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.

Keywords: Lupus nephritis; biologics; novel therapies; small molecules; systemic lupus erythematosus (SLE).

Figure 1

The pathogenic stages of lupus nephritis (LN) as a guide to therapy. Systemic lupus erythematosus and LN (upper boxes) occur in patients with a genetic predisposition to autoimmunity and presumably an environmental trigger to initiate disease (stage 0). Because these patients cannot be identified with accuracy in the general population, there currently are no therapies (lower boxes) that can be applied at this stage. After initiation, autoimmunity develops as the pathogenic processes listed under stage 1 occur. This would be an ideal point to intervene with drugs that target these pathways, such as B- and T-cell–directed therapies, but patients usually do not have clinical manifestations during stage 1 and the disease is relatively silent. Kidney involvement reaches clinical attention during stage 2, and clinical manifestations are due primarily to inflammatory processes initiated within the kidney (shown in the stage 2 box, above the dotted line). The induction therapy of LN therefore must control inflammation. In addition to intrarenal inflammation, the autoimmune processes of stage 1 likely are still active and kidney-specific autoimmunity may be developing (stage 2 box, below the dotted line). Thus, in addition to anti-inflammatory therapy, the antiautoimmune therapies that were applied to stage 1 also can be used in stage 2. These therapies would contribute less to controlling inflammation, but ideally would prevent further LN flares. Active inflammation also can lead to scarring of the kidneys. Addition of an antifibrotic agent, especially if interstitial fibrosis or glomerulosclerosis were confirmed by biopsy or novel biomarker, could stabilize kidney function and decrease the rate of chronic kidney disease progression. Abbreviation: IFNα, interferon α.

Figure 2

A model of combinatorial B-cell–directed therapy for lupus nephritis. This algorithm represents a hypothetical approach to using B-cell–directed therapies in a lupus nephritis trial. The algorithm matches therapies to the pathogenic stage of the clinical disease and uses novel biomarkers of B-cell activity to guide initiation and termination of specific drugs. The timeline provided is a (non–evidence-based) guide to the desired or ideal clinical milestones after initiation of treatment. At flare, patients would receive a proteasome inhibitor to reduce/eliminate plasma cells producing autoantibodies and an anti-inflammatory drug to synergize with the anti–NF-κB (nuclear factor κ light-chain enhancer of activated B cells) effects of the proteasome inhibitor and attenuate renal inflammation. Baseline data on B-cell numbers, B-cell activating factor (BAFF) levels, and antichromatin antibodies would be obtained. After 2-3 months, clinical parameters should be improving. If antichromatin antibodies become undetectable, the proteasome inhibitor would be discontinued and rituximab would be initiated to eliminate B cells and prevent repopulation of autoreactive plasma cells that had been killed by the proteasome inhibitor. Because BAFF levels increase as rituximab depletes B cells confounding the antiautoimmune effects of rituximab, belimumab would be started as BAFF levels increase over the time 0 baseline values. B-Cell and BAFF levels would be followed up prospectively, and after reconstitution of B cells in a BAFF-free environment, belimumab could be stopped. At 6 months, clinical parameters should be consistent with a complete renal response. At this time, the anti-inflammatory agents can be tapered off over time. Ideally, because inflammation will have been attenuated and autoreactive B cells eliminated, the patient will remain flare-free on no immunosuppression. Abbreviation: TWEAK, tumor necrosis factor–like weak inducer of apoptosis.