J Am Soc Nephrol. Epub Apr Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Comment in Nefrologia. Recent studies have suggested that mycophenolate mofetil MMF may offer advantages over intravenous cyclophosphamide IVC for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase induction and maintenance study.
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Search Menu Abstract Current treatment of lupus nephritis consists of both induction and maintenance therapy, with the latter being designed to consolidate remissions and prevent relapses. Long-term maintenance treatment with intravenous cyclophosphamide was effective but associated with considerable toxicity.
A small but well-designed controlled trial found that for post-induction maintenance therapy, both oral mycophenolate mofetil MMF and oral azathioprine were superior in efficacy and had reduced toxicity than a regimen of continued every third month intravenous cyclophosphamide.
Although these oral agents were rapidly accepted and utilized as maintenance medications, their usage was based on scant evidence and there were no comparisons between the two.
Recently, two relatively large, randomized, well-controlled, multicenter trials dealing with maintenance therapy for severe lupus nephritis have been completed. Relapses are associated with an increase in morbidity as well as a greater risk of progressive chronic kidney disease [ 7—9 ]. It has been proposed that maintenance immunosuppression will prevent relapses and flares of the disease and lead to improved survival rates, while avoiding the toxicity of repeated cycles of high-dose immunosuppressive induction regimens.
In the past, maintenance treatment often consisted of repeated doses of intravenous cyclophosphamide and was associated with considerable mortality and morbidity. Unfortunately, until recently, few studies have dealt specifically with maintenance regimens. Both trials compared azathioprine AZA with MMF in patients diagnosed with proliferative lupus nephritis who had undergone successful induction therapy.
Publication of the results represents a major progress in establishing a high-quality evidence base to inform therapeutic strategies for this disease. In this review, we will examine the impact of these two trials on current strategies for the maintenance therapy of lupus nephritis. Unfortunately, such regimens have considerable toxicity in terms of infertility, risk of infections and the long-term risk of bladder and other tumors [ 12—15 ].
In , Contreras et al. Lupus nephritis was severe in most patients: the mean baseline creatinine was 1. All patients received induction therapy, which consisted of up to seven monthly boluses of IVC 0. The patients were subsequently randomized to receive one of the three maintenance therapy regimens: IVC 0.
All three groups received oral prednisone up to 0. Perhaps most importantly, the improved clinical outcomes of AZA and MMF over IVC were complemented by a marked reduction of adverse effects, including the crucially important categories of hospitalization days, amenorrhea and total and major infections. Overall, this important trial demonstrated the efficacy of oral maintenance therapies in the treatment of lupus nephritis, with better safety profiles compared with cyclophosphamide.
For many clinicians, this study quickly relegated IVC to a role in induction therapy of severe lupus nephritis. However, it left a number of important questions unanswered. What is the dose of the oral agents necessary to prevent relapse or flares? How long is maintenance therapy to be continued? Which of the oral agents used is superior in efficacy? Which gives fewer side effects? These questions set the stage for larger and more definitive trials to compare MMF and AZA in the maintenance of lupus nephritis.
THE ALMS TRIAL The Aspreva Lupus Management Study [ 11 , 17 ], one of the largest trials ever conducted in lupus nephritis, was a prospective randomized trial performed at 88 centers across the globe which utilized a two-phase design to test both induction strategies and maintenance strategies.
The primary endpoint was renal response at 6 months. The renal response was achieved in There were similar rates of serious adverse events and mortality in both groups. As the second large trial showing no superiority of the alkylating agent in the treatment of lupus nephritis, it established MMF as a potential first-line therapy for many patients with the disease. Randomization was stratified by race, biopsy class and induction therapy to ensure approximately equal number of patients in each arm who had been previously treated with MMF or cyclophosphamide.
The treatment groups were well balanced in terms of both demographic and clinical parameters. The mean SCr was 0. The primary endpoint was time to treatment failure, defined as renal flare proteinuric or nephritic , sustained doubling of SCr, initiation of rescue therapy, end-stage renal disease ESRD or death. The rates of renal flare were The incidence of adverse events—infection being the most common—was similar in the two groups, but the proportion of patients with adverse events leading to withdrawal was notably higher in the AZA group In summary, the maintenance phase of the ALMS trial demonstrated that, regardless of induction therapy, MMF was superior to AZA in maintaining the renal response and preventing relapse of proliferative lupus nephritis.
The superiority of MMF was irrespective of race, gender or region. The pattern and frequency of adverse events were consistent with what has been previously reported for AZA and MMF, with more withdrawals due to adverse events in the AZA group. The core group of investigators of the MAINTAIN trial had previously conducted the Euro-Lupus nephritis trial [ 18 ], which demonstrated that corticosteroids plus low-dose IVC mg every 2 weeks for six doses was as effective as corticosteroids plus high-dose IVC for induction therapy in a European population.
Importantly, AZA was the medication used to maintain remission for all subjects in the Euro-Lupus trial. This was an investigator-initiated trial performed at 27 European centers. Corticosteroids were administered on a defined taper. Only patients with at least 0. At a mean follow-up time of 48 months, there was no significant difference between the AZA and MMF groups with respect to the primary outcome. There were also no significant differences in the number of patients achieving renal remission or withdrawing from glucocorticoids.
Only one patient from each group developed ESRD. Adverse events were well balanced between the groups with the exception of hematological cytopenias, which were more frequent in the AZA group. In both groups, the activity index decreased and the chronicity index increased, with no significant differences detected between the two treatment groups [ 20 ].
Some important differences between the design and conduction of these trials merit further discussion.
A Study of Mycophenolate Mofetil (CellCept) in Management of Patients With Lupus Nephritis.
Dose specific for each arm. Dosing started at mg BID for the first week, increasing by mg in subsequent weeks until the final target dose was reached. Active Comparator: Induction Phase: Cyclophosphamide Participants received monthly infusions of cyclophosphamide, 0. Drug: Cyclophosphamide Intravenous cyclophosphamide IVC was administered every four weeks monthly to a total of six infusions. Dosing was started at 0.
ASPREVA LUPUS MANAGEMENT STUDY PDF
Nesida Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive asprevz Parameters such as the duration of the induction phase and the response criteria were based on previously reported trials 12lupuss ; however, 24 wk may be too short to differentiate between the treatments, because the disease may continue to improve and AEs may continue to emerge. Neither of these was objectively addressed in this study because of the length of follow-up and limited health maangement assessments undertaken. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Statistical Analysis The primary end point analysis was performed on the intention-to-treat population. Reasons for early withdrawal and hence nonresponse included AEs leading to withdrawal, intolerance of either therapy, stduy requirement to receive prohibited treatments. Recent studies have suggested that mycophenolate mofetil MMF may offer advantages over intravenous cyclophosphamide IVC for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. The institutional review boards at all participating centers approved the protocol, and all patients provided written informed consent.