The dawn of a new era of therapies in systemic lupus erythematosus

Mok, Chi Chiu

doi:10.2478/rir-2020-0005

Cited by 4 publications

(3 citation statements)

References 54 publications

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“…Many novel agents have halted progression for the negative results from pivotal RCTs. With the improvement in patient stratification, adjustment of background immunosuppression, and assessment of study endpoints, we are now having more approved drugs in SLE [ 171 ]. A number of targeted small molecules are undergoing clinical trials in patients with SLE.…”

Section: Discussionmentioning

confidence: 99%

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Mok

2023

Drugs

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Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton’s tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood–brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

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Section: Discussionmentioning

confidence: 99%

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Mok

2023

Drugs

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“…[ 15 ] After the IL-2R has been engaged, cell signaling involves the phosphorylation of the Janus-Activated Kinase (JAK) 1 and JAK3 that activate the downstream mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, leading to activation and nuclear translocation of STAT5 [ 16 ] ( JAK inhibitors are currently being tested in clinical trials in SLE). [ 17 ] The binding of signal transducer and activator of transcription 5 (STAT5) to the Foxp3 locus in response to IL-2 induces the expression of the Treg master regulator FoxP3, [ 18 ] which is important not only during the initial stages of activation but also for a long-term maintenance of functional T regs . [ 13 ]…”

Section: T Regsmentioning

confidence: 99%

Low-dose interleukin-2 therapy in systemic lupus erythematosus

La Cava

2023

Rheumatology and Immunology Research

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In systemic lupus erythematosus (SLE), T regulatory cells (Tregs) contribute to the inhibition of autoimmune responses by suppressing self-reactive immune cells. Interleukin (IL)-2 plays an essential role in the generation, function and homeostasis of the Tregs and is reduced in SLE. Several clinical studies, including randomized trials, have shown that low-dose IL-2 therapy in SLE patients is safe and effective and can reduce disease manifestations. This review discusses the rationale for the use of low-dose IL-2 therapy in SLE, the clinical responses in patients, and the effects of this therapy on different types of T cells. Considerations are made on the current and future directions of use of low-dose IL-2 regimens in SLE.

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“…However, as mentioned before, the type I interferon receptor inhibition decreases microglia related synaptic loss and attenuates anxiety-like behavior and cognitive deficits in lupus-prone mice [ 38 ]. This implies that type I interferon inhibition may be an option for the treatment of NPSLE in the future [ 106 ], especially in patients with a strong type I interferon signature.…”

Section: Promising Targeted Therapiesmentioning

confidence: 99%

Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus

Wang

Zhang

et al. 2022

JCM

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Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improving understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. In this review, we aimed to present the latest pathogenetic mechanisms of NPSLE and discuss the progress in its management.

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The dawn of a new era of therapies in systemic lupus erythematosus

Cited by 4 publications

References 54 publications

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Low-dose interleukin-2 therapy in systemic lupus erythematosus

Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus

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