Lupus nephritis is the most important complication of systemic lupus erythematosus because it is closely linked to survival and morbidity in patients with the autoimmune disease. It is also one of the most controversial, according to Dr. David R.W. Jayne, director of the Vasculitis and Lupus Clinic at Addenbrooke’s Hospital in Cambridge, England.
Specifically, recent data indicate that more than 40% of SLE patients who develop nephritis develop progressive kidney disease, and 20% die within 12 years, "which means that more than half of the [SLE] patients diagnosed with lupus nephritis reach a hard end point, let alone the other problems that are inherent to the disease," said Dr. Jayne, a nephrologist. Variations in disease presentation, histologic patterns, course, and outcomes complicate management, as does the absence of a single, accepted standard of care and well-defined treatment aims, he said, noting that "there is more uncertainty about how to treat [lupus nephritis] than any other subject within nephrology."
In this month’s column, Dr. Jayne will address some of the reasons behind this uncertainty and the current management options.
QUESTION: At the 2011 Annual European Congress of Rheumatology in London, you stressed that lupus nephritis is a controversial topic within rheumatology and nephrology, and joked that your presentations on the topic are the only forum "where people scream at me." What makes lupus nephritis such a hot-button topic?
Dr. Jayne: We’re dealing with young, often female patients with a potentially devastating disease for which we’ve really had poor evidence to base treatments, and that drives anxiety. Also, the treatment (such as high-dose steroids and cyclophosphamide) carries major toxic risks. The reality is that lupus nephritis is heterogenous and the pathology is complex. The current classification system divides the condition into six classes according to the severity of the lesions observed (Kidney Int. 2004;65:521-30). Most studies focus on proliferative nephritis (classes III and IV) and membranous nephritis (class V) because these are associated with an increased risk of kidney failure, yet are amenable to therapy. In reality, the pathology is more complex because of mixed membranous and proliferative lesions and other kidney glomerular and nonglomerular problems that can occur at the same time. These problems – including thrombotic microangiopathy, podocytopathy, tubulointerstitial nephritis, and vascular disease – are not reflected in the current classification, yet they have an impact on long-term outcomes.
QUESTION: Given the complexity of the disease, what is the optimal management course?
Dr. Jayne: In general, the treatment of lupus nephritis comprises a period of intensive immunosuppressive treatment followed by a period of less-intense immunosuppressive therapy. Opinions regarding optimal treatment vary widely. The reality is, we spend all of our time talking about which immunosuppressive to use and how much steroid to use. But in many ways, that’s one of the less-important aspects of managing the disease. It’s so multifaceted, and there are many other things that contribute to a good outcome. It’s the speed of diagnosis, referral, and initiation of treatment that actually drives improvements in outcome.
QUESTION: What are the current evidence-based treatment options?
Dr. Jayne: There is a shopping list of options. Among them are the National Institutes of Health "long" protocol, which consists of 15 g of pulse cyclophosphamide titrated over 2 years; the NIH "short" protocol, consisting of six pulses of cyclophosphamide, for a total of 7.5 g, followed by a switch to a safer immunosuppressive agent, such as azathioprine or mycophenolate mofetil; and the low-dose Euro-Lupus regimen, including six fixed-dose pulses of 500-mg cyclophosphamide, for a total of 3 g over 12 weeks, followed by azathioprine or mycophenolate.
The recent ALMS (Aspreva Lupus Management Study) compared mycophenolate mofetil vs. intravenous cyclophosphamide with the same dose of background steroids. An alternative option is starting with mycophenolate mofetil at 3 g/day, then stepping down at 6 months to 2 g/day in responders. The data suggest that mycophenolate mofetil is as effective as high-dose intravenous cyclophosphamide for inducing remission.
As maintenance treatment, mycophenolate mofetil appears to be superior to azathioprine, which itself is similarly effective to ciclosporin for preventing or reducing relapse risk (J. Am. Soc. Nephrol. 2009;20:1103-12).
QUESTION: What is the role of steroids in lupus nephritis treatment?
Dr. Jayne: That’s one of the big unanswered questions: what to do with steroids? Whenever we’re involved with trial design, the longest, most agonizing discussions focus on the steroid regimen. There is considerable variability in prednisone regimens, with beginning doses ranging from 0.5 mg/kg per day to 1 mg/kg per day, and tapering over a period of months to maintain control of nephritis and extrarenal symptoms. Studies have shown, not surprisingly, that the higher steroid doses are linked to higher response rates but also with an increased likelihood of severe adverse events. There is also no consensus about when to stop steroids. We generally taper down to 10-15 mg/day by 6 months and continue a lower steroid dose for 2 or more years, but there is also considerable variability in this as well.