatively associated with disease duration. Patients taking steroids were associated with lower Z-scores. In conclusion, SOS shows a significant correlation with BMD as measured by DXA, albeit with wide 95% confidence intervals in this small pilot study. QUS was also well tolerated and was technically easy to perform in these children. With the added advantage that it is free from radiation risk, further assessment of this potentially valuable tool for measuring bone status in children is warranted.

An investigation into variability in microvascular skin blood flow and the responses to transdermal delivery of acetylcholine at different sites in the forearm and hand.

AIMS: Transdermal iontophoresis in combination with laser Doppler fluxmetry (LDF) are useful techniques for examining dermal microcirculatory responses to different vasodilators. Differences in skin and microcirculation structure could influence the recorded baseline flux, and the observed vasodilatation. To examine this we compared baseline flux and the response of microvascular blood flow to a single vasodilator, acetylcholine, at sites in the forearm and hand. METHODS: Baseline microcirculation flow was recorded by LDF in a temperature controlled laboratory. The change in flux with iontophoresis of identical doses of acetylcholine, 150 microA for 40 s, was recorded at 12 different sites in the forearm and hand in 10 female and 3 male subjects. RESULTS: Baseline flux patterns and the vasodilatation to identical periods of iontophoresis of acetylcholine were site dependent. Palmar sites showed a higher baseline flux, but no vasodilatation to iontophoresis of acetylcholine. In contrast the volar forearm, dorsal hand and finger sites showed lower site-dependent baseline flux, but did vasodilate. CONCLUSIONS: Patterns of baseline flux are specific to sites on the hand and forearm reflecting differences in underlying microvascular structure. The vasodilatation to transdermal delivery of acetylcholine is also site dependent, but differences in skin structure may be more important than the underlying microvasculature in determining the response.

Correlation between CD29 density on CD8+ lymphocytes and serum IgG in systemic lupus erythematosus.

The purpose of this paper is to establish whether there is increased lymphocyte adhesion molecule density in systemic lupus erythematosus (SLE), which could alter the migration pathways and activation thresholds of lymphocytes and thus contribute to the pathogenesis of the disease. We analysed the CD11a, CD29 and CD2 bound antibody molecule (bam) density on the CD4+ and CD8+ CAMhigh (primed) lymphocytes of 28 SLE patients (8 active and 20 inactive by BILAG), using reproducible flow cytometric measurements, standardized with fluorescent beads and antibodies of known fluorescein: protein ratios. In a second patient cohort (17 patients), we investigated whether CD29 density on CD8+ cells correlated with measures of humoral (serum IgG) or cellular (urine neopterin) activation. In the first cohort, 36% of patients had elevated CD29 (beta 1 integrin) density on CD8+ cells. In the second cohort, CD29 density on CD8+ cells was found to be closely associated with total plasma IgG (r = 0.71, P = 0.001), but not with urine neopterin, disease activity (BILAG) or drug treatment. We conclude that CD29 on CD8+ cells is associated with B cell activation in SLE.

Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behçet's disease: use of neurophysiological studies to detect thalidomide neuropathy.

OBJECTIVE: To examine the efficacy, dose, and safety profile, including neurophysiological testing of thalidomide used in 59 patients (including 23 with Behçet's disease) to treat severe oral or genital ulceration (OGU). METHODS: We identified prospectively subjects (including women of childbearing potential) who had persistent OGU over periods lasting one to 40 years and whose active ulceration was not controlled by other therapies. They were treated with thalidomide. Retrospectively, we identified the number of subjects with complete resolution of the ulcers at one and two months of thalidomide therapy, and the dose required to maintain that improvement in those individuals who relapsed after stopping thalidomide. The decrease from the baseline sensory nerve action potential (baseline SNAP) amplitude value (derived from median, radial and sural nerve SNAPs) at which the development of paraesthesiae was likely to occur was also determined. RESULTS: Complete resolution of the ulcers occurred in 81% of patients within one month of thalidomide therapy at doses of 200 mg/day. No further thalidomide was required by 20% of patients responding and in the remainder improvement was maintained with smaller doses (7-200 mg/day). Using an approximate 50% decrease from baseline SNAP as an indication to discontinue thalidomide, the incidence of symptomatic neuropathy was 13.5%. No patients with a decrease of less than 42% developed neuropathy, and a further 13.5% were asymptomatic with a decrease in SNAP between 42 and 69%. Other side effects were seen in 44% of patients. There were no pregnancies and no requirement for urgent pregnancy testing. CONCLUSIONS: Thalidomide provided a useful therapeutic option in severe oral and genital ulceration which had not responded to other therapies. The physician must remain vigilant to the continuing danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy.