Background A major unmet need in SLE is the identification of a biomarker that consistently tracks with disease activity. One current approach is measuring complement activation by evaluating consumption of serum C3 and C4. However, since they are acute phase reactants, interpretation of these levels is challenging as serum levels may not decrease until late in a disease flare. iC3b is a proteolytically derived molecule of C3b and increases with complement activation. iC3b/C3 ratio measures complement consumption relative to production, which may provide for a more accurate assessment of complement activation. We hypothesize that blood iC3b and iC3b/C3 levels will provide a more specific and reliable marker of complement activation and disease activity in SLE.
Methods 159 consecutive subjects with American College of Rheumatology or Systemic Lupus International Collaborating Clinics classified SLE were enrolled into CASTLE (Complement Activation Signatures in Systemic Lupus Erythematosus), a prospective observational study. Patients with 1–7 study visits were included in this longitudinal analysis. 48 healthy volunteers were enrolled to establish the normal reference iC3b/C3 ratio. Serum C3 and C4 were measured by nephelometry and blood iC3b levels by a lateral flow assay. SLE disease activity was monitored utilizing the Systemic Lupus Erythematosus Disease Activity Index 2K Responder Index-50 instrument.
Results iC3b/C3 ratio, double-stranded (ds)DNA antibodies (Abs), and supraphysiologic prednisone dose (>7.5 mg/day) each independently correlated with SLE disease activity, employing multilevel multiple logistic regression analysis. Only the iC3b/C3 ratio was significantly associated with clinically meaningful improvements in disease activity among subjects receiving supraphysiologic doses of prednisone. iC3b/C3 outperformed C3 and C4 levels discriminating both active versus inactive SLE disease and major flares versus no disease activity. iC3/C3, dsDNA Abs, ESR, and supraphysiologic prednisone dose were independently associated with lupus nephritis, while none were associated with SLE rash. The association of iC3b/C3 with nephritis was independent of other observed clinical manifestations. Finally, we observed a stronger association of the iC3b/C3 ratio with SLE disease activity in African-Americans compared to Whites.
Conclusions Blood iC3b/C3 correlates with SLE disease activity and clinically meaningful changes. Furthermore, it discriminates between active versus inactive SLE, and major flares compared to those patients without active disease. Differences in the strength of association was observed between races and manifestations.
Funding Source(s): Kypha, Inc. and National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under Award Number R21AR069833.
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