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Abstract
Lupus nephritis is an important cause of both acute kidney injury and chronic kidney disease that can result in end-stage renal disease. Its pathogenic mechanisms are characterized by aberrant activation of both innate and adaptive immune responses, dysregulation of inflammatory signaling pathways, and increased cytokine production. Treatment of lupus nephritis remains a challenging issue in the management of systemic lupus erythematosus since the clinical presentation, response to treatment, and prognosis all vary considerably between patients and are influenced by ethnicity, gender, the degree of chronic kidney damage, pharmacogenomics, and non-immunological modulating factors. Elucidation of the various immunopathogenic pathways in lupus nephritis has resulted in the development of novel therapies, including biologics that target specific antigens on B lymphocytes to achieve B cell depletion, agents that modulate B cell proliferation and development, drugs that block co-stimulatory pathways, drugs that target T lymphocytes primarily, and therapies that target complement activation, signaling pathways, pro-inflammatory cytokines, and neutrophil extracellular traps. This review will discuss recent advances in the understanding of disease pathogenesis in lupus nephritis in the context of potential emerging therapies.
Highlights
Kidney involvement, termed lupus nephritis (LN), is one of the most severe forms of organ involvement in systemic lupus erythematosus (SLE) as reflected by the associated morbidities, its detrimental effects on patient and kidney survival, and the quantity of immunosuppressive agents required for treatment[1,2]
Even when immunosuppressive treatments are successful in inducing remission, the cumulative kidney damage resulting from repeated nephritic flares, as evident from glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis in the kidney biopsy, portends progressive chronic kidney disease eventually culminating in end-stage renal failure[3]
A phase III clinical trial which investigated the efficacy of belimumab in LN (BLISS-LN; NCT01639339) was completed recently, and the results showed that a higher number of patients met its primary and secondary endpoints when treated with belimumab plus standard induction therapy compared to placebo and standard induction therapy[39]
Summary
Kidney involvement, termed lupus nephritis (LN), is one of the most severe forms of organ involvement in systemic lupus erythematosus (SLE) as reflected by the associated morbidities, its detrimental effects on patient and kidney survival, and the quantity of immunosuppressive agents required for treatment[1,2]. Results from a phase II RCT (NCT02908100) showed that fenebrutinib treatment in patients with moderate or severe active SLE was associated with a significant reduction in CD19+ B cells, anti-dsDNA levels, and BTK-dependent signature in plasmablasts, but the primary clinical efficacy endpoint (SRI-4) was not met Target Complement. Data from a recent phase II study (NCT02804763) demonstrated that dapirolizumab pegol (a pegylated Fab anti-CD40L) treatment in active SLE patients was associated with numerically higher response rates and greater improvement in several clinical outcome measures compared with placebo, but the difference in primary efficacy endpoint of British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response between the two groups did not reach statistical significance[93]. In the MUSE trial, SLE patients with a high type I IFN signature showed higher plasma levels of neutrophil granule constituents such as myeloperoxidase, human neutrophil elastase, and citrullinated histone H3 levels, and treatment with anifrolumab for 1 year resulted in a significant decrease in circulating neutrophil NET complexes compared to the placebo group[146]
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