Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis. (49/1603)

BACKGROUND: In kidney biopsies of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis, a variety of histopathological lesions occur, and their relationship to renal outcome is virtually unknown. This multicenter European study reports a clinicopathological analysis of biopsies from 157 patients with systemic vasculitis. METHODS: The biopsies were evaluated according to a previously standardized scoring protocol. Serum creatinine values were measured at the time of biopsy and one year later. In addition, the lowest creatinine level during follow-up was taken into account as the optimum level of renal function recovery. The clinical prognostic value of the histopathological parameters was analyzed with the Kruskal-Wallis one-way analysis of variance and the Mann-Whitney U-test. RESULTS: The percentage of normal glomeruli correlated most significantly with renal outcome at all points of measurement (all P < 0.001). Other lesions predicting for renal function were glomerular sclerosis (P < 0.0005 at one year after the biopsy), diffuse interstitial infiltrates (P < 0.0001 at entry, P < 0.0003 at one year), tubular necrosis (P < 0.0025 at entry), and tubular atrophy (P < 0.002 at entry, P < 0.0002 at one year). CONCLUSION: Traditionally, attention is focused on the extent of active lesions in the renal biopsy in order to determine the severity of renal disease and its implication for renal outcome. Because of their significant impact on renal function, combined with their easy recognition, we recommend the use of the percentage of normal glomeruli in an adequate biopsy in predicting renal function of patients with systemic vasculitis.  (+info)

Mast cells induce autoantibody-mediated vasculitis syndrome through tumor necrosis factor production upon triggering Fcgamma receptors. (50/1603)

The generation of autoantibodies and deposition of immune complexes (ICs) in tissue play a primary role in autoimmune diseases. However, the IC-triggered response consists of complex mechanisms that make it difficult to identify the pathogenesis and develop specific therapy. We clarified here a sequential mechanism for the induction of hypersensitivity angiitis by analyzing the responsible Fc receptor (FcR), effector cells, and mediators in an animal model using FcR-deficient mice. In this model, rheumatoid factor-mediated skin vasculitis was induced in wild-type mice, whereas FcRgamma-deficient mice did not develop the vasculitis. Adoptive transfer of various FcR(+) cells into FcRgamma-deficient mice showed that mast cells but not macrophages derived from wild-type mice triggered skin vasculitis. Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcgammaRIII. TNF produced by such activated mast cells was mainly responsible for the pathogenesis of autoantibody-mediated vasculitis. These findings illustrate the clinical significance of mast cells, Fcgamma receptors, and TNF in IC-induced vasculitis syndrome.  (+info)

The pituitary-adrenal axis in idiopathic retinal vasculitis. (51/1603)

AIMS: To determine whether patients with idiopathic retinal vasculitis have altered production of cortisol and dehydroepiandrosterone sulphate (DHEA-S), and whether differences in these variables occur between those who are sensitive (SS) and resistant (SR) to steroids. METHODS: 20 patients with retinal vasculitis (off treatment) and 10 control subjects were prospectively recruited. Morning cortisol and DHEA-S levels were measured, and cortisol secretion rates and short synacthen tests (SST) carried out in patients before treatment, when on prednisolone 20 mg/day, and in controls. RESULTS: There were no differences in any variables between patients and controls. For retinal vasculitis patients pretreatment, the SST was lower in SR patients (p=0.02). More of the SR patients had ischaemic retinal vasculitis ( p<0.001). CONCLUSIONS: Cortisol and DHEA-S are not involved in the pathogenesis of retinal vasculitis. SR in retinal vasculitis may be associated with a defective hypothalamic-pituitary-adrenal axis.  (+info)

Peripheral ulcerative keratitis 'corneal melt' and rheumatoid arthritis: a case series. (52/1603)

OBJECTIVES: (1) To review the visual and systemic outcomes of patients who developed rheumatoid arthritis (RA)-associated peripheral ulcerative keratitis (PUK). (2) To describe the clinical and serological characteristics of the patients' arthropathy at the time of presentation of this rare condition. (3) To review the aetiology and management of RA-associated PUK. Patients and methods. A case series is given of all nine patients within our unit who have developed RA-associated PUK since 1996. Details of the patients' arthropathy and the serological characteristics of the RA at presentation of PUK were noted. The patients' visual outcomes and the development of any significant systemic complications were recorded. RESULTS: All patients had long-standing seropositive, erosive RA. PUK was associated with a poor visual outcome in most patients, five requiring emergency corneal surgery to prevent perforation of the globe. Two patients developed systemic vasculitis within 1 month of PUK onset, one of whom died. CONCLUSION: RA-associated PUK often has a poor visual outcome and its appearance may herald the transformation of a patient's RA into the systemic vasculitic phase. RA-associated PUK should be managed with aggressive immunosuppression if the associated morbidity and mortality are to be avoided. Cell-mediated mechanisms appear to be important in the aetiopathogenesis of PUK and a combination of corticosteroids and cyclosporin is therefore probably the regimen of choice.  (+info)

Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. (53/1603)

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.  (+info)

Unusual complications in an inflammatory abdominal aortic aneurysm. (54/1603)

An unusual case of an inflammatory abdominal aortic aneurysm (IAAA) associated with coronary aneurysms and pathological fracture of the adjacent lumbar vertebrae. The associated coronary lesions in cases of IAAA are usually occlusions. In the present case, it was concluded that a possible cause of the coronary aneurysm was coronary arteritis and the etiology of the pathological fracture of the lumbar vertebrae was occlusion of the lumbar penetrating arteries due to vasculitis resulting in aseptic necrosis. Inflammatory AAA can be associated with aneurysms in addition to occlusive disease in systemic arteries. The preoperative evaluation of systemic arterial lesions and the function of systemic organs is essential.  (+info)

Vascular inflammation inhibits gene transfer to the pulmonary circulation in vivo. (55/1603)

We report gene transfer to the normal and injured murine pulmonary circulation via systemic (intravascular) and airway (intratracheal) delivery of novel polycationic liposomes (imidazolium chloride, imidazolinium chloride-cholesterol, and ethyl phosphocholine). With use of the reporter genes chloramphenicol acetyltransferase (CAT) or human placental alkaline phosphatase (hpAP), intravascular injection of lipid-DNA complexes resulted in gene expression primarily in the lung, with lesser expression in the heart (11% of lung, P < 0.05) and spleen (8% of lung, P < 0.05). Histochemical staining for the hpAP reporter gene showed localized transgene expression in the microvascular endothelium. Monocrotaline (80 mg/kg body wt sc) treatment produced endovascular inflammation and reduced lung CAT activity (2 days postintravascular transfection) by 75 +/- 8 and 86 +/- 6% at 7 and 21 days, respectively, after monocrotaline (P < 0. 05). Despite the apparent decrease in functional CAT protein, Southern blot analysis suggested maintained plasmid delivery, whereas quantitative PCR (TaqMan) showed decreased CAT mRNA levels in monocrotaline mice. In contrast, intratracheal delivery of lipid-DNA complexes showed enhanced CAT expression in monocrotaline mice. Transfection in alternate pulmonary vascular disorders was studied by inducing hypoxic pulmonary hypertension (4 wk at barometric pressure of 410 mmHg). Efficiency and duration of gene transfer, assessed by CAT activity, were similar in pulmonary hypertensive and normal lungs. We conclude that imidazolinium-derived polycationic liposomes provide a means of relatively selective and efficient gene transfer to the normal and injured murine microvascular circulation, although translation of transgene mRNA may be reduced by preexisting endothelial injury.  (+info)

Serum thrombomodulin-a reliable marker of disease activity in systemic lupus erythematosus (SLE): advantage over established serological parameters to indicate disease activity. (56/1603)

To date no specific serological parameter is available to assess disease activity in SLE. Soluble serum thrombomodulin is a new marker of endothelial cell injury and vasculitis. The objective of this study was to compare in vivo soluble thrombomodulin as marker of disease activity in SLE with established and recent serological parameters. One hundred and twenty-four sera of 30 patients with proven SLE with different disease activities were tested for serum levels of thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), IL-2R, IL-6, IL-10, dsDNA by ELISA and dsDNA additionally by radioimmunoassay (RIA). C-reactive protein (CRP), complement component C3, IgG, creatinine, anti-nuclear antibodies (ANA) and intermediate filament antibodies were measured by standard laboratory tests. The clinical disease activity was evaluated by the Systemic Lupus Activity Measure (SLAM). Correlations of the different serological SLE disease activity parameters with the SLAM scores revealed the highest significance for serum thrombomodulin (correlation coefficient 0.82). This was further confirmed by the intra-individual analysis of follow-up sera. In addition, a moderate correlation could be found for IL-6, IL-10, ICAM-1, CRP and erythrocyte sedimentation rate (ESR). In summary, soluble thrombomodulin is the most important serological parameter of disease activity in SLE currently available, as shown by the in vivo studies. Soluble thrombomodulin might be a valuable serological parameter for therapeutical considerations.  (+info)