Background/Purpose: Circulating immune complexes (IC) are detectable in a variety of systemic inflammatory diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), reflecting the autoimmune process, e.g. autoantibodies binding to self-antigens. ICs are main contributors to the disease pathogenesis through engaging FcgR-bearing cells, as well as activating the complement system, mediating inflammation and organ damage, including erosion and nephritis. The main aim of the current study was to explore the clinical utility of analyzing levels of circulating ICs in patients with rheumatic diseases using a novel flow cytometry-based assay developed in our lab.

Methods: Levels of ICs were analyzed by an in-house flow cytometry-based method, analyzing IC binding to FcgRIIA. Three cross-sectional SLE cohorts (n=92-142), one cross-sectional RA cohort (n=247), and healthy controls (n=100), were analyzed. To determine the capacity of ICs to predict disease flare in SLE, a forth, longitudinal SLE cohort (n=47) was recruited at time-point of low disease activity and followed over three months, with 14 patients remaining in remission, and 33 patients developing worsening of disease. A longitudinal inception RA cohort (n=247), seen for a follow-up a median of 8 years later, was used for predictive analyses. Type I interferon (IFN) activity was analyzed using a cell reporter system (WISH).

Results: Levels of ICs were elevated in SLE as compared to healthy controls (p< 0.0001). Whereas only 5% of the healthy controls had elevated levels of ICs, 61% of the SLE patients were positive for ICs, reaching more than 80% in patients with active disease. In contrast, anti-dsDNA antibodies, commonly used to monitor disease activity, were only detectable in 14% of the patients at time-point of blood draw. Though anti-dsDNA antibodies were associated with active disease (OR=3.5, p< 0.0001), dual positivity for both anti-dsDNA antibodies and ICs further strengthened the association with active disease (OR=5.9., p< 0.0001). Levels of ICs reflected active disease as determined by SLEDAI (r=0.45, p< 0.0001), and were associated with ongoing type I IFN activity (r=0.25, p=0.003), complement activation (r=0.53, p< 0.0001) and active lupus nephritis (p=0.02). Levels of ICs were elevated in patients with a history of nephritis (p=0.002) and anti-dsDNA antibodies (p< 0.0001). In the longitudinal setting, baseline levels of ICs, at time-point of quiescent disease, could predict worsening of disease within three months (OR=4.4, p=0.03). Levels of ICs were elevated also in RA patients (p< 0.0001), though the frequency of patients having circulating ICs was lower as compared to SLE patients (21.7%). Importantly, RA patients with elevated levels of ICs at baseline identified patients developing a severe and erosive disease with joint space narrowing (p< 0.05).

Conclusion: ICs are instrumental in RA and SLE pathogenesis. Analyzing IC levels may facilitate monitoring of disease activity, as well as identify patients at risk of developing flare and/or severe disease, including erosion and nephritis, allowing for early preventive interventions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-method-to-analyze-circulating-immune-complexes-predicts-disease-activity-and-severity-in-systemic-lupus-erythematosus-and-rheumatoid-arthritis/