Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors

Abstract

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19 phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.

Rituximab/Bendamustine treatment of chronic lymphatic leukemia leads to sustained remission of antiphospholipid antibodies

“…RTX/BDM treatment) induced a significant reduction of aPL over a four‐year period and parallels the concept postulated in the study by Alexander et al. in which the authors used Bortezomib for the management of SLE .…”

The short‐term efficacy of combined treatments targeting B cell and plasma cell in severe and refractory Anti‐N‐methyl‐D‐aspartate receptor encephalitis: Two case reports

“…Researches have shown that for antibody‐related autoimmune diseases, the combined treatment strategy targeting B cells and plasma cells is superior to B‐cell depletion therapy alone . Based on our clinical observations, we propose that it also can improve the prognosis of severe and refractory anti‐NMDAR encephalitis.…”

“…It was associated with a significant depletion of short-and long-lived plasma cells in peripheral blood and bone marrow. 8 In past two years, there are a few reports of bortezomib for the treatment of severe anti-NMDAR encephalitis 9,10 and they confirmed that it could reduce antibody titers. Monitoring of CD138+ plasma cells in peripheral blood in our study confirmed its targeted therapeutic effect on plasma cells.…”

“…Bortezomib, as a proteasome inhibitor, it blocks the activation of antiapoptotic nuclear factor kappa B (NF‐κB) and activates the terminal unfolded protein response leading to apoptosis. It was associated with a significant depletion of short‐ and long‐lived plasma cells in peripheral blood and bone marrow . In past two years, there are a few reports of bortezomib for the treatment of severe anti‐NMDAR encephalitis , and they confirmed that it could reduce antibody titers.…”

Neue Erkenntnisse zur Pathogenese des SLE und ihre Auswirkungen auf die Entwicklung neuer Therapie-Konzepte

“…B. mit Bortezomib kommt es sowohl in der Lupus-Maus als auch bei aktiven SLE-Patienten zu einer raschen Auffüllung des langlebigen Plasmazell-Kompartiments, wenn als Folge der bestehenden B-Zell-Aktivierung autoreaktive Plasmablasten produziert werden, die in das Knochenmark einwandern und dort die frei gewordenen Nischen besetzen, um als langlebige Plasmazellen zu überleben. Dies konnte durch die Kombination mit einer Therapie, die B-Zellen als Target hat (Immunsuppressiva, B-Zell-Depletion mit dem Anti-CD20-Antikörper Rituximab, Inhibition der B-Zell-Aktivierung durch BAFF/ BLyS mit Belimumab), aber auch durch die Hemmung der Einwanderung neu gebildeter Plasmablasten in das Knochenmark mittels Blockade der CXCR4-CXCL12-Achse verhindert werden [22][23][24][25] [28,29]. Aufgrund der Bedeutung der Typ-I Interferone für die Aktivierung von Autoimmunität stellen sie ein interessantes therapeutisches Target beim SLE dar.…”