Curr Rheumatol Rep (2013) 15:358 DOI 10.1007/s11926-013-0358-7
SYSTEMIC LUPUS ERYTHEMATOSUS (M PETRI, SECTION EDITOR)
Top 10 Developments in Lupus Nephritis Teresa K. Chen & Derek M. Fine
Published online: 28 July 2013 # Springer Science+Business Media New York 2013
Abstract Lupus nephritis affects up to 60 % of patients with systemic lupus erythematosus and is associated with worse clinical outcomes. Traditionally, it has been treated with high-dose immunosuppression consisting of cyclophosphamide and prednisone; however, recent trials have demonstrated mycophenolate mofetil as a safe and effective alternative for both induction and maintenance of disease. Other progress has been made in our understanding of the pathogenesis of lupus nephritis, outcomes in renal transplantation, and associations with genetic risk factors. This review highlights key developments in our understanding of lupus nephritis over the past decade. Keywords Lupus nephritis . Kidney . Proliferative lupus nephritis . Membranous lupus nephritis . Renal transplantation . APOL1 . Induction therapy . Maintenance therapy . Systemic lupus erythematosus . SLE . Mycophenolate mofetil . Rituximab . Treatment . Multitargeted therapy . Epidemiology
Introduction Systemic lupus erythematosus (SLE) often presents with renal involvement, with up to 10–60 % of patients with lupus nephritis ultimately developing end-stage renal disease (ESRD) [1]. Moreover, lupus nephritis is associated with increased morbidity and mortality [2•]. This review highlights the key recent advancements in lupus nephritis research that
This article is part of the Topical Collection on Systemic Lupus Erythematosus T. K. Chen (*) : D. M. Fine Division of Nephrology, The Johns Hopkins University School of Medicine, 1830 E. Monument Street, Suite 416, Baltimore, MD 21205, USA e-mail:
[email protected]
have allowed rheumatologists and nephrologists to provide better evidence-based care to the patient with lupus nephritis. Successful Induction with Mycophenolate Mofetil Therapy Intravenous cyclophosphamide has traditionally been considered the standard of care when it comes to the treatment of severe lupus nephritis. Its use, however, is often limited by its many potential toxicities. These include the possibility of premature gonadal failure, hemorrhagic cystitis, malignancy, and increased risk for infection [3, 4]. As such, efforts have been made to identify other agents for induction therapy in lupus nephritis. One of the most important developments has been the advent of mycophenolate mofetil as an induction agent in lupus nephritis [5, 6]. After successful use in solid-organ transplantation, mycophenolate mofetil generated interest as a potential therapy for lupus nephritis. The use of mycophenolate mofetil in the treatment of human glomerular disease was pioneered by Briggs and colleagues, the first to effectively treat 2 patients with proliferative lupus nephritis with this agent [7]. Dooley et al. subsequently reported their experiences with mycophenolate mofetil in a series of 13 lupus nephritis patients who failed to respond or refused cyclophosphamide therapy [8]. Finally, Chan et al. conducted a small, randomized controlled trial in 2000 demonstrating that mycophenolate mofetil was as effective as oral cyclophosphamide for induction of remission in Chinese patients with diffuse proliferative lupus nephritis [9]. Since then, two key studies have further explored the use of mycophenolate mofetil as an alternative to intravenous cyclophosphamide as induction therapy [5, 6]. First, Ginzler et al. conducted a randomized controlled noninferiority trial of 140 individuals with active lupus nephritis. All participants had biopsy proven World Health Organization class III (focal proliferative), IV (diffuse proliferative), or V (membranous) lupus nephritis with clinical and/or laboratory features to support active disease. They were randomized to receive daily
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oral mycophenolate mofetil (target of 3,000 mg/day) or intravenous monthly cyclophosphamide (0.5–1.0 g/m2 monthly) for 24 weeks [3–5]. Both groups also received prednisone at 1 mg/kg/day. The primary outcome was complete remission, defined as an improvement in serum creatinine, proteinuria, and urine sediment to within 10 % of normal values. The secondary outcome was partial remission, defined as an improvement in these same laboratory parameters by 50 %. At 24 weeks, 22.5 % in the mycophenolate mofetil group and 5.8 % in the cyclophosphamide group had achieved a complete remission (p=0.005). Partial remission rates were similar between the two groups (29.6 % for mycophenolate mofetil vs. 24.6 % for cyclophosphamide; p=0.51). Of note, there were 2 deaths in the cyclophosphamide group and none in the mycophenolate mofetil group. Moreover, individuals randomized to cyclophosphamide were more likely to have severe infections and lymphopenia, whereas those randomized to mycophenolate mofetil were more likely to have diarrhea. These findings provided support that mycophenolate mofetil was not inferior to intravenous cyclophosphamide for induction therapy in lupus nephritis, and perhaps even preferred given its better adverse event profile [5]. In a second study, the Aspreva Lupus Management Study Group (ALMS) investigated whether mycophenolate mofetil was superior to intravenous cyclophosphamide for the induction of remission in lupus nephritis. In this larger multinational randomized controlled superiority trial, 370 individuals with active lupus nephritis [International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III– V] were randomized to receive oral mycophenolate mofetil (target of 3,000 mg/day) or intravenous cyclophosphamide (0.5–1.0 g/m2 monthly) for 24 weeks. The participants in this study also received concurrent prednisone therapy with a maximum starting dose of 60 mg/day that was tapered as tolerated. The primary endpoint was response to treatment, defined as a stable or improving serum creatinine, accompanied by an improvement in proteinuria to
