Background/Purpose : There is a need to
identify biomarkers that track disease response in systemic lupus erythematosus
(SLE).  The value of various biomarkers
in monitoring of SLE subjects with active disease was assessed. This consisted
of cell bound complement activation products (CB-CAPS, erythrocytes EC4d,
EC3d), complement (C3 and C4) levels anti-dsDNA, anti-chromatin, anti-C1q and
Complement Receptor 1 (ECR1).

Methods : SLE patients enrolled in this prospective biomarker study all
presented with active disease. At baseline, all subjects were screened for
abnormal CBCAPS (e.g. erythrocytes C4d [EC4d]> 14 MFI). Those with disease
activity accompanied by elevated CBCAPS were followed monthly for 12
consecutive visits at 4 week intervals. At each visit, the non-serological (ns)
SELENA-SLEDAI (without anti-dsDNA and low complement components) and the BILAG
score index were determined as was a random protein to creatinine (P/C) ratio.
Short form 36 questionnaires (SF-36) were also collected. All soluble markers
were determined using immunoassays, while cellular markers (EC4d, EC3d and
ECR1) were determined using flow cytometry. Statistical analysis consisted of
generalized linear mixed models with random intercept and fixed slopes. All
investigators were blinded to CBCAPS, anti-C1q and anti-chromatin throughout
the study. Anti-dsDNA titers and serum C3/C4 levels were available to
investigators throughout the study.

Results : A total of 36 CB-CAPS positive SLE patients
(mean age 34 years; 94% female) were enrolled and evaluated monthly for a total
of 385 consecutive study visits (average 11 visits per patient). The majority
of these subjects presented with anti-dsDNA positivity (64%) and low complement
(72%). Clinical improvements were observed during the study, with significant
decrease in ns-SELENA SLEDAI scores, BILAG index score, P/C ratio, and increase
in all domains of the SF-36 (p<0.01). By univariate analysis, the
longitudinal changes in the ns-SELENA-SLEDAI were significantly associated with
all biomarkers measured (p<0.05). The change in BILAG index score correlated
with 6/8 biomarkers (p>0.05 for anti-dsDNA and anti-chromatin) while the changes
in proteinuria correlated with EC4d, ECR1, C3, C4 and anti-C1q. EC4d and EC3d
levels were each associated with improving quality of life in 6/8 domains of
the SF-36. In contrast, the other markers were each associated with 2 or fewer
SF-36 domains. By multivariate analysis both complement C4 and EC3d were
associated with the ns-SELENA-SLEDAI and
BILAG index scores (p<0.06)(Table). Similarly, both
complement C4 and EC4d were associated with proteinuria (p<0.01).

Conclusion : CBCAPS are helpful in monitoring SLE disease in combination with
complement C3 and C4.

Table:
Multivariate analysis of the clinical improvements

*For 10 mg/dl
increase in C4 (predictor 1) and one log Net MFI decrease in CBCAPS (predictor
2), the ns-SELENA-SLEDAI change was –0.11x[10] +
0.65x[-1]=-1.75