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PubMed2004

Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis.

UNLABELLED: Tumor necrosis factor alpha (TNFalpha) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNFalpha blockade is a potential therapy for these disorders. METHODS: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] > or = 10; n = 16); study II examined persistent disease (BVAS > or = 4; n = 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. RESULTS: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] = 10.5 to 14.0) at entry to 0.3 (CI = 0.2 to 0.9) at wk 14 (P < 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI = 16.8 to 42.0) at entry to 7.0 (CI = 3.3 to 10.9) by wk 14 (P = 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI = 15.0 to 32.5) at entry to 8.8 (CI = 5.9 to 11.7) at wk 14 (P = 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. CONCLUSION: TNFalpha blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.

Adult↗

PubMed2005

PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.

OBJECTIVE: Type II mixed cryoglobulinemia (MC) is a systemic vasculitis usually associated with hepatitis C virus (HCV), which may involve the skin, kidneys, and nervous system. Molecular evidence of antigen-driven B cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears to be the key trigger. The present trial was established to investigate the efficacy of therapy with PEGylated interferon alfa-2b (PEG-IFN alfa-2b) plus ribavirin in patients with HCV-related MC vasculitis. METHODS: Nine consecutive patients with HCV-related MC received PEG-IFN alfa-2b (1.5 microg/kg/week) subcutaneously plus oral ribavirin (800-1,200 mg/day) for at least 6 months. The response to treatment was analyzed by comparing clinical, immunologic, and virologic parameters at the initial evaluation with those observed during followup. RESULTS: The mean +/- SD duration of therapy with PEG-IFN alfa-2b plus ribavirin was 13.5 +/- 2.8 months. After a mean period of 18.6 months following discontinuation of treatment, all 9 patients are alive. Seven patients (78%) had a sustained virologic response and were complete clinical responders. Serum cryoglobulin disappeared in 5 of 9 patients (56%), and complement levels normalized in 80% of the patients. One patient had a partial virologic response with a complete clinical response. In another patient, a clinical relapse of MC vasculitis occurred in association with the reappearance of HCV RNA. Treatment was well tolerated, and no patient had side effects for which discontinuation of therapy was required. CONCLUSION: Treatment with PEG-IFN alfa-2b plus ribavirin can achieve a complete clinical response in most patients with HCV-related MC vasculitis. Complete clinical response correlates with the eradication of HCV and requires a shorter treatment period than that previously reported for IFNalpha plus ribavirin.

Aged↗

PubMed1996

New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy.

Intravenous immune globulin (IVIG) is now under evaluation for the treatment of patients with the forms of systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). Although IVIG may produce effects by a variety of mechanisms, including control of T-cell function, interference with cytokine action, and Fc receptor blockade, it is the regulation of autoantibody production by B cells, through idiotypic-anti-idiotypic reactions, that makes this treatment attractive for patients with systemic vasculitis. The author and others have shown the importance of ANCA idiotypic-anti-idiotypic reactions in vitro and demonstrated that these could be influenced by anti-idiotypic determinants present in IVIG. Thus F(ab')2 fragments of IVIG could block ANCA binding to antigen, in a dose-dependent fashion. The degree of inhibition was variable, ranging up to 100% for the ANCA-containing sera of certain patients. Similar inhibitory activity could be found in the sera of patients in remission after treatment, as well as in occasional patients whose disease remitted spontaneously, without drugs being used. Thus, IVIG appears to be particularly valuable in the management of vasculitis in the elderly, the very young and for pregnant women, as well as for those at any age who are vulnerable to infection.

Humans↗

PubMed2005

Intravital microscopy in the study of ANCA-associated systemic vasculitis.

In addition to being useful clinical markers of systemic vasculitis, anti-neutrophil cytoplasm antibodies (ANCA) may play a role in the initiation of vasculitic injury. These autoantibodies can induce neutrophil degranulation, dysregulated neutrophil apoptosis and neutrophil adhesion to endothelium in static cellular systems. This mini-review will place these sentinel findings in the context of more recent studies using the parallel plate flow chamber and novel animal models of ANCA-associated vasculitis (AASV). Rodent models lend themselves well to investigation of leukocyte endothelial interaction using intravital microscopy. In this way, one can study ANCA-induced leukocyte adhesion/transmigration, and microvascular injury in real time. These studies may then be extended to look at the impact of novel therapeutic agents on these processes.

Animals↗

PubMed1997

[ANCA (antineutrophil cytoplasmic antibodies). Contribution of ANCA to the understanding of pathogenic mechanisms of systemic vasculitis].

ANCA (antineutrophil cytoplasmic antibodies) are a growing class of interest; these antibodies target lysosomial enzymes from polymorphonuclear cells. They represent diagnosis tools and prognosis markers in systemic vasculitis (Wegener's granulomatosis and microscopic polyangiitis). They are also detected in other chronic inflammatory diseases as lupus and rheumatoid arthritis. Their description, ten years ago, led to a huge amount of clinical and experimental work. The role of ANCA as pathogenic auto-antibodies in the disease is supported in numerous studies giving new insights into the pathogenesis of systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2005

Bone mineral density in children and adolescents with systemic lupus erythematosus, juvenile dermatomyositis, and systemic vasculitis: relationship to disease duration, cumulative corticosteroid dose, calcium intake, and exercise.

OBJECTIVE: To describe the frequency of abnormal bone mineralization in a population of children with juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), and systemic vasculitis; and to investigate the relationship of bone mineral density (BMD) to cumulative corticosteroid dose, disease duration, Tanner stage, calcium intake, and exercise in these patients. METHODS: A retrospective chart review of children attending the pediatric rheumatology clinic at British Columbia's Children's Hospital was conducted to obtain demographic data (sex, ethnicity, disease duration, cumulative corticosteroid dose, and mean daily corticosteroid dose). All patients had at least one BMD measurement by dual energy x-ray absorptiometry (DEXA) at lumbar spine, hip, and total body. BMD was expressed as g/cm2 and Z scores; an abnormal Z score was defined as </= -1.5. Daily calcium intake was calculated. Physical activity was scored using a validated 7 day physical activities questionnaire. RESULTS: A total of 36 patients were studied. Twenty-five patients had SLE, 7 had JDM, and 4 had systemic vasculitis. Fourteen subjects were Caucasian, 13 Asian, 6 East Indian, and 3 Canadian First Nations. An abnormal Z score at one or more sites was found in 10/25 (40%) with JSLE, and in 3/11 (27%) JDM/vasculitis patients. The mean Z scores (+/- SD) for lumbar spine were -1.02 (+/- 1.2), for hip -0.88 (+/- 1.3), and for total body -0.77 (+/- 1.5). Compared to children with normal bone densities, those with lower bone density tended to be younger (13.5 +/- 2.2 vs 15.5 +/- 1.7 yrs), received higher corticosteroid dosages at the time of the study (0.78 +/- 0.6 vs 0.35 +/- 0.2 mg/kg), and were more often prepubertal (OR for total body scores 5, 95% CI 0.7-46). CONCLUSION: Decreased bone density is common in children with SLE and other systemic rheumatic diseases. Age, corticosteroid dose, and pubertal stage all appear to have some influence on bone mass in these children.

Adolescent↗

PubMed1984

Precipitating antibodies to nuclear antigens in systemic vasculitis.

We have examined sera from 61 patients with systemic vasculitis for precipitating antibodies to components of saline tissue extracts. Precipitins were rare in patients with polyarteritis nodosa (PAN) and their absence helped to distinguish PAN from vasculitis associated with other connective tissue diseases. Precipitins were detected in some patients with other vasculitides. Previously described precipitating antibodies (anti-Ro [SSA] and anti-La [SSB]) were restricted to a few patients with features of systemic lupus erythematosus (SLE). A different, as yet unidentified, precipitin which reacted with a component of rabbit thymus extract but not calf thymus or human spleen extracts was detected in many patients with rheumatoid disease. This precipitin was present in all patients with active rheumatoid vasculitis (RV) as well as 52% of patients with uncomplicated but active rheumatoid synovitis. Higher titres of precipitating antibody were present in patients with active RV than those with inactive RV or uncomplicated rheumatoid synovitis, and serial studies showed a good correlation between a fall in antibody titre and healing of vasculitis with treatment. These studies suggest that this unidentified precipitin may be an important marker of RV.

Antigens↗

PubMed1999

Familial occurrence of systemic vasculitis and rapidly progressive glomerulonephritis.

Two familial clusters of systemic vasculitis are described. In one family, microscopic polyangiitis and rapidly progressive glomerulonephritis occurred in HLA-identical siblings; in the second family, 3 second- and fourth-degree related members were affected by Wegener's granulomatosis. Published clusters of systemic vasculitides and Goodpasture's syndrome are reviewed, and, together with the observed families, the evidence for genetic susceptibility and a causative role of environmental factors for these diseases with special emphasis on the HLA system is discussed.

Adult↗

PubMed2003

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.

Adult↗

PubMed2006

[Systemic vasculitis due to hepatitis C virus].

Hepatitis C virus (HCV) is the leading cause of chronic liver disease in industrialized countries. HCV also causes a variety of extrahepatic disorders, of which systemic vasculitis, of the cryoglobulin or polyarteritis nodosa type, is the most severe. This article reviews the main diagnostic, pathophysiologic and therapeutic aspects of HCV-induced systemic vasculitis.

Cryoglobulinemia↗

PubMed1980

Diffuse intrapulmonary hemorrhage, renal failure and a systemic vasculitis. A case report and review of the literature.

A 63 year old women was hospitalized with massive hemoptysis, anemia and renal failure. Despite intensive supportive care, she died soon after admission. Autopsy revealed diffuse necrotizing alveolitis, rapidly progressive glomerulonephritis and a systemic vasculitis. Massive intrapulmonary hemorrhage with hemoptysis is an unusual complication of a systemic vasculitis. The case is discussed and the literature reviewed.

Acute Kidney Injury↗

PubMed2000

Systemic vasculitis with bilateral perirenal haemorrhage in chronic myelomonocytic leukaemia.

The cases of two patients with chronic myelomonocytic leukaemia associated with periarteritis nodosa-like, antineutrophil cytoplasmic antibody negative, systemic vasculitis, are reported. A 61 year old man was admitted with fever, diffuse myalgia, and abdominal pain. Blood and bone marrow examination showed chronic myelomonocytic leukaemia. Vasculitis of the gall bladder was responsible for acalculous cholecystitis. A massive spontaneous bilateral perirenal haemorrhage occurred. A 73 year old woman with chronic myelomonocytic leukaemia had been followed up for one year when unexplained fever occurred. Two months after the onset of fever, sudden abdominal pain was ascribed to spontaneous bilateral renal haematoma related to bilateral renal arterial aneurysms. Neuromuscular biopsy showed non-necrotising periarteriolar inflammation. To our knowledge, systemic vasculitis has never been reported in chronic myelomonocytic leukaemia. In our two cases a non-random association is suggested because (a) chronic myelomonocytic leukaemia is a rare myelodysplastic syndrome, (b) spontaneous bilateral perirenal haematoma is not a usual feature of periarteritis nodosa.

Aged↗

PubMed2002

Evaluation of the Sørensen diagnostic criteria in the classification of systemic vasculitis.

OBJECTIVES: To evaluate the use of the diagnostic criteria for Wegener's granulomatosis (WG) and microscopic polyangiitis (mPA) proposed by Sørensen et al. in the classification of primary systemic vasculitis (PSV). METHODS: We applied to our cohort of PSV patients the American College of Rheumatology (ACR) criteria for WG, Churg-Strauss syndrome (CSS) and polyarteritis nodosa (PAN), the Chapel Hill Consensus Conference (CHCC) definitions for WG, mPA and CSS, the Hammersmith criteria for CSS and the Sørensen criteria for WG and mPA. RESULTS: Ninety-nine PSV cases were identified. Fifty-six fulfilled criteria for WG (ACR), 60 for PAN (ACR) and 15 for CSS (ACR). Four fulfilled the Hammersmith criteria for CSS. Thirty-nine were defined as mPA (CHCC). Fifty-three patients fulfilled the Sørensen criteria for WG and three for mPA. Five of six patients classified as WG (ACR) who did not meet the Sørensen criteria were excluded by eosinophilia. Six patients who did not fulfil WG (ACR) met the Sørensen criteria for WG. CONCLUSION: The classification of systemic vasculitis is complicated and many cases fulfil more than one set of criteria. The Sørensen criteria for WG is limited by its exclusion of eosinophilia despite reports of an association. We recommend that tissue eosinophilia or peripheral eosinophilia of <1.5x10(9)/l should not exclude a diagnosis of WG. With this modification, the Sørensen criteria for WG may be a useful method of classification, especially in confirming the classification of WG in patients who fulfil both WG (ACR) and mPA (CHCC). Few patients fulfilled the Sørensen criteria for mPA which suggests that they are not of value in classification.

Churg-Strauss Syndrome↗

PubMed1989

Autoantibodies to neutrophil cytoplasmic antigens in systemic vasculitis have the same target specificity.

Many patients with systemic vasculitis have antibodies to neutrophil cytoplasm antigens (ANCA) detectable by indirect immunofluorescence. We sought to characterize further the nature of these antigens. Western blots of neutrophil protein extracts indicated that nine patients' sera, positive for ANCA by immunofluorescence, all reacted with a 45 kDa and a 27-31 kDa protein. Negative control sera, and sera taken in remission, did not react with either of these antigens. The results suggest that ANCA in vasculitis have the same target specificity and may therefore permit greater accuracy of diagnosis and increase our understanding of the pathogenesis of the conditions.

Antibody Specificity↗

PubMed1999

Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.

Adolescent↗

PubMed2001

Activity, damage and outcome in systemic vasculitis.

Current therapy has transformed the prognosis of the systemic vasculitides from diseases that had a high acute mortality rate to chronic relapsing diseases with high rates of morbidity. This improved survival has highlighted the need for better methods of monitoring disease activity and recording the accumulation of organ damage that occurs during the course of the disease. Several clinical indices have been developed that record disease activity, damage and the extent of disease. These validated indices allow a detailed assessment of the patient's response to therapy and provide an essential tool for insuring uniformity of patient monitoring in multi-centre trials. In addition, more data are now available supporting the use of these assessment tools as prognostic and outcome criteria for clinical studies. The development, properties, application and inter-relationships of the available clinical assessment tools for patients with systemic vasculitis are reviewed in this chapter.

Humans↗

PubMed2006

Persistent T-cell activation and clinical correlations in patients with ANCA-associated systemic vasculitis.

BACKGROUND: Although in antineutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AASV) patients, activation of T-cells has been described, persistence of these alterations has not been well characterized. This study was conducted to define persistent T-cell activation (PTA) in AASV patients and to assess whether this correlates with disease activity, disease severity, age or therapy. METHODS: The expression of CD4, CD45RO, CD25, CD26, CD28, CCR7 and HLA-DR was examined longitudinally in 38 consecutive AASV patients. Clinical parameters were compared by univariate and multiple analysis and Kaplan-Meier curves for relapse-free survival were calculated. RESULTS: PTA could be defined as either of two activation phenotypes, i.e. a low percentage of CD4+ CD45RO- T-cells or a high percentage of CD25 in the naïve CD4+ population (n = 26), since only these phenotypes were stable over time and were not associated with active disease. In patients with PTA, major organ involvement was significantly more often found than in patients without PTA. Moreover, the cumulative cyclophosphamide dose (26.86 vs 8.53 P < 0.01) was significantly increased in these patients, suggesting that PTA was associated with disease severity. In general, patients with PTA were older than those without (62.92 +/- 9.4 years vs 48.42 +/- 16.9 years respectively, P < 0.01). PTA was independent of disease duration. Interestingly, patients with a low percentage of CD4+CD45RO- T-cells were significantly more often diagnosed as microscopic polyangiitis (P < 0.01). CONCLUSION: We identified two independent phenotypes of T-cell activation in AASV patients. These phenotypes are persistent and do not reflect disease activity. PTA predominantly occurs in patients with severe disease. This might explain the higher cumulative cyclophosphamide dose found in these patients.

Adult↗

PubMed1995

Systemic vasculitis presenting with massive bowel infarction.

Gastrointestinal involvement in systemic vasculitis occurs in up to 30% of patients. Fortunately intestinal infarction is a rare complication, but if present carries a high mortality, and swift management of the underlying vasculitis is crucial. Two such cases are described.

Abdominal Pain↗