Reviews and feature article
Current and novel therapeutics in the treatment of systemic lupus erythematosus

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant clinical heterogeneity. Recent advances in our understanding of the genetic, molecular, and cellular bases of autoimmune diseases and especially SLE have led to the application of novel and targeted treatments. Although many treatment modalities are effective in lupus-prone mice, the situation is more complex in human subjects. This article reviews the general approach to the therapy of SLE, focusing on current approved therapies and novel approaches that might be used in the future.

Section snippets

Antimalarial drugs–hydroxychloroquine

Antimalarial drugs remain the first-line treatment for patients with mild SLE along with nonsteroidal anti-inflammatory drugs. Hydroxychloroquine is effective in the treatment of mild SLE manifestations, as well as in preventing the occurrence of new mild SLE manifestations, but it is ineffective in preventing the occurrence of severe SLE manifestations.1, 2 Antimalarial drugs inhibit phagosome function, thereby inhibiting Toll-like receptor (TLR) activation, leading to a downregulation of

Immune cell–targeted therapies

B cells are at the center of SLE pathogenesis. In addition to secretion of autoantibodies, B cells can take up autoantigens through cell-surface immunoglobulin (the B-cell receptor [BCR]) and present them to T cells, as well as regulate and organize inflammatory responses through cytokine secretion and regulation of other immune cells. Ideally, B cell–targeted therapies would eliminate pathogenic B cells, promote the expansion and function of protective B cells, or both. Current therapies that

Targeting costimulatory signaling pathways

CD40 binding to CD40 ligand is one of the most important costimulatory signals on B cells, inducing activation, proliferation, and class switching. Neutralizing CD40 ligand (CD40L) can interfere with germinal center reactions and will also diminish activation of marginal-zone B cells. Direct inhibition of collaboration between B and T cells through inhibition of the CD40-CD40L pathway has been demonstrated to be effective in murine models of lupus.28, 29

Two studies of anti-CD40L antibodies in

Anti-cytokine therapy

The alternate way to directly target immune cells is to interfere with their messengers.

Immune cells exert many of their effector and immunoregulatory functions through cytokine release. Most cytokines investigated have been found to be dysregulated in patients with SLE.

Summary

In this review article the general approach to the treatment of SLE, focusing on current approved therapies, ongoing clinical trials, treatment successes and failures, and novel approaches that have a potential to be used in the future, are discussed in detail (Table I). Advances in our understanding of the mechanisms of SLE have offered better drug targets for treatment. Several important questions remain, such as what the initiating stimuli for autoimmunity are and how the cascade of events

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    Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

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