Sofia Lionaki

Association of Silica Exposure with Anti–Neutrophil Cytoplasmic Autoantibody Small-Vessel Vasculitis: A Population-Based, Case-Control Study

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are associated with a category of small-vessel vasculitis (SVV) with frequent glomerulonephritis. The goal of this study was to evaluate the association of lifetime silica exposure with development of ANCA-SVV, with particular attention to exposure dosage, intensity, and time since last exposure. A southeastern United States, population-based, case-control study was conducted. Case patients had ANCA-SVV with pauci-immune crescentic glomerulonephritis. Population-based control subjects were frequency-matched to case patients by age, gender, and state. Jobs were assessed in a telephone interview. Silica exposure scores incorporated exposure duration, intensity, and probability for each job and then were categorized as none, low/medium, or high lifetime exposure. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Silica exposure was found in 78 (60%) of 129 case patients and in 49 (45%) of 109 control subjects. There was no increased risk for disease from low/medium exposure relative to no exposure (OR 1.0; 95% CI 0.4 to 2.2) but increased risk with high exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Crop harvesting was associated with elevated risk (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03). However, both agricultural and traditional occupational sources contributed to the cumulative silica exposure scores; therefore, the overall effect could not be attributed to agricultural exposures alone. There was no evidence of decreasing by duration of time since last exposure. High lifetime silica exposure was associated with ANCA-SVV. Exposure to silica from specific farming tasks related to harvesting may be of particular importance in the southeastern United States. Interval of time since last exposure did not influence development of ANCA-SVV.

The clinical course of ANCA small-vessel vasculitis on chronic dialysis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis frequently affects the kidney. Here we describe the rates of infection, disease relapse, and death in patients with ANCA small-vessel vasculitis before and after end-stage renal disease (ESRD) in an inception cohort study and compare them to those of patients with preserved renal function. All patients had biopsy-proven ANCA small-vessel vasculitis. Fishers exact tests and Wilcoxon rank sum tests were used to compare the characteristics by ESRD status. ESRD follow-up included time on dialysis with transplants censored. Over a median follow-up time of 40 months, 136 of 523 patients reached ESRD. ESRD was associated with new-onset ANCA small-vessel vasculitis in 51% of patients, progressive chronic kidney disease without active vasculitis in 43%, and renal relapse in 6% of patients. Relapse rates of ANCA small-vessel vasculitis, reported as episodes/person-year, were significantly lower on chronic dialysis (0.08 episodes) compared with the rate of the same patients before ESRD (0.20 episodes) or with patients with preserved renal function (0.16 episodes). Infections were almost twice as frequent among patients with ESRD on maintenance immunosuppressants and were an important cause of death. Given the lower risk of relapse and higher risk of infection and death, we suggest that immunosuppression be geared to patients with ESRD who present with active vasculitis.

Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study

BACKGROUND Subsequent to cyclophosphamide-based induction therapy of lupus nephritis, and despite maintenance chronic immunosuppressive treatment, many patients experience relapses. METHODS This prospective, observational study included 10 women with biopsy-proven relapse of proliferative lupus nephritis occurring during maintenance with mycophenolate mofetil (MMF) or azathioprine. The long-term outcome after a single course of the B-cell depleting anti-CD20 antibody rituximab (4 weekly infusions of 375 mg/m(2)), combined with daily MMF (2 g) and prednisolone (0.5 mg/ kg/day for 4 weeks, tapered thereafter) is presented. RESULTS While renal function was not severely impaired at baseline, partial remission (>50% improvement in all abnormal renal parameters) was achieved in eight patients at a median of 3.5 months. In seven patients, with 24-h urinary protein of 2.5 +/- 1.1 g (mean +/- SD), complete remission, associated with increases in serum complement levels and decreases in anti-dsDNA titres, was subsequently established (normal serum creatinine/albumin levels, inactive urine sediment and 24-h urinary protein <0.5 g). Complete nephritis remission was sustained at the follow-up end (median of 38 months) in six patients. Combination treatment was well tolerated. CONCLUSIONS The efficacy of this low-toxicity combination was particularly evident in patients with subnephrotic proteinuria due to proliferative lupus nephritis relapse. Controlled trials to define the role of rituximab/MMF in this condition are warranted.

Anti-neutrophil cytoplasmic (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies in necrotizing and crescentic glomerulonephritis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) and anti-glomerular basement membrane (GBM) necrotizing and crescentic glomerulonephritis are aggressive and destructive glomerular diseases that are associated with and probably caused by circulating ANCA and anti-GBM antibodies. These necrotizing lesions are manifested by acute nephritis and deteriorating kidney function often accompanied by distinctive clinical features of systemic disease. Prompt diagnosis requires clinical acumen that allows for the prompt institution of therapy aimed at removing circulating autoantibodies and quelling the inflammatory process. Continuing exploration of the etiology and pathogenesis of these aggressive inflammatory diseases have gradually uncovered new paradigms for the cause of and more specific therapy for these particular glomerular disorders and for autoimmune glomerular diseases in general.

ANCA patients have T cells responsive to complementary PR-3 antigen

Some patients with proteinase 3 specific anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA) also have antibodies that react to complementary-PR3 (cPR3), a protein encoded by the antisense RNA of the PR3 gene. To study whether patients with anti-cPR3 antibodies have cPR3-responsive memory T cells we selected conditions that allowed cultivation of memory cells but not naïve cells. About half of the patients were found to have CD4+TH1 memory cells responsive to the cPR3(138-169)-peptide; while only a third of the patients had HI-PR3 protein responsive T cells. A significant number of T cells from patients responded to cPR3(138-169) peptide and to HI-PR3 protein by proliferation and/or secretion of IFN-gamma, compared to healthy controls while there was no response to scrambled peptide. Cells responsive to cPR3(138-169)-peptide were not detected in MPO-ANCA patients suggesting that this response is specific. The HLADRB1(*) 15 allele was significantly overrepresented in our patient group and is predicted to bind cPR3(138-169) peptide with high affinity. Regression analysis showed a significant likelihood that anti-cPR3 antibodies and cPR3-specific T cells coexist in individuals, consistent with an immunological history of encounter with a PR3-complementary protein. We suggest that the presence of cells reacting to potential complementary protein pairs might provide an alternative mechanism for auto-immune diseases.

Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy

Primary membranous nephropathy is associated with increased risk of venous thromboembolic events, which are inversely correlated with serum albumin levels. To evaluate the potential benefit of prophylactic anticoagulation (venous thromboembolic events prevented) relative to the risk (major bleeds), we constructed a Markov decision model. The venous thromboembolic event risk according to serum albumin was obtained from an inception cohort of 898 patients with primary membranous nephropathy. Risk estimates of hemorrhage were obtained from a systematic literature review. Benefit-to-risk ratios were predicted according to bleeding risk and serum albumin. This ratio increased with worsening hypoalbuminemia from 4.5:1 for an albumin under 3 g/dl to 13.1:1 for an albumin under 2 g/dl in patients at low bleeding risk. Patients at intermediate bleeding risk with an albumin under 2 g/dl have a moderately favorable benefit-to-risk ratio (under 5:1). Patients at high bleeding risk are unlikely to benefit from prophylactic anticoagulation regardless of albuminemia. Probabilistic sensitivity analysis, to account for uncertainty in risk estimates, confirmed these trends. From these data, we constructed a tool to estimate the likelihood of benefit based on an individuals bleeding risk profile, serum albumin level, and acceptable benefit-to-risk ratio (www.gntools.com). This tool provides an approach to the decision of prophylactic anticoagulation personalized to the individuals needs and adaptable to dynamic changes in health status and risk profile.

Removing antibody and preserving glomeruli in ANCA small-vessel vasculitis.

If anti-neutrophil cytoplasmic autoantibodies (ANCA) participate in the pathogenesis of small-vessel vasculitis, then it would stand to reason that removal of these antibodies should ameliorate disease. There is substantial evidence that ANCA are capable of activating leukocytes in vitro .[1][1],[2

Inhibition of tumour necrosis factor alpha in idiopathic membranous nephropathy: a pilot study

BACKGROUND Tumour necrosis alpha has been implicated in the pathogenesis of autoimmune disorders was to evaluate the safety, tolerability and potential efficacy of the tumour necrosis factor alpha (TNF-alpha) inhibitor, etanercept (ET), in patients with idiopathic membranous nephropathy (MN). METHODS Patients with biopsy-proven MN, nephrotic-range proteinuria and clearance of creatinine 50 ml/min or more were included in the study. Exclusion criteria were treatment with steroids or cyclosporine during the previous 3 months, or cytotoxic agents within 6 months prior to entry. ET was administered subcutaneously, 25 mg twice per week for 3 months. Plasma levels of TNF-alpha, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), soluble intercellular adhesion molecule type 1 (sICAM-1), E-selectin, and the soluble form of tumour necrosis factor receptor-55 (sTNFR-55) were measured on entry and at Months 3, 6, and 9 after commencing therapy. RESULTS Twelve patients were entered in the study (four females/eight males, mean time from diagnosis 8.3 months). The therapy was well tolerated; no infections or other adverse events were recorded by the end of follow-up. Two patients exhibited complete remission of proteinuria for at least 4 years. No significant change was found in the levels of TNF-alpha, IL-1, IL-6, IL-8 and IL-10 during the study. Similarly the levels of E-selectin and sICAM-1 were not significantly altered by therapy. Although we found no change in sTNFR-55 at 3 and 6 months, the levels of sTNFR-55 were found significantly decreased 9 months after therapy (mean difference from baseline: 334 +/- 527 pg/ml, P = 0.028). CONCLUSION Short-term use of ET in a small series of patients reduced sTNFR-55 levels but did not exhibit any significant clinical effect in the majority of patients.

Plasma exchange led to a higher rate of renal recovery than intravenous methylpredisolone in severe vasculitis.

Source Citation Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 20...