ALMS Induction

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Appel, GB et al. "Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.". Journal of American Society of Nephrology. 2009. 20(5):1103–1112.
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Clinical Question

Among patients with active lupus nephritis, is mycophenolate mofetil superior to IV cyclophosphamide in response to treatment?

Bottom Line

Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis. However, prespecified subgroup analysis did show that "other race"-predominantly black or Latin American mixed race- were less likely to respond to IV cyclophosphamide than to mycophenolate mofetil.

Major Points

Guidelines

KDIGO (2012), adapted[1]

Class III LN (focal LN) and class IV LN (diffuse LN)—initial therapy 12.3.1: We recommend initial therapy with corticosteroids (1A), combined with either cyclophosphamide (1B) or MMF (1B). 12.3.2: We suggest that, if patients have worsening LN (rising SCr, worsening proteinuria) during the first 3 months of treatment, a change be made to an alternative recommended initial therapy, or a repeat kidney biopsy be performed to guide further treatment. (2D)

Class V LN (membranous LN) 12.5.1: We recommend that patients with class V LN, normal kidney function, and non–nephrotic-range proteinuria be treated with antiproteinuric and antihypertensive medications, and only receive corticosteroids and immunosuppressives as dictated by the extrarenal manifestations of systemic lupus. (2D) 12.5.2: We suggest that patients with pure class V LN and persistent nephrotic proteinuria be treated with corticosteroids plus an additional immunosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF (2D), or azathioprine (2D).

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=370
    • Mycophenolate mofetil(n=185)
    • IV cyclophosphamide (n=185)
  • Setting: 88 centers in 20 countries in North America, Latin America, Asia, Australia and Europe
  • Enrollment: All enrolled had active proliferative (Class III/IV) and membranous (Class V) LN
  • Mean follow-up:156.2d for MMR; 167.5d for the IVC
  • Analysis: Intention to treat
  • Primary outcome: Response to treatment, defined by decrease in urine protein/creatinine ratio (from 24-h urine collection) to
    • <3 in patients with baseline nephrotic range proteinuria (>=3) OR
    • >=50% reduction of P/Cr in patients with baseline subnephrotic range proteinuria (<3)

AND

  • stabilization (+/- 25%) or improvement in serum creatinine at 24 weeks

Population

Inclusion Criteria

  • Patients age 12-75 with diagnosis of SLE
  • Lupus nephritis (active or active/chronic) was confirmed by kidney biopsy within 6 mo before randomization
    • Class III, IV-S or IV-G, V, III+V, or IV+V. Patients with class III or V lupus nephritis must have had proteinuria (at least 2 g/d)

Exclusion Criteria

  • Treatment with mycophenolate mofetil or or IV cyclophosphamide within the previous year
  • Continuous dialysis for >2 wk before randomization or anticipated duration longer than 8 wk
  • Pancreatitis, gastrointestinal hemorrhage within 6 mo or active peptic ulcer within 3 mo
  • Severe viral infection
  • Seevere cardiovascular disease
  • Bone marrow insufficiency with cytopenias not attributable to SLE,
  • Current infection requiring intravenous antibiotics.
  • Pulse intravenous corticosteroids 2 wk before first randomization and throughout the study.

Baseline Characteristics

  • Mean age: 31.9; 84.6% 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.
  • Biopsy class: 15.7% II/III+V; 68.1% IV/IV+ V; 16.2% V only. 33% with scarring on renal biopsy.

Interventions

Primary Outcomes

Mycophenolate mofetil vs. IV cyclophosphamide

Overall response

  • 56.2% vs. 53.0% OR 1.2 ; 95% CI 0.8 to 1.8; P= 0.58

Racial Groups

  • Asian: 53.2% vs.  63.9% (OR 0.6; 95% CI 0.3 to 1.3; P = 0.24)
  • White p56.0% vs. [54.2% (OR 1.1; 95% CI 0.6 to 2.1; P = 0.83)
  • "Other” (mostly black (n = 46) and mixed-race (n = 37)): 60.4% vs. 38.5% (OR 2.4; 95% CI 1.1 to 5.4; P = 0.033). 
  • Hispanic: 60.9% vs. 38.8% (OR 2.5; 95% CI 1.2 to 5.1; P = 0.011).

Secondary Outcomes

Responders with class III or IV lupus nephritis
OR 1.1 (0.7-1.8)
Responders with class V lupus nephritis
15 vs. 16 patients
Annual rate of cardiovascular death

Subgroup Analysis

Adverse Events

Criticisms

This is overall a very well done study and the largest multi-center randomized controlled trial to date comparing mycophenolate mofetil 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.

Funding

Aspreva Pharmaceuticals Corporation

Further Reading

  1. Eckard KU, Kasiske BL, et al. "KDIGO clinical practice guideline for glomerulonephritis." Kidney International. 2012;2(sup 2):259-274.