Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Abstract

Objective-Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.Methods-The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).Results-At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and EC4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti-double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA-SLEDAI. In a multivariable analysis, E-© 2010, American College of Rheumatology Address correspondence and reprint requests to Amy H. Kao, MD, MPH, S721 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, PA 15261. ahk7@pitt.edu. Ms Navratil has received royalties (less than $10,000) for the cell-bound C4d/C3d assay licensed to Cypress Bioscience, Inc. Dr. Hawkins has received consulting fees from Cellatope, Inc. (more than $10,000). Dr. Ahearn has received consulting fees, speaking fees, and/or honoraria from Cellatope, Inc. (more than $10,000) and has received licensing fees from Cypress Bioscience, Inc. Dr. Manzi has received consulting fees, speaking fees, and/or honoraria from Cellatope, Inc. (more than $10,000) and has received licensing fees from Cypress Bioscience, Inc. AUTHOR CONTRIBUTIONSAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA-SLEDAI.Conclusion-Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE. In lieu of more useful lupus biomar...

The Important Roles of C4d in Systemic Lupus Erythematosus

“…In a multivariable analysis of patients with SLE, E-C4d was significantly associated with the Systemic Lupus Activity Measure (SLAM) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) after adjusting for serum C3, C4 and anti-dsDNA antibodies [20]. Study on E-C4d from Taiwan demonstrated the same results and found that E-C4d had limited value in monitoring disease activity in SLE patients with hemolytic anemia [21].…”

“…Peripheral free C4d Plasma Monitor disease activity; predict disease flare [12,13] Serum Monitor disease activity [14] Plasma No correlation with SLE during pregnancy [15] C4d binding to blood cells E-C4d Diagnose SLE; monitor disease activity [18,20,31] R-C4d Monitor disease activity [24] P-C4d Diagnose SLE; monitor disease activity; marker for venous thrombosis in SLE; associated with all-cause mortality and ischemic stroke [25][26][27][28] T/B-C4d Diagnose SLE; monitor disease activity [29][30][31] C4d deposition in tissues…”

Plasma C4d as marker for lupus nephritis in Systemic Lupus Erythematosus

“…However, no direct comparison with a commercial assay was done for the patient samples used in the present study. Another promising approach is the measurement of C4d bound to the surface of various blood cells, such as erythrocytes, reticulocytes, and platelets [23][24][25][26]. However, the drawback of this methodology is that it is work-intensive and requires advanced equipment.…”

Biomarkers for systemic lupus erythematosus: an update

“…However, complement activation occurs in other comorbidities such as infection, and complement activation products have low specificity, providing only a rough estimate of disease activity in SLE [70]. Recently, many studies demonstrated that cell-bound complement activation products, such as E-C4d and B-C4d, are potential markers for lupus diagnosis or evaluation of disease activity [71,72]. These cell-bound complement activation products are determined using flow cytometry.…”