Synergetic B-cell Immunomodulation in SLE - 2nd Study.

Rationale: The SynBioSe-1 study is the first study to comprehensively describe the clinical and immunological effects of combining rituximab (RTX) and belimumab (BLM) in patients with systemic lupus erythematosus (SLE). From the pioneering SynBioSe-1 study, we have learned that combining RTX+BLM was safe and well-tolerated with important clinical responses. Immunologically, we unexpectedly observed that long-term B-cell depletion was not achieved due to migration of mature B-cells triggered by depletion of BAFF serum levels. The latter observation was in contrast to the study's null-hypothesis that combination therapy would lead to long-term B-cell depletion. The contrary was demonstrated, namely the relative early recirculation of mature B-cells. As such, the immunological and clinical lessons from the SynBioSe-1 study in conjunction with accumulating data from several large studies on combination B-cell targeted treatment have led to the postulation that starting treatment with RTX+BLM would result in an improved B-cell targeting strategy, notably on tissue-resident autoreactive B-cells, associated with improved long-term clinical disease amelioration. Therefore, the present SynBioSe-2 study is designed to further investigate the long-term clinical and imunological efficacy of combination B-cell targeting by starting treatment with belimumab followed by rituximab. Objectives: The primary objective is to assess whether combination treatment BLM+RTX will lead to reduced treatment failure and the improvement of pivotal, SLE-specific autoimmune phenomena compared to SLE patients treated with standard of care. Study design: a multi-center, randomized, controlled, open-label study Study population: SLE patients with a severe flare with major organ involvement or persistent high disease activity despite conventional treatment Intervention: In addition to standard therapy, SLE patients will receive self-administered, subcutaneous injections of belimumab every week for the entire study period and 2 infusions of rituximab 1000 mg on day 28 (week 4) and day 42 (week 6). Main study parameters: The primary clinical efficacy parameter is the treatment failure rate during the 2 years study period. Secondary endpoints are clinical and non-biased immunological effects of the treatment summarized as follows: reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibody production at 28 weeks, total renal response rate at 28 weeks, regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation at 28 weeks; sustained, long-term B-cell depletion during 104 weeks; sustained reduction of relevant anti-nuclear autoantibodies, including seroconversion during 104 weeks; and sustained regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation during 104 weeks. Additionally, the study will perform safety and toxicity monitoring according to Common toxicity Criteria (CTC) developed by the National Cancer Institute (NCI) with the use of Common Terminology Criteria for Adverse Events (CTCAE) and evaluate the reduction of concomitant immunosuppression and the number of moderate and severe flares during study follow-up. Study duration: 104 weeks. Nature and extent of the burden and risks associated with participation and potential benefits: The study will include SLE patients with a severe flare necessitating remission induction treatment with intensive immunosuppression. The use of belimumab followed by rituximab can ameliorate disease activity even more than conventional treatment in the short-term and contribute to the successful tapering of concomitant immunosuppressive treatment. The latter will possibly lead to the reduction of infectious complication as compared to conventional treatment. The risks are predominantly related to the side effect profile of rituximab and belimumab and infectious complications of long-term B-cell depletion.