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

Abstract

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.

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

“…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.…”

“…1 ) [30]. Patients are considered tier 1 positive if titer of specific autoantibodies is above cut-off (anti-dsDNA > 301 units and positivity is confirmed by the Crithidia luciliae immunofluorescence test, or anti-Smith > 10 units), or if CB-CAPs are strongly positive (EC4d > 75 units or BC4d > 200 units).…”

SLE-key® rule-out serologic test for excluding the diagnosis of systemic lupus erythematosus: Developing the ImmunArray iCHIP®

“…The performance of an assay panel comprised of cell-bound complement activation products alongside established markers, such as anti-dsDNA, ANA and anti-MCV, demonstrated 86% specificity and 80% sensitivity in distinguishing SLE from other autoimmune rheumatic disease (Kalunian et al, 2012; Putterman et al, 2014). The test proved 33% more specific than ANA-based tests and 48% more sensitive than the anti-dsDNA test.…”

Biomarkers in connective tissue diseases

“…40 These findings have been confirmed and refined to a commercially available, weighted SLE risk score with a two tier design. 41 …”