Lupus Nephritis: The Evolving Role of Novel Therapeutics

Abstract

Immune complex accumulation in the kidney is the hallmark of lupus nephritis and triggers a series of events that result in kidney inflammation and injury. Cytotoxic agents and corticosteroids are standard of care for lupus nephritis treatment, but are associated with considerable morbidity and suboptimal outcomes. Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. These therapies can be broadly categorized as anti-inflammatory (laquinamod, anti–tumor necrosis factor–like weak inducer of apotosis, anti-C5, and retinoids), antiautoimmunity (anti-CD20, anti–interferon α, and costimulatory blockers), or both (anti–interleukin 6 and proteasome inhibitors). Recent lupus nephritis clinical trials applied biologics or small molecules of any category to induction treatment, seeking short-term end points of complete renal response. These trials in general have not succeeded. When lupus nephritis comes to clinical attention during the inflammatory stage of the disease, the autoimmune stage leading to kidney inflammation will have been active for some time. The optimal approach for using novel therapies may be to initially target kidney inflammation to preserve renal parenchyma, followed by suppression of autoimmunity. In this review, we discuss novel lupus nephritis therapies and how they fit into a combinatorial treatment strategy based on the pathogenic stage.

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

“…Neutrophils also accumulate in proliferative lupus nephritis (3), with recent transcriptional profiling of blood from lupus patients showing a gradual enrichment of neutrophil transcripts during progression to active nephritis (57). Reducing the renal burden and cytotoxic function of neutrophils may also preserve long-term kidney function by dampening intrarenal autoimmunity in predisposed individuals (3,58,59). As with other compounds in the Bcr-Abl class of inhibitors, bosutinib can also target other kinases such as salt-inducible kinases and TEC-family kinases (32) and very likely has antiinflammatory effects beyond the inhibition of FcγRIIA and neutrophils (60,61).…”

The Spectrum of Glomerulopathies in Kashmir: A Tertiary Care Experience

“…Recently, there has been interest in using novel biologic agents and small molecules to treat lupus nephritis. The optimal approach for using novel therapies may be to initially target kidney inflammation in order to preserve renal parenchyma, followed by the suppression of autoimmunity [20], hence making kidney biopsy a valuable tool of assessment.…”

IL-6 Trans-Signaling Drives Murine Crescentic GN

“…43 The first clinical trial on pan-IL-6 inhibition in human lupus nephritis turned out negative. 44,45 So far, substantial benefit of IL-6 inhibition in human necrotizing GN has only been reported by two case vignettes on tocilizumab in rheumatoid arthritis-associated systemic vasculitis with 46 and without 47 anti-MPO ANCA. This rare condition, however, substantially depends on the activity of the underlying rheumatic disease, 47 making it difficult to judge if the benefits are GN-specific or just related to mitigation of rheumatic disease by the well established anti-rheumatic biologic tocilizumab.…”