Treatment of Lupus Nephritis in the 21st Century
Treatment of Lupus Nephritis in the 21st Century
Systemic lupus erythematosus is a complex autoimmune disorder affecting multiple organ systems. Glomerulonephritis leading to severe proteinuria, chronic renal failure and end-stage renal disease remains one of the most severe complications of systemic lupus erythematosus and is associated with significant morbidity and mortality. Conventional lupus nephritis (LN) treatment based on cyclophosphamide, steroids and, recently, mycophenolatemofetil has improved the outcome of the disease over the last 50 years, although failure to achieve remission or treatment resistance has been reported in 18–57% of patients. Chronic complications such as long-term toxicity dampen their ability to maintain disease remission. There is a need to develop more specific pharmacological agents for patients to provide choices that are equally effective, less toxic and have fewer complications. During the last 10 years, experimental studies based on different pathogenesis pathways of LN have provided an enormous amount of knowledge and have offered the possibility to target the disease with selective approaches. In this article, we summarize the new experimental strategies that have recently been utilized to target LN, focusing on mechanisms of action.
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). LN can lead to proteinuria, chronic renal failure and end-stage renal disease, and is associated with significant morbidity and mortality. It usually arises within 5–10 years of diagnosis and its prevalence varies depending on the population and the published studies, from 30 to 60% of SLE patients.
In LN, the major immunological features comprise a loss of self-tolerance to autoantigens. Insufficient clearance of apoptotic cells has been postulated as the possible cause of a T-cell response leading to the formation of autoantibodies, which then bind to the glomerular basement membrane and promote inflammation. Anti-dsDNA antibodies are probably the most pathogenic type of antibody produced and correlate with the progression of the disease. The activation of the complement pathway, the formation of immune complexes and their defective clearance are also likely to play an important part in the disease pathogenicity. Renal infiltration by B and T cells, macrophages and dendritic cells (DCs) is a prominent feature of progressive LN leading to renal failure. Some studies have highlighted the importance of T cells in stimulating the production of polyclonal autoantibodies by B cells in SLE.
Among the therapeutic armamentarium available to treat LN, cyclophosphamide (CYP) and steroids can effectively delay the progression of renal disease, although failure to achieve remission has been reported in 18–57% of patients. Furthermore, the long-term toxicity of CYP and high-dose steroids discourages their chronic use to maintain disease remission. Thus, we need new tailored drugs or to discover other specific targets that offer possible future therapeutic benefits addressing therapy with a selective approach. This review will focus on the recent experimental developments in the treatment of LN, with brief descriptions of basic immunologic and the underlying mechanisms of action of these therapeutic agents.
Abstract and Introduction
Abstract
Systemic lupus erythematosus is a complex autoimmune disorder affecting multiple organ systems. Glomerulonephritis leading to severe proteinuria, chronic renal failure and end-stage renal disease remains one of the most severe complications of systemic lupus erythematosus and is associated with significant morbidity and mortality. Conventional lupus nephritis (LN) treatment based on cyclophosphamide, steroids and, recently, mycophenolatemofetil has improved the outcome of the disease over the last 50 years, although failure to achieve remission or treatment resistance has been reported in 18–57% of patients. Chronic complications such as long-term toxicity dampen their ability to maintain disease remission. There is a need to develop more specific pharmacological agents for patients to provide choices that are equally effective, less toxic and have fewer complications. During the last 10 years, experimental studies based on different pathogenesis pathways of LN have provided an enormous amount of knowledge and have offered the possibility to target the disease with selective approaches. In this article, we summarize the new experimental strategies that have recently been utilized to target LN, focusing on mechanisms of action.
Introduction
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). LN can lead to proteinuria, chronic renal failure and end-stage renal disease, and is associated with significant morbidity and mortality. It usually arises within 5–10 years of diagnosis and its prevalence varies depending on the population and the published studies, from 30 to 60% of SLE patients.
In LN, the major immunological features comprise a loss of self-tolerance to autoantigens. Insufficient clearance of apoptotic cells has been postulated as the possible cause of a T-cell response leading to the formation of autoantibodies, which then bind to the glomerular basement membrane and promote inflammation. Anti-dsDNA antibodies are probably the most pathogenic type of antibody produced and correlate with the progression of the disease. The activation of the complement pathway, the formation of immune complexes and their defective clearance are also likely to play an important part in the disease pathogenicity. Renal infiltration by B and T cells, macrophages and dendritic cells (DCs) is a prominent feature of progressive LN leading to renal failure. Some studies have highlighted the importance of T cells in stimulating the production of polyclonal autoantibodies by B cells in SLE.
Among the therapeutic armamentarium available to treat LN, cyclophosphamide (CYP) and steroids can effectively delay the progression of renal disease, although failure to achieve remission has been reported in 18–57% of patients. Furthermore, the long-term toxicity of CYP and high-dose steroids discourages their chronic use to maintain disease remission. Thus, we need new tailored drugs or to discover other specific targets that offer possible future therapeutic benefits addressing therapy with a selective approach. This review will focus on the recent experimental developments in the treatment of LN, with brief descriptions of basic immunologic and the underlying mechanisms of action of these therapeutic agents.