Purpose To investigate the therapeutic relevance of targeting long-lived plasma cells (PC), which contribute to the chronicity of SLE through continuous secretion of pathogenic antibodies, using immunoablation with antithymocyte-globulin (ATG) in the context of haematopoietic stem cell transplantation (HSCT) or proteasome inhibition with Bortezomib.
Methods Prospective analysis of outcome in 10 SLE patients after receiving autologous HSCT between 1998 and 2012 and 8 SLE patients after receiving a median 2 cycles (range 1–4) of Bortezomib 1.3 mg/m2 between 2009 and 2012 at the Charité – University Medicine Berlin. Multiparametric flow cytometry was applied to characterise peripheral blood or bone marrow PC subsets and B cells. Autoantibodies and vaccine titres were investigated with ELISA.
Results In all HSCT treated patients clinical remissions (SLEDAI <3) were achieved, accompanied by a complete normalisation of anti-dsDNA antibody titres (92.6% reduction) and a significant reduction of antinuclear antibodies and vaccine titres (measles 82.3%). Peripheral blood B and PCs were virtually absent and bone marrow PCs largely depleted (97.6% reduction, n=1) shortly after HSCT and regenerating B cells almost exclusively displayed a naïve phenotype. Upon proteasome inhibition, clinical improvements were associated with a significant reduction of anti-dsDNA autoantibodies (69.3%) and vaccine titers (measles 32.5%). While B cell number/phenotype remained stable, both bone marrow and circulating PC were significantly reduced (~50%) but rapidly regenerated after proteasome inhibition, which could be prevented by additional rituximab therapy in one patient applied.
Conclusions Although less prominent compared to HSCT, proteasome inhibition with Bortezomib promoted a therapeutically relevant PC depletion in refractory SLE. Nevertheless, for sustained responses, PC depletion needs to be combined with therapeutic strategies targeting their precursor B cells, e.g. with rituximab, as indicated by our preclinical studies in murine lupus.
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