Background The proteasome inhibitor bortezomib, approved for the treatment of multiple myeloma, has been demonstrated to deplete short- and long-lived plasma cells (PCs) and ameliorate nephritis in murine models of systemic lupus erythematosus (SLE). Here, we aimed to analyse the effect of bortezomib in refractory SLE patients.
Methods In this single-centre cohort study, eight SLE patients with active disease despite immunosuppressive treatment received up to four 21-day cycles of bortezomib 1.3mg/m2, on days 1, 4, 8, and 11 by intravenous injection as an “off-label” treatment. Multicolor flow cytometry was performed to analyse peripheral blood B and PC subsets as well as Siglec-1 expression on monocytes. Autoantibody and vaccine titres as well as B cell activating factor (BAFF) levels in serum were analysed with ELISA.
Results From 2009 until 2012, eight SLE patients received a median of two bortezomib cycles (range one to four). Under proteasome inhibition, disease activity significantly improved with a median SLEDAI reduction from 13 to 4 (p>0.001). Bortezomib treatment had profound effects on antibody titers, with greater reduction in pathogenic (anti-dsDNA-abs. 58.7%) than protective antibody titers (e.g. anti-Tetanus-abs. 29.2%). In addition, total immunoglobulin levels and Siglec-1 expression on monocytes (as surrogate for type I interferon) significantly decreased (p = 0.016), whereas BAFF and complement levels significantly increased. While circulating B-cell numbers remained unaffected, bortezomib treatment resulted in a significant depletion of both HLA-DR+ short-lived (55.5% reduction, p = 0.024) and HLA-DR- long-lived (53.5% reduction, p = 0.038) peripheral blood PCs. Also IgA secreting PCs were depleted (61.8% reduction). Nevertheless, PCs were rapidly regenerated with a median increase of 268.8% within 10 days from the last bortezomib application.
Conclusion Proteasome inhibition with bortezomib has beneficial effects on disease manifestations in SLE by PC depletion and inhibition of type I interferon but regeneration of PCs is not prevented. Overall, proteasome inhibition has demonstrated the therapeutic relevance of targeting autoreactive memory plasma cells as such, and it constitutes a new therapeutic option. Nevertheless, fur sustained efficacy, proteasome inhibition needs to be combined with therapeutic approaches targeting B cell activation and differentiation to inhibit PC regeneration.
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