CD4+CD28null T Cells are related to previous cytomegalovirus infection but not to accelerated atherosclerosis in ANCA-associated vasculitis.

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4+CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4+CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4+CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4+CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4+CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4+CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4+CD28null T cells are increased in AAV and related to the previous CMV infection.

Phosphorylcholine antibodies are diminished in ANCA-associated vasculitis.

BACKGROUND/AIM: ANCA-associated (AAV) vasculitis is an autoimmune small-vessel vasculitis and may be associated with accelerated atherosclerosis as suggested by current literature. Antibodies against oxidized lipoproteins (OxLDL) and phosphorylcholine (Pc) protect from atherosclerosis. This study characterizes these antibodies in AAV. METHODS: Pc- and anti-OxLDL antibodies were determined in sera of 39 AAV patients and 44 healthy controls (HC). Intima-media thickness (IMT, carotids) and pulse wave velocity (PWV, A. femoralis) were measured. RESULTS: Pc-/OxLDL IgM antibodies were significantly reduced in AAV. IMT and PWV were negatively associated with anti-Pc antibodies in HC only. CONCLUSION: Atheroprotective anti-Pc/anti-OxLDL antibodies are significantly reduced in AAV possibly explaining accelerated atherosclerosis in vasculitis patients.

Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis.

T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.

Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis.

BACKGROUND: In a substantial proportion of patients with crescentic glomerulonephritis (CGN), both anti-glomerular basement membrane (GBM) antibodies and antineutrophil cytoplasmic antibodies (ANCAs) with specificity for myeloperoxidase (MPO-ANCA) are detected. In the present study, we questioned whether histological and clinical features of patients with both ANCA and anti-GBM antibodies differ from those of patients with either ANCA or anti-GBM alone. METHODS: We reviewed the Limburg renal biopsy registry (1978 to 2003; n = 1,373) for cases of CGN. The presence of linear fluorescence on renal biopsy and the presence of ANCA and/or anti-GBM antibodies were measured. Subsequently, we assessed patient characteristics and follow-up and compared histological findings among the different groups. RESULTS: We identified 46 MPO-ANCA-positive, 10 double-positive, and 13 anti-GBM-positive patients. Mean ages were 63, 64, and 52 years (P = 0.04), and serum creatinine levels were 5.0, 10.3, and 9.6 mg/dL (445, 910, and 850 micromol/L), respectively (P = 0.01). Granulomatous periglomerular inflammation was found in either MPO-ANCA- or double-positive patients, but not in anti-GBM-positive patients with CGN without MPO-ANCAs. Patient survival among the 3 groups was different, although not statistically significant (log rank P = 0.17, with 75%, 79%, and 100% alive at 1 year, respectively). Renal survival analysis showed significant differences among the 3 groups (P = 0.04, with 65%, 10%, and 15% off dialysis therapy at 1 year, respectively). CONCLUSION: In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. However, renal survival in these patients is not better than that in anti-GBM-positive patients and is worse compared with patients with MPO-ANCAs only.

The pediatric mechanical circulatory support program in Innsbruck, Austria, and the impact of such programs on lack of donor hearts in Europe.

Strategy and results of the Innsbruck Mechanical Circulatory Support Program are presented, and the impact of such programs on pediatric heart transplantation (HTX) in Europe is discussed. Venoarterial extracorporeal membrane oxygenation (vaECMO) and ventricular assist devices (VADs) were used in 21 pediatric patients (median age 3.3 years, 2 days to 17 years) for acute heart failure (AHF) following a bridge or bridge-to-bridge strategy. Twelve patients were treated with vaECMO: eight were weaned after 2-10 days, two died, and two were switched to a VAD. Of the last, one was weaned 47 days later and the other underwent HTX 168 days later. In nine patients, VAD was implanted without preceding vaECMO. One such patient died (cerebral hemorrhage) after 236 days; of the remaining eight patients three were weaned and five underwent HTX. Waiting time for HTX (high-urgency status) varied from 4 to 372 days. Fifteen patients were discharged (follow up: 2-74 months); 14 are doing very well (New York Heart Association (NYHA) Functional Classification Class I, neurologically normal), whereas one suffers from severe neurologic damage, presumably from resuscitation before vaECMO. Data from Eurotransplant on pediatric HTX in 2004, 2005, and 2006 (33, 49, and 34 transplanted hearts, respectively; recipients <16 years of age) are discussed. Mechanical circulatory support (MCS) substantially improves survival with AHF in pediatric patients. Medium-term support (up to 400 days in our patients) is possible and outcome of survivors is excellent. Wide spread use of MCS might slightly aggravate the lack of donor organs, which could result in longer support times.

Evaluation of antibodies against human HSP60 in patients with MPO-ANCA associated glomerulonephritis: a cohort study.

BACKGROUND: Human Heat Shock Protein 60 (hHSP60) has been implicated in autoimmunity through molecular mimicry, based on the high degree of homology with HSP65 of micro-organisms leading to autoimmune recognition of the human protein. Additionally, sequence homology between hHSP60 and myeloperoxidase (MPO) has been described. MPO is a major autoantigen in vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). We hypothesized that infections may trigger the ANCA response against MPO through hHSP60. METHODS: In 86 consecutive patients with ANCA-associated vasculitis (AAV), anti-hHSP60 and anti-mycobacterial HSP65 were measured by ELISA. Patients were compared with 69 healthy controls (HC). Continuous data between groups were compared using Wilcoxon signed rank test and Kruskal-Wallis test with Dunn's post-test when appropriate. Correlations between data were derived using Spearman correlation. Odds ratios and 95% confidence intervals were obtained using Fisher's exact test. RESULTS: At diagnosis, median anti-mHSP65 level was higher in AAV (median [range]: 42.5 [0-500]), and subsequently in MPO-ANCA (44 [7-500]), compared to HC (22 [0-430]). Anti-hHSP60 levels in AAV were not higher compared to HC (18 [0-319] and 18.5 [0-98], respectively). However, in MPO-ANCA anti-hHSP60 levels were increased (32.5 [0-319]) compared to PR3-ANCA (13 [0-79]) and HC. We could not detect cross-reactivity between hHSP60 and MPO-ANCA. There was a correlation between anti-mHSP65 and anti-hHSP60 levels (r = 0.32, P = 0.003) but not between anti-hHSP60 and MPO-ANCA (r = -0.064, P = 0.69). CONCLUSION: Antibodies against mHSP65 are higher in AAV compared to HC, and anti-hHSP60 antibodies are higher in patients with MPO-ANCA than in patients with PR3-ANCA and HC. Although this finding may be indicative for cross-reactivity between MPO-ANCA and hHSP60, additional assays did not support this hypothesis.

Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long-term followup study.

OBJECTIVE: To test whether antineutrophil cytoplasmic antibodies (ANCA) and ANCA-associated vasculitis (AAV) are not only induced during treatment with antithyroid drugs, but can also become evident when medication has been ceased, possibly after years. METHODS: Patients who visited our hospital for the treatment of hyperthyroidism were included (n = 207). Treatment consisted of antithyroid medications, radioactive iodide, thyroidectomy, or a combination of these treatment options. Patients were retested 3-6 years later to evaluate long-term effects of antithyroid drugs. Patients were tested for the presence of ANCA and, if positive, evaluated for the presence of AAV. RESULTS: Of 209 patients with hyperthyroidism, 12 patients (6%) were positive for myeloperoxidase- (MPO-), proteinase 3-, or human leukocyte elastase-ANCA. Seventy-seven of 209 patients were retested; 1 patient who had not been treated with antithyroid drugs had developed MPO-ANCA. In 3 of 6 patients previously positive, ANCA could still be detected. The presence of ANCA was highly associated with treatment with antithyroid drugs (odds ratio 11.8 [95% confidence interval 1.5-93.3]). Of 13 patients with a positive ANCA result on enzyme-linked immunosorbent assay, AAV with glomerulonephritis was diagnosed in 4 (31%). CONCLUSION: The presence of ANCA with or without vasculitis is associated with previous treatment with antithyroid drugs, possibly after years.

Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement.

BACKGROUND: Severe renal disease is a feature of anti-neutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis. We evaluated patient and renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement at diagnosis during long-term follow-up. METHODS: Eighty-five patients were diagnosed between 1982 and 1996 and followed until 2001 allowing >or=5 years of follow-up. All patients were treated with prednisolone and cyclophosphamide. Univariate and multivariate analyses with patient and renal survival as dependent variables were performed. RESULTS: Of the 85 patients in this study, 17 (20%) died within one year after diagnosis. Of the 25 patients (29%) who were dialysis dependent at diagnosis, two remained dependent and two again became dialysis dependent after less than one year; nine died early without renal recovery. Risk factors for death occurring within one year in univariate analysis (RR, 95% CI) were age>65 years (6.5, 1.6-13.7) and dialysis dependency at diagnosis (3.6, 1.0-13). Twenty patients died beyond one year during the long-term follow-up. Male gender (4.7, 1.6-10) and developing dialysis dependency during follow-up (4.1, 1.4-12) were associated with poor outcome. Risk factor for renal failure within one year was dialysis dependency at diagnosis (29, 3.6-229). Of 64 patients dialysis independent one year after diagnosis, 12 patients became dialysis dependent during follow-up. A renal relapse was strongly associated with development of renal failure in long-term follow-up (17, 3.5-81). CONCLUSIONS: Early death and failure to recover renal function in PR3-ANCA associated vasculitis is associated with age> 65 years and dialysis dependency at diagnosis. Long-term renal survival is determined by renal relapses during follow-up only. Slow, progressive renal failure without relapses is rarely observed in this group.

Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis.

OBJECTIVE: To analyze disease-free survival in patients with antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide. METHODS: We analyzed disease-free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990-1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997-2000). All patients received at least 12 months of followup. RESULTS: Of the total 128 patients, 53 (41%) relapsed. Forty-four of the 128 patients (34%) had been switched to azathioprine therapy. Disease-free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C-ANCA)-associated vasculitis who were switched to azathioprine (n = 33), a positive C-ANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1-8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease-free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA-positive at the time of treatment switch, disease-free survival at 2 and 4 years was only 58% and 17%. CONCLUSION: Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3-ANCA-associated vasculitis who are still ANCA-positive at the time of treatment switch is associated with a high risk of relapse.