Lupus Nephritis: Many Unanswered Questions

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.

Interestingly, we conducted a questionnaire study in which we asked 71 lupus experts whether they would stop steroids in a 21-year-old female with class IV nephritis who was in stable remission for 2 years, and there was an exact balance of opinion: One-third each would stop, wouldn’t stop, and didn’t know. When we looked for differences among the responders, we found that physicians in the United States and Canada had more enthusiasm for stopping steroids, while those in Europe prefer to keep them going. Also, by specialty, nephrologists were keener to stop them and rheumatologists were keener to keep going. In other words, there is no universal standard of care to answer this question.

QUESTION: What is the best measure for assessing treatment response?

Dr. Jayne: Typically, the criteria are proteinuria, urinary sediment, and renal function. The majority of patients will have normal renal function or near-normal renal function when they come to us, so the [glomerular filtration rate] is turning out not to be a useful marker for renal response. Yes, the loss of hematuria is useful and that’s part of a complete response definition, but really it’s the reduction of proteinuria that drives renal response definitions. So a reduction by 50% from baseline to subnephrotic levels (less than 3 g/day) is a partial response, and a complete response is down to less than 0.5 g/day.

Proteinuria means a lot of different things. One of the confusions in managing lupus nephritis is that proteinuria does not just reflect activity. You can switch off all of the activity in the kidney, but the proteinuria declines quite slowly. It takes a long time – up to 3 years – for the proteinuria to get as good as it’s going to get, but too many studies have short, 6-month end points. We really look at 2 years as being the induction period. Initially, proteinuria is reflecting disease activity, but subsequently reflects the recovery phase of the glomerulus. The immune complexes are being solubilized and removed. This is the remodeling phase, which lasts a long time. Then there is the fibrotic phase that contributes a relatively small amount to proteinuria.

For this reason, nephrologists would really love repeat renal biopsies. Several small studies have demonstrated that patients often have persistent disease activity even when proteinuria has gone down to relatively low levels. So even when the parameters we measure have gotten better, the activity may not be gone. A renal biopsy will tell you whether there has been a change in scarring or chronicity.

QUESTION: What’s on the horizon for the management of lupus nephritis?

Dr. Jayne: There are some new treatment directions, including tacrolimus (Prograf). This drug, which is widely used in the prevention of renal transplant rejections, also appears to have benefits for lupus nephritis. Tacrolimus has direct effects on the podocyte where it influences the cytoskeleton and the permeability of the glomerular basement membrane, as well as immunosuppressant effects, so it has a dual action in lupus nephritis, but we need more data.

The role of B-cell depletion has also been explored. Many physicians have been using rituximab (Rituxan) in their clinics for a number of years, and data from retrospective cohort studies suggest that it is effective for relapsing or refractory disease. However, the findings of double-blind, placebo-controlled trials of rituximab and another B-cell–depleting drug, ocrelizumab, when added on top of either mycophenolate mofetil or cyclophosphamide, suggested only relatively small treatment differences between the study drug and placebo. The failure of the trials may be associated with aspects of their design, such as short follow-up and small sample size.

QUESTION: Who should manage lupus nephritis?

Dr. Jayne: Should it be the nephrologist or the rheumatologist? That’s the most controversial issue of all. In reality, it should be a partnership.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Jayne reported no financial conflicts of interest.

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.

Interestingly, we conducted a questionnaire study in which we asked 71 lupus experts whether they would stop steroids in a 21-year-old female with class IV nephritis who was in stable remission for 2 years, and there was an exact balance of opinion: One-third each would stop, wouldn’t stop, and didn’t know. When we looked for differences among the responders, we found that physicians in the United States and Canada had more enthusiasm for stopping steroids, while those in Europe prefer to keep them going. Also, by specialty, nephrologists were keener to stop them and rheumatologists were keener to keep going. In other words, there is no universal standard of care to answer this question.

QUESTION: What is the best measure for assessing treatment response?

Dr. Jayne: Typically, the criteria are proteinuria, urinary sediment, and renal function. The majority of patients will have normal renal function or near-normal renal function when they come to us, so the [glomerular filtration rate] is turning out not to be a useful marker for renal response. Yes, the loss of hematuria is useful and that’s part of a complete response definition, but really it’s the reduction of proteinuria that drives renal response definitions. So a reduction by 50% from baseline to subnephrotic levels (less than 3 g/day) is a partial response, and a complete response is down to less than 0.5 g/day.

Proteinuria means a lot of different things. One of the confusions in managing lupus nephritis is that proteinuria does not just reflect activity. You can switch off all of the activity in the kidney, but the proteinuria declines quite slowly. It takes a long time – up to 3 years – for the proteinuria to get as good as it’s going to get, but too many studies have short, 6-month end points. We really look at 2 years as being the induction period. Initially, proteinuria is reflecting disease activity, but subsequently reflects the recovery phase of the glomerulus. The immune complexes are being solubilized and removed. This is the remodeling phase, which lasts a long time. Then there is the fibrotic phase that contributes a relatively small amount to proteinuria.

For this reason, nephrologists would really love repeat renal biopsies. Several small studies have demonstrated that patients often have persistent disease activity even when proteinuria has gone down to relatively low levels. So even when the parameters we measure have gotten better, the activity may not be gone. A renal biopsy will tell you whether there has been a change in scarring or chronicity.

QUESTION: What’s on the horizon for the management of lupus nephritis?

Dr. Jayne: There are some new treatment directions, including tacrolimus (Prograf). This drug, which is widely used in the prevention of renal transplant rejections, also appears to have benefits for lupus nephritis. Tacrolimus has direct effects on the podocyte where it influences the cytoskeleton and the permeability of the glomerular basement membrane, as well as immunosuppressant effects, so it has a dual action in lupus nephritis, but we need more data.

The role of B-cell depletion has also been explored. Many physicians have been using rituximab (Rituxan) in their clinics for a number of years, and data from retrospective cohort studies suggest that it is effective for relapsing or refractory disease. However, the findings of double-blind, placebo-controlled trials of rituximab and another B-cell–depleting drug, ocrelizumab, when added on top of either mycophenolate mofetil or cyclophosphamide, suggested only relatively small treatment differences between the study drug and placebo. The failure of the trials may be associated with aspects of their design, such as short follow-up and small sample size.

QUESTION: Who should manage lupus nephritis?

Dr. Jayne: Should it be the nephrologist or the rheumatologist? That’s the most controversial issue of all. In reality, it should be a partnership.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Jayne reported no financial conflicts of interest.

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.

Interestingly, we conducted a questionnaire study in which we asked 71 lupus experts whether they would stop steroids in a 21-year-old female with class IV nephritis who was in stable remission for 2 years, and there was an exact balance of opinion: One-third each would stop, wouldn’t stop, and didn’t know. When we looked for differences among the responders, we found that physicians in the United States and Canada had more enthusiasm for stopping steroids, while those in Europe prefer to keep them going. Also, by specialty, nephrologists were keener to stop them and rheumatologists were keener to keep going. In other words, there is no universal standard of care to answer this question.

QUESTION: What is the best measure for assessing treatment response?

Dr. Jayne: Typically, the criteria are proteinuria, urinary sediment, and renal function. The majority of patients will have normal renal function or near-normal renal function when they come to us, so the [glomerular filtration rate] is turning out not to be a useful marker for renal response. Yes, the loss of hematuria is useful and that’s part of a complete response definition, but really it’s the reduction of proteinuria that drives renal response definitions. So a reduction by 50% from baseline to subnephrotic levels (less than 3 g/day) is a partial response, and a complete response is down to less than 0.5 g/day.

Proteinuria means a lot of different things. One of the confusions in managing lupus nephritis is that proteinuria does not just reflect activity. You can switch off all of the activity in the kidney, but the proteinuria declines quite slowly. It takes a long time – up to 3 years – for the proteinuria to get as good as it’s going to get, but too many studies have short, 6-month end points. We really look at 2 years as being the induction period. Initially, proteinuria is reflecting disease activity, but subsequently reflects the recovery phase of the glomerulus. The immune complexes are being solubilized and removed. This is the remodeling phase, which lasts a long time. Then there is the fibrotic phase that contributes a relatively small amount to proteinuria.

For this reason, nephrologists would really love repeat renal biopsies. Several small studies have demonstrated that patients often have persistent disease activity even when proteinuria has gone down to relatively low levels. So even when the parameters we measure have gotten better, the activity may not be gone. A renal biopsy will tell you whether there has been a change in scarring or chronicity.

QUESTION: What’s on the horizon for the management of lupus nephritis?

Dr. Jayne: There are some new treatment directions, including tacrolimus (Prograf). This drug, which is widely used in the prevention of renal transplant rejections, also appears to have benefits for lupus nephritis. Tacrolimus has direct effects on the podocyte where it influences the cytoskeleton and the permeability of the glomerular basement membrane, as well as immunosuppressant effects, so it has a dual action in lupus nephritis, but we need more data.

The role of B-cell depletion has also been explored. Many physicians have been using rituximab (Rituxan) in their clinics for a number of years, and data from retrospective cohort studies suggest that it is effective for relapsing or refractory disease. However, the findings of double-blind, placebo-controlled trials of rituximab and another B-cell–depleting drug, ocrelizumab, when added on top of either mycophenolate mofetil or cyclophosphamide, suggested only relatively small treatment differences between the study drug and placebo. The failure of the trials may be associated with aspects of their design, such as short follow-up and small sample size.

QUESTION: Who should manage lupus nephritis?

Dr. Jayne: Should it be the nephrologist or the rheumatologist? That’s the most controversial issue of all. In reality, it should be a partnership.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Jayne reported no financial conflicts of interest.