Synthetic Pharmacotherapy for Systemic Lupus Erythematosus: Potential Mechanisms of Action, Efficacy, and Safety

Abstract

The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy.

Keywords: antimalarial drug; efficacy; glucocorticoid; immunosuppressant agent; safety; systemic lupus erythematosus.

Figure 1

Mechanism of action of antimalarial immunomodulation during autoimmunity. HCQ accumulates in lysosomes and inhibits the degradation of cargo derived externally (via endocytosis or phagocytosis) or internally (via the autophagy pathway) in autolysosomes by increasing the pH to prevent the activity of lysosomal enzymes. Inhibition of lysosomal activity can prevent MHC class II-mediated autoantigen presentation. Adapted from Schrezenmeier et al. [6]. Created with BioRender.com (accessed on 17 October 2022).

Figure 2

Genomic mechanisms of glucocorticoid-induced anti-inflammation. GCs bind to their cytosolic glucocorticoid receptor (GCR), which subsequently loses its chaperoning proteins, such as heat shock proteins (Hsp). Homodimers are formed, travel to the nucleus, bind to the glucocorticoid response element (GRE), and upregulate the expression of certain genes (e.g., lipocortin-1 and genes involved in metabolism), a mechanism called transactivation. Monomeric GC–GCR complex (mGC-GCR) can bind to transcription factors as AP-1 and NF-kβ, inhibiting the transcription of their target genes (e.g., IL-2 and TNFα) by a mechanism called transrepression. Further, direct binding of mGC-GCR alongside AP-1 on composite GREs lead to transrepression. Created with BioRender.com (accessed on 17 October 2022).