Advances in the Pathogenesis and Treatment of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a genetically predisposed, female-predominant disease, characterized by multiple organ damage, that in its most severe forms can be life-threatening. The pathogenesis of SLE is complex and involves cells of both innate and adaptive immunity. The distinguishing feature of SLE is the production of autoantibodies, with the formation of immune complexes that precipitate at the vascular level, causing organ damage. Although progress in understanding the pathogenesis of SLE has been slower than in other rheumatic diseases, new knowledge has recently led to the development of effective targeted therapies, that hold out hope for personalized therapy. However, the new drugs available to date are still an adjunct to conventional therapy, which is known to be toxic in the short and long term. The purpose of this review is to summarize recent advances in understanding the pathogenesis of the disease and discuss the results obtained from the use of new targeted drugs, with a look at future therapies that may be used in the absence of the current standard of care or may even cure this serious systemic autoimmune disease.

Keywords: B-cells; T-cells; cell-based therapy; plasmacytoid cells; systemic lupus erythematosus; type-I interferon.

Figure 1

SLE classification according to EULAR/ACR 2019 criteria and measurement of disease activity and organ damage. The entry criterion consists of antinuclear antibody (ANA) positivity on at least one occasion. Definitive diagnosis requires 10 points derived from clinical and immunologic criteria. Disease activity is assessed by the SLE Disease Activity Index-2000 (SLEDAI-2K), British Isles Lupus Activity Group 2004 (BILAG 2004), and Physician Global Assessment (PGA). Organ damage is assessed by the SLICC/ACR damage index (SDI).

Figure 2

Both innate and adaptive immunity participate in the pathogenesis of SLE. In individuals with a genetic predisposition, and with the contribution of environmental factors, there is an accumulation of apoptotic cells and activation of NET production, by neutrophils. Cell nucleic acids are then exposed to the immune system and activate dendritic cells via toll-like receptors, to produce type-I IFN. This cytokine is responsible for activation of specific genes for pro-inflammatory factors by target cells (IFN signature). Dendritic cells also produce BAFF, which is necessary for B-cell activation and survival, and activate T cells, through the presentation of nuclear self-antigens. Self-reactive B cells are then activated to produce antibodies, and differentiate into long-lived plasma cells, localized in niches in the bone marrow, which are an additional source of autoantibodies. Autoantibodies form immunocomplexes with specific nuclear self-antigens that precipitate in tissues, contributing to organ damage.