A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE

Abstract

Objectives SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell–targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation. Methods Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation. Results Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ. Conclusion This study demonstrated the impact of different B cell–targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…Low disease activity, including a significant reduction in auto-antibody titers, was achieved in over 50% of patients in the study. Further analysis of sera from the patients in this study revealed that the combination of rituximab and belimumab significantly decreased anti-dsDNA, anti-histones, anti-nucleosomes and anti-C1q titers ( 155 ). In addition, the ability of patient sera to induce NET formation in vitro was decreased by around 75% following combination therapy with rituximab and belimumab ( 155 ).…”

“…Excess NET production represents an exciting prospect for therapeutic development, with the potential to break the chain leading to auto-antigen recognition, activation of pDCs, interferon production, auto-antibody production and damage to local tissues, such as cartilage and microvessels within the kidney. As mentioned earlier, a clinical trial of rituximab and belimumab inhibited NET production in SLE, and this was associated with lower auto-antibody titers (including lower anti-dsDNA and anti-histones) and a decrease in disease activity (154,155). NET production may also be targeted by inhibitors of PAD4, MPO and neutrophil elastase.…”

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies

“…In particular, one of our patients received at the same time rituximab and belimumab. This combination has been recently tested and demonstrated to reduce immune-complex-mediated inflammation and NETs formation [ 21 ].…”

Role of Proteasomes in Inflammation

“…Clinical data from a small study involving 12 patients with SLE [ 64 ] and a randomized double-blind controlled trial with 14 patients with SLE [ 162 ] have shown a beneficial effect of bortezomib on disease outcome. Similarly, in another study, bortezomib was shown to deplete PCs and reduce autoantibody production [ 127 , 163 ]. As discussed earlier, this effect can be easily explained by the fact that antigen-producing PCs need a high proteasomal capacity to degrade misfolded antibodies, which renders them susceptible to proteasome inhibition [ 127 ].…”