Among patients with active lupus nephritis, is mycophenolate superior to cyclophosphamide for the induction of a renal response?
Among patients with active lupus nephritis, remission induction with either mycophenolate or cyclophosphamide yields similar response rates, and subgroup analyses suggest mycophenolate may yield superior results in African American and Hispanic patients.
Clinically significant renal involvement occurs in approximately half of patients with lupus, and renal histology in patients with lupus nephritis predicts responsiveness to therapy. Focal proliferative (class III) and diffuse proliferative (class IV) lupus nephritis are mediated by immune and inflammatory mechanisms responsive to immunosuppression and antiinflammatory therapy, and preferred therapy has generally been with a combination of prednisone plus cyclophosphamide based upon a landmark study from the NIH. Due to the toxicities of cyclophosphamide including an increased risk of bladder toxicity and ovarian failure, alternative strategies have been investigated such as reduced-dose and short-course cyclophosphamide, as well as alternative immunosuppressants such as mycophenolate mofetil (MMF). Several studies have compared cyclophosphamide and MMF, generally finding that MMF is equivalent to cyclophosphamide in terms of efficacy, with a lower risk of ovarian failure.
Published in 2009, the Aspreva Lupus Management Study (ALMS) induction study randomized 370 patients with biopsy-proven active lupus nephritis (mostly class III-IV, some class V) to induction with either MMF or intravenous cyclophosphamide. Patients in both groups received corticosteroids as well as conventional antiproteinuric and antihypertensive therapies as part of standard care. During the open-label 24-week induction period, patients were followed for the primary outcome of renal response. Renal response was defined as a decrease in urine protein/creatinine ratio (P/Cr) to <3 in patients with baseline nephrotic-range proteinuria or by ≥50% in patients with a baseline P/Cr less than 3, as well as stabilization (within a margin of 25%) or improvement in serum creatinine at the end of the 24-week induction period. The study was powered to demonstrate a 15% difference between groups in renal response rate, with the hypothesis being that MMF would yield a superior response rate compared to cyclophosphamide. At the end of the 24-week induction period, renal responses were observed in 56.2% of patients receiving MMF, compared with 53% of patients receiving cyclophosphamide (P=0.58). A post hoc subgroup analysis indicated that African American and Hispanic patients had a more favorable response to MMF over cyclophosphamide. Rates of adverse events were similar between groups (>90%), although more patients died in the MMF group (9) compared to the cyclophosphamide group (5). Although the rationale for MMF included decreased gonadal toxicity, this outcome was not reported in this study since such toxicity was not expected to be observed at 24 weeks.
The investigators conclude, and guidelines support that MMF is a reasonable alternative to cyclophosphamide in the treatment of patients with active lupus nephritis, particularly among women of childbearing age. African American and Hispanic patients may benefit from MMF over cyclophosphamide.
KDIGO Clinical Practice Guideline for Glomerulonephritis (2012, adapted)
Class III LN (focal LN) and class IV LN (diffuse LN)—initial therapy:
- Recommend corticosteroids (1A), combined with either cyclophosphamide (1B) or MMF (1B).
Class V LN (membranous LN):
- Recommend that patients with normal kidney function and non-nephrotic proteinuria be treated with antiproteinuric and antihypertensive regimens (2D).
- Recommend corticosteroids plus additional immunosuppressive agent such as cyclophosphamide (2C), calcineurin inhibitor (2C), MMF (2D), or azathioprine (2D) for patients with pure class V LN and persistent nephrotic proteinuria.
- Multicenter, open-label, parallel-group, randomized, controlled trial
- N=370 patients with biopsy-confirmed active lupus nephritis
- Mycophenolate mofetil (n=185)
- Cyclophosphamide (n=185)
- Setting: 88 centers in 20 countries in North America, Latin America, Asia, Australia, and Europe
- Enrollment: 2005-2006
- Mean follow-up: 156.2d for MMR; 167.5d for the IVC
- Analysis: Intention to treat
- Primary outcome: Renal response defined by a defined reduction in urine protein/creatinine ratio and stabilization or improvement in serum creatinine
- Age 12-75 years
- Diagnosis of systemic lupus erythematosis
- Active lupus nephritis confirmed by kidney biopsy within 6 months prior to randomization.
- Required renal histology: class III, IV-S, IV-G, V, III+V, or IV+V
- ≥2 g/day proteinuria required for patients with class III or V histology
- Treatment with MMF or cyclophosphamide within the prior year
- Continuous dialysis for >2 weeks before randomization or anticipated duration longer than 8 weeks
- Pancreatitis or gastrointestinal hemorrhage within 6 months or active peptic ulcer within 3 months
- Severe viral infection
- Severe cardiovascular disease
- Bone marrow insufficiency with cytopenias not attributable to lupus
- Current infection requiring IV antibiotics.
- Pulse IV corticosteroids 2 weeks before first randomization and throughout the study
- Age: 32 years (mean)
- Sex: 85% female
- Race: 39.7% White, 33.2% Asian, 27% Other; 35.4% Hispanic
- Mean urine P/Cr ratio: 4.1
- eGFR: 45% ≥90; 28.5% 60-90; 17.9% 30-60; 8.7% <30.
- Renal histology: 15.7% II/III+V; 68.1% IV/IV+V; 16.2% V only. 33% with scarring on renal biopsy.
- Randomization to one of two groups:
- Oral mycophenolate mofetil 500 mg BID ×1 week, 1000 mg BID ×1 week, and 1500 mg BID thereafter (or if not tolerated, then 1000 mg BID-TID)
- Intravenous cyclophosphamide monthly; 0.75 g/m2 first dose, followed by five infusions of 0.5-1 g/m2
- Patients in both groups received glucocorticoids:
- Oral prednisolone (or equivalent) 60 mg/d ×2 weeks, then taper by 10 mg/d every 2 weeks until 40 mg/d is reached, then by 5 mg/day until 10 mg/day is reached, with further tapering once patient stable for 4 weeks.
Comparisons are MMF vs. cyclophosphamide.
- Overall response
- Renal response defined by a defined reduction in urine protein/creatinine ratio and stabilization or improvement in serum creatinine
- 56.2% vs. 53.0% (OR 1.2; 95% CI 0.8-1.8; P=0.58)
- Overall response by racial subgroup
- Asian: 53.2% vs. 63.9% (OR 0.6; 95% CI 0.3-1.3; P=0.24)
- White: 56.0% vs. 54.2% (OR 1.1; 95% CI 0.6-2.1; P=0.83)
- Other (Black and mixed-race): 60.4% vs. 38.5% (OR 2.4; 95% CI 1.1-5.4; P=0.033)
- Hispanic: 60.9% vs. 38.8% (OR 2.5; 95% CI 1.2-5.1; P=0.011)
- Any AE
- 96.2% vs. 95.0%
- Serious AE
- 27.7% vs. 22.8% (difference 4.9%; 95% CI -4.01-13.81%; P=0.28)
- 68.5% vs. 61.7%
- GI disorders
- 61.4% vs. 66.7%
- Gonadal toxicity and malignancy
- Not reported (not expected within 24-week induction period)
- 9 vs. 5 patients
This is overall a very well done study and the largest multi-center randomized controlled trial to date comparing MMF vs. cyclophosphamide. However, it has been suggested by the authors and others that a longer induction period may better distinguish the two treatment arms. Moreover, although the subgroups are prespecified, the study is not specifically powered to detect differences and the somewhat increased death rate and difference in adverse event profile compared to other studies is not explained.
Aspreva Pharmaceuticals Corporation
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- Henderson LK et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am. J. Kidney Dis. 2013. 61:74-87.
- Henderson L et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012. 12:CD002922.
- Eknoyan G, Lameire N, Eckardt, K, Kasiske BL, et al. "KDIGO clinical practice guideline for glomerulonephritis." Kidney International Supplements. 2012;2(suppl 2).