Associations between clinical features and therapy with macrophage subpopulations and T cells in inflammatory lesions in the aorta from patients with Takayasu arteritis.

Takayasu arteritis (TAK) is a large-vessel granulomatous vasculitis; the inflammatory infiltration in arteries comprises macrophages, multi-nucleated giant cells, CD4+ and CD8+ T cells, γδ T cells, natural killer (NK) cells and neutrophils. However, it is unknown which subtype of macrophages predominates. This study aims to evaluate macrophages subpopulations in the aorta in TAK. Immunohistochemistry was performed in the aorta from TAK patients (n = 22), patients with atherosclerotic disease (n = 9) and heart transplant donors (n = 8) using the markers CD68, CD86, CD206, CD3, CD20 and CD56. Active disease was observed in 54·5% of patients and active histological lesions were found in 40·9%. TAK patients presented atherosclerotic lesions in 27·3% of cases. The frequency of macrophages, M1 macrophages, T, B and NK cells was higher in the aorta from TAK and atherosclerotic patients compared to heart transplant donors. In TAK, macrophages and T cells were the most abundant cells in the aorta, and the expression of CD206 was higher than CD86 (P = 0·0007). No associations were found between the expression of cell markers and active disease or with atherosclerotic lesions. In TAK patients, histological disease activity led to higher T cell counts than chronic fibrotic lesions (P = 0.030), whereas prednisone use was associated with lower T cell counts (P = 0·035). In conclusion, M1 macrophages were more frequent in TAK and atherosclerotic patients compared to heart transplant donors, while M2 macrophages dominated M1 macrophages in TAK. T cells were associated with histological disease activity and with prednisone use in TAK.

Neurologic manifestations of antiphospholipid syndrome.

Neurological involvement in antiphospholipid antibody syndrome (APS) is common, and its occurrence increases morbidity and mortality. Patients may present variable neurological involvement, such as cerebrovascular disease, cognitive dysfunction, headache, seizures, movement disorders, multiple sclerosis-like syndrome, transverse myelitis and ocular symptoms. Most neurological manifestations are associated with thrombosis of the microcirculation or of large vessels; nonetheless, there is compelling evidence suggesting that, in some cases, symptoms are secondary to an immune-mediated pathogenesis, with direct binding of aPL on neurons and glia. Herein we describe clinical characteristics and management of neurological APS manifestations.

Are urinary levels of high mobility group box 1 markers of active nephritis in anti-neutrophil cytoplasmic antibody-associated vasculitis?

The objective of this study is to evaluate urinary high mobility group box 1 (HMGB1) levels as markers for active nephritis in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in comparison with urinary CD4(+) effector memory T cells and urinary monocyte chemoattractant protein-1 (MCP-1). Twenty-four AAV patients with active nephritis and 12 healthy controls (HC) were evaluated. In nine patients, samples were also obtained during remission. Urinary levels of HMGB1 were measured by Western blot. CD4(+) T cells and CD4(+) effector memory T cells (CD4(+) CD45RO(+) CCR7(-) ) were determined in urine and whole blood by flow cytometry. Measurement of urinary levels of MCP-1 and serum HMGB1 levels were performed by enzyme-linked immunosorbent assay (ELISA). AAV patients with active nephritis had higher median intensity of HMGB1 in urine than HC [10·3 (7·05-18·50) versus 5·8 (4·48-7·01); P = 0·004]. Both urinary HMGB1 and MCP-1 levels decreased significantly from active nephritis to remission. The urinary MCP-1/creatinine ratio correlated with Birmingham Vasculitis Activity Score (BVAS) (P = 0·042). No correlation was found between the HMGB1/creatinine ratio and 24-h proteinuria, estimated glomerular filtration rate (eGFR), MCP-1/creatinine ratio, BVAS and serum HMGB1. A positive correlation was found between urinary HMGB1/creatinine ratio and CD4(+) T cells/creatinine ratio (P = 0·028) and effector memory T cells/creatinine ratio (P = 0·039) in urine. Urinary HMGB1 levels are increased in AAV patients with active nephritis when compared with HC and patients in remission, and urinary HMGB1 levels are associated with CD4(+) T cells and CD4(+) effector memory T cells in urine. Measurement of urinary HMGB1 may be of additional value in identifying active glomerulonephritis in AAV patients.

HMGB1 in vascular diseases: Its role in vascular inflammation and atherosclerosis.

The nuclear protein high mobility group box 1 (HMGB1) has been suggested to be involved in the pathogenesis of several vascular diseases such as systemic vasculitis and atherosclerosis. In systemic vasculitides including ANCA-associated vasculitis and Kawasaki disease, serum HMGB1 levels are higher in patients with active disease compared to healthy controls. In atherosclerotic disease, HMGB1 displays increased expression in nuclei and cytoplasm of macrophages and smooth muscle cells in the atherosclerotic lesions, and is implicated in the progression of the atherosclerotic plaque. Experimental models of acute coronary syndromes and cerebrovascular accidents show that HMGB1 is not only involved in the amplification of the inflammatory response during acute ischemic injury, but also in the recovery and remodeling process after ischemia. Patients with acute coronary syndromes or stroke present significantly higher serum levels of HMGB1 than healthy controls and levels are associated with disease severity and mortality. Here we review clinical and experimental studies dealing with the role of HMGB1 in vascular diseases.

Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study.

OBJECTIVES: To evaluate the efficacy of leflunomide in controlling disease activity in patients with Takayasu arteritis (TA) refractory or intolerant to conventional treatment. METHODS: We conducted a prospective open-label study of 15 TA patients (mean age 36.2 years) with active disease based on clinical assessment, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and magnetic resonance angiography (MRA). Patients received leflunomide 20 mg/day for at least 6 months and were followed up for a mean of 9.1 months. Adverse events attributable to leflunomide were recorded. RESULTS: At baseline, 14 TA patients had active disease despite therapy with corticosteroids and immunosuppressive agents, while one patient had intolerance to current treatment. In the follow-up visit, we found a significant decrease in the frequency of patients with active TA (93% vs. 20%, p = 0.002), in the mean daily dose of prednisone (34.2 vs. 13.9 mg, p < 0.001) and in the median values of ESR (29.0 vs. 27.0 mm/h, p = 0.012) and CRP (10.3 vs. 5.3 mg/L, p = 0.012). Two patients (13.3%) developed new angiographic lesions in the follow-up MRA. Three patients (20%) experienced mild adverse events during the study and none discontinued therapy. CONCLUSIONS: This is the first open-label study to demonstrate improvement in disease activity and acute phase reactants with 20 mg/day of leflunomide in TA patients who were refractory or intolerant to conventional therapy with corticosteroids and immunosuppressive agents. Leflunomide was safe and a steroid-sparing effect was observed. A double-blind controlled study is desirable to confirm this finding.

Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases.

BACKGROUND AND PURPOSES: Anti-aquaporin 4 antibodies are specific markers for Devic's disease. This study aimed to test if this high specificity holds in the context of a large spectrum of systemic autoimmune and non-autoimmune diseases. METHODS: Anti-aquaporin-4 antibodies (NMO-IgG) were determined by indirect immunofluorescence (IIF) on mouse cerebellum in 673 samples, as follows: group I (clinically defined Devic's disease, n=47); group II [inflammatory/demyelinating central nervous system (CNS) diseases, n=41]; group III (systemic and organ-specific autoimmune diseases, n=250); group IV (chronic or acute viral diseases, n=35); and group V (randomly selected samples from a general clinical laboratory, n=300). RESULTS: MNO-IgG was present in 40/47 patients with classic Devic's disease (85.1% sensitivity) and in 13/22 (59.1%) patients with disorders related to Devic's disease. The latter 13 positive samples had diagnosis of longitudinally extensive transverse myelitis (n=10) and isolated idiopathic optic neuritis (n=3). One patient with multiple sclerosis and none of the remaining 602 samples with autoimmune and miscellaneous diseases presented NMO-IgG (99.8% specificity). The autoimmune disease subset included five systemic lupus erythematosus individuals with isolated or combined optic neuritis and myelitis and four primary Sjögren's syndrome (SS) patients with cranial/peripheral neuropathy. CONCLUSIONS: The available data clearly point to the high specificity of anti-aquaporin-4 antibodies for Devic's disease and related syndromes also in the context of miscellaneous non-neurologic autoimmune and non-autoimmune disorders.

Impact of hypertension and hyperhomocysteinemia on arterial thrombosis in primary antiphospholipid syndrome.

The aim of this study was to evaluate traditional risk factors for coronary artery disease (CAD), homocysteine, anti-oxidized low-density lipoprotein (anti-oxLDL), anti-lipoprotein lipase (anti-LPL) and endothelin-1 (ET-1) in patients with primary anti-phospholipid syndrome (APS), furthermore verify possible association among these variables and arterial thrombosis. Thirty-eight women with primary APS and 30 age-and-sex-matched controls were evaluated. Patients presented higher-LDL and triglycerides levels and lower-HDL levels than controls. Anti-LPL antibodies were not detected in both groups. The mean number of risk factors was higher in patients than in controls (P = 0.030). Anti-oxLDL antibodies, homocysteine and ET-1 mean levels were similar between groups, but abnormal homocysteine levels were found only among primary APS patients (P = 0.031). Hypertension and the presence of at least one risk factor for CAD were more prevalent in patients with arterial involvement than those without. Homocysteine levels and mean number of risk factors for CAD were significantly higher in patients with arterial thrombosis than controls. In a multivariate analysis hypertension was the only independently associated with arterial thrombosis (OR 14.8, 95% CI = 2.1-100.0, P = 0.006). This study showed that in primary APS patients other risk factors besides anti-phospholipid antibodies contribute for the occurrence of arterial events and the most important factor was hypertension.