Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wegener's granulomatosis (WG) is among the most common forms of systemic vasculitis. WG is associated with a high mortality in patients who do not receive appropriate treatment. Substantial morbidity results from standard disease therapies, however, and there is a high risk of relapse (exceeding 50%) following the taper of standard medications. The greatest challenges in the management of WG are the maintenance of disease remission and the avoidance of treatment-related morbidity and mortality. The Wegener's Granulomatosis Etanercept Trial (WGET) is a randomized, double-masked, placebo-controlled trial designed to test the ability of etanercept, a soluble inhibitor of tumor necrosis factor, to maintain disease remission when used with conventional treatments. Eight WGET clinical centers plan to enroll 180 patients over a 30-month period. The randomization is stratified by clinic and by disease severity. Patients are assigned randomly to receive etanercept or placebo in an allocation ratio of 1:1. They continue to receive standard WG therapies in regimens defined by the protocol. Upon the achievement of remission, these standard medications are tapered according to protocol guidelines. The primary outcome is sustained remission. Secondary and tertiary outcomes include a number of disease- and treatment-related measures. The trial will have a common closing date 12 months after the last patient is randomized. The primary analysis will be performed on an intention-to-treat basis. WGET is the first randomized trial in WG in the United States and the first multicenter trial of a biologic agent in WG. One year after the start of enrollment, 106 patients have been randomized. The objectives of this paper are: (1) to describe the design of the WGET; (2) to discuss issues related to the trial's development; and (3) to review some aspects of its conduct to date.
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PMID:Design of the Wegener's Granulomatosis Etanercept Trial (WGET). 1216 Oct 90

Granulomatous vasculitis is a subset of systemic necrotizing vasculitis and has granulomatous inflammation as the main histopathologic feature. Etiopathogenesis remains poorly understood, although recent advances suggest an important role for certain pro-inflammatory cytokines, such as tumor necrosis factor-alpha. They are a heterogeneous group of clinical disorders with protean manifestations. Serologic abnormalities are present, and the presence of granular cytoplasmic staining-antineutrophil cytoplasmic antibodies is most important and is particularly useful for the diagnosis of active Wegener's granulomatosis. Corticosteroids and cyclophosphamide remain very useful in the treatment of most of these disorders.
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PMID:Granulomatous vasculitis. 1262 43

Infliximab is an antibody to tumor necrosis factor (TNF) that is used in the treatment of Crohn disease and rheumatoid arthritis. This medication neutralizes TNF-alpha by binding to TNF receptors and inhibiting further induction of proinflammatory cytokines. We describe a patient with Crohn disease who developed hypersensitivity vasculitis with biopsy-proven leukocytoclastic vasculitis 9 days after her initial dose of infliximab. To our knowledge, this is the first reported case of infliximab-induced hypersensitivity vasculitis with leukocytoclastic vasculitis that occurred after the first dose of drug. It is important to note that hypersensitivity vasculitis can occur secondary to administration of this drug, even after the initial exposure.
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PMID:Hypersensitivity vasculitis with leukocytoclastic vasculitis secondary to infliximab. 1270 83

Proinflammatory cytokines are supposed to play a major role in the pathophysiology of vasculitis and in the development of neuropathic pain. Here we studied the cytokine expression in sural nerve biopsy specimens from patients with vasculitic and other inflammatory and non-inflammatory neuropathies, and investigated whether an increased cytokine expression was correlated with the presence of neuropathic pain. We used immunohistochemistry including double labeling and morphometry to localize and quantify the expression of interleukin-1 beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF) in sural nerve biopsy samples of 41 patients with vasculitic neuropathy (VANP), chronic inflammatory demyelinating neuropathy (CIDP), non-inflammatory chronic axonal neuropathy (CANP), and 3 controls. Overall cytokine immunoreactivity was highest in VANP, less strong in CIDP and lowest in CANP. Cytokine immunoreactivity was directly correlated with the degree of axonal degeneration, endoneurial macrophages and epineurial T cells. In VANP and CANP, a higher cytokine content was associated with neuropathic pain.
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PMID:Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies. 1273 66

Wegener's granulomatosis (WG) is a small-vessel vasculitis associated with various clinical manifestations, among which the most common are respiratory tract disease and glomerulonephritis leading to renal failure. The pathogenesis of vascular injury in WG is ascribed to antineutrophil cytoplasmic antibodies (ANCA) directed mainly against proteinase 3 (PR3), an enzyme from neutrophil granules. The reasons for the breakdown of self tolerance to PR3 are unknown, and together with the molecular mechanisms underlying this immunoinflammation, are the subject of research. Standard treatment of WG consists of cyclophosphamide and corticosteroids. In patients resistant to this therapy or with refractory disease, some alternative strategies involving tumor necrosis factor blockade, polyclonal antithymocyte globulin or monoclonal anti-T cell antibodies are applied.
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PMID:Wegener's granulomatosis--autoimmunity to neutrophil proteinase 3. 1289 70

As experience with anti-tumor necrosis factor (TNF-alpha) therapy increases, there has been the expected emergence of reports on uncommon side effects. Large clinical trials identified the development of autoantibodies and postmarketing surveillance has identified problems including tuberculosis. There have been several case reports of drug-induced systemic lupus erythematosus. We describe eight patients with rheumatoid arthritis treated with anti-TNF therapies who developed presumed vasculitis, with different pathophysiologic causes. We discuss the literature and potential causal mechanisms, including disease activity, the role of autoantibodies, and shifts in T cell responses.
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PMID:Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series. 1522 72

Wegener's granulomatosis is an organ- and/or life-threatening autoimmune disease of as yet unknown etiology. The classic clinical triad consists of necrotizing granulomatous inflammation of the upper and/or lower respiratory tract, necrotizing glomerulonephritis, and an autoimmune necrotizing systemic vasculitis affecting predominantly small vessels. The detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA) is highly specific for Wegener's granulomatosis. ANCA positivity is found only in about 50% of the patients with localized Wegener's granulomatosis (which is restricted to the respiratory tract and affects < or = 5% of the patients), whereas PR3-ANCA positivity is seen in 95% of the patients with generalized Wegener's granulomatosis. Studies showing an expansion of circulating tumor necrosis factor-(TNF-)alpha-producing Th1-type CD4(+)CD28(-) T-cell effector memory T-cells and their presence as Th1-type cytokine profile- driving cell population within granulomatous lesions provide the rationale for using TNF-alpha-blocking agents in Wegener's granulomatosis refractory to standard induction therapy with cyclophosphamide and corticosteroids ("Fauci's scheme"). Vasculitis is an independent risk factor for diffuse endothelial dysfunction and may be a consequence of TNF-alpha action on endothelial cells. Recently, another study has shown intima-media thickening of the wall of the common carotid artery and bulb, as well as a significantly increased incidence of stroke, myocardial infarction and occlusive artery disease in Wegener's granulomatosis. This study suggests that systemic inflammation and vasculitis contribute to accelerated arteriosclerosis in Wegener's granulomatosis.
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PMID:Wegener's granulomatosis. 1496 41

Recent evidence strongly implicates the inflammatory response to intrauterine infection in the pathogenesis of neonatal brain and lung injury. We hypothesized that lung and brain injury in preterm infants occurs during a common developmental window of vulnerability as the result of an inflammatory response in different compartments. To determine whether inflammatory markers in these compartments are associated with bronchopulmonary dysplasia (BPD) or cranial ultrasound (CUS) abnormalities in infants <33 wk gestation age (GA) and <1501 g birth weight, we analyzed placental pathology and serum and cerebrospinal fluid (CSF) IL-6, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) concentrations in 276 infants. Logistic regressions were performed stratified by GA. Histologic chorioamnionitis was significantly associated with BPD in infants </=28 wk GA (OR 3.6, p = 0.027). Maternal stage of chorioamnionitis significantly correlated with severity of BPD. Presence of a fetal inflammatory response indicated by fetal vasculitis or elevated cytokines was not associated with the development of BPD. Serum IL-6 >/=17 pg/mL was associated with an abnormal CUS in infants >28 wk GA (OR 3.36, p = 0.023) but not </=28 wk GA. CSF concentrations of IL-6 >/=6.5 pg/mL and TNF-alpha >/=3 pg/mL were associated with abnormal CUS in infants </=28 wk GA (IL-6 OR 3.0; TNF-alpha OR 3.5; p < 0.05 each case) but not >/=28 wk GA. These data suggest that in infants </=28 wks GA, BPD may be initiated by inflammatory mediators in amniotic fluid, but brain injury may involve variations in the systemic inflammatory response.
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PMID:Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. 1515 69

Wegener's granulomatosis is a systemic necrotising vasculitis of small vessels that leads to severe impairment of affected organ systems. Conventional treatment is based on immunosuppression with a combination of steroids, cyclophosphamide, azathioprine or methotrexate over a prolonged time course. Early recurrence or disease refractory to therapy often results in a fatal outcome. As in other inflammatory disorders, tumor necrosis factor (TNF) plays an early and crucial role in progression of disease activity. We report on a patient with severe orbital Wegener's granulomatosis who developed acute renal failure despite intense conventional immunosuppression with cyclophosphamide and steroids. To stop vasculitic activity, by disrupting the autoimmune inflammatory cascade, a TNF-blocking antibody (Infliximab) was administered six times in a six-month period at 3 mg/kg body weight. Conventional immunosuppressive therapy with steroids and cyclophosphamide was continued, the latter being changed to azathioprine after three months. The first infusion of TNF antibody induced improvement of renal function, which continued throughout the course of therapy. The modification of diet in renal disease-glomerular filtration rate (MDRD-GFR) increased from 15.3 ml/min/1.73 m2 before the start of TNF-blockade to 55.5 ml/min/1.73 m2 after six months of therapy. Serum creatinine levels, proteinuria and cANCA titer decreased concomitantly. Clinical remission of Wegener's granulomatosis was induced without any major adverse events. A slight flare of orbital inflammation was successfully treated with an increased dose of azathioprine. Thus, in this case of refractory Wegener's granulomatosis TNF-blockade by monoclonal chimeric TNF-antibody (Infliximab) served as an effective tool to rescue kidney function and induce clinical remission.
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PMID:Refractory Wegener's granulomatosis responds to tumor necrosis factor blockade. 1523 61

The gold standard for inducing remission in systemic necrotizing vasculitis (SNV) and severe lupus nephritis is (and remains) the combination of cyclophosphamide and glucocorticoids. Long-term treatment with cyclophosphamide is limited because of toxicity. Recent prospective studies in antineutrophil cytoplasmic antibody (ANCA)-associated SNV revealed that after achievement of clinical remission (usually within 3-4 months after starting cyclophosphamide) cyclophosphamide can be replaced by azathioprine with no increase in relapse rates if treatment is continued for at least 1 year. Methotrexate is inferior to cyclophosphamide because of increased relapse rates-particularly in those with renal involvement-during follow-up. An ongoing study comparing mycophenolate mofetil (MMF) with azathioprine will clarify whether MMF is as successful as azathioprine or even better. The concomitant use of tumor necrosis factor (TNF)-alpha blockers increases the efficacy of immunosuppression. TNF-alpha blockers may be added if SNV is refractory to standard immunosuppressive therapy. However, with this addition to therapy, systemic infections are more frequent. In patients with severe lupus nephritis (WHO IV) the efficacy of combined i.v. therapy with cyclophosphamide and glucocorticoids was shown by NIH trials. This NIH regimen competes with the EURO-Lupus nephritis schedule with a lower dose of i.v. cyclophosphamide followed by maintenance therapy with azathioprine. Long-term follow-up is, however, still lacking in the EURO-Lupus trial. Ongoing prospective studies will reveal whether cyclophosphamide may be substituted by MMF from the very beginning or whether MMF is superior to azathioprine during maintenance therapy of lupus nephritis.
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PMID:Cyclophosphamide treatment in systemic necrotizing vasculitis and lupus nephritis. How long? How much? 1525 54


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