Background: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti... Show moreBackground: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate. Methods: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections. Discussion: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE. Show less
First, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of... Show moreFirst, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of confocal microscopy with multiple z-stacks, makes it a sensitive method. We provided a context of how NETs can be quantified in SLE and AAV. We demonstrated that not all NETs are created equally and translation of NET formation to a digital quantification creates a narrow view. We showed higher ex vivo NET formation in AAV patients with active disease compared to AAV patients with an underlying infection supporting that excessive NET formation is an autoimmune phenomenon. Also, we demonstrated that the observed excessive NET formation is independent of ANCAs.In the next part of this thesis, we focused on new treatments in lupus nephritis. Most importantly, the results of the Sybiose study are shown; a phase 2 proof-of-concept study that included 15 patients with severe, refractory SLE treated with rituximab and belimumab. We showed that RTX+BLM has the ability to reduce autoantibodies, thereby indirectly reducing excessive NET formation in SLE, presumably due to the targeting of autoreactive B cells. Further, we observed a clinical response in our patients while tapering immunosuppressive medication. Show less
