Systemic lupus erythematosus (SLE): emerging therapeutic targets

ABSTRACT

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a heterogeneous clinical presentation whose etiologies are multifactorial. A myriad of genetic, hormonal, immunologic, and environmental factors contribute to its pathogenesis, and its diverse biological basis and phenotypic presentations make development of therapeutics difficult. In the past decade, tens of therapeutic targets with hundreds of individual candidate therapeutics have been investigated.

Areas covered

We used a PUBMED database search through April 2020 to review the relevant literature. This review discusses therapeutic targets in the adaptive and innate immune systems, specifically: B cell surface antigens, B cell survival factors, Bruton’s tyrosine kinase, costimulators, IL-12/IL-23, the calcineurin pathway, the JAK/STAT pathway, and interferons.

Expert opinion

Our ever-improving understanding of SLE pathophysiology in the past decade has allowed us to identify new therapeutic targets. Multiple new drugs are on the horizon that target different elements of the adaptive and innate immune systems. SLE research remains challenging due to the heterogenous clinical presentation of SLE, confounding from background immunosuppressives being taken by SLE patients, animal models that inadequately recapitulate human disease, and imperfect and complicated outcome measures. Despite these limitations, research is promising and ongoing. The search for new therapies that target specific elements of SLE pathophysiology are discussed as well as key findings, pitfalls, and questions surrounding these targets.

KEYWORDS:

• Lupus
• therapeutic target
• adaptive immune system
• innate immune system
• intracellular signaling

Article highlights

• Emerging therapies for SLE target the innate immune system, the adaptive immune system, and intracellular signaling pathways.

• Of the 42 promising therapeutics discussed in this review, we believe that voclosporin and anifrolumab are the most likely ones to emerge as successful therapies in the near future.

• Conventional wisdom is not always wise, and more is not always better. As an example, whereas rituximab – which robustly depletes B cells – failed in two phase 3 clinical trials, belimumab – which only modestly depletes B cells – emerged as the first FDA-approved biologic for SLE. We need to focus on data rather than on preconceived notions.

• Stratification of patients into clinical trials remains an issue in developing new SLE therapies. Our inability to categorize SLE patients into the appropriate ‘flavors’ undoubtedly has led to failure in clinical trials of potentially beneficial drugs.

• Omics analyses, including profiling of the epigenome, transcriptome, and metabolome, should enhance our knowledge of SLE and help us uncover novel targets and biomarkers.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Selena Gomez Fund and the USC Thomas D Beardmore, MD Memorial endowment fund.