Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus

Yang, Deng‐Ho; Chang, Deh‐Ming; Lai, Jenn‐Haung; Lin, Fu-Huang; Chen, Chen‐Hung

doi:10.1093/rheumatology/kep161

Cited by 30 publications

(27 citation statements)

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“…Many patients with SLE experience activation of the classical complement pathway, resulting in reduced complement levels and formation of complement C4 activation products (CBCAPS) that are stably deposited on various cell membranes including erythrocytes (EC4d) and B-lymphocytes (BC4d). [10][11][12] In particular, the deposition of C4d on erythrocytes has a significant impact on erythrocyte membrane deformability, 13 thereby potentially impairing the ability of red blood cells to deliver oxygen to tissues. These CBCAPS were initially reported as valuable in SLE diagnostics, 11 and their performance characteristics were recently validated in a prospective multicentre study.…”

Section: Key Messagesmentioning

confidence: 99%

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

et al. 2014

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ObjectiveTo compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).MethodsThe study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.ResultsAUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).ConclusionsCBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.

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Section: Key Messagesmentioning

confidence: 99%

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

et al. 2014

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“…Although low levels of complement proteins C3 and C4 may be an indication of ongoing inflammation in SLE and have been incorporated in the SLICC classification criteria [9], measurement of C3 and C4 per se has several drawbacks, including low sensitivity, high inter-subject variability, and increased synthesis during inflammation to compensate for increased consumption [26, 27]. Complement activation results in the formation of complement activation products that bind covalently to blood cells [11, 28, 29]. The performance characteristics of these cell-bound complement activation products (CB-CAPs) have recently been validated in a prospective multicenter clinical study [30] that showed that elevated B lymphocyte complement 4 derived ligand (BC4d) or erythrocyte complement 4 derived ligand (EC4d) have 22% higher sensitivity than low complement for the diagnosis of SLE.…”

Section: Introductionmentioning

confidence: 99%

The Avise Lupus Test and Cell-bound Complement Activation Products Aid the Diagnosis of Systemic Lupus Erythematosus

Mossell

Goldman

Barken³

et al. 2016

TORJ

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Background:Systemic lupus erythematosus (SLE) is a multifaceted disease, and its diagnosis may be challenging. A blood test for the diagnosis of SLE, the Avise Lupus test, has been recently commercialized and validated in clinical studies.Objectives:To evaluate the use of the Avise Lupus test by community rheumatologists.Methods:The study is a longitudinal, case-control, retrospective review of medical charts. Cases had a positive test result, and controls had a negative result; all patients were anti-nuclear antibodies (ANA) positive but negative for SLE-specific autoantibodies. Features of SLE, diagnosis, and medications at two time points were recorded.Results:Twenty of the 23 cases (87%) and 4 of the 23 controls (17%) were diagnosed with SLE (sensitivity=83%; specificity=86%). More cases than controls (43% vs. 17%) fulfilled 4 American College of Rheumatology (ACR) classification criteria of SLE. Sensitivity of the test was significantly higher than the ACR score (83% vs. 42%, p=0.006). A higher percentage of patients who met the classification criteria had elevated cell-bound complement activation products (CB-CAPs) compared to patients who did not. Anti-rheumatic medications were used in a higher percentage of cases than controls (83% vs. 35% at baseline, p=0.002), suggesting that cases were treated more aggressively early on.Conclusion:A positive Avise Lupus test result aids in formulating a SLE diagnosis when diagnosis based on standard-of-care tests and clinical features may be challenging, and impacts patient management. Prospective studies will be performed to better evaluate the clinical utility of the test and of CB-CAPs as biomarkers of SLE.

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“…The novel biomarkers to evaluate disease activity include serum cytokine, soluble cytokine receptor, soluble cell surface molecules (CD27, CD154 and BAFF), endothelial activation markers (sVCAM, sICAM and thrombomodulin), and cell markers (CD27 high plasma cells and erythrocyte-C4d) 8,9. Traditional biomarkers for the survey of disease activity include anti-dsDNA antibodies and serum complement levels (C3 and C4).…”

Section: Introductionmentioning

confidence: 99%

Significantly Higher Percentage of Circulating CD27^highPlasma Cells in Systemic Lupus Erythematosus Patients with Infection than with Disease Flare-Up

et al. 2010

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PurposeTo distinguish lupus flare-up from infection in systemic lupus erythematosus (SLE), we analyze the expression of circulating CD27high plasma cells in SLE patients with and without infection, in comparison to non-SLE patients with infection.Materials and MethodsThe percentage of circulating CD27high plasma cells was measured by flow cytometry in the following four groups: 36 SLE patients without infection, 23 SLE patients with infection, eight non-SLE patients with infection, and 26 healthy controls.ResultsThe frequency of CD27high plasma cells had a correlation with the SLE disease activity index (SLEDAI) (r = 0.866, p < 0.05), level of anti-dsDNA (r = 0.886, p < 0.05), C3 (r = - 0.392, p < 0.05), and C4 (r = - 0.337, p < 0.05) in SLE patients without infection, but there was no correlation with disease activity in SLE patients with infection. Among three groups in particular-SLE without infection, SLE with infection, and non-SLE with infection-the percentages of CD27high plasma cells were elevated. The percentage of CD27high plasma cells was higher in SLE patients with infection, when compared to SLE patients without infection.ConclusionThe percentage of CD27high plasma cells is a biomarker for disease activity of SLE without infection, under correlation with SLEDAI, anti-dsDNA, and C3 and C4 level. However, when the SLE patients have an infection, the percentage of CD27high plasma cells is not an adequate biomarker for the survey of disease activity. The percentage of CD27high plasma cells may serve as a potential parameter to distinguish a lupus flare-up from infection.

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Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus

Abstract: E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA.

Cited by 30 publications

References 27 publications

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

The Avise Lupus Test and Cell-bound Complement Activation Products Aid the Diagnosis of Systemic Lupus Erythematosus

Significantly Higher Percentage of Circulating CD27^highPlasma Cells in Systemic Lupus Erythematosus Patients with Infection than with Disease Flare-Up

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Usefulness of erythrocyte-bound C4d as a biomarker to predict disease activity in patients with systemic lupus erythematosus

Abstract: E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA.

Cited by 30 publications

References 27 publications

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

The Avise Lupus Test and Cell-bound Complement Activation Products Aid the Diagnosis of Systemic Lupus Erythematosus

Significantly Higher Percentage of Circulating CD27highPlasma Cells in Systemic Lupus Erythematosus Patients with Infection than with Disease Flare-Up

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Significantly Higher Percentage of Circulating CD27^highPlasma Cells in Systemic Lupus Erythematosus Patients with Infection than with Disease Flare-Up