54 Blood concentrations of complement split product iC3b and serum C3 associate with systemic lupus erythematosus disease activity

Abstract

Objective. To examine correlations between blood levels of complement split product iC3b and serum component C3 with clinically meaningful changes in disease activity in patients with systemic lupus erythematosus (SLE).Methods. A total of 159 consecutive patients with SLE, diagnosed according to the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria, were enrolled in CAS-TLE (Complement Activation Signatures in Systemic Lupus Erythematosus), a prospective observational study. Patients with 1-7 study visits were included in this longitudinal analysis. In addition, 48 healthy volunteers were enrolled to establish a normal reference value for the ratio of blood iC3b to serum C3 concentrations. Serum C3 and C4 levels were measured by nephelometry, and blood iC3b levels were measured by a lateral flow assay. SLE disease activity was monitored with the Responder Index 50 instrument of the SLE Disease Activity Index 2000.Results. Relative changes in the iC3b:C3 ratio, levels of anti-double-stranded DNA (anti-dsDNA) antibodies, and use of a supraphysiologic dose of prednisone (>7.5 mg/day) each independently correlated with SLE disease activity, as determined in multilevel multiple logistic regression analyses. Only the iC3b:C3 ratio was significantly associated with clinically meaningful improvements in disease activity among patients with SLE who were receiving a supraphysiologic dose of prednisone. The iC3b:C3 ratio outperformed C3 and C4 levels with regard to discriminating active SLE from inactive SLE, and major flares from no disease activity. The iC3:C3 ratio, anti-dsDNA antibody levels, erythrocyte sedimentation rate, and use of a supraphysiologic prednisone dose were each independently associated with the presence of lupus nephritis, whereas none of these measures was associated with SLE rash. The association of the iC3b:C3 ratio with lupus nephritis was independent of other observed clinical manifestations.Conclusion. The ratio of blood iC3b to serum C3 concentrations correlates with the extent of SLE disease activity and with clinically meaningful changes in disease activity in patients with SLE. Furthermore, the iC3b:C3 ratio may discriminate between active and inactive SLE, and between major flares and no active disease.

Complement Receptor 2 Based Immunoassay Measuring Activation of the Complement System at C3-Level in Plasma Samples From Mice and Humans

“…The different assays may indeed be useful in different settings (55,56). Research has previously shown that measuring complement activation products in complement-related diseases like SLE could be advantageous in terms of sensitivity and specificity as compared to measuring low levels of C3 and C4, since the levels of these proteins are the net result of both consumption and synthesis (11,(57)(58)(59). However, when it comes to studying complementrelated diseases in the preferred in vivo model -mice -low levels of C3 or C4 are still often used to estimate the systemic levels of complement activation (60).…”

Clinical promise of next-generation complement therapeutics

“…Undeniably, advancing novel therapies into clinical trials is tightly intertwined with a need for robust and more reliable diagnostic platforms that will standardize universally applied biomarkers for patient diagnosis and staging 217 . Indeed, more focus should be placed on monitoring dynamic changes in complement biomarkers and on ratios of activated versus total protein, rather than absolute protein levels in fluids or tissues, since the latter are merely snapshots that can misguide treatment by causing clinicians to overlook underlying pathogenic mechanisms 217,218 . The varied plasma half-lives of complement activation fragments (C3b, iC3b, C3dg and C3a/C5a) and their differential clearance rates from tissues should be taken into account when ongoing disease activity is measured by immunoassays that quantitate specific activation fragments or complexes (for example, C5b-9) 218,219 .…”

“…Indeed, more focus should be placed on monitoring dynamic changes in complement biomarkers and on ratios of activated versus total protein, rather than absolute protein levels in fluids or tissues, since the latter are merely snapshots that can misguide treatment by causing clinicians to overlook underlying pathogenic mechanisms 217,218 . The varied plasma half-lives of complement activation fragments (C3b, iC3b, C3dg and C3a/C5a) and their differential clearance rates from tissues should be taken into account when ongoing disease activity is measured by immunoassays that quantitate specific activation fragments or complexes (for example, C5b-9) 218,219 . In this direction, the advent of high-dimensional multi-omics technologies, such as single-cell RNA sequencing (RNAseq) and mass cytometry, coupled with the availability of powerful genome editing tools such as the CRISPR-Cas9 system, are expected to leverage complement diagnostics for identifying new therapeutic targets and informing complement intervention in new and unexplored indications 220,221 .…”

Association of Autoantibody Quantification With Systemic Lupus Erythematosus Disease Activity: Comment on the Article by Kim et al

“…We read with great interest the recent article by Dr. Kim and colleagues regarding the association of blood concentrations of complement split product iC3b and serum C3 with systemic lupus erythematosus (SLE) disease activity . SLE is a prototypic autoimmune disease characterized by excess autoantibody production.…”