期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 74, 期 7, 页码 1474-1478出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2014-206016
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资金
- German Research Foundation (DFG) [SFB650 TP12, SFB650 TP17, FOR 831 TP 8 [VO673/3-2]]
- German Research Foundation (DFG) Transregio SFB [TRR 130, TP12, TP15]
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 (1.3 mg/m(2)) with the coadministration of dexamethasone (20 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 6 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 (similar to 60%) than vaccine-induced protective antibody titres (similar to 30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (similar to 50%), 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.
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