Background Cell-bound complement activation products (CB-CAPs), including erythrocyte-bound C4d (EC4d) and B-lymphocyte-bound C4d (BC4d), in a multi-analyte assay with algorithm (MAP) represent an important addition to the diagnostic armamentarium of SLE. The clinical and serologic phenotype of SLE patients with elevated levels of CB-CAPs has not been well described. Herein, we assessed the demographics, clinical manifestations, medical therapy, and laboratory variables of SLE patients with and without elevated CB-CAPs.

Materials and Methods This was a cross-sectional study of adult SLE patients (2012 SLICC or 2019 ACR/EULAR criteria) from June 2020 to July 2022. Patients completed the polysymptomatic distress scale. The managing physician scored the PGA and SLEDAI scores. Autoantibodies including ANA and anti-RNA-binding proteins were determined by ELISA. Anti-dsDNA was measured by immunofluorescence using the Crithidia luciliea assays. CB-CAPs were determined by flow cytometry. The multi-analyte assay panel (MAP) was determined using a 2-tier algorithm. All autoantibodies, EC4d, and BC4d were tested in Exagen’s clinical laboratory. Fisher’s exact test and Kruskal-Wallis test were used to analyze differences in clinical and laboratory variables between CB-CAPs positive and CB-CAPs negative patients.

Results In this cohort of 185 SLE patients (90% female, 60% Black, mean age 44 years), 70% were MAP positive and 46% were BC4d and/or EC4d positive. CB-CAPs positive patients were younger, but there were no differences in sex, ethnicity, race, or mean length of disease between CB-CAPs positive and negative patients. Although almost all patients met both SLICC and ACR/EULAR classification criteria, the total ACR/EULAR classification score was greater for CB-CAPs positive patients. Higher rates of nephritis, serositis, alopecia and hematologic criteria were observed in the CB-CAPs positive patients.

Additionally, CB-CAPs positive patient demonstrated evidence of SLE disease activity with significantly higher SLEDAI scores. Numerically more CB-CAPs positive patients had SLEDAI rash and met SLEDAI renal criteria. There was no difference in medication use or features of polysymptomatic distress such as widespread pain, fatigue, or depression (table 1).

Serologic activity emerged as a hallmark of CB-CAPs positivity. CB-CAPs positive patients were more likely to have positive ANA, anti-Sm, anti-U1RNP, anti-RNP70, anti-C1q and anti-phospholipid antibodies than those who were CB-CAPs negative (table 2). Serologic markers of disease activity including elevated levels of anti-dsDNA and decreased C3 or C4 also tracked with CB-CAPs positivity (table 2).

Conclusion Narrowing the heterogenous clinical and immunologic features of SLE into endotypical subgroups is a crucial step toward precision medicine and personalized care in SLE. CB-CAPs positive patients represent an important subset of patients who are characterized by greater serologic activity and internal organ pathology. Moreover, the cumulative burden of SLE activity is greater in those with CB-CAPS positivity, as measured by the ACR/EULAR criteria score. CB-CAPs positivity could provide both diagnostic and prognostic information with implications for improved disease monitoring. Further studies are needed to assess the effects of targeted therapeutics and the long-term outcomes of the CB- CAPs positive endotype.

Acknowledgements None.