RESUMO
OBJECTIVES: To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE). METHODS: Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3â mg/m(2)) with the coadministration of dexamethasone (20â mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity. RESULTS: Upon proteasome inhibition, disease activity significantly declined and remained stable for 6â months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (â¼60%) than vaccine-induced protective antibody titres (â¼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (â¼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined. CONCLUSIONS: These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.