Seven clinical conundrums in the treatment of ANCA-associated vasculitis.

Granulomatosis with polyangiitis and microscopic polyangiitis are two autoimmune diseases characterised by necrotising small-vessel vasculitis and presence of antineutrophil cytoplasm autoantibodies (ANCA). Current immunosuppressive regimes that combine cyclophosphamide and glucocorticoids have dramatically improved the outcome for these patients. However, these treatments are associated with toxic effects and do not lead to permanent remission in the majority of cases. Newer approaches have been sought during the last 15 years, with improvement in medication protocols and inclusion of novel therapies. This review develops on seven clinical conundrums of evidence-based therapeutic strategies for ANCA-vasculitis, posed as questions on aspects such as the role of established drugs in both remission induction and maintenance: glucocorticoids (and its duration), oral cyclophosphamide, methotrexate, TNF-α blockers, plasma exchange, mycophenolate mofetil, plus one related to newer developments in treatment with agents blocking the complement system and the possible role of sequential or combined therapies, mainly directed against B cells.

Takayasu arteritis: clinical features in 110 Mexican Mestizo patients and cardiovascular impact on survival and prognosis.

OBJECTIVE: Takayasu Arteritis (TA) is a rare disease that mainly affects large elastic arteries. It is more frequently seen in Asia, the Mediterranean basin, South Africa and Latin America. We have characterized its clinical manifestations and identified the cardiovascular mortality predictors in a cohort of 110 Mexican Mestizo patients. MATERIAL AND METHOD: Retrospective review of 110 charts of TA patients complying with the American College of Rheumatology (ACR) criteria, seen in a single hospital between 1976 and 2003. Demographic, clinical, and radiological characteristics were described. With the use of actuarial table analysis at 2, 5, and 10 years, and Kaplan Meier methods applying t function for probability, plus Cox regression analysis, the following factors were identified as mortality predictors: systemic arterial hypertension, coronary heart disease and aortic valve regurgitation. Informed consent and approval from the institutional Internal Review Board (IRB) were obtained. RESULTS: We observed a slowly progressive widespread obstructive arterial disease with cardiovascular (48%), neuro-ophthalmic (36%), and skin morbidity (13%). Systemic hypertension and heart disease were significant mortality predictors. Twenty-six percent of cases died due to myocardial infarction, chronic renal failure, stroke, or surgical complications. CONCLUSION: TA in Mexican Mestizos shows a clinical pattern similar to the one recognized in the Far East. Management strategies must be directed at reducing the identified mortality risk factors.

Sclerodermatomyositis, ocular manifestations. / Esclerodermatomiositis con manifestaciones oculares predominantes.

BACKGROUND: Sclerodermatomyositis is an overlap syndrome of myositis and scleroderma, with dermatological, muscular and joint involvement, but may also present with ocular manifestations. CLINICAL CASE: A 57 year-old woman presented with ophthalmological manifestations, including scleral thinning 360°, and the presence of cells in the anterior and posterior chamber. Oriented physical examination and laboratory studies led to the diagnosis, with the need for systemic treatment. CONCLUSION: Sclerodermatomyositis is a rare disease. Its diagnosis needs thorough clinical and laboratory studies, and its management should be multidisciplinary when inflammatory ocular manifestations may be present.

[Do serial ANCA titres predict relapse in ANCA-associated vasculitis?]. / Les titres d'ANCA répétés peuvent-ils prédire la rechute des vascularites ANCA positives?

Antineutrophil cytoplasm autoantibodies (ANCA) are essential for the diagnosis of small-vessel vasculitis. Information for and against their usefulness to predict relapse exists. Different approaches, using various methods and definitions, have been used to answer the role of ANCA in predicting disease relapse. Multinational, multicentric prospective studies are needed to address this question using uniform definitions and preferably the best latest tools for ANCA detection.

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.

High prevalence of infections in patients with systemic lupus erythematosus and pulmonary haemorrhage.

The main objective of this study is to describe the presence of infections in patients with pulmonary haemorrhage and systemic lupus erythematosus. Patients with systemic lupus erythematosus and pulmonary haemorrhage were thoroughly evaluated in the first 48 hours with imaging plus bronchoscopy and bronchoalveolar fluid analysis. If needed, videoassisted thoracoscopy and lung biopsy were performed too. In all, search for bacterial, mycobacterial and fungal infections proceeded. Appropriate blood, bronchoalveolar fluid and tissue cultures were taken. Patients were treated with antibiotics and corticosteroids in case of infection. Otherwise, they received initial intravenous methylprednsiolone pulses for 3 days as standard therapy for pulmonary haemorrhage in systemic lupus erythematosus. Additional treatment with immunosuppressives was further decided by the treating physicians. Fourteen events in 13 patients were evaluated. In eight events (57%), an infection was demonstrated. Aetiological agents included Pseudomonas sp. and Aspergillus fumigatus. Four patients died, three of them because of the pulmonary infection and one because of cerebral haemorrhage secondary to severe systemic hypertension, 48 hours after methylprednisolone treatment. Patients with systemic lupus erythematosus and pulmonary haemorrhage have a high prevalence of infections. The influence of pulmonary haemorrhage in the setting of systemic lupus erythematosus needs further study to establish adequate treatment and to reduce the high mortality of this complication.

New developments in pathogenesis of systemic vasculitis.

Aspects of pathogenesis of primary systemic vasculitis are highlighted in this review. The cause of these entities is still obscure, although new information on the possible role of infections has emerged. Success of antimicrobial treatment to ameliorate systemic vasculitis, for which proof was recently provided, adds to the new information. Apart from new data that point to a precipitating role for environmental toxins the background for development of these diseases is most likely genetic predisposition. Reports on hereditary alpha 1-antitrypsin deficiency, the link between systemic vasculitis and human leukocyte antigen molecules, and an animal model of spontaneous granulomatous arteritis in mice with a hereditary deficit in Fas-mediated apoptosis, are some of the new data that strongly favor genetic predisposition. Progress has been made in the process of identification of the agonists and antagonists in the front line of vasculitic inflammation. The interaction of blood cells (e.g., neutrophils and monocytes) with vascular endothelium has become more evident as have the signals for the release of harmful proteolytic enzymes. Antineutrophil cytoplasmic antibodies, which are important markers of disease, may be actively involved in these processes.

Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis.

OBJECTIVE: To determine the prevalence of antineutrophil cytoplasmic autoantibodies (ANCA) in sera of patients with tuberculosis compared with healthy control subjects and a group of patients with atopic asthma. METHODS: The presence of ANCA was examined in patients with tuberculosis, and in asthmatic patients and healthy subjects as control groups, by means of indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to detect anti-proteinase 3 (PR3-ANCA) and antimyeloperoxidase (MPO-ANCA) antibodies. RESULTS: ANCA were present in 20 (44.4%) of 45 tuberculosis patients by IIF (16 c-ANCA, four p-ANCA) and in 18 (40%) patients by ELISA (15 PR3-ANCA, three MPO-ANCA). High odds ratios for ANCA positivity were observed for tuberculosis patients when compared with both control groups. ANCA results were not related to the category of tuberculosis, stage of disease, presence of concomitant diseases or pharmacotherapy. CONCLUSIONS: As many clinical similarities between tuberculosis and Wegener's granulomatosis exist, we propose that a positive ANCA test in patients living in countries with a high prevalence of tuberculosis must be carefully interpreted as indicative of systemic vasculitis, especially when no signs of extrapulmonary involvement occur.

Effects of anti-neutrophil cytoplasm autoantibodies on tissue factor activity by HL-60 cells in vitro.

The effects of cytoplasmic anti-neutrophil cytoplasm autoantibodies (C-ANCA) and perinuclear ANCA (P-ANCA) immunoglobulin G (IgG) on tissue factor (TF) activity using HL-60 cells in vitro were compared with those of medium, lipopolysaccharide (LPS) and control IgG. Cells were also incubated with both ANCA IgG and control IgG in the presence of a submaximal concentration of LPS capable of upregulating TF procoagulant activity (TF-PCA) measured in arbitrary units of TF equivalent (AU-TFEq). The purpose was to search for an additive effect between LPS and ANCA IgG. All IgG preparations increased HL-60 cell TF-PCA in comparison with the medium. When cells were incubated with P-ANCA IgG and LPS (1 micro g/ml), a larger increase was seen (151.23 +/- 31.6 SEM (standard error of the mean) AU-TFEq) than when incubated with control IgG plus LPS (91.01 +/- 18.4 SEM AU-TFEq; P < 0.005), P-ANCA IgG alone (73.68 +/- 12.7 SEM AU-TFEq; P < 0.005) or LPS (1 micro g/ml) (58.11 +/- 7.9 SEM AU-TFEq; P < 0.005). There was concordance between PCA and TF total antigen content by enzyme-linked immunosorbent assay (ELISA). The fact that P-ANCA IgGs upregulate the function of TF in HL-60 cells in combination with LPS adds to information regarding the possible role of ANCAs in the enhancement of TF by different cells, although it does not support the fact that ANCAs alone play a role in mononuclear cell TF upregulation. The additive effects of LPS underline the possible role of pro-inflammatory stimuli in the pathogenesis of ANCA-associated diseases.

ANCA titres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA) are presumed to reflect disease-activity and to be useful for guidance of immunosuppressive therapy of ANCA-associated systemic vasculitis (AASV), but with respect to conventional ANCA assays this is controversial. ANCA titres, measured in the IgG3 subclass and modern capture ELISAs, have been said to be superior predictors of relapses of AASV. METHODS: In this retrospective study serial measurements of ANCA parameters and soluble CD14 (sCD14) were performed in 169 consecutive sera over a median of 21 months in 18 patients with AASV and related to disease activity, assessed by Birmingham Vasculitis Activity Score (BVAS) for new or deteriorated (BVAS1), and for chronic disease activity (BVAS2). Fourteen patients had Wegener's granulomatosis (WG) and were C-ANCA positive with Pr 3-antibodies and four patients had microscopic polyangiitis (MPA) with P-ANCA and MPO-antibodies. In WG patients ANCA by IIF, Pr 3-ELISA for IgG, IgG1, IgG3, IgG4 and sCD14 were measured, as well as capture ELISA for Pr 3, and in MPA patients ANCA by IIF, MPO-ELISA for IgG and IgG1, IgG3, IgG4, and sCD14 respectively. In eight patients, data collection started at diagnosis, in 10 patients at remission. RESULTS: The parameters predicted neither the nine major relapses (increase of immunosuppression necessary), nor the 26 minor relapses (increase of BVAS1>2) with sufficient sensitivity (>80%) or specificity (> 90%90%), and they also failed to predict relapses within the following 2 months. ANCA-IgG3 and capture ELISA for Pr 3 were not advantageous for prediction of relapses (sensitivity 0.45 and 0.19 respectively), and sCD14 remained elevated in all samples irrespective of disease activity. CONCLUSIONS: There is no rationale for serial measurements of ANCA in AASV. For changes of therapy, the ANCA parameters should only be used in conjunction with clinical information.