Associated Systemic Vasculitis Research Articles

Risk factors of peritonitis during earlyperitoneal dialysis in patients with ANCA-associated systemic vasculitis .

This study investigated the risk factors of peritonitis during early peritoneal dialysis for renal failure in patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV). This study enrolled hospitalized AASV patients with renal failure who underwent peritoneal dialysis at the Department of Nephrology of our hospital between 2008 and 2015. The primary aim of this study was to perform a retrospective analysis to characterize peritonitis during the early period (≤8weeks) of dialysis, and to compare the differences in initial clinical manifestations, vasculitis activity, immunosuppressive therapies prior to the renal replacement therapy, and prognosis between patients with or without peritonitis. The secondary aim of this study was to conduct a literature review of peritoneal dialysis in patients with vasculitis. All 14 enrolled AASV patients had myeloperoxidase (MPO)-positive microscopic polyangiitis (MPA). Six patients (of whom 2 died) withdrew from peritoneal dialysis due to peritonitis caused by enteric bacteria during the early period of dialysis. Their mean Birmingham vasculitis activity score (BVAS) during the early AASV onset was 31.67±3.98, with significant symptoms of gastrointestinal involvement. Also, their BVAS score, anti-MPO antibody titer, erythrocyte sedimentation rate, C-reactive protein level, serum ANCA level, and glucocorticoid dose were higher than the AASV patients without peritonitis (all p<0.05). AASV patients with a higher level of vasculitis (BVAS score >30) during onset as well as gastrointestinal symptoms had a higher risk for intestinal peritonitis. Therefore, peritoneal dialysis is not recommended as a first-choice renal replacement therapy for such patients. .

ANCA-negative Churg-Strauss Syndrome

A rare and a disease of unknown etiology, Churg-Strauss syndrome (CSS) is a granulomatous necrotizing small vessel vasculitis characterized by the presence of asthma, sinusitis, and hypereosinophilia, which is initially described by Churg and Strauss in 1951. Because of its clinical and pathological features that overlap with those of the other anti-neutrophil antibody (ANCA)-associated systemic vasculitides (AASVs) and now the disease is classified as AASVs. The ANCA status may dictate the clinical phenotype. ANCA-positive patients are significantly more likely to have disease manifesta­tions associated with small-vessel vasculitis, including oecrotising glomemlonephritis, mononeuritis and purpura, whereas ANCA-negative cases predominantly likely to have cardiac and lung involvement. The objective of this case report is to point out the possibility of vasculitic rash in ANCA-negative CSS in a 35-year-old man and the disease rarely occurs in Bangladeshi population. We analyze the history, clinical examinations and relevant investigations related to the patient to establish the diagnosis in our department. The clinical scenario and biopsy help us to attain the diagnosis. But due to unavailability of patients' cohort we have limitations of comparison of ANCA status in Bangladeshi populations. Though ANCA-positive and ANCA-negative CSS differ phenotypically, primary therapy for both the conditions is systemic glucocorticoids. Additional immunosuppressive agents like cyclophosphamide, mycophenolate mofetil, azathioprine, rituxin1ab are occasionally added in patients with more advanced or refractory disease.

Etiologies and clinical features of 19 cases with bilateral acute sensorineural hearing loss

To investigate the etiologies and clinical features for bilateral acute sensorineural hearing loss (bi-ASNHL). The clinical data of 19 cases presenting with bi-ASNHL were retrospectively analyzed, including the clinical features, systemic examinations, laboratory examinations, audiology and radiology results, as well as the prognosis. There were 15 non-otologic diseases in 19 patients, accounting for 78.9% of the total cases, most of which were disorders with multisystem and multi-organ disorder. The central nervous system diseases including fungal meningitis, tuberculous meningitis, and viral encephalitis in 3 patients. The clinical features of deafness were bilateral, progressive, accompanied with fever, headache, dizziness, nausea, vomiting and change of mental status. There was a decrease in speech recognition score (SRS), and speech recognition threshold (SRT) was obviously inferior to pure tone average (PTA) disproportionally. Diseases of immune system including antineural cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV), relapsing polychondritis (RP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in 5 patients. They showed the characteristics of bilateral, progressive and simultaneous autoimmune disease. Hematological and endocrine system diseases including diabetes mellitus, leukemia, and thyroid hypofunction in 5 patients. The deafness had the characteristics of symmetry and progressivity. Otologic diseases including large vestibular aqueduct syndrome (LVAS) and sudden sensorineural hearing loss (SSNHL) in 4 patients; Drug-induced sensorineural deafness happened in 2 patients. After the treatment aimed at the causes, 1 case was cured, 3 patients were markedly effective, 7 patients were effective, and 8 patients were ineffective(including dead and refusal cases), with a total effective rate of 57.9%. The most of bi-ASNHL cases are often associated with systemic diseases. Clinicians should analyze the history and clinical characteristics in detail, and complete specific laboratory examinations, audiology and imaging examinations in order to reveal the causative diseases. It should be treated aimed at the etiology.

FRI0342 Identification of target antigens of anti-endothelial cell antibodies in patients with anca-associated systemic vasculitis: a proteomic approach

BackgroundAnti-endothelial cell antibodies (AECA) are frequently detected in anti-neutrophil cytoplasm antibodies (ANCA)-associated systemic vasculitis (AAV) and are considered to play pathological roles but their antigenic specificities are still unknown.ObjectivesWe used...

Marfan syndrome with antineutrophil cytoplasmic antibody-associated systemic vasculitis presenting as severe anaemia and haematuria after the Bentall procedure

One month previously, a 28-year old male underwent an emergency modified Bentall procedure because of Marfan syndrome with acute aortic dissection Stanford Class A. Computed tomography of the chest did not reveal severe graft stenosis of the anastomosis. To explore the cause of anaemia, renal dysfunction and macroscopic haematuria, the patient was tested for antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV). Antimyeloperoxidase antibodies (MPO)-ANCA and antiproteinase 3 antibodies (PR3)-ANCA were strongly positive. Corticosteroid therapy was applied, followed by cyclophosphamide and azathioprine. In response to treatment, the MPO-ANCA and PR3-ANCA levels gradually decreased, proteinuria was alleviated and haemoglobin levels returned to normal after 6 months. This is the first report to highlight haemolytic anaemia and AASV with Marfan syndrome after surgery for aortic dissection.

Complications of long-term therapy for ANCA-associated systemic vasculitis

The antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides (AASVs) include granulomatosis with polyangiitis and microscopic polyangiitis. These conditions are characterized by small-vessel inflammation and necrosis, predominantly in pulmonary and renal vascular beds. Untreated AASV has a poor prognosis, although the advent of effective immunosuppressive therapy (the mainstay of which remains cyclophosphamide with high-dose corticosteroids) has markedly improved patients' survival (78% at 5 years). Patients with AASV, however, continue to have an increased mortality compared to the general population. Mortality is greatest in the first year after diagnosis and remains consistently elevated in subsequent years. Patients with AASV also experience increased rates of infections, malignancies and cardiovascular events as compared to the general population. Current treatments for AASV, although effective in controlling the aggressive systemic disease, incur substantial long-term toxic effects. Long-term immunosuppressive therapy also has notable deleterious effects on bone health and fertility. The long-term safety profiles of biological therapies (such as rituximab) are yet to be evaluated in patients with AASV, but represent a promising treatment option. The challenge for the future is to develop specific therapies with improved safety profiles that can cure these diseases.

The association of HLA-DRB1 alleles with antineutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese patients

Antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV) is a group of autoimmune diseases. The human leukocyte antigen (HLA) system is devoted to the pathogenesis of these autoimmune diseases. The present study aimed to investigate the distribution of HLA-DRB1 alleles in Chinese AASV patients and its potential association with clinical and pathologic characteristics. This study included 152 Chinese patients with AASV and 200 healthy controls. Typing of HLA-DRB1 alleles was performed by bidirectional sequencing of exon 2. Compared with normal controls, DRB1*1454 was significantly less prevalent in AASV patients (0/304 vs 14/400, p = 4.6 × 10 −4, p corrected ( p c) = 0.017), whereas DRB1*1101 was significantly more frequent in patients with MPA (32/214 vs 26/400, p = 6.4 × 10 −4, p c = 0.023). In patients with Wegener's granulomatosis (WG) who were PR3-ANCA positive, DRB1*1202 (8/38 vs 20/400, p = 1.3 × 10 −3, p c = 0.047) was more prevalent than in normal controls. Compared with normal controls, HLA-DRB1*1454 was less prevalent in AASV patients, whereas DRB1*1101 was significantly more frequent in patients with microscopic polyangiitis. HLA-DRB1*1202 was prevalent among patients with PR3-ANCA-positive WG.

Rituximab for rescue and maintenance therapy in rapidly progressive life-threatening antineutrophil cytoplasmic autoantibody-associated systemic vasculitis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitides (AASV) consists of small-vessel systemic inflammatory disorders which commonly affect the kidneys and without treatment have a poor prognosis. Rituximab is a novel biological agent which is being used experimentally in the management of AASV. This report presents the case of a young woman with rapidly progressive life-threatening AASV. Despite prompt diagnosis and initial treatment with steroids and alkylating agents her condition became life threatening. With addition of rituximab therapy she showed an excellent sustained response. Rituximab appears an effective and safe treatment choice for the induction of remission in severe AASV that is not responding to standard agents, at the initial presentation and for maintenance therapy, without the development of common serious side-effects associated with immunosuppression.

Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression

Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177-mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.

Churg–Strauss angiitis

Churg-Strauss angiitis or syndrome (CSA) is defined as an eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotising vasculitis affecting small- to medium-sized vessels, and is associated with asthma and eosinophilia. It is usually classified among the so-called anti-neutrophil antibody (ANCA)-associated systemic vasculitides (AASVs) because of its clinical and pathological features that overlap with those of the other AASVs. However, two recent studies on large cohorts of patients have found that ANCAs, usually P-ANCAs/MPO-ANCAs, were present in only 38% of patients. Moreover, the ANCA status was shown to segregate with clinical phenotype. ANCA-positive patients were significantly more likely to have disease manifestations associated with small-vessel vasculitis, including necrotising glomerulonephritis, mononeuritis and purpura, whereas ANCA-negative cases were significantly more likely to have cardiac and lung involvement. Vasculitis was documented less frequently in histological specimens from ANCA-negative patients in comparison with ANCA-positive ones. These findings have led to postulate the predominance of distinct pathogenetic mechanisms in the two subsets of patients: an ANCA-mediated process in ANCA-positive patients and tissue infiltration by eosinophils with subsequent release of toxic product in ANCA-negative cases. Preliminary results suggest that ANCA-positive and ANCA-negative patients also might have a different genetic background. Corticosteroids remain the cornerstone of the initial treatment of CSA. The addition of cyclophosphamide is indicated in treatment of patients with poor-prognosis factors or in patients without poor-prognosis factors but those that are prone to relapses. The length of the maintenance therapy remains to be established. However, the vast majority of patients require long-term corticosteroids treatment to control asthma.

Vasculitis of the upper and lower airway

The pulmonary vasculitides are a heterogeneous group of rare disorders that result from an inflammatory process damaging the vessel wall and consequent impaired blood flow, ischaemia and tissue necrosis. The clinical manifestation of these vasculitides depends on the site, size, type and severity of the inflammatory process. Vasculitis involving the airways is a common feature of the anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides (AASVs) and can predate the diagnosis by years. Secondary causes of vasculitis associated with connective tissue disorders are also capable of presenting with pulmonary features. Recognition of involvement, investigation and treatment are important to ameliorate symptoms for patients. This article concentrates on the assessment and specific management of upper and lower airway problems of AASV.

Contrasting genetic association of IL2RA with SLE and ANCA-associated vasculitis.

BackgroundAutoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibody (ANCA) – associated systemic vasculitis (AAV) with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA.MethodsUsing a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients), and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D) and rs2104286 with multiple sclerosis (MS) and T1D.ResultsWe show that SLE is associated with rs11594656 (P = 3.87 × 10-7) and there is some evidence of association of rs41295061 with AAV (P = 0.0122), which both have prior association with T1D. rs2104286, an MS and T1D – associated SNP in the IL2RA locus, is not associated with either SLE or AAV.ConclusionWe have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease.

Review article: The role of CD4+ T cells in ANCA‐associated systemic vasculitis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis (AASV) constitutes a group of primary vasculitides associated with antineutrophil cytoplasmic autoantibodies, which are either directed to proteinase-3 or myeloperoxidase. In contrast to other forms of vasculitis, immuohistologic evaluation of affected tissues in patients with AASV, particularly the kidneys, demonstrated an absence or paucity of immunoglobulins, which could suggest involvement of cell-mediated injury in this disorder. Several studies have shed light on T cell-mediated immune responses playing a role in the pathophysiology of AASV. Imbalance of CD4(+) T-cell subsets has been demonstrated in the peripheral blood of patients with AASV. The trigger that leads to this imbalance remains to be defined, but clinical evidence shows that nasal carriage of Staphylococcus aureus constitutes a risk factor for disease exacerbation. Recent data show that superantigens and peptidoglycans from these Gram-positive bacteria can induce skewing of T-cell responses towards pathogenic interleukin (IL)-17-producing T-helper cells (Th17). Overproduction of IL-17 in response to this infection might aggravate inflammatory responses and contribute to the production of autoantibodies as well as to granuloma formation and tissue injury in patients with AASV. Next to Th17 cells, memory CD4(+) T cells with the effector cytotoxic phenotype (CD4(+) T(EM)) have also been demonstrated to constitute a major effector pathway of tissue injury in patients with pauci-immune glomerulonephritis. Therefore, future perspectives for treatment of AASV could be built on neutralization of IL-17 and depletion of CD4(+) T(EM) cells.

Imatinib mesylate, a new kid on the block for the treatment of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis?

Persistent T cell activation is a common finding in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AAV) patients. Because imatinib, a selective inhibitor of the ABL, ARG, PDGFR and c-KIT tyrosine kinases, inhibits T cell activation, this study was conducted to evaluate the potential use of imatinib for the treatment AAV patients refractory to conventional therapy. In particular, we investigated the inhibition of T cell activation by this drug and its efficacy on activated T cells from anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitides (AASV) patients. T cell stimulation has been induced by anti-CD3/anti-CD28 antibodies or by phorbol myristate acetate (PMA)/ionomycin. T cell proliferation was analysed by tritiumthymidine incorporation. Cell cycle progression was determined by propidium iodide staining using fluorescence activated cell sorter (FACS) analysis and by RNAse protection assay (RPA). Cytokine levels were assessed by enzyme-linked immunosorbent assay. T cell proliferation was inhibited significantly by imatinib, due most probably to cell cycle arrest in the G1-phase. This was paralleled by inhibition in the expression of cyclin-dependent kinases 1 and 2 mRNA. The expression of CD25 in naive and memory T cells was decreased significantly by imatinib in activated T cells. Similarly, conversion from naive to memory T cells after T cell activation was impaired by imatinib. Imatinib did not influence interleukin-2 and tumour necrosis factor-alpha production but increased interferon-gamma production. These observed effects of imatinib were similar in T cells from AASV patients and from healthy individuals. Imatinib might be an alternative therapeutical option for AASV patients refractory to conventional therapy.

Analyzing Fatal Cases of Chinese Patients with Primary Antineutrophil Cytoplasmic Antibodies-Associated Renal Vasculitis: A 10-Year Retrospective Study

Background/Aims: Primary antineutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV) used to have poor prognosis, and renal involvement is its most common manifestation. Few studies have been published focusing on AASV patients with poor prognosis. Methods: From 1997 to 2006, 101 patients with ANCA-associated renal vasculitis (70 microscopic polyangiitis, MPA; 14 Wegener’s granulomatosis, WG; 3 Churg-Strauss syndrome, CSS; 14 renal limited vasculitis, RLV) were diagnosed in Shanghai Ruijin Hospital and 26 deaths were recorded among them. Patients’ data were retrospectively analyzed. Results: Patients with WG, MPA and RLV made up for 23.1% (6/26), 65.4% (17/26) and 11.5% (3/26) of all deaths. No deaths were observed among CSS patients. Infection alone accounted for 13 deaths. Infection together with pulmonary involvement of active vasculitis accounted for 3. Organ-specific involvement of active vasculitis alone caused 8 deaths. Others died of acute myocardial infarction or gastric carcinoma. Compared with patients who survived, nonsurvivors had more severe renal insufficiency and older age (p < 0.01). There was no significant difference regarding clinical presentation at diagnosis and cause of death between patients who survived first remission-induction treatment and those who did not. Infection remained the major cause of death. Conclusion: Infection is the major cause of death in patients with ANCA-associated renal vasculitis, and treatment response might not correlate to severity of disease in patients with poor prognosis. Rational use of immunosuppressants could improve the prognosis.

Characteristics and Outcome of Chinese Patients with Both Antineutrophil Cytoplasmic Antibody and Antiglomerular Basement Membrane Antibodies

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV) is a systemic autoimmune disease. A number of cases have been found to have antiglomerular basement membrane (GBM) antibody-positive serum. The purpose of the current article is to investigate the prevalence of anti-GBM antibodies in sera from a large cohort of Chinese patients with AASV and to characterize the clinical and pathological features of the ‘double positive’ patients. Methods: Sera from 652 patients with AASV were screened by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot analysis using purified human α(IV)NC1 as antigen. Antigen specificity of anti-GBM antibodies was determined by ELISA using recombinant human α3(IV)NC1 as solid phase ligand. Clinical and pathological data of patients with both ANCA and anti-GBM antibodies were analyzed retrospectively. Results: 61/652 (9.36%) sera from patients with AASV were serum anti-GBM antibody positive and all recognized recombinant human α3(IV)NC1. All the cases had renal involvement, 37/48 (77.1%) cases had pulmonary involvement, non-specific symptoms and other multisystem involvements were common. The renal survival was 14.6% (7/48) and patient survival was 37.5% (18/48) respectively at the end of 1 year. The following factors predicted poor prognosis: (1) serum creatinine >700 µmol/l (p = 0.034); (2) oliguria or anuria on diagnosis (p = 0.001); (3) high percentage (>85%) of glomeruli with crescents (p = 0.011); (4) high titer anti-GBM antibodies (p = 0.003), and (5) hemoptysis (p = 0.049). Conclusion: Patients with double antibodies were not rare in AASV. They had multisystem involvement but poor short-term prognosis.Anti-GBM antibodies should be detected on diagnosis of AASV, especially for old ages.

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

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. 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. 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). 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.

IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis

In antineutrophil cytoplasm autoantibody (ANCA)-associated systemic vasculitis (ASV), autoantibody-induced neutrophil activation is believed to cause organ damage. In vitro, tumor necrosis factor alpha (TNFalpha) primes neutrophils for ANCA stimulation and TNFalpha blockade has been successfully used to treat ASV. Nonetheless, irreversible organ damage can still occur, suggesting that other cytokines may circumvent TNFalpha blockade. We report that interleukin (IL)-18 deposition, as assessed by immunoperoxidase staining, is increased in renal biopsies from ASV patients. Immunofluorescence microscopy demonstrated that podocytes are the predominant glomerular IL-18-positive cell type, whereas in the interstitium, myofibroblasts, distal tubular epithelium, and infiltrating macrophages stained for IL-18. In vitro, IL-18 primed superoxide production by ANCA-activated neutrophils comparably to TNFalpha. IL-18-primed, ANCA-induced superoxide production was unaffected by anti-TNFalpha antibody, which abrogated TNFalpha priming. Furthermore, TNFalpha and IL-18 phosphorylated neutrophil p38 mitogen-activated protein kinase (MAPK), but IL-18-mediated p38 MAPK phosphorylation was unaffected by anti-TNFalpha antibody. The p38 MAPK inhibitor, SB20358, reduced IL-18-primed, ANCA-induced superoxide production in a concentration-dependent manner. ANCA-induced superoxide release was also sensitive to the Leukotriene B4 (LTB4) inhibitor MK-886. IL-18 priming was not associated with increased ANCA antigen expression on isolated neutrophils. We conclude that IL-18 is likely to be important for neutrophil recruitment and priming in ASV. Therapies targeting single priming agents may have limited efficacy in controlling disease.

Therapeutic Effect of Anti–TNF-α Antibodies in an Experimental Model of Anti-Neutrophil Cytoplasm Antibody–Associated Systemic Vasculitis

The therapeutic options for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) remain limited and hampered by adverse effects. One potential novel therapeutic avenue involves inhibition of TNF-alpha, with encouraging uncontrolled data in humans with one agent (infliximab) but disappointing controlled data from another (etanercept). For investigating the potential role of TNF-alpha as a therapeutic target in AASV, the effect of an anti-rat TNF-alpha mAb (CNTO 1081) in a rat model of AASV was investigated. For testing the effect of TNF-alpha blockade in this model, starting on day 28 after immunization (a point when glomerulonephritis is established), animals were randomized to treatment with CNTO 1081 or control mouse IgG. Treatment with CNTO 1081 significantly reduced albuminuria (mean 1.1 +/- 0.3 mg/24 h CNTO 1081 versus 8.0 +/- 1.9 controls; P < 0.05) and crescent formation (0% CNTO 1081 versus 60% controls; P < 0.05). Lung hemorrhage was also reduced (CNTO 1081: median score 0, range 0 to 2; controls: 2, range 1 to 3; P < 0.05). When analyzed by intravital microscopy, there was a 43% inhibition of leukocyte transmigration in mesenteric venules in response to topical CXCL1 (a neutrophil chemoattractant) in the CNTO 1081 group compared with controls (P < 0.001). Anti-myeloperoxidase antibody titers were similar in both groups throughout the study. In conclusion, these findings indicate that TNF-alpha plays an important role in the pathogenesis of experimental autoimmune vasculitis and suggest that blockade of this cytokine with an mAb is effective in treating established vasculitis. The therapeutic action of anti-TNF-alpha reagents may be mediated, in part, by suppression of the enhanced leukocyte-endothelial interactions in this disorder.