Measurement of cell‐bound complement activation products enhances diagnostic performance in systemic lupus erythematosus

Kalunian, Kenneth C.; Chatham, W. Winn; Massarotti, Elena; Reyes-Thomas, Joyce; Harris, Cole; Furie, Richard; Chitkara, Puja; Putterman, Chaim; Gross, R; Somers, Emily C.; Kirou, Kyriakos A.; Ramsey‐Goldman, Rosalind; Hsieh, Christine; Buyon, Jill P.; Dervieux, Thierry; Weinstein, Arthur

doi:10.1002/art.34669

Cited by 72 publications

(54 citation statements)

References 21 publications

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“…The usefulness of these for actual SLE diagnosis may however be questioned. Instead, a panel of parameters including C4d-deposition on B cells and erythrocytes has been suggested 103. Since activation of complement contributes to disease activity, therapeutics such as a monoclonal antibody against C5 (eculizumab) that blocks the pro-inflammatory activation of complement has been tested with promising results in a murine lupus model 104.…”

Section: Complement In Diagnostics and Therapeuticsmentioning

confidence: 99%

The complement system in systemic lupus erythematosus: an update

2014

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The complement system plays a major role in the autoimmune disease, systemic lupus erythematosus (SLE). However, the role of complement in SLE is complex since it may both prevent and exacerbate the disease. In this review, we explore the latest findings in complement-focused research in SLE. C1q deficiency is the strongest genetic risk factor for SLE, although such deficiency is very rare. Various recently discovered genetic associations include mutations in the complement receptors 2 and 3 as well as complement inhibitors, the latter related to earlier onset of nephritis. Further, autoantibodies are a distinct feature of SLE that are produced as the result of an adaptive immune response and how complement can affect that response is also being reviewed. SLE generates numerous disease manifestations involving contributions from complement such as glomerulonephritis and the increased risk of thrombosis. Furthermore, since most of the complement system is present in plasma, complement is very accessible and may be suitable as biomarker for diagnosis or monitoring of disease activity. This review highlights the many roles of complement for SLE pathogenesis and how research has progressed during recent years.

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Section: Complement In Diagnostics and Therapeuticsmentioning

confidence: 99%

The complement system in systemic lupus erythematosus: an update

2014

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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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“…5,6 We have recently reported that significant levels of C4d are present specifically on the surfaces of erythrocytes, 7 reticulocytes, 8 platelets, 9 and lymphocytes 10 of patients with SLE. A recent multicenter study validated cell-bound complement activation products (CB-CAPs) as diagnostic biomarkers for lupus, 11 and additional reports have demonstrated their significant potential as biomarkers of lupus disease activity and stratification. 12,13 In addition to their roles as lupus biomarkers, CBCAPs have been shown to confer functional abnormalities to circulating cells such as erythrocytes and T lymphocytes, suggesting a role in lupus pathogenesis.…”

Section: Introductionmentioning

confidence: 99%