Novel and emerging treatment strategies for lupus nephritis

ABSTRACT

Introduction

Lupus nephritis (LN) is a key predictor for kidney failure and death in patients with systemic lupus erythematosus. While conventional immunosuppressive treatments have improved the outcome of LN, novel therapies continue to emerge. These new agents targetspecific immune-reactive cells, cytokines and signaling pathways in LN pathogenesis.

Areas covered

New therapeutic approaches that target B cells, T cells, crucial cytokines and their signaling pathways in LN.

Expert opinion

Although earlier studies of rituximab fail to show benefit, a newer generation anti-CD20 biologic, obinutuzumab, is promising in LN. Inhibition of B-cell activating factor by belimumab confers superior renal response when added to the standard of care (SOC) regimens, leading to its recent approval for LN. Therapies targeting plasma cells (proteasome inhibitors, anti-CD38) in LN are being developed. A newer generation calcineurin inhibitor, voclosporin, when combined with SOC, results in better renal responses in LN. Other innovative strategies include targeting type I interferon, co-stimulatory signals, complement cascade (anti-C5b) and intracellular proliferation signals (e.g. mTOR, JAK1/2, BTK). While these novel agents improve the short-term renal responses without increased toxicities, long-term data on disease progression and safety remain to be established. Patient stratification by clinical phenotypes, biomarkers and molecular profiles helps enhance the efficacy and cost-effectiveness of novel therapies of LN.

KEYWORDS:

• Novel
• lupus
• nephritis
• anti-CD20
• calcineurin
• BAFF
• belimumab

Article highlights

• Despite existing therapies, end stage kidney disease still develops in 5-30% of LN patients after 10 years. There is an unmet need of novel therapeutic agents to improve the efficacy but reduce toxicity in LN patients.

• Inhibition of B-cell activating factor (belimumab) or calcineurin (voclosporin), in combination with standard-of-care (SOC) regimens, has been shown to enhance the renal response rates in active LN.

• Obinutuzumab, a newer generation anti-CD20 monoclonal antibody, is promising in a phase 2 study of LN.

• Other novel therapeutic approaches include targeting type I interferon, co-stimulatory signals, complement cascade and intracellular signal pathways.

• Long-term data on renal function preservation and safety of these emerging therapies are eagerly awaited.

• Patient stratification by clinical phenotypes, biomarkers and molecular profiles helps enhancing the efficacy and cost-effectiveness of novel therapies of LN.

Declaration of interest

DYH Yap has received research donations from the Wai Im Charitable Foundation and the Chan Sui Kau Family Benefits and Charitable Foundation. DYH Yap also received research funding support from the Mr and Mrs Tam Wing Fun Edmund Renal Research Fund. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.