Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology–Classified Systemic Lupus Erythematosus

Abstract

Objective To evaluate the frequency of cell‐bound complement activation products (CB‐CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. Methods Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB‐CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB‐CAPs, was also evaluated. Probable SLE cases were followed up prospectively. Results The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB‐CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). Conclusion Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB‐CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.

Finding lupus in the ANA haystack

“…Similar findings were seen in a recent report which documented that high scores on the multianalyte panel that included CBCAPs in patients with three ACR classification criteria was predictive of development of the fourth criterion within 18 months 11. Together, these two studies add weight to the concept that SLE is a disease in evolution with evidence of immune system activation (in this case immune complex-driven complement deposition) preceding the accumulation of sufficient clinical and laboratory classification criteria.…”

“…Similarly, serum levels of complement proteins C3 and C4 correlate with formation of immune complexes that are central to the pathogenesis of SLE, but while low complement levels are informative about activity in established SLE, early, undifferentiated disease may be less commonly associated with depressed complement levels. In a recent study of patients with three American College of Rheumatology (ACR) classification criteria, who were considered to have probable SLE, less than 10% had hypocomplementemia 11…”

Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses

“…Complement activation and consumption is a hallmark of SLE [54]. Lower levels of complement factors C3 and C4, indicating classic complement consumption, was found in sera of a subset of SLE patients with impaired NETs clearance [26].…”

A Combination of Complement Activation Products With Autoantibodies Predicts Transition of Probable Lupus to Systemic Lupus Erythematosus: Comment on the Article by Lambers et al

“…We welcome the attempt to develop a diagnostic test that can predict progression to SLE. Early identification of SLE is one of the main challenges faced by clinicians and is hindered by both the heterogeneous presenting symptoms of the disease, as well as overlap with other diseases (1,2). Timely treatment, however, is important in order to limit disease progression and prevent organ damage and mortality (3).…”