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 E-C4d 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-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.

Figure 1

Levels of lupus biomarkers in patients with systemic lupus erythematosus, according to disease activity categories as defined by Systemic Lupus Activity Measure and Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index scores at the initial visit. Data are presented as box plots, where the boxes represent the 25th to 75th percentiles (interquartile range [IQR]), the lines within the boxes represent the median, and the lines outside the boxes represent the 10th and 90th percentiles. Circles indicate outliers. E-C3d = erythrocyte-bound C3d.