Current and Emerging Therapies for Lupus Nephritis

Abstract

The introduction of corticosteroids and later, cyclophosphamide dramatically improved survival in patients with proliferative lupus nephritis, and combined administration of these agents became the standard-of-care treatment for this disease. However, treatment failures were still common and the rate of progression to ESRD remained unacceptably high. Additionally, treatment was associated with significant morbidity. Therefore, as patient survival improved, the goals for advancing lupus nephritis treatment shifted to identifying therapies that could improve long-term renal outcomes and minimize treatment-related toxicity. Unfortunately, progress has been slow and the current approaches to the management of lupus nephritis continue to rely on high-dose corticosteroids plus a broad-spectrum immunosuppressive agent. Over the past decade, an improved understanding of lupus nephritis pathogenesis fueled several clinical trials of novel drugs, but none have been found to be superior to the combination of a cytotoxic agent and corticosteroids. Despite these trial failures, efforts to translate mechanistic advances into new treatment approaches continue. In this review, we discuss current therapeutic strategies for lupus nephritis, briefly review recent advances in understanding the pathogenesis of this disease, and describe emerging approaches developed on the basis of these advances that promise to improve upon the standard-of-care lupus nephritis treatments.

Keywords: clinical trial; glomerular disease; immunosuppression; lupus nephritis; systemic lupus erythematosus.

Figure 1.

Current standard of care treatment protocols for LN induction therapy. Patients with proliferative forms of LN are treated with oral corticosteroids, typically prednisone starting at 1 mg/kg per day and tapered over weeks to months. In severe disease with rapid deterioration of kidney function, high-dose intravenous methylprednisolone (0.25–1 g/d) is often given for 1–3 days preceding oral corticosteroids. In addition to corticosteroids one of four immunosuppressive regimens using cyclophosphamide or MMF is generally used. The NIH high-dose regimen consists of monthly intravenous pulses of cyclophosphamide dosed at 0.5–1 g/m² for 6 months. Oral cyclophosphamide dosed at 1–1.5 mg/kg per day for 2–4 months provides a cumulative cyclophosphamide burden similar to the NIH regimen. In both cases cyclophosphamide is dosed based on nonobese body weight. The Euro-Lupus (low-dose) intravenous cyclophosphamide regimen is dosed at 500 mg every 2 weeks for six total doses. Cumulative cyclophosphamide for the Euro-Lupus regimen is 3 g, which is at least 50% lower than the NIH regimen. MMF is given for 6 months and dosed at 2–3 g/d.

Figure 2.

Novel therapies target the principal components of the immune system that contribute to LN pathogenesis. This schema illustrates current thoughts on the cells, cytokines, and growth factors and their interactions that amplify kidney injury and facilitate ongoing autoimmunity in LN. During LN circulating plasmacytoid dendritic cells enter the kidney and release IFN-α, and IFN-α then stimulates antigen presenting cells, promotes B cell differentiation into plasma cells, and facilitates production of T_H1 and T_H2 cells. B cells also present autoantigens to T cells which leads to T cell activation and release of proinflammatory cytokines such as IL-6. B cell and T cell proliferation is dependent upon costimulation which occurs independently from antigen presentation through interactions between CD28:B7 and CD40L:CD40 located on T and B cells respectively. Additionally, the B cell stimulators Blys and APRIL function to activate B cells and prolong survival. Autoreactive plasma cells produce autoantibodies that bind autoantigens and form immune complexes. These immune complexes deposit in the renal parenchyma, activate the alternative complement pathway, and recruit proinflammatory cells to the kidney leading to tissue damage and inflammation. The putative points of interaction of novel therapeutics and pathogenic mechanisms are indicated. Therapies with an asterisk have already been studied in clinical trials. Other therapies that are currently being studied or that we would like to see studied are also shown.