CLINICAL RESEARCH

Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis

Gerald B. Appel, Gabriel Contreras, Mary Anne Dooley, Ellen M. Ginzler, David Isenberg, David Jayne, Lei-Shi Li, Eduardo Mysler, Jorge Sánchez-Guerrero, Neil Solomons, David Wofsy and ; the Aspreva Lupus Management Study Group
JASN May 2009, 20 (5) 1103-1112; DOI: https://doi.org/10.1681/ASN.2008101028

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  • Table 1.

    Demographics and baseline disease characteristicsa

    CharacteristicMMF (n = 185)IVC (n = 185)Total (N = 370)
    Gender (n [%])
        male28 (15.1)29 (15.7)57 (15.4)
        female157 (84.9)156 (84.3)313 (84.6)
    Race (n [%])
        white75 (40.5)72 (38.9)147 (39.7)
        Asian62 (33.5)61 (33.0)123 (33.2)
        otherb48 (25.9)52 (28.1)100 (27.0)
    Ethnicity (n [%])
        Hispanic64 (34.6)67 (36.2)131 (35.4)
        non-Hispanic121 (65.4)118 (63.8)239 (64.6)
    Region (n [%])
        Asia57 (30.8)60 (32.4)117 (31.6)
        Latin America56 (30.3)50 (27.0)106 (28.6)
        United States/Canada37 (20.0)38 (20.5)75 (20.3)
        rest of world35 (18.9)37 (20.0)72 (19.5)
    Renal biopsy class (n [%])
        III/III + V32 (17.3)26 (14.1)58 (15.7)
        IV/IV + V124 (67.0)128 (69.2)252 (68.1)
        V only29 (15.7)31 (16.8)60 (16.2)
    Scarring on renal biopsy (n [%])c66 (35.7)56 (30.3)d122 (33.0)d
    Serum creatinine (μmol/L [mg/dl]; mean ± SD)108.6 ± 1.2 (97.2 ± 1.1)92.7 ± 1.0 (56.9 ± 0.6)d100.6 ± 1.1 (80.0 ± 0.9)d
    Urine protein/creatinine ratio (mean ± SD)4.1 ± 4.2e4.1 ± 3.2f4.1 ± 3.7e,f
    Range of GFR (ml/min per 1.73 m2; n [%])d,g
        ≥9080 (43.2)86 (46.7)166 (45.0)
        ≥60 to <9053 (28.6)52 (28.3)105 (28.5)
        ≥30 to <6032 (17.3)34 (18.5)66 (17.9)
        <3020 (10.8)12 (6.5)32 (8.7)
    Range of anti-dsDNA antibody titer (IU/ml; n [%])h
        <30 (negative)32 (18.4)23 (13.5)55 (15.9)
        30 to 60 (low positive)25 (14.4)24 (14.0)49 (14.2)
        >60 to 200 (positive)52 (29.9)40 (23.4)92 (26.7)
        >200 (strong positive)65 (37.4)84 (49.1)149 (43.2)
    Range of C3 concentration (g/L; n [%])i
        >1.81 (0.6)1 (0.6)2 (0.6)
        0.9 to 1.8 (normal)50 (28.4)34 (19.5)84 (24.0)
        <0.9 (low)125 (71.0)139 (79.9)264 (75.4)
    Range of C4 concentration (g/L; n [%])j
        >0.472 (1.1)1 (0.6)3 (0.9)
        0.16 to 0.47 (normal)70 (39.8)47 (27.2)117 (33.5)
        <0.16104 (59.1)125 (72.3)229 (65.6)
    Age at enrollment (yr; mean ± SD)32.4 ± 11.231.3 ± 10.331.9 ± 10.7
    Age at diagnosis of lupus nephritis (yr; mean ± SD)30.2 ± 11.028.8 ± 10.229.5 ± 10.6
    Time since diagnosis of lupus nephritis (yr; median [range])k1.0 (1 to 21)1.0 (1 to 23)1.0 (1 to 23)

    • ↵a Anti-dsDNA, antibodies reactive to double-stranded DNA; C3, complement factor 3; C4, complement factor 4.

    • ↵b Race self-reported as black (46), Mexican-Mestizo (28), mixed race (9), Hispanic (3), North African (2), Chinese (1), South/Central America/Caribbean (3), Native American (1), Pacific Islander (1), Eritrean (1), East Indian (1), Middle Eastern (1), Latin (1), brown (1), or white (1).

    • ↵c Scarring defined according to ISN classification of class III/IV active/chronic lupus nephritis.20

    • ↵d Data missing for one patient in the IVC group.

    • ↵e n = 180.

    • ↵f n = 181.

    • ↵g GFR was estimated by the Modification of Diet in Renal Disease method.21

    • ↵h Data missing for 11 patients in the MMF group and for 14 patients in the IVC group.

    • ↵i Data missing for nine patients in the MMF group and for 11 patients in the IVC group.

    • ↵j Data missing for nine patients in the MMF group and for 12 patients in the IVC group.

    • ↵k Time since diagnosis was rounded up to 1.0 yr for patients whose time was <1 yr.

  • Table 2.

    Summary of reasons for premature withdrawal from treatment (intention-to-treat population)

    ParameterMMF (n = 185; n [%])IVC (n = 185; n [%])
    Completed 24-wk open-label induction phase150 (81.1)156 (84.3)
    Total no. of patients withdrawn prematurely35 (18.9)29 (15.7)
    Reasons for withdrawal from induction phase
        adverse event21 (60.0)12 (41.4)
        deterioration with respect to serum creatinine after 12 and 16 wk of treatment0 (0.0)2 (6.9)
        dosage reduction of MMF <2 g/d for >14 d1 (2.9)0 (0.0)
        lost to follow-up1 (2.9)2 (6.9)
        patient died3 (8.6)1 (3.4)
        patient withdrew consent6 (17.1)5 (17.2)
        physician decision1 (2.9)3 (10.3)
        sponsor decision2 (5.7)1 (3.4)
        noncompliance0 (0.0)1 (3.4)
        reason not noted0 (0.0)2 (6.9)
  • Table 3.

    Summary of results of secondary efficacy end pointsa

    ParameterMMF (n = 185)IVC (n = 185)Odds Ratio (95% CI)
    Responders with renal biopsy class III or IV88 (56.4)b83 (53.9)c1.1 (0.7 to 1.8)
    Patients with renal biopsy class V16 (55.2)d15 (48.4)e
    Renal remission criterion metTreatment difference (% [95% CI])
        serum creatinine130 (70.3)125 (67.6)2.7 (−6.7 to 12.1)
        urine protein44 (23.8)50 (27.0)−3.2 (−12.1 to 5.6)
        urine sediment58 (31.4)44 (23.8)7.6 (−1.5 to 16.6)
        all three criteria16 (8.6)15 (8.1)0.5 (−5.1 to 6.2)
    Renal and extrarenal remission
        complete absence of BILAG As and Bs54 (29.7)f45 (24.9)g4.8 (4.3 to 14.0)
    SELENA-SLEDAIDifference between means (95% CI)
        change in score from baseline to end point (mean ± SD)−6.2 ± 10.1h−6.6 ± 8.0i0.41 (−1.48 to 2.30)
    Anti-dsDNA
        patients with dsDNA >60 IU/ml at baselinej117 (67.2)k124 (72.5)l
        patients with dsDNA >60 IU/ml at end point72 (41.4)k91 (53.2)l
    C3
        patients with low C3 at baselinem125 (71.0)n139 (79.9)k
        patients with low C3 at end pointm70 (39.8)n90 (51.7)k
    C4
        patients with low C4 at baselineo104 (59.1)n125 (72.3)p
        patients with low C4 at end pointo51 (29.0)n72 (41.6)p

    • ↵a Data are n(%), unless specified otherwise. BILAG, British Isles Lupus Assessment Group Scale; SELENA-SLEDAI, Safety of Exogenous Estrogens in Lupus Erythematosus National Assessment / Systemic Lupus Erythematosus Disease Activity Index.

    • ↵b n = 156.

    • ↵c n = 154.

    • ↵d n = 29.

    • ↵e n = 31.

    • ↵f n = 182.

    • ↵g n = 181.

    • ↵h n = 179.

    • ↵i n = 178.

    • ↵j The threshold >60 IU/ml was twice the upper limit of the range defined as normal.

    • ↵k n = 174.

    • ↵l n = 171.

    • ↵m Low C3 was defined as <0.9 g/L.

    • ↵n n = 176.

    • ↵o Low C4 was defined as <0.16 g/L in one laboratory and <0.10 g/L in the other; each patient's baseline and end point samples were analyzed at the same laboratory.

    • ↵p n = 173.

  • Table 4.

    Incidences of adverse events reported by >10% of patientsa

    ParameterPatients Who Experienced at Least One AE
    MMF (n = 184)IVC (n = 180)
    Deaths9 (4.9)5 (2.8)
    Withdrawals as a result of AEs24 (13.0)13 (7.2)
    All AEs177 (96.2)171 (95.0)
        diarrhea52 (28.3)23 (12.8)
        headache38 (20.7)47 (26.1)
        peripheral edema35 (19.0)30 (16.7)
        arthralgia29 (15.8)43 (23.9)
        nausea27 (14.7)82 (45.6)
        hypertension26 (14.1)25 (13.9)
        nasopharyngitis25 (13.6)29 (16.1)
        vomiting25 (13.6)68 (37.8)
        cough24 (13.0)16 (8.9)
        anemia23 (12.5)12 (6.7)
        alopecia20 (10.9)64 (35.6)
        abdominal pain19 (10.3)13 (7.2)
        back pain19 (10.3)16 (8.9)
        muscle spasms19 (10.3)17 (9.4)
        rash19 (10.3)21 (11.7)
        urinary tract infection19 (10.3)17 (9.4)

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Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis
Gerald B. Appel, Gabriel Contreras, Mary Anne Dooley, Ellen M. Ginzler, David Isenberg, David Jayne, Lei-Shi Li, Eduardo Mysler, Jorge Sánchez-Guerrero, Neil Solomons, David Wofsy
JASN May 2009, 20 (5) 1103-1112; DOI: 10.1681/ASN.2008101028
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