Autoantibodies of various specificities play key roles in the pathogenesis of systemic lupus erythematosus (SLE). They are directly responsible for manifestations such as autoimmune thrombocytopenia, autoimmune haemolytic anaemia, antiphospholipid syndrome, neonatal lupus/congenital heart block and most cases of transversal myelitis. In addition, autoantibodies to dsDNA and nucleosomes may essentially contribute to lupus nephritis.

Antibodies are produced by plasma cells. Short-lived plasma cells die within a few days after their differentiation, whereas long-lived plasma cells can live as long as the organism does. Most importantly, long-lived plasma cells are resistant to most conventional treatments including high-dose prednisolone, cyclophosphamide and anti-CD20 antibodies, because plasma cells are mostly devoid of CD20. Hence, refractory SLE may often be caused by long-lived plasma cells secreting pathogenic antibodies. For these reasons plasma cells represent an attractive target for the treatment of SLE and other antibody-mediated diseases.

Meanwhile, there are several treatments available, at least in clinical trials, which eliminate plasma cells including the long-lived ones:

1. High-dose cyclophosphamide combined with anti-thymocyte globulin (also containing antibodies against plasma cells) and subsequent autologous stem cell transplantation. This vigorous procedure has substantial treatment-related morbidity and lethality, but, it can also cause an ‘immunological reset’ leading to long-term drug-free remissions of SLE. Of course, stem-cell transplantation affects most cells of the immune system, not only plasma cells.¹

2. Proteasome inhibitors: Due to their extremely high production of antibodies within the endoplasmic reticulum, plasma cells are highly sensitive towards proteasome inhibition, which blocks the degradation of misfolded proteins, thereby inducing endoplasmic reticulum stress and the terminal unfolded proteins’ response leading to apoptotic cell death.² Proteasome inhibitors affect predominantly plasma cells, however, they may target also other cells with a very high synthesis of secretory proteins. We demonstrated that the proteasome inhibitor bortezomib, which is approved for treatment of multiple myeloma, can efficiently deplete short- as well as long-lived plasma cells in mice and thereby ameliorates murine lupus nephritis.³ Moreover, in a case series the outcomes of 15 SLE patients were analysed, who had not sufficiently responded to standard treatment and hence, were offered treatment with bortezomib.⁴ The disease activity score SLEDAI and anti-dsDNA antibody titers decreased upon treatment. In all patients with active lupus nephritis proteinuria declined within 6 weeks after start of bortezomib. Total IgG concentrations decreased in most patients by approximately 25%, however, they usually remained within normal limits. All adverse events were mild or moderate. A proteasome inhibitor that targets preferentially immunoproteasomes is currently under investigation in clinical trials for the treatment of autoimmune diseases.

3. TACI-Ig (atacicept) is a soluble fusion protein of the extracellular domain of TACI and the Fc part of human IgG. Atacicept binds and neutralises the TACI ligands BAFF and, even more importantly, APRIL, which is a key survival factor for plasma cells. Atacicept eliminates quite specifically plasma cells and – as a consequence – causes often hypogammaglobulinemia with increased risk of infections. There is some evidence from placebo-controlled multi-centre clinical trials that atacicept may ameliorate SLE disease activity.

4. Anti-CD38 antibodies: CD38 is an ectoenzyme on the plasma membrane of different cell types such as many B and T cell subsets including plasma blasts and plasma cells. The anti-CD38 antibody daratumumab is approved for the treatment of multiple myeloma. Case reports indicate that daratumumab may be also beneficial in antibody-mediated autoimmune diseases such as severe autoimmune thrombocytopenia, autoimmune haemolytic anaemia and SLE.

In summary, plasma cell-targeted treatments may represent a new and highly effective treatment approach in SLE as well as other antibody-mediated diseases. Placebo controlled clinical trials are required to prove the efficacy and safety of plasma-cell depleting treatments in refractory SLE.

Learning Objectives

• Explain why plasma cells represent an attractive target for the treatment of SLE and other antibody-mediated diseases

• Discuss existing treatments, in clinical trials, which eliminate plasma cells and describe their potential for treating patients with SLE

References

1. Alexander T, Thiel A, Rosen O, et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 2009;113(1):214–23.

2. Meister S, Schubert U, Neubert K, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 2007;67(4):1783–92.

3. Neubert K, Meister S, Moser K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 2008;14(7):748–55.

4. Alexander T, Sarfert R, Klotsche J, et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 2015;74(7):1474–8.