Objective: In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and 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, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease.
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 BlyS 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 a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, 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. Trial registration: ClinicalTrials.gov NCT02284984.

Additional Metadata
Keywords Autoantibody, Belimumab, Clinical trial, Lupus nephritis, Neutrophil extracellular traps, Refractory lupus, Rituximab, Systemic lupus erythematosus
Persistent URL dx.doi.org/10.1016/j.jaut.2018.03.003, hdl.handle.net/1765/105715
Journal Journal of Autoimmunity
Kraaij, T. (Tineke), Kamerling, J.P, de Rooij, E.N.M. (Esther N.M.), van Daele, P.L.A, Bredewold, O.W. (Obbo W.), Bakker, J.A, … Teng, Y.K.O. (2018). The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. Journal of Autoimmunity. doi:10.1016/j.jaut.2018.03.003