FRI0329 The net-effect of combining rituximab with belimumab in severe systemic lupus erythematosus

Background In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed while their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, we hypothesised that interfering with ICx formation should regress NET formation and potentially ameliorate disease. Objectives: Investigate the effect of Rituximab+Belimumab therapy on pathogenic autoantibodies in relation to NET formation in severe refractory SLE Methods A phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor with belimumab. Besides safety, the study’s endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation. Results We demonstrated that SLE-derived immobilised IgG, but not soluble IgG, induced excessive NET formation, confirming ex vivo that ICx mediate excessive NET formation in SLE. We showed that therapeutic intervention with RTX+BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX+BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients. Conclusions This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX+BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology. Acknowledgements We thank professor C. Pusey (Imperial College London, UK) for kindly providing the Syk inhibitor R406 for our experiments. Disclosure of Interest O. Teng Grant/research support from: GlaxoSmithKline, Consultant for: Aurinia Pharmaceuticals, GlaxoSmithKline, T. Kraaij: None declared, S. Kamerling: None declared, E. de Rooy: None declared, P. van Daele: None declared, O. Bredewold: None declared, J. Bakker: None declared, I. Bajema: None declared, H. Scherer: None declared, R. Toes: None declared, T. Huizinga: None declared, T. Rabelink: None declared, C. van Kooten: None declared