Mod Rheumatol (2013) 23:89–96

DOI 10.1007/s10165-012-0634-9

ORIGINAL ARTICLE

Mycophenolate mofetil versus intravenous cyclophosphamide

for induction treatment of proliferative lupus nephritis
in a Japanese population: a retrospective study
Akira Onishi • Daisuke Sugiyama • Go Tsuji • Takashi Nakazawa • Yoshinori Kogata • Kosaku Tsuda •
Ikuko Naka • Keisuke Nishimura • Kenta Misaki • Chiyo Kurimoto • Hiroki Hayashi • Goichi Kageyama •

Jun Saegusa • Takeshi Sugimoto • Seiji Kawano • Shunichi Kumagai • Akio Morinobu

Received: 22 December 2011 / Accepted: 8 March 2012 / Published online: 25 March 2012
Ó Japan College of Rheumatology 2012

Abstract Methods The primary endpoint was expressed as the

Objectives Recent studies have shown that mycopheno- percentage of responders, who in turn were defined as the
late mofetil (MMF) is similar to intravenous cyclophos- patients who met complete or partial response criteria
phamide (IVC) for the treatment of lupus nephritis (LN), according to the European consensus statement. The sec-
but that treatment response may vary according to location ondary endpoints comprised the renal activity component
and race/ethnicity. Moreover, no studies have been con- and serological activity.
ducted to compare the efficacy of MMF with that of IVC Results The primary endpoint was achieved in nine
for a Japanese population. We therefore conducted a ret- (81.8 %) patients receiving MMF and in four (40.0 %)
rospective study to clarify the efficacy and safety of MMF receiving IVC, with no significant difference between the
compared with that of IVC for induction therapy for active two groups (p = 0.081), while there was also no significant
LN, classes III and IV, in a Japanese population of 21 difference between them in terms of secondary endpoints.
patients, 11 of whom received MMF and 10 IVC. However, the MMF group suffered significantly fewer
hematologic toxic effects than the IVC group.
Conclusions MMF may be used as an alternative to IVC
for inducing renal remission of LN in Japanese patients.
A. Onishi
D. Sugiyama
J. Saegusa
S. Kumagai
Department of Evidence Based Laboratory Medicine, Kobe
Keywords Cyclophosphamide
Japanese population

University Graduate School of Medicine, 7-5-1 Kusunoki-cho,
Chuo-ku, Kobe 650-0017, Japan Lupus nephritis
Mycophenolate mofetil

Systemic lupus erythematosus
A. Onishi
Y. Kogata
K. Tsuda
I. Naka
K. Nishimura

K. Misaki
C. Kurimoto
G. Kageyama
J. Saegusa

Abbreviations
T. Sugimoto
S. Kawano
A. Morinobu (&)
Department of Clinical Pathology and Immunology, Kobe LN Lupus nephritis
University Graduate School of Medicine, 7-5-1 Kusunoki-cho, SLE Systemic lupus erythematosus
Chuo-ku, Kobe 650-0017, Japan IVC Intravenous pulse cyclophosphamide
e-mail: morinobu@med.kobe-u.ac.jp
MMF Mycophenolate mofetil
G. Tsuji
S. Kumagai GFR Glomerular filtration rate
Department of Rheumatic Diseases, Shinko Hospital, OR Odds ratio
1-4-47 Wakihama-cho, Chuo-ku, Kobe 651-0072, Japan CI Confidence interval
AE Adverse event
T. Nakazawa
Department of Rheumatology, Kurashiki Central Hospital,
1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan
Introduction
H. Hayashi
Department of Nephrology, Fujita Health University Hospital,
1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Lupus nephritis (LN) occurs in up to 60 % of patients with
Aichi 470-1192, Japan systemic lupus erythematosus (SLE) [1], while severe

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proliferative LN is associated with a poor renal prognosis
and requires aggressive therapy [2]. The National Institutes
of Health studies reported that intravenous pulse cyclo-
phosphamide (IVC) improved renal survival compared
with treatment using steroids alone [3, 4]. However,
cyclophosphamide is associated with amenorrhea and ste-
rility, increased risk of infections such as herpes zoster,
hemorrhagic cystitis, bladder cancer, leukemia, and other
malignancies.
Mycophenolate mofetil (MMF) is a relatively specific
inhibitor of lymphocyte proliferation, and has been found
to be as effective as IVC for induction treatment in pre-
vious randomized controlled trials and meta-analyses [5,
6]. Furthermore, the European Leagues Against Rheuma-
tism recommendation reports that MMF has demonstrated
an efficacy at least similar to and a toxicity profile that is
more favorable than that of IVC in short- and medium-term
trials [7].
However, the prevalence of LN and treatment response
varies depending on age, gender, location, and race/eth-
nicity [2]. For example, the risk of LN development is
higher for Asian than for white patients. Isenberg et al. [8]
indicated that MMF and IVC response rates might be
similar for Asian and white patients, while black and
Hispanic patients might respond better to MMF than to
IVC. However, most of the Asian patients enrolled in this
study were Chinese. Moreover, no studies have compared
the efficacy of MMF with that of IVC for a Japanese
population. We therefore conducted a retrospective study
to clarify the efficacy and safety of MMF compared with
that of IVC for induction treatment of active LN, classes III
and IV, in a Japanese population.
Patients and methods
Study population
Patients were enrolled consecutively between 2000 and
2011 at Kobe University Hospital if they met all of the
following criteria: (1) diagnosis of SLE based on the
American College of Rheumatology criteria [9]; (2) LN
(active or active/chronic) was confirmed as International
Society of Nephrology/Renal Pathology Society 2003 class
III, IV-S, IV-G, III ? V, or IV ? V [10] by kidney biopsy
within six months prior to treatment.
Oral MMF was administered at a dose of 0.5–1.5 mg twice
daily and IVC in biweekly or monthly pulses of 0.2–1.0 g/m2.
Both groups received oral prednisolone, with a pre-deter-
mined tapering schedule of 1 mg/kg/day from the maximum
starting dosage. Pulse methylprednisolone (1,000 mg/day for
three days) and plasma exchange were performed when
required. Antiplatelet agents, anticoagulants and angiotensin-
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Mod Rheumatol (2013) 23:89–96
converting enzyme inhibitors, and angiotensin II receptor
blockers were used concomitantly if deemed necessary.
Patients were excluded if they had received another immu-
nosuppressant within the induction phase.
Clinical assessment
The induction phase was defined as a period of
12–24 weeks [11], and the SLE disease activity index was
assessed before treatment [12]. After screening and treat-
ment initiation, all patients underwent clinical, laboratory,
and immunological assessments at least every four weeks.
These included complete blood counts, liver function tests
(transaminases and bilirubin), and measurements of serum
creatinine, blood urea nitrogen, total serum protein, serum
albumin, electrolytes, blood sugar, serum complement (C3
and C4), complement hemolytic activity (CH50), anti-
dsDNA titer, urinary protein concentration, urinary creati-
nine concentration, and urine sediments. Urine samples
were collected at every visit, when patients were also
interviewed to monitor adverse events (AEs). Safety
evaluation included the assessment of vital signs, labora-
tory tests, and spontaneous reporting of AEs. Leukopenia,
anemia, thrombocytopenia, and hypogammaglobulinemia
was defined as a white blood cell count of \4,000/ll,
hemoglobin of \11.8 g/dl, platelet count of \13 9 104/ll,
and immunoglobulin G of \700 mg/dl, retrospectively.
Severe AEs were defined as grade 3, 4, or 5 according to
the Common Terminology Criteria for Adverse Events
v.3.0 [13].
Treatment response
The objective of this study was to test whether MMF was
superior to IVC in terms of the primary endpoint; that is,
the percentage of responders defined as patients who met
complete or partial response criteria according to the
European consensus statement [11]. Complete response
was evidenced by inactive urinary sediment (\5 each of
white and red blood cells per high-power field, and the
absence of red cell casts), a decrease in the urine protein/
creatinine ratio to B0.2 mg/mg, and a normal or stable
glomerular filtration rate (GFR) (within 10 % of normal
GFR if the previous renal function was abnormal). Partial
response means a level of improvement usually defined as
an inactive sediment proteinuria of B0.5 mg/mg accom-
panied by normal (GFR [90 ml/min) or stable (\10 %
deterioration from baseline GFR if renal function was
previously abnormal) GFR. GFR was estimated with the
aid of the revised equations for estimating GFR from serum
creatinine in Japan [14].
The secondary endpoints included the proportion of
patients who achieved any one of the complete response
Mod Rheumatol (2013) 23:89–96 91

criteria items, and mean changes in the titer of serum anti- as the odds ratio (OR) with the 95 % confidence interval
dsDNA antibody and serum C3, C4, and CH50 concen- (CI). The R v.2.13.1 statistical software package was used
trations [5, 15]. to analyze the data.

Statistical analysis
Comparisons between groups were made with Fisher’s
exact test for categorical variables, and with the t test or
Mann–Whitney U test for continuous variables. With renal
response as the dependent variable, possible clinical and
biochemical variables were initially tested in univariate
analyses. Significant clinical and biochemical variables,
defined as those showing a significant association at p val-
ues of less than 0.05, were then included in a multiple
logistic regression analysis in view of multicollinearity.
Clinically important variables were also included as
explanatory covariates in a multiple logistic regression
analysis regardless of the p values. The results are expressed
Results
Patient characteristics
Twenty-one patients (11 in the MMF group and 10 in the
IVC group) met the inclusion criteria, and their clinical
characteristics are shown in Table 1. All patients with
MMF received treatment after 2006, and patients were
treated with IVC at any time between 2000 and 2011. All
patients were women with a mean age of 29.4 years for the
MMF group and 34.1 years for the IVC group. Both
groups showed high activity, with a mean SLE disease
activity index score of 15.9 for the MMF and 20.3 for the

Table 1 Demographics and baseline disease characteristics

Characteristics MMF (n = 11) IVC (n = 10) p value

Gender [no., female (%)] 11 (100.0) 10 (100.0) 1.000

Age (years, mean ± SD) 29.4 ± 8.7 34.1 ± 7.9 0.209
Duration of lupus nephritis [months, median (IQR)] 3.0 (1.0–18.5) 3.0 (1.3–4.8) 0.831
Duration of confirmed SLE [months, median (IQR)] 39.0 (15.5–108.0) 54.5 (2.5–102.0) 0.622
Flare or resistance to induction therapy [no. (%)]a 5 (45.5) 3 (30.0) 0.659
Renal biopsy class [no. (%)] 1.000
III/III ? V 3 (27.3) 2 (20.0)
IV/IV ? V 8 (72.7) 8 (80.0)
Scarring on renal biopsy [no. (%)]b 8 (72.7) 8 (80.0) 1.000
Urine protein/creatinine ratio [mg/mg, median (IQR)] 0.65 (0.28–2.75) 3.86 (1.98–7.23) 0.013*
Urine RBC count [count/hpf, median (IQR)] 14.5 (2.5–14.5) 49.5 (17.0–74.5) 0.097
Serum creatinine (mg/dl, mean ± SD) 0.67 ± 0.18 0.89 ± 0.37 0.091
GFR [ml/min per 1.73 m2, mean ± SD]c 98.1 ± 25.9 74.4 ± 28.7 0.061
Serum anti-dsDNA antibody titer (RIA) [IU/ml, median (IQR)] 50.5 (25.6–191.8) 96.9 (22.4–172.9) 1.000
Serum C3 concentration (mg/dl, mean ± SD) 45.7 ± 11.3 39.1 ± 17.3 0.307
Serum C4 concentration (mg/dl, mean ± SD) 7.2 ± 2.6 6.2 ± 3.5 0.468
Serum CH50 concentration (U/ml, mean ± SD) 21.7 ± 15.8 12.6 ± 8.2 0.116
SLE disease activity index (mean ± SD) 15.9 ± 7.8 20.3 ± 5.0 0.147
Initial corticosteroid dose (mg/kg/day, mean ± SD) 0.93 ± 0.17 0.98 ± 0.06 0.363
Pulse methylprednisolone therapy [no. (%)] 4 (36.4) 6 (60.0) 0.395
Addition of plasma exchange [no. (%)] 0 (0.0) 4 (40.0) 0.035*
Addition of an ACE inhibitor or ARB [no. (%)] 7 (63.6) 3 (30.0) 0.198
MMF mycophenolate mofetil, IVC intravenous pulse cyclophosphamide, SD standard deviation, IQR interquartile range, SLE systemic lupus
erythematosus, RBC red blood cell, GFR glomerular filtration rate, RIA radioimmunoassay, ACE angiotensin-converting enzyme, ARB angio-
tensin II receptor blocker
* p \ 0.05
a
Flare defined according to European consensus statement. Resistance was defined as patients who did not meet the complete or partial response
criteria despite induction therapy
b
Scarring defined according to ISN classification of class III/IV active/chronic lupus nephritis
c
GFR was estimated from the revised equations for estimating GFR from serum creatinine for Japanese patients

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IVC group. No significant differences were found between Efficacy

the groups except in relation to urine protein/creatinine
ratio and the addition of plasma exchange. Urine protein/
creatinine ratio was significantly higher for the IVC than
the MMF group (p = 0.013). Plasma exchange was per-
formed more frequently for the IVC group (p = 0.035) in
patients with a severe active complication: two patients
with rapidly progressive glomerulonephritis, one patient
with diffuse alveolar hemorrhage, and one patient with
demyelinating peripheral neuropathy attributable to neu-
ropsychiatric SLE. A total of 2–6 daily or alternate-day
plasma exchanges were performed with replacement fluid
consisting of 50–60 ml/kg of fresh frozen plasma or 5 %
albumin. MMF was administered at a median dosage of
2,000 mg/day (interquartile 2,000–2,500 mg/day), and
IVC from two to six times in biweekly or monthly pulses
of 0.2–1.0 g/m2 until withdrawal or throughout the
induction phase. MMF was tapered or titrated at a target
dosage of 2,000 mg/day according to efficacy and AEs.
All patients in the MMF group received treatment for
24 weeks, except for one patient for 20 weeks due to a
rapid complete response. Most patients in the IVC group
received six pulses at a target dosage of 0.75 g/m2
monthly, which was modified according to efficacy and
AEs. One patient received six pulses at a dosage of
500 mg/body biweekly according to the Euro-Lupus
Nephritis Trial [16]. One patient received two pulses at
dosage of 0.2 and 0.3 g/m2 monthly, which was deter-
mined by attending physicians. One patient received two
pulses of 0.75 g/m2 monthly and withdrew from the study
because of severe herpes zoster infection. One patient
received three pulses of 0.75 g/m2 monthly, but developed
diffuse alveolar hemorrhage, and IVC was switched to
rituximab. The need for pulse methylprednisolone was
determined by attending physicians.
The primary endpoint was attained by nine (81.8 %)
patients receiving MMF compared with four (40.0 %)
receiving IVC, with no statistically significant difference
observed between the two groups (OR 6.09, 95 % CI
0.69–88.72, p = 0.081; Table 2).
All demographic, clinical, and laboratory characteristics
were evaluated by univariate analyses, with renal response
as the dependent variable (Table 3). Serum C3 concentra-
tion and serum CH50 concentration showed a significant
association with renal response without multicollinearity
between them (r = 0.72, 95 % CI 0.42–0.88), while mul-
tivariate analysis adjusted for serum C3 concentration and
serum CH50 concentration showed no statistically signifi-
cant difference between the two groups (OR 4.94, 95 % CI
0.49–49.42, p = 0.174; Table 4). We also conducted
multivariate analyses adjusted for potential confounding
risk factors. Multivariate model 2 adjusted for age, urine
protein/creatinine ratio, GFR, serum C3 concentration,
serum CH50 concentration, and the addition of plasma
exchange showed no statistically significant differences
between the two groups (p = 0.165); nor did multivariate
model 3 adjusted for age, SLE disease activity index, and
the addition of plasma exchange (p = 0.076). Stratification
based on urine protein/creatinine ratio (B3 or [3 mg/mg)
findings did not produce statistically significant differences
(p = 0.491 for the subgroup with a urine protein/creatinine
ratio of B3 mg/mg and p = 0.500 for the subgroup with a
urine protein/creatinine ratio of[3 mg/mg). When patients
treated with plasma exchange were excluded, no statisti-
cally significant differences were noted, either (p = 0.109).
Univariate analyses with renal response as dosage of MMF
or IVC showed no statistically significant association
(MMF: p = 0.362; IVC: p = 0.526).

Table 2 Summary of results for primary and secondary efficacy endpoints

Parameter MMF (n = 11) IVC (n = 10) p value

Responder (complete response ? partial response) [no. (%)] 9 (81.8) 4 (40.0) 0.081
Complete response [no. (%)] 7 (63.6) 2 (20.0)
Partial response [no. (%)] 2 (18.2) 2 (20.0)
Normalization rates for complete response criteria item
Renal function [no. (%)] 8 (72.7) 7 (70.0) 1.000
Urinary protein [no. (%)] 10 (90.9) 5 (50.0) 0.063
Urinary sediment [no. (%)] 10 (90.9) 5 (50.0) 0.063
Change in titer of serum anti-dsDNA antibody [IU/ml, median (IQR)] -58.2 (-175.4 to -21.9) -89.9 (-143.2 to -16.5) 0.863
Change in serum C3 concentration (mg/dl, mean ± SD) 44.6 ± 18.1 33.0 ± 16.7 0.143
Change in serum C4 concentration (mg/dl, mean ± SD) 13.3 ± 7.6 8.7 ± 3.9 0.105
Change in serum CH50 concentration (U/ml, mean ± SD) 22.5 ± 8.6 21.5 ± 6.0 0.758
MMF mycophenolate mofetil, IVC intravenous pulse cyclophosphamide

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Table 3 Results of univariate

Potential confounding factor Odds ratio (95 % CI) p value
analyses for potential
confounding factors for the Age (years) 0.96 (0.86–1.07) 0.483
primary endpoint
Duration of lupus nephritis (months) 1.00 (0.98–1.01) 0.564
Duration of confirmed SLE (months) 0.99 (0.98–1.01) 0.295
Flare or resistance to induction therapy 0.44 (0.07–2.74) 0.382
Renal biopsy class (IV/IV ? V vs. III/III ?V) 0.32 (0.03–3.55) 0.355
a
Scarring on renal biopsy 0.32 (0.03–3.55) 0.355
Urine protein/creatinine ratio (mg/mg) 0.86 (0.64–1.17) 0.348
Urine RBC count (count/hpf) 0.99 (0.97–1.02) 0.567
SLE systemic lupus Serum creatinine (mg/dl) 0.84 (0.04–17.17) 0.911
erythematosus, RBC red blood
cell, GFR glomerular filtration GFR (ml/min per 1.73 m2)b 1.01 (0.98–1.04) 0.459
rate, ACE angiotensin- Serum anti-dsDNA antibody titer (RIA) (IU/ml) 1.00 (0.99–1.00) 0.251
converting enzyme, ARB Serum C3 concentration (mg/dl) 1.10 (1.01–1.19) 0.029*
angiotensin II receptor blocker
Serum C4 concentration (mg/dl) 1.47 (0.92–2.35) 0.106
* p \ 0.05
a
Serum CH50 concentration (U/ml) 1.16 (1.01–1.34) 0.034*
Scarring defined according to
SLE disease activity index 0.91 (0.78–1.05) 0.196
ISN classification of class III/IV
active/chronic lupus nephritis Initial corticosteroid dose (mg/kg/day) 65.3 (0.02–1.72 9 105) 0.299
b
GFR was estimated with the Pulse methylprednisolone therapy 0.37 (0.06–2.30) 0.290
revised equations for estimating Addition of plasma exchange 0.51 (0.09–3.11) 0.469
GFR from serum creatinine for Addition of an ACE inhibitor or ARB 0.55 (0.06–4.91) 0.589
Japanese patients

Table 4 Multivariate analyses to compare MMF and IVC in terms of (interquartile -143.2 to -16.5 IU/ml) for the IVC group,
response rate which again were not significantly different (p = 0.863);
neither were the changes in the serum C3, C4, and CH50
Adjustment Odds ratio (95 % CI) p value
concentrations from baseline to the final evaluation.
Crude 6.09 (0.69–88.72) 0.081 Figure 1 shows the changes in the levels of urinary
Multivariate model 1a 4.94 (0.49–49.42) 0.174 protein/creatinine ratio, the serum C3 concentration, and
Multivariate model 2b 107.38 (0.15–7.95 9 104) 0.165 the titers of serum anti-dsDNA antibody. No significant
Multivariate model 3c 10.82 (0.78–150.17) 0.076 differences were found between the two groups for any of
a
Model 1: adjustment for serum C3 concentration, and serum CH50 these three variables at the final evaluation.
concentration
b
Model 2: adjustment for age, urine protein/creatinine ratio, GFR, Adverse events
serum C3 concentration, serum CH50 concentration, and addition of
plasma exchange Table 5 summarizes the safety profiles of patients treated
c
Model 3: adjustment for age, SLEDAI, and addition of plasma with MMF and IVC in this study. Overall, all patients
exchange
experienced at least one AE in both the MMF and IVC
groups, with significantly more AEs for the IVC group (6.7
There were no statistically significant differences events/person) than the MMF group (3.5 events/person)
between the two groups for any of the secondary efficacy during the study period (p = 0.004). Severe AEs, consist-
end points (Table 2). Eight (72.7 %) patients in the MMF ing of severe herpes zoster, leukopenia, anemia, and
group showed normal or stable GFR, compared with seven thrombocytopenia, were observed only in the IVC group.
(70.0 %) in the IVC group (p = 1.000); ten (90.9 %) Simple regression analyses showed no significant rela-
patients in the MMF group had a urine protein/creatinine tionship between dosage of MMF and overall AE
ratio of B0.2 g/day, compared with five (50.0 %) in the (p = 0.938). Although a positive correlation was found
IVC group (p = 0.063); and ten (90.9 %) patients in the between the dosage of IVC and overall AE (b = 11.79,
MMF group had inactive urinary sediment, compared with 95 % CI 6.50–17.07, p = 0.002), there was no significant
five (50.0 %) in the IVC group (p = 0.063). Changes in the relationship between the dosage of IVC and serious AE
titer of serum anti-dsDNA antibody from baseline to the (p = 0.557). In both treatment groups, the most common
final evaluation were -58.2 IU/ml (interquartile -175.4 types of AE were infections (MMF 63.6 %, IVC 60.0 %,
to -21.9 IU/ml) for the MMF group and -89.9 IU/ml p = 1.000), gastrointestinal disorders (MMF 36.3 %, IVC

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Table 5 Adverse events

MMF IVC

Withdrawal as a result of adverse events 0 1

All adverse events 38 67
Severe adverse eventsa 0 8
Infection
Upper respiratory infection 4 2
Herpes zoster 1 4
Oral candidiasis 3 2
Gastrointestinal
Nausea 2 2
Diarrhea 2 4
Appetite loss 0 1
Abdominal pain 2 1
Hypertension 0 1
Headache 1 2
Muscle cramp 0 3
Menstrual irregularity 2 1
Alopecia 1 1
Acne 1 2
Ophthalmological
Glaucoma 1 1
Cataract 0 1
Laboratory data
Leukopenia (white blood cell count \4,000/ll) 0 5
Anemia (hemoglobin \11.8 g/dl) 0 4
Thrombocytopenia (platelet count \13 9 104/ll) 0 2
Abnormal liver function test 1 5
Hypogammaglobulinemia (immunoglobulin G 5 7
\700 mg/dl)
MMF mycophenolate mofetil, IVC intravenous pulse cyclophos-
phamide
a
Severe adverse events were defined as grade 3, 4, or 5 according to
the Common Terminology Criteria for Adverse Events v.3.0
Fig. 1 a Changes in urinary protein/creatinine ratio [median (inter-
quartile)]. b Changes in serum C3 concentration [mean (SE)].
c Changes in the titer of serum anti-dsDNA antibody [median Discussion
(interquartile)]. Statistical analyses were performed to compare the
two groups at the final evaluation
In this retrospective study, MMF did not prove to be superior
to IVC in terms of the percentage of responders to induction
60.0 %, p = 0.395), and hypogammaglobulinemia (MMF treatment of active LN, classes III, IV, and V, in a Japanese
45.5 %, IVC 70.0 %, p = 0.387). Hematologic toxic population. The results of multivariate analyses adjusted for
effects (leukopenia, anemia, and thrombocytopenia) potential confounding risk factors did not show any change
were observed only in the IVC group (MMF 0.0 %, IVC in this outcome. There were no statistically significant dif-
60.0 %, p = 0.001). Only one IVC-treated patient with- ferences between the two groups for any of the secondary
drew from the study because of severe herpes zoster efficacy endpoints either. Although the results of all ran-
infection which necessitated intravenous antiviral drugs domized controlled trials and observational studies to com-
and caused severe persistent neuralgia, while none of the pare MMF with IVC for the treatment of LN do not agree
MMF-treated patients withdrew. One patient in each completely, a recent large-scale study [5] and meta-analysis
group developed alopecia, while menstrual irregularity was [6] showed that MMF presents a similar efficacy at achieving
observed in two MMF-treated patients and one IVC-treated renal remission to that of IVC in the treatment of prolifera-
patient. tive LN, which is consistent with our results.

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As far as we know, ours is the first study to compare the
efficacy of MMF and IVC for induction treatment of active
LN, classes III, IV, and V, in a Japanese population.
Although several studies have demonstrated the efficacy of
IVC [17], tacrolimus [15], mizoribine [18], and cyclosporine
[19] for LN in a Japanese population, only a few case series
[20] have provided evidence of the efficacy of MMF in a
Japanese population, while the European League Against
Rheumatism recommends the use of MMF or IVC for
induction treatment of proliferative LN [7]. In addition,
various observations have suggested that the mechanisms of
LN may differ among racial and ethnic subsets. Some data
from randomized controlled trials and meta-analyses have
suggested that patients of different ethnicities show different
responses [8, 21]. These studies showed that MMF and IVC
response rates were similar for Asians, while non-Asian
patients responded better to MMF than to IVC. However, the
studies of Asian subjects included patients from only China,
Malaysia, and Hong Kong. Matsuyama et al. [17] reported
that the long-term prognosis of Japanese LN patients treated
with IVC differed from those reported in other countries.
Genome-wide association studies suggested that there are
differences in genetic susceptibility between Japanese and
non-Japanese Asian patients. The integrin aM gene was
found to be associated with SLE susceptibility in Hong Kong
Chinese and Thai populations, but not in Japanese or Korean
populations [22, 23]. There are only a few case reports of LN
with positive anti-neutrophil cytoplasmic antibody in Japan
[24, 25], while 20–30 % of Chinese LN patients showed
positivity for this antibody, which is associated with fibri-
noid degeneration and/or crescent formation and poor renal
outcome [26, 27]. Despite genetic, regional, and socioeco-
nomic differences between Japanese and non-Japanese
Asian patients, our results were similar to the results of the
studies performed outside Japan [8, 21].
Our results showed that the MMF group experienced
significantly fewer hematologic toxic effects than the IVC
group, and tended to have a better safety profile, while the
incidences of infection and gastrointestinal disorders were
not significantly different. The overall AE profiles of both
MMF and IVC in this study were consistent with those
reported for previous studies [5, 6]. The Aspreva Lupus
Management Study observed a more frequent occurrence
of AEs in the IVC group (2,088 events) than in the MMF
group (1,485 events), and the most common AEs were
infections (68.5 % with MMF, 61.7 % with IVC) and
gastrointestinal disorders (61.4 % with MMF, 66.7 % with
IVC) [5]. While nausea and vomiting were the most
common gastrointestinal disorders associated with IVC,
and diarrhea was predominant with MMF in non-Asian
patients, diarrhea reportedly occurred less frequently in
Asian patients than in other racial groups [8]. One meta-
analysis showed that the relative risk of leukopenia was
95
significantly lower for MMF than for IVC (relative risk
0.65, 95 % CI 0.44–0.96), while infection and gastroin-
testinal disorders did not show any significant differences
[6]. No significant differences in death, hematological
complications, infections, and gastrointestinal disorders
were detected between Asian and non-Asian patients [21].
Although the Aspreva Lupus Management Study also
found that alopecia was more commonly associated with
IVC than MMF, regardless of race (10.9 % with MMF,
35.6 % with IVC), our results did not show such a ten-
dency, which may be attributable to the small sample size
of our study. Although our results also showed AEs that
included acne and glaucoma, they can be considered to be
associated with prednisolone.
This study has several limitations. First, this was a ret-
rospective study with a relatively small number of patients.
Retrospective studies involve several biases, such as
selection bias and confounding bias. IVC was administered
in our study at various dosages, and the IVC group showed
a significantly higher urine protein/creatinine ratio and a
lower GFR, and received more plasma exchange therapy,
which affected both the degree of efficacy and the occur-
rence of AE. Although multivariate analyses adjusted for
potential confounding risk factors showed similar renal
response rates for MMF and IVC, confounding factors may
not have been adjusted sufficiently due to the small sample
size of this study. Second, because MMF is a relatively
new treatment modality compared with IVC, MMF tended
to be administered more recently than IVC. This difference
in timing may result in change in factors affecting efficacy,
such as patient characteristics, adjunct treatment, and
nursing system, which lead to biases.
To summarize, we demonstrated that MMF is not
superior to IVC for induction treatment of active LN,
classes III, IV, and V, in a Japanese population. Our results
also showed that the MMF group experienced hematologic
toxic effects less frequently than the IVC group, and tended
to have a better overall safety profile, although rates of
infection and gastrointestinal disorders were not signifi-
cantly different. MMF may thus serve as a safe alternative
to IVC for inducing renal remission of LN in Japanese
patients. Because our study has several limitations, these
results should be interpreted with caution, while a large-
scale prospective clinical study of a Japanese population is
clearly warranted.
Conflict of interest None.
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