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• W2754856887 abstract "Background Neutrophil extracellular traps (NETs) are extracellular, decondensed DNA strands covered with antimicrobial proteins that are part of the first-line defence against pathogens. However, in SLE, overall release of NETs is increased and degradation of NETs is impaired leading to a high amount of extracellular nuclear material, potentially leading to formation of SLE-specific antibodies. These pathogenic autoantibodies deposit in glomeruli in lupus nephritis (LN) and perpetuate autoimmunity by inducing more NETs. The present study hypothesized that combining anti-CD20 mediated B-cell depletion with BAFF (B-cell activating factor) inhibition can target autoreactive plasma cells and thereby effectively reduce pathogenic autoantibodies and NET induction in severe SLE. Objectives The present study aimed to investigate whether Rituximab (RTX) + Belimumab (BLM) affected pathogenic antibodies in relation to NET induction in severe refractory SLE. Methods As part of a phase 2 proof-of-concept study, the SynBioSe study, serum levels of anti-DNA autoantibodies were measured in severe, refractory SLE patients before and after treatment with RTX following BLM. Additionally, ex vivo NET induction was assessed before and after treatment with a novel highly sensitive method based on 3D confocal laser scanning microscopy. In this assay, healthy neutrophils are incubated with 10% serum of patients and healthy controls. Furthermore, we investigated whether NET induction was mediated by immune complexes. Results The study included 10 severe, refractory SLE patients with lupus nephritis and 1 patient with neuropsychiatric lupus. NET induction was found to be high at baseline with a median fold induction of 4.5 [range 2.6–11.7]. After 24 weeks, NET induction was significantly decreased (median fold NET induction of 1.6 [0.4–6.1], p=0.01). In addition, treatment with RTX+BLM led to significant reduction of anti-dsDNA antibodies at week 24 with a median of 35 IU/ml [range 10–374] compared to 120 [18–505] at baseline (p=0.012). Total immunoglobulin levels temporarily declined but returned to screening levels at week 24. NET induction correlated significantly with anti-dsDNA antibody levels (r=0.42, p=0.03) and with SLEDAI scores (r=0.53, p=0.003). Therefore, we examined whether the observed NET induction could be explained by circulating immune complexes (ICx). ICx were degraded by pre-incubating anti-dsDNA positive SLE sera with nuclease, resulting in a significant decrease in NET induction (median % decrease of 91.7 [range 67.6–98.1]). In addition, depletion of IgG from anti-dsDNA positive SLE sera resulted in significantly lower NET induction. Finally, immobilized IgG isolated from anti-dsDNA positive SLE sera, but not of control serum, resulted in significant NET induction. Conclusions Within refractory SLE patients, RTX + BLM resulted in concordant reductions in pathogenic anti-dsDNA antibodies and NET-inducing capacity. This study strongly suggests that NET induction in SLE is mediated by immune complexes, providing a possible explanation underpinning the clinical benefits of RTX+BLM in SLE. Trial registration:ClinicalTrials.gov NCT02284984 Disclosure of Interest None declared" @default.
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• W2754856887 date "2017-06-01" @default.
• W2754856887 modified "2023-09-26" @default.
• W2754856887 title "OP0302 Significant reductions of pathogenic autoantibodies by synergetic rituximab and belimumab treatment effectively inhibits neutrophil extracellular traps in severe, refractory sle - the synbiose study" @default.
• W2754856887 doi "https://doi.org/10.1136/annrheumdis-2017-eular.5706" @default.
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