Anti-neutrophil cytoplasmic antibodies: tools for diagnosis and follow-up in systemic vasculitis.
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Biomedical subjects
Publications and source records attributed to C A Stegeman.
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Anti-neutrophil cytoplasmic antibodies (ANCA) constitute a new group of antibodies that are directed against myeloid proteins. Several antigens recognized by ANCA have been described. Antibodies directed to proteinase 3, myeloperoxidase and/or elastase are closely associated with necrotizing systemic vasculitis and/or necrotizing and crescentic glomerulonephritis. Changes in levels of anti-proteinase 3 in generally reflect disease activity in Wegener's granulomatosis. The diagnostic significance of other or still unknown specificities has not yet been definitely established. Recent data from in vitro and in vivo models suggest a role for ANCA in the pathogenesis of systemic vasculitides and/or necrotising and crescentic glomerulonephritis.
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Levels of soluble IL-2 receptor (sIL-2R), soluble CD4 (sCD4) and CD8 (sCD8) were measured by sandwich ELISA as markers for T-cell activation in serial serum samples drawn monthly from 16 patients showing 18 histologically proven relapses of Wegener's granulomatosis (WG). Levels of sIL-2R increased from 1162 U/ml (median, 95% CI 843 to 1814 U/ml) at three months before the relapse to 1684 U/ml (95% CI 1254 to 2202 U/ml) at the time of relapse for the whole group (P = 0.10). The 8 major relapses showed a profound rise in sIL-2R levels (P < 0.01). The level of sIL-2R at the moment of relapse correlated with the level of C-reactive protein (r = 0.547, P < 0.05) and with the disease activity score (r = 0.814, P < 0.001). There were no significant changes in levels of sCD4 or sCD8.
Levels of soluble IL-2 receptor (sIL-2R), soluble CD4 (sCD4) and CD8 (sCD8) were measured by sandwich ELISA as markers for T cell activation in serial serum samples from 16 patients showing 18 histologically proven relapses of Wegener's granulomatosis (WG). Levels of sIL-2R increased from 1065 U/ml (median, range 373-2345 U/ml) 6 months before the relapse to 1684 U/ml (median, range 486-3404 U/ml) at the moment of relapse for the whole group (P = 0.10). The eight major relapses showed a profound rise in sIL-2R levels, from 1008 U/ml (median, range 686-1553 U/ml) 6 months before the relapse, to 1994 U/ml (median, range 1469-3404 U/ml) at the moment of relapse (P < 0.01). The levels of sIL-2R at the moment of relapse were significantly higher at the eight major relapses than at the time of the 10 minor relapses (P < 0.05). Minor relapses were not accompanied by a significant rise in sIL-2R levels. Titres of antineutrophil cytoplasmic antibodies (ANCA) rose by two or more titresteps or from negative to positive in 15/18 patients during the 6 months period before the relapse. In all seven cases with both a rise of the ANCA titre and an at least 25% increase in sIL-2R levels, the rise in ANCA preceded the rise in sIL-2R by at least 1 month. The level of sIL-2R at the moment of relapse correlated with the level of C-reactive protein (r = 0.488, P < 0.05) and with the disease activity score (r = 0.824, P < 0.002). There were no significant changes in levels of sCD4 or sCD8, although the levels of sCD4 tended to be higher at the time of major relapses. We conclude that major relapses of Wegener's granulomatosis are accompanied by systemic T cell activation. T cell activation, however, does not appear to precede the rise in ANCA titre.
In the sera of patients with Wegener's granulomatosis (WG), C-ANCA can be detected that are directed against proteinase 3 (PR3). We have previously observed that C-ANCA interfere with PR3 proteolytic activity and with complexation of PR3 with its major physiologic inhibitor, alpha 1-antitrypsin (alpha 1AT). In the present study we investigated whether this inhibitory effect of C-ANCA on PR3-alpha 1AT complexation correlates with clinical activity of WG. Serial serum samples of eight consecutive patients with histologically proven relapses of WG were tested. At the moment of relapse all sera revealed inhibitory activity towards PR3-alpha 1AT complexation (median 22%, range 10-59%). Disease activity score (r = 0.87, P < 0.02) and C-reactive protein (CRP) levels (r = 0.66, P < 0.1) correlated with C-ANCA inhibition of PR3-alpha 1AT complexation, while they did not correlate with the C-ANCA titre detected by indirect immunofluorescence (IIF) nor with IgG anti-PR3 antibody level measured by ELISA. The inhibitory effect of C-ANCA on PR3-alpha 1AT complexation had risen significantly at the moment of relapse compared with values 3 months (P < 0.05) and 6 months (P < 0.01) before relapse. Eight patients with established WG and positive for C-ANCA but without clinical evidence of relapse served as controls. In this group no inhibitory effect of C-ANCA on PR3-alpha 1AT complexation was observed in 7/8 patients sera. Sera of one control patient contained moderate C-ANCA inhibitory activity towards PR3-alpha 1AT complexation, which remained at a constant level during the 6 months period of observation. Thus, disease activity in WG appears to be more closely related to C-ANCA inhibitory activity towards PR3-alpha 1AT complexation.
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Severe theophylline intoxication is a medical emergency that can lead to cardiac arrhythmias, convulsions and cardiovascular collapse not infrequently leading to permanent morbidity or mortality. We describe a 30-yr-old patient with a peak serum theophylline level of 87 mg/l treated with haemoperfusion using a coated charcoal-filled column. A review of the literature concerning theophylline toxicity, supportive care, outcome and the possible indications for the use of extracorporeal haemoperfusion is given. A summary of possible conservative measures is given. It is concluded that haemoperfusion is the extracorporeal treatment of choice and should be considered in case of theophylline serum levels above 80 mg/l even without signs of major toxicity. For certain patients with conditions increasing the risks of prolonged or severe toxicity even lower serum theophylline levels may warrant the use of haemoperfusion.
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