NEWS & VIEWS LUPUS NEPHRITIS
MAINTAINing perspective in lupus nephritis trials Brad H. Rovin and Isabelle Ayoub Refers to Tamirou, F. et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-206897
Despite aggressive therapy, lupus nephritis (LN) remains an important predictor of morbidity in patients with systemic lupus erythematosus. Clinical trials of novel drugs have not improved LN outcomes; however, re-analysis of well-characterized cohorts has identified surrogate end points of long-term renal survival, which will facilitate testing and qualification of novel treatments. The landscape of clinical trials for lupus nephritis (LN) is littered with the remains of failed therapies. The past decade has seen many novel biologics and small molecules tested for the treatment of LN with no success,1 despite good pathophysiologic and immunologic rationales. Most of these clinical trials tried to demonstrate improvement in the rates of complete and partial renal responses compared to standard-of-care after 6–12 months of treatment; however, no consensus definition of complete or partial renal response exists. More concerning has been the focus on short-term renal responses, when the major goal of therapy should be long-term preservation of kidney function. Clinical trialists have lost sight of this important outcome for patients with LN in the face of the difficult logistics and the prohibitive costs of conducting lengthy clinical trials. However, a newly published follow-up of the MAINTAIN Nephritis trial puts long-term renal survival back into perspective.2 The MAINTAIN trial was initiated in 2002 to compare azathioprine and mycophenolate mofetil (MMF) as maintenance agents in patients with LN who had been induced with low-dose cyclophosphamide using the Euro–Lupus regimen.3 The primary end point of the MAINTAIN trial was time to renal flare, and after a mean of 4 years, no difference was found between azathioprine and MMF maintenance thera pies.3 Although the MAINTAIN protocol ended after 5 years, the participants continued standard-of-care follow-up for a median
of 110 months (range 18–156 months). Long-term follow-up data from 83% of the original cohort were available for analysis in 2014, and demonstrated no difference in LN flares or the development of end-stage renal disease between patients originally randomly assigned to receive azathioprine or to MMF.2 The original, and now the extended follow-up MAINTAIN results are seemingly at odds with the results of the ALMS Maintenance trial.4 In the latter trial, after positively responding to induction therapy with MMF or high-dose cyclophosphamide (using the NIH regimen), patients were randomly assigned to receive maintenance therapy with either MMF or azathioprine. MMF-treated patients did significantly, albeit modestly better than those treated with azathioprine.4 These seemingly discordant findings of the MAINTAIN and ALMS Maintenance trials caused considerable angst among the lupus community;
however, their designs are sufficiently different so as to prohibit direct comparison (Table 1). Rather, the results from both trials should be synthesized into clinically practical recommendations. MMF is the maintenance drug of choice for non-white patients, whereas azathioprine is as effective as MMF in whites and is a reasonable alternative for any patients who cannot tolerate MMF or who are planning a pregnancy. The extended follow-up of the MAINTAIN cohort provides insights into long-term kidney outcomes that are far more important than the MMF–a zathioprine controversy. The MAINTAIN investigators analysed their data for surrogate markers that were predictive of good long-term kidney outcomes. Using several definitions of good renal outcomes, a decrease in proteinuria to ≤0.5 g per day after 12 months of therapy had a 92% positive predictive value for good long-term outcomes. The predictive power of this decline in proteinuria was not significantly increased after accounting for improvement in serum creatinine level or a decrease in urine red blood cells.2 The negative predictive value of proteinuria ≤0.5 g per day was low, consistent with the observation that although patients might not achieve an early decline in proteinuria, many will still enjoy good kidney function for years to come. These findings echo a recent post hoc analysis of the Euro–Lupus Nephritis Trial (ELNT) cohort. 5 ELNT originally compared low-dose cyclophosphamide (the Euro–Lupus regimen) to standard highdose cyclophosphamide (the NIH regimen) for the treatment of moderately severe LN.6 This cohort was separated into patients who
Table 1 | Important differences between the ALMS Maintenance and MAINTAIN Nephritis trials Study characteristic
ALMS Maintenance4
MAINTAIN Nephritis3
Design
Blinded
Not blinded
Participants
277 patients, multiple races/ethnicities
105 patients, mostly white
Induction regimen
Various induction regimens used
Same induction regimen used in entire cohort
Treatment
Randomized to MMF or AZA only after responding to induction therapy
Randomized to MMF or AZA at entry
End point
Composite (ESRD, doubling of serum creatinine levels, renal flare, use of rescue medications)
Renal flare
Abbreviations: AZA, azathioprine; ESRD, end-stage renal disease; MMF, mycophenolate mofetil.
NATURE REVIEWS | NEPHROLOGY
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NEWS & VIEWS had a serum creatinine level ≤88.4 μmol/l (≤1 mg/dl) and those with a serum creatinine level >88.4 μmol/l (>1 mg/dl) after at least 7 years of follow-up. A proteinuria level of less than 800 mg per day after 12 months of treatment was the best predictor for differentiating these groups. Serum creatinine level did not improve the predictive value of proteinuria, and adding a requirement of fewer than five urine red blood cells per high power field decreased the predictive value of proteinuria.5 The follow-up results of the MAINTAIN and ELNT trials could have important implications for the design and operational logistics of future LN trials. They suggest that the level of proteinuria achieved at 12 months could be a sufficient surrogate marker of sustained kidney function over time—the ultimate goal of LN treatment. A urinalysis end point may therefore not be necessary or even desirable in large, multi-centre clinical trials of LN. Before rushing back to the drawing board to redesign LN trials, however, several issues deserve consideration. These surrogate markers of good outcome were derived from lupus cohorts that comprised mostly white participants. Because LN may be more severe in other races and ethnicities, it is possible that surrogate markers for sustained long-term kidney function will
need to be individualized by race and/or ethnicity. Additionally, whether these same proteinuria criteria will apply to patients with pure Class V LN is not clear. Finally, two very recently published studies suggest that calcineurin inhibitors are effective induction drugs for proliferative LN. 7,8 Calcineurin inhibitors lower proteinuria through multiple mechanisms, only one of which involves modulation of the immune response, which is presumably necessary for effective treatment of LN. A proteinuria-only surrogate end point will therefore almost certainly not be adequate for trials using these drugs. In fact, depending on a drug’s mechanism of action, it is conceivable that a repeat kidney biopsy may be a necessary component of a study end point. In summary, the examination of wellcharacterized lupus cohorts with long-term follow-up is critical for defining surrogate short-term end points of sustained renal health that can be used in clinical trials to qualify new drugs for the treatment of LN. Nephrology Division, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Columbus, OH 43210, USA (B.H.R., I.A.). Correspondence to: B.H.R. [email protected] doi:10.1038/nrneph.2015.65 Published online 28 April 2015
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Competing interests The authors declare no competing interests. 1.
Rovin, B. H. & Parikh, S. V. Lupus nephritis: the evolving role of novel therapeutics. Am. J. Kidney Dis. 63, 677–690 (2014). 2. Tamirou, F. et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2014-206897. 3. Houssiau, F. A. et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann. Rheum. Dis. 69, 2083–2089 (2010). 4. Dooley, M. A. et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N. Engl. J. Med. 365, 1886–1895 (2011). 5. Dall’Era, M. et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro–Lupus nephritis cohort. Arthritis Rheumatol. http://dx.doi.org/10.1002/ art.39026. 6. Houssiau, F. A. et al. Immunosuppressive therapy in lupus nephritis: the Euro–Lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 46, 2121–2131 (2002). 7. Mok, C. C. et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis2014-206456. 8. Liu, Z. et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann. Intern. Med. 162, 18–26 (2015).
www.nature.com/nrneph © 2015 Macmillan Publishers Limited. All rights reserved
MAINTAINing perspective in lupus nephritis trials Brad H. Rovin and Isabelle Ayoub Refers to Tamirou, F. et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2014-206897
Despite aggressive therapy, lupus nephritis (LN) remains an important predictor of morbidity in patients with systemic lupus erythematosus. Clinical trials of novel drugs have not improved LN outcomes; however, re-analysis of well-characterized cohorts has identified surrogate end points of long-term renal survival, which will facilitate testing and qualification of novel treatments. The landscape of clinical trials for lupus nephritis (LN) is littered with the remains of failed therapies. The past decade has seen many novel biologics and small molecules tested for the treatment of LN with no success,1 despite good pathophysiologic and immunologic rationales. Most of these clinical trials tried to demonstrate improvement in the rates of complete and partial renal responses compared to standard-of-care after 6–12 months of treatment; however, no consensus definition of complete or partial renal response exists. More concerning has been the focus on short-term renal responses, when the major goal of therapy should be long-term preservation of kidney function. Clinical trialists have lost sight of this important outcome for patients with LN in the face of the difficult logistics and the prohibitive costs of conducting lengthy clinical trials. However, a newly published follow-up of the MAINTAIN Nephritis trial puts long-term renal survival back into perspective.2 The MAINTAIN trial was initiated in 2002 to compare azathioprine and mycophenolate mofetil (MMF) as maintenance agents in patients with LN who had been induced with low-dose cyclophosphamide using the Euro–Lupus regimen.3 The primary end point of the MAINTAIN trial was time to renal flare, and after a mean of 4 years, no difference was found between azathioprine and MMF maintenance thera pies.3 Although the MAINTAIN protocol ended after 5 years, the participants continued standard-of-care follow-up for a median
of 110 months (range 18–156 months). Long-term follow-up data from 83% of the original cohort were available for analysis in 2014, and demonstrated no difference in LN flares or the development of end-stage renal disease between patients originally randomly assigned to receive azathioprine or to MMF.2 The original, and now the extended follow-up MAINTAIN results are seemingly at odds with the results of the ALMS Maintenance trial.4 In the latter trial, after positively responding to induction therapy with MMF or high-dose cyclophosphamide (using the NIH regimen), patients were randomly assigned to receive maintenance therapy with either MMF or azathioprine. MMF-treated patients did significantly, albeit modestly better than those treated with azathioprine.4 These seemingly discordant findings of the MAINTAIN and ALMS Maintenance trials caused considerable angst among the lupus community;
however, their designs are sufficiently different so as to prohibit direct comparison (Table 1). Rather, the results from both trials should be synthesized into clinically practical recommendations. MMF is the maintenance drug of choice for non-white patients, whereas azathioprine is as effective as MMF in whites and is a reasonable alternative for any patients who cannot tolerate MMF or who are planning a pregnancy. The extended follow-up of the MAINTAIN cohort provides insights into long-term kidney outcomes that are far more important than the MMF–a zathioprine controversy. The MAINTAIN investigators analysed their data for surrogate markers that were predictive of good long-term kidney outcomes. Using several definitions of good renal outcomes, a decrease in proteinuria to ≤0.5 g per day after 12 months of therapy had a 92% positive predictive value for good long-term outcomes. The predictive power of this decline in proteinuria was not significantly increased after accounting for improvement in serum creatinine level or a decrease in urine red blood cells.2 The negative predictive value of proteinuria ≤0.5 g per day was low, consistent with the observation that although patients might not achieve an early decline in proteinuria, many will still enjoy good kidney function for years to come. These findings echo a recent post hoc analysis of the Euro–Lupus Nephritis Trial (ELNT) cohort. 5 ELNT originally compared low-dose cyclophosphamide (the Euro–Lupus regimen) to standard highdose cyclophosphamide (the NIH regimen) for the treatment of moderately severe LN.6 This cohort was separated into patients who
Table 1 | Important differences between the ALMS Maintenance and MAINTAIN Nephritis trials Study characteristic
ALMS Maintenance4
MAINTAIN Nephritis3
Design
Blinded
Not blinded
Participants
277 patients, multiple races/ethnicities
105 patients, mostly white
Induction regimen
Various induction regimens used
Same induction regimen used in entire cohort
Treatment
Randomized to MMF or AZA only after responding to induction therapy
Randomized to MMF or AZA at entry
End point
Composite (ESRD, doubling of serum creatinine levels, renal flare, use of rescue medications)
Renal flare
Abbreviations: AZA, azathioprine; ESRD, end-stage renal disease; MMF, mycophenolate mofetil.
NATURE REVIEWS | NEPHROLOGY
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS had a serum creatinine level ≤88.4 μmol/l (≤1 mg/dl) and those with a serum creatinine level >88.4 μmol/l (>1 mg/dl) after at least 7 years of follow-up. A proteinuria level of less than 800 mg per day after 12 months of treatment was the best predictor for differentiating these groups. Serum creatinine level did not improve the predictive value of proteinuria, and adding a requirement of fewer than five urine red blood cells per high power field decreased the predictive value of proteinuria.5 The follow-up results of the MAINTAIN and ELNT trials could have important implications for the design and operational logistics of future LN trials. They suggest that the level of proteinuria achieved at 12 months could be a sufficient surrogate marker of sustained kidney function over time—the ultimate goal of LN treatment. A urinalysis end point may therefore not be necessary or even desirable in large, multi-centre clinical trials of LN. Before rushing back to the drawing board to redesign LN trials, however, several issues deserve consideration. These surrogate markers of good outcome were derived from lupus cohorts that comprised mostly white participants. Because LN may be more severe in other races and ethnicities, it is possible that surrogate markers for sustained long-term kidney function will
need to be individualized by race and/or ethnicity. Additionally, whether these same proteinuria criteria will apply to patients with pure Class V LN is not clear. Finally, two very recently published studies suggest that calcineurin inhibitors are effective induction drugs for proliferative LN. 7,8 Calcineurin inhibitors lower proteinuria through multiple mechanisms, only one of which involves modulation of the immune response, which is presumably necessary for effective treatment of LN. A proteinuria-only surrogate end point will therefore almost certainly not be adequate for trials using these drugs. In fact, depending on a drug’s mechanism of action, it is conceivable that a repeat kidney biopsy may be a necessary component of a study end point. In summary, the examination of wellcharacterized lupus cohorts with long-term follow-up is critical for defining surrogate short-term end points of sustained renal health that can be used in clinical trials to qualify new drugs for the treatment of LN. Nephrology Division, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Columbus, OH 43210, USA (B.H.R., I.A.). Correspondence to: B.H.R. [email protected] doi:10.1038/nrneph.2015.65 Published online 28 April 2015
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Competing interests The authors declare no competing interests. 1.
Rovin, B. H. & Parikh, S. V. Lupus nephritis: the evolving role of novel therapeutics. Am. J. Kidney Dis. 63, 677–690 (2014). 2. Tamirou, F. et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/ annrheumdis-2014-206897. 3. Houssiau, F. A. et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann. Rheum. Dis. 69, 2083–2089 (2010). 4. Dooley, M. A. et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N. Engl. J. Med. 365, 1886–1895 (2011). 5. Dall’Era, M. et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro–Lupus nephritis cohort. Arthritis Rheumatol. http://dx.doi.org/10.1002/ art.39026. 6. Houssiau, F. A. et al. Immunosuppressive therapy in lupus nephritis: the Euro–Lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 46, 2121–2131 (2002). 7. Mok, C. C. et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis2014-206456. 8. Liu, Z. et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann. Intern. Med. 162, 18–26 (2015).
www.nature.com/nrneph © 2015 Macmillan Publishers Limited. All rights reserved
