ORIGINAL ARTICLE
Cyclophosphamide Versus Mycophenolate Versus Rituximab
in Lupus Nephritis Remission Induction
A Historical Head-to-Head Comparative Study
Rudra Prosad Goswami, DM, Geetabali Sircar, MD, Hiramanik Sit, MD,
Alakendu Ghosh, DNB, and Parasar Ghosh, DM
Objective: We report comparative efficacy between high-dose cyclophos-
phamide (HDCyC), low-dose cyclophosphamide (LDCyC), mycophenolate
mofetil (MMF) and rituximab in patients with lupus nephritis (LN).
Methods: We analyzed comparative efficacy of 4 induction regimens of
biopsy-proven LN: LDCyC: 500 mg fortnightly, HDCyC: 750 to 1200 mg
monthly, MMF: 1.5 to 3 g/d, and rituximab. Outcomes of 4 groups were an-
alyzed at the sixth month.
Results: Among total 222 patients, 26 received LDCyC (3-g total dose),
113 received HDCyC (mean, 5.1-g total dose), 61 received MMF (mean,
2.2 g/d), and 22 received rituximab (mean, 1.9-g total dose). Relapsing/
refractory LN was 11 in HDCyC, 1 in LDCyC, 10 in MMF, and 14 in
the rituximab group. Overall 16.2% had no improvement of proteinuria,
18% had partial response, and 65.8% (146/222) had complete response.
Renal response (RR) was higher in HDCyC (90.3%) and rituximab
(90.9%) groups compared with LDCyC (73%) and MMF (72%) groups.
Rituximab was effective in relapsing disease (100% RR). Infection was
highest with the HDCyC, followed by LDCyC and rituximab (P = 0.15),
whereas the MMF group had a higher incidence of gastrointestinal adverse
effects (P < 0.001). The following predictors of RR were identified: rituximab
(odds ratio [OR], 20.4; 95% confidence interval [CI], 1.9–215.7;
P = 0.012), renal Baseline Systemic Lupus Erythematosus Disease Activity
Index at baseline (OR, 0.86; 95% CI, 0.75–0.99; P = 0.034), and duration of
disease (OR, 0.98; 95% CI, 0.97–0.99; P = 0.009).
Conclusions: High-dose cyclophosphamide and rituximab were the
most effective therapeutic strategies in patients with LN, especially in the
Indian context. Rituximab was highly effective in relapsing disease.
Key Words: cyclophosphamide, lupus nephritis, mycophenolate,
remission induction, renal response, rituximab
(J Clin Rheumatol 2018;00: 00–00)
R enal involvement in systemic lupus erythematosus (SLE) is a
major cause of mortality and morbidity. Lupus nephritis
(LN) occurs in 40% to 60% of patients with SLE. Asian ancestry
has increased risk of LN compared with white population.1
Whereas 25% to 30% of patients with proliferative LN develop
end-stage renal disease over the next 20 years of follow-up,2 failure
to achieve renal response (RR) within the first year of therapy
portends worse prognosis.3 One recent study from our institute
(Department of Nephrology) suggested that patients with proliferative
From the Department of Rheumatology, Institute of Post Graduate Medical
Education and Research, Kolkata, India.
The authors declare no conflict of interest.
Author contributions: Research idea and study design: R.P.G., G.S., A.G., P.G.;
data acquisition: R.P.G., G.S., H.S., P.G.; data analysis: R.P.G.;
interpretation: R.P.G., G.S., P.G., A.G.; statistical analysis: R.P.G.;
supervision or mentorship: R.P.G., H.S.
Correspondence: Rudra Prosad Goswami, DM, SR, Abhyudoy Housing, Flat
18/14, ECTP, Ph IV, Type B, EM Bypass, Kolkata 700107, West Bengal,
India. E‐mail: rudra.goswami@gmail.com.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1076-1608
DOI: 10.1097/RHU.0000000000000760
JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
lupus in Eastern India presented differently with a lower estimated
glomerular filtration rate.4 Hence, optimum induction therapy is
the mainstay for the control of disease in time.
Current standard of care of LN, mostly based on data generated
from Europe and North America, consists of high-dose prednisolone,
associated with intravenous (IV) cyclophosphamide (either monthly
“moderate- to high-dose” modified National Institutes of Health
[NIH] protocol or the biweekly “low-dose” EUROLUPUS protocol)
or oral mycophenolate.5–10 A number of studies showed that my-
cophenolate is comparable in efficacy with cyclophosphamide.
One Indian study, however, showed that the low-dose cyclophos-
phamide (LDCyC) regimen was comparable in efficacy to myco-
phenolate and was less toxic.11 Rituximab, an anti-CD20
monoclonal antibody, is an attractive new targeted therapy of LN.
Western data, however, are conflicted between both positive and
negative results.10–14 Because of lack of direct head-to-head com-
parison of therapeutic strategies, physicians of nonwhite globe tend
to extrapolate data from Western studies. It is widely assumed that
clinical and treatment-related phenotype might be different between
patients with SLE from the West and the East.15,16
To address this research gap, we compared efficacy and safety
of 4 available treatment strategies, namely, HDCyC and LDCyC,
mycophenolate, and rituximab in Indian patients with active LN.
MATERIALS AND METHODS
This historical observational study was conducted at the Institu-
tion of Post Graduate Medical Education and Research (IPGMER),
Kolkata, India. Patients diagnosed as and treated for LN in the De-
partment of Rheumatology, IPGMER, between January 2013 and
May 2016 were included retrospectively through electronic records.
Records were included if the patients' data confirmed a diagno-
sis of SLE fulfilling the Systemic Lupus International Collaborating
Clinics 2012 criteria and showed a record of renal biopsy.17 Records
with following deficits were excluded: any record not fulfilling the
Systemic Lupus International Collaborating Clinics 2012 criteria,
baseline proteinuria of less than 500 mg/d, renal biopsy report not
conforming to LN, International Society of Nephrology/Renal
Pathology Society class 2 or 6 LN,18 comorbid hepatitis B or
hepatitis C infection, and lack of follow-up data.
The following data were extracted: demographic (age, sex,
duration of disease), clinical (renal and nonrenal manifestations
of lupus, previous immunosuppression history), biochemical
(renal biopsy class, C3 level, anti-dsDNA antibody positivity,
urine routine microscopy and 24-hour urine protein estimation
both at baseline and at the end of induction regimen), and
treatment-related data (induction regimen drugs and doses for
LN and 6-month prednisolone dose). The following 4 different in-
duction regimens were included: LDCyC: 6 biweekly pulses of
500 mg cyclophosphamide followed by azathioprine 50 to
100 mg/d or mycophenolate mofetil (MMF) 1 to 1.5 g/d; HDCyC:
6 pulses of 750 to 1200 mg monthly cyclophosphamide; MMF:
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Goswami et al JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018

1.5 to 3 g/d and rituximab with or without any of the above. Baseline
Systemic Lupus Erythematosus Disease Activity Index 2000
(SLEDAI-2K) was calculated for each patient, and baseline and
6-month renal SLEDAI (simple sum of renal items of SLEDAI) were
also calculated. The following outcome measures were analyzed:
complete renal response (CR) at 6 months: serum creatinine of less
than 1.3 mg/dL, normal urinalysis, and 24-hour urine protein esti-
mation of less than 500 mg/d; partial renal response (PR): serum
creatinine of less than 1.3 mg/dL, normal urinalysis, and reduction
of proteinuria by more than 50% but 24-hour urine protein excre-
tion 500 mg/d or greater but less than 2000 mg/d; no response: not
achieving at least PR by 6 months; any RR: achievement of at
least PR by the end of 6 months.
the 4 treatment arms, and baseline SLEDAI is a known impor-
tant outcome measure, these 3 variables were also included as ad-
ditional independent variables. All statistical calculations were
done with SPSS version 21 (IBM Corp, Armonk, NY).
Ethics Statement
Approval of the Institutional Ethics Committee of IPGMER
was sought and accorded for historical analysis of routine data
(approval no. IPGME&R/IEC/2017/362). The research was con-
ducted in accordance with the Declaration of Helsinki.
RESULTS

Statistical Methods
Continuous data were expressed as mean ± SD and categorical
data as % (fraction). Shapiro-Wilk test was used as test for normality.
Comparisons of means among the 4 treatment groups were computed
with Kruskal-Wallis test, and post hoc Mann-Whitney U tests were
done. Comparisons of proportions among the treatment groups were
done with χ2 test or Fisher exact test as appropriate. Post hoc bivari-
ate tests were done after applying Bonferroni correction for multiple
comparisons. For example, in the entire cohort and in the treatment-
naive subgroup, 6 possible bivariate comparisons are possible among
the 4 treatment groups, and therefore to reduce the false discovery
rate (type I error), the P value cutoff is corrected to 0.05/6 = 0.008.
In the treatment-experienced/relapse subgroup, there are 3 possible
bivariate comparisons (among HDCyC, MMF, and rituximab), and
the P value cutoff is reduced to 0.05/3 = 0.016.
Predictors of renal outcome were tested in univariate analysis.
Those who achieved any RR versus those who did not were
compared, and variables with P < 0.2 were included in the first
multivariate model. Because prednisolone dose at baseline and
renal SLEDAI at baseline were significantly different among
Patient Characteristics
Complete data of 222 patients (female 205/222 [92.3%])
were available. Mean age of the population was 25.9 ± 8.9 years,
and mean duration of disease was 22.6 ± 29.5 months. Baseline
characteristics are given in Table 1. Patients receiving rituximab
had longer disease duration (38.86 ± 27.31 months) and higher
mean proteinuria (3.5 ± 2.7 g/d). Patients in the rituximab group
also had significantly higher level of microscopic hematuria
compared with patients in the HDCyC group (72.7% vs.
39.8%, P = 0.004). Complement C3 was lowest in the patients
on HDCyC (52.84 ± 29.73 mg/dL), but anti-dsDNA antibody
positivity was equally distributed, as was proliferative lesion
in renal biopsy. The following renal biopsy classes were observed:
class III, 17.6% (39/222); class IV, 66.7% (148/222); class V,
9.9% (22/222); class III + V, 1.8% (4/222); and class IV + V,
4% (9/222). The following nonrenal manifestations were noted
at baseline: fever 43.2% (96/222); arthralgia 31.5% (70/222);
mucocutaneous: acute cutaneous lupus 22.5% (50/222), subacute
cutaneous lupus 11.7% (26/222), discoid lupus 5% (11/222), alopecia
15.8% (35/222), oral ulcer 17.6% (39/222); cardiopulmonary:
pericarditis 12.6% (28/222), pleuritis 7.2% (16/222), myocarditis

TABLE 1. Baseline Characteristics of Patients Included in the Study

LDCyC HDCyC MMF Rituximab Total

Parameters n = 26 n = 113 n = 61 n = 22 N = 222 P
Age, y 23.85 ± 8.15 26.07 ± 9.24 26.33 ± 8.6 26.32 ± 9.04 25.91 ± 8.9 0.75
Duration of disease, mo 16.04 ± 29.35 16.81 ± 24.08 30.54 ± 35.51 38.86 ± 27.31 22.68 ± 29.5 <0.001a
Hemoglobin, g/dL 8.9 ± 1.27 8.35 ± 2.9 9.2 ± 2.1 9.73 ± 2.5 8.78 ± 2.54 0.326
Creatinine, mg/dL 0.9 ± 0.22 1.11 ± 0.72 0.99 ± 0.47 1.15 ± 0.63 1.05 ± 0.61 0.69
C3, mg/dL 59.77 ± 32.4 52.84 ± 29.73 58.61 ± 25.74 77.39 ± 39.02 57.71 ± 30.71 0.012b
Proteinuria, g/d 2.3 ± 1.4 1.9 ± 1.7 2 ± 1.8 3.5 ± 2.7 2.2 ± 1.8 0.007c
Pyuria (>5 pus cell/HPF) 57.7% (15/26) 41.6% (47/113) 49.2% (30/61) 59.1% (13/22) 47.3% (105/222) 0.27
Microscopic hematuria (>5/HPF) 50% (13/26) 39.8% (45/113) 52.5% (32/61) 72.7% (16/22) 47.2% (102/222) 0.03d
SLEDAI 17.69 ± 8.36 18.38 ± 7.01 18.77 ± 6.15 18.52 ± 7.57 18.42 ± 6.97 0.68
Renal SLEDAI 8.3 ± 3.5 7.3 ± 3.7 8.3 ± 3.7 9.8 ± 4 7.9 ± 3.7 0.019e
Anti-dsDNA positivity 88.5% (23/26) 87.6% (99/113) 85.2% (52/61) 68.2% (15/22) 85.1% (189/222) 0.12
Proliferative lesion in renal biopsy 92.3% (24/26) 91.2% (102/113) 85.2% (52/61) 95.5% (21/22) 90.1% (200/222) 0.46
a
Mann-Whitney U test: LDCyC and MMF (P = 0.015), LDCyC and rituximab (P < 0.001), HDCyC and MMF (0.01) and HDCyC and rituximab
(P < 0.001).
b
Mann-Whitney U test: significant difference between HDCyC and rituximab (P = 0.004) and MMF and rituximab (P = 0.036).
c
Mann-Whitney U test: significant differences between HDCyC and rituximab (P = 0.002) and MMF and rituximab (P = 0.01).
d
Significance level for multiple corrections was set at 0.008. Bivariate P value comparing rituximab group versus HDCyC group attained significance
(P = 0.004).
e
Mann-Whitney U test: significant difference between HDCyC and rituximab (P = 0.006).
HPF indicates high-power field.

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JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018 Lupus Nephritis Remission Induction

TABLE 2. Comparison of Baseline Characteristics Between Patients With Relapsing Disease/Treatment-Experienced Patients Versus
Treatment-Naive Patients

Treatment-Experienced/Relapsing Disease Treatment Naive

Parameters n = 36 n = 186 P
Age, y 24.08 ± 7.7 26.25 ± 9.08 0.18
Duration of disease, mo 35.13 ± 32.39 20.26 ± 28.37 0.005
Hemoglobin, g/dL 9.6 ± 2.2 8.6 ± 2.6 0.028
Creatinine, mg/dL 1.12 ± 0.54 1.04 ± 0.62 0.428
C3, mg/dL 64.82 ± 29.44 56.36 ± 30.83 0.136
Proteinuria, g/d 3.2 ± 2.3 1.9 ± 1.7 <0.001
Pyuria (>5 pus cell/HPF) 69.4% (25/36) 43.0% (80/186) 0.004
Microscopic hematuria (>5/HPF) 61.1% (22/36) 45.2% (84/186) 0.08
SLEDAI 19.5 ± 9.03 18.3 ± 6.5 0.299
Renal SLEDAI 9.9 ± 3.9 7.5 ± 3.6 0.001
Anti-dsDNA positivity 83.3% (30/36) 85.5% (159/186) 0.74
Proliferative lesion in renal biopsy 97.2% (35/36) 88.7% (165/186) 0.12

(2.7%); and neuromuscular: myositis 14.9% (33/222), seizure
8.6% (19/222), psychosis (2.3%), and each of peripheral and optic
neuropathy 1.4% (3/222).
Interventions and Previously Received Medications
Low-dose cyclophosphamide (3 g cyclophosphamide in all)
was given in 26 patients, HDCyC (mean dose, 5.1 ± 1 g) in
113 patients, MMF (mean dose, 2188 ± 439.3 mg/d) in
61 patients, and 22 patients received rituximab (mean dose,
1.9 ± 0.25 g). Rituximab was given as a stand-alone drug in
6 patients, and in the other 16, it was coadministered with the fol-
lowing medications: MMF in 4 and cyclophosphamide 500 mg in
1, 1000 mg in 4, 1500 mg in 1, and 2000 mg in 6. Eleven patients
with HDCyC had relapsing LN and were previously treated with ta-
crolimus and azathioprine followed by HDCyC (n = 1),
azathioprine followed by HDCyC (n = 1), MMF (n = 2), LDCyC
(n = 2), and HDCyC (n = 5). One patient in the LDCyC group
was previously treated for LN (with MMF and later with HDCyC).
Ten patients on MMF had relapsing disease with LN and received
the following therapies previously: HDCyC (n = 5), LDCyC
(n = 4), and tacrolimus (n = 1). Fourteen patients in the rituximab
group were previously treated for LN (1 patient with LDCyC and
then HDCyC, 1 with LDCyC, HDCyC and MMF consecutively, 3
with HDCyC followed by MMF, 3 with HDCyC, 2 with LDCyC,
and 4 patients with MMF). Baseline characteristics of these
treatment-experienced/refractory patients are given in Table 2. Com-
pared with treatment-naive patients, refractory LN patients had higher
disease duration; higher magnitude of proteinuria, pyuria, and hema-
turia; and higher mean renal SLEDAI, but overall SLEDAI scores
were comparable.

FIGURE 1. Flow diagram of 4 different treatment regimens compared in patients with active LN. Data are presented as mean (SD) for
continuous variables. DD indicates duration of disease in months; rS, renal SLEDAI; UP, 24-hour urine protein estimation in grams per day.

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Goswami et al JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018

TABLE 3. Treatment-Related Data and Outcome Parameters of the 4 Treatment Groups at the Sixth Month

LDCyC HDCyC MMF Rituximab

Parameters n = 26 n = 113 n = 61 n = 22 P
CR 53.8% (14) 71.7% (81) 59% (36) 72.7% (16) 0.16
RR 73.1% (19) 90.3% (102) 72.1% (44) 90.9% (20) 0.006a
Hypocomplementemia at 6 mo 57.7% (15) 50.4% (57) 34.4% (21) 9.1% (2) 0.001b
Positive anti-dsDNA antibody at 6 mo 38.4% (10) 30.1% (34) 42.6% (26) 18.2% (4) 0.14
Creatinine at 6 mo, mg/dL 0.8 ± 0.2 0.8 ± 0.3 0.7 ± 0.2 0.9 ± 0.3 0.18
Proteinuria at 6 mo, g/d 0.98 ± 1.7 0.43 ± 0.8 0.66 ± 0.8 0.42 ± 0.34 0.12
Six-month renal SLEDAI 3.2 ± 4.1 1.5 ± 2.7 3.1 ± 4 1.5 ± 2.3 0.015c
Percentage reduction of renal SLEDAI 65 ± 40 80 ± 37 60 ± 53 83 ± 32 0.018d
Percentage reduction of proteinuria 58 ± 57 76 ± 31 55 ± 67 84 ± 18 0.239
Baseline daily prednisolone dose, mg 25.4 ± 8.9 41.6 ± 9.9 42.2 ± 11.6 37.1 ± 12.1 <0.001e
Six-month daily prednisolone dose, mg 11.9 ± 7.5 9.9 ± 7.3 9.4 ± 5.7 10 ± 2.6 0.15
a
The following bivariate comparisons attained statistical significance at P < 0.05: HDCyC and LDCyC (P = 0.019) and HDCyC versus MMF
(P = 0.001). Applying Bonferroni correction for multiple comparisons, the cutoff P value was at 0.008.
b
The following bivariate comparisons attained statistical significance after correcting for multiple comparisons: LDCyC versus rituximab (P = 0.006),
HDCyC versus rituximab (P = 0.0004), and MMF versus rituximab (P < 0.00001).
c
Mann-Whitney U test: significant differences between LDCyC and HDCyC (P = 0.022) and HDCyC and MMF (P = 0.006).
d
Mann-Whitney U test: significant differences between LDCyC and HDCyC (P = 0.034) and HDCyC and MMF (P = 0.007).
e
Mann-Whitney U test: significant differences between LDCyC and HDCyC (P < 0.001), LDCyC and MMF (P < 0.001), and LDCyC and rituximab
(P < 0.001).

Treatment Outcome in the Entire Cohort
Distribution of patients in different treatment-related classes
and the result of their 6-month follow-up are graphically represented
in Figure 1. At the end of 6 months, overall 16.2% (36/222) had no
improvement of proteinuria, 18% (40/222) had PR, and 65.8%
(146/222) had CR. Patients with proliferative or membranous glo-
merulonephritis had similar proportion of patients achieving CR
(68% vs. 65.5%, P = 0.64). Zero renal SLEDAI was obtained in
63.5%, and creatinine of less than 1.3 mg/dL was present in 94.6%.
There were no deaths during the observation period (Table 3).
Any RR seen in patients treated with HDCyC (90.3% [102/113])
or rituximab (90.9% [20/22]) was higher compared with patients
treated with LDCyC (73.1% [19/26]) or MMF (72.1% [41/66]),
and the difference achieved statistical significance (P = 0.006).
However, after correcting for multiple corrections, only the differ-
ence between HDCyC and MMF was statistically significant
(P = 0.001). In bivariate comparison, a trend toward higher RR
in the rituximab group compared with the MMF group was seen
(90.9% vs. 72.1%, P = 0.07). At 6 months, proteinuria of greater
than 500 mg/d was still persistent in 46.2% in the LDCyC group,
41% in the MMF group, 27.3% in the rituximab group, and
23.9% in the HDCyC group (P = 0.12). Persistent serological ac-
tivity in the form of hypocomplementemia and anti-dsDNA anti-
body positivity was least in the rituximab group (9.1% and 18.2%,
respectively). In bivariate analysis, rituximab had significantly
better effect on persistent hypocomplementemia compared with
all other regimens (vs. LDCyC, P = 0.006; vs. HDCyC,
P = 0.0004; and vs. MMF, P < 0.0001).
Treatment Outcome in the Subgroup of Patients
With Relapsing/Treatment-Experienced LN
In the subgroup of relapsing LN (35 patients), rituximab
achieved highest RR (100% [14/14]) followed by HDCyC
(72.7% [8/11]) and MMF (50% [5/10]), and the difference
achieved statistical significance (P = 0.014). In bivariate analysis,
RR to rituximab was higher compared with both HDCyC
(P = 0.037) and MMF (P = 0.002). However, after correcting
for multiple comparisons (P cutoff set at 0.016), the difference be-
tween rituximab and MMF remained statistically significant
(P = 0.002). Only 1 patient received LDCyC and was excluded
from analysis. Comparison of renal outcomes is graphically repre-
sented in Figure 2.
Treatment Outcome in the Subgroup of
Treatment-Naive Patients With LN
In the subgroup of treatment-naive LN patients, HDCyC had
the highest rate of RR (92.2% [94/102]), followed by MMF
(78.4% [40/51]), rituximab (75% [6/8]), and LDCyC (72% [18/25]),
and the difference achieved statistical significance (P = 0.011).
In bivariate analysis, RR to HDCyC was significantly higher com-
pared with LDCyC (P = 0.005) and MMF (P = 0.015). However,
after correcting for multiple comparisons (P cutoff set at 0.008),
only the difference between HDCyC and LDCyC remained statis-
tically significant (P = 0.005).
Predictors of Renal Outcome
Univariate tests were done to analyze various parameters be-
tween patients who did and those who did not achieve RR at
6 months. Those achieving RR had significantly shorter duration
of disease, and higher proportions received either HDCyC or ri-
tuximab. In the first logistic regression model (model 1), variables
with P < 0.2 in univariate analyses were included, namely, dura-
tion of disease, renal biopsy class, and induction regimen. Of
these, duration of disease, HDCyC, and rituximab as induction
regimens significantly predicted achievement of RR. The final
multivariate logistic regression model (model 2) was done with
any RR as dependent variable and the following independent vari-
ables: induction regimens and renal biopsy class as categorical inde-
pendent variables and initial prednisolone dose, disease duration,
baseline SLEDAI, and baseline renal SLEDAI as continuous inde-
pendent variables. The following significant predictors were identi-
fied: rituximab (odds ratio [OR], 20.4; confidence interval [CI],

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JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018 Lupus Nephritis Remission Induction

FIGURE 2. Comparison of treatment outcomes in the 4 treatment groups, stratified on baseline treatment experience. In the treatment-naive
group, any RR on HDCyC was significantly higher than LDCyC (absolute difference, 20.2%; 95% CI, 2.8%–42.03%; P = 0.005) and MMF
(absolute difference, 13.8%; 95% CI, 1.3%–28.2%; P = 0.015). In the treatment-experienced/refractory group, rituximab had the highest RR.
This was significantly higher than both MMF (absolute difference, 50%; 95% CI, 11.07%–81%; P = 0.0036) and HDCyC (absolute
difference, 27.3%; 95% CI, −4.1% to 61%; P = 0.04).

1.9–215.7; P = 0.012), renal SLEDAI at baseline (OR, 0.86; 95%
CI, 0.75–0.99; P = 0.034), and duration of disease (OR, 0.98;
95% CI, 0.97–0.99; P = 0.009) (Table 4).
Adverse Events
Adverse effects are summarized in Table 5. Infections and
gastrointestinal events were the commonest. Gastrointestinal
events were significantly higher in the MMF group (P < 0.001).
However, severe gastrointestinal intolerance leading to therapeutic
interruption for more than 2 to 3 weeks occurred in only 3 patients.
Only 1 patient was switched over to mycophenolate sodium.
DISCUSSION
In this historical analysis, we compared LDCyC, HDCyC,
mycophenolate, and rituximab in Indian patients with LN. High-
dose cyclophosphamide and rituximab were associated with better
clinical efficacy compared with LDCyC and mycophenolate espe-
cially in relapsing or refractory LN.
In recent years, a number of randomized controlled trials on
the treatment of LN have been conducted. In European and North
American studies, the efficacy of both high-dose monthly cyclophos-
phamide (NIH studies) and low-dose biweekly cyclophosphamide
(European Lupus Nephritis Trial [ELNT]) regimens has been estab-
lished.5,6 Ten-year follow-up of the ELNT trial showed that both
the HDCyC and LDCyC arms succeeded equally in preventing
end-stage renal disease.19 Mycophenolate, with a distinct advantage
of being an oral drug, compared with IV requirement of cyclophos-
phamide, has also been tested in LN. In the Asperva Lupus Manage-
ment Study (ALMS), oral mycophenolate was compared with IV
cyclophosphamide (modified NIH protocol), and at the end of study
(6 months), both arms achieved similar rates of RR (56% vs. 53%,
respectively). However, there were 40.6% more adverse effects in
the cyclophosphamide arm compared with the mycophenolate
arm.7 Another US study compared oral mycophenolate with modi-
fied NIH cyclophosphamide protocol and showed superiority for my-
cophenolate in achieving complete remission (22.5% vs. 5.8%,
respectively).20 However, the number of Asian patients included in
these landmark studies is rather low, for example, 14 in the US myco-
phenolate study, 6 in the ELNT, and 2 in the NIH study.5,6,20 The
ALMS trial included self-classification of race; 62 Asian patients re-
ceived mycophenolate, and 61 received cyclophosphamide, and the
response rates were 53.2% versus 64%.7 These studies did not have
patients from the Indian subcontinent. Data on use of mycophenolate
or LDCyC from Asia or in particular from India are sparse. In 2005,
the Hong Kong study group in a small cohort of patients showed high
efficacy of mycophenolate treatment in LN (73% CR rate) and signif-
icantly less infection rate compared with cyclophosphamide.21 Sub-
sequent reports from other parts of Asia showed modest efficacy
and acceptable safety of mycophenolate in the treatment of LN with
RR rates of 58% (Malaysia) and 51.4% (Taiwan).22,23 The only
Indian study compared mycophenolate with LDCyC protocol in
100 patients with LN and achieved 54% and 50% RR rates at
6 months, respectively.11
In 2 prospective trials (LUNAR and EXPLORER), rituximab
emerged as ineffective compared with placebo.12,13 Heterogeneity
of study designs and population included in these studies may have
had a significant impact on the results. Although these studies failed
to show an additive benefit of rituximab on standard immunosup-
pression, numerous case reports and series reported favorably on ef-
ficacy of rituximab.10 On the other hand, the pilot study on treating
LN without corticosteroid showed a surprisingly high RR rate of
90% in patients with LN treated with two 1000-mg doses of ritux-
imab followed by oral mycophenolate with no oral steroids.14
In a direct head-to-head comparison of rituximab, LDCyC,
and mycophenolate in an Italian study, higher complete remission
rates were achieved in the rituximab and cyclophosphamide groups
(71% and 65% vs. 53% in the mycophenolate group).10 Remark-
ably, patients in the rituximab group were older, had a longer dura-
tion of LN, and had more flares compared with the other 2 groups.
To the best of our knowledge, direct head-to-head compari-
son of the 4 available remission-inducing therapeutic strategies
has not been done previously. Two recent meta-analysis and net-
work systematic reviews gave contradictory reports. Whereas
one reports that MMF, calcineurin inhibitors, or their combination
was the most effective therapy for induction of remission com-
pared with IV cyclophosphamide, the other found no difference
between tacrolimus, mycophenolate, and cyclophosphamide.24,25
None of these studies included analysis of rituximab-treated cases,
and pooling of LDCyC and HDCyC might have affected the result
of the former review. We observed a uniformly modest response
of mycophenolate and LDCyC. Ninety percent of our patients
with LN on HDCyC or rituximab achieved RR, which is akin to
what was achieved by the RITUXILUP trial protocol, compared with
approximately 70% each in LDCyC and mycophenolate. Difference
between the HDCyC arm and mycophenolate arm reached statis-
tical significance. Various factors may be responsible, such as
dose of mycophenolate, compliance, and ethnicity. In our patients,
16 (26.2%) of 61 achieved a target of dose of 2.5 to 3 g/d, which is
less than the US mycophenolate study and the ALMS (91%).7,20

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Goswami et al JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018

protocol, again RR rate in our study was comparable to the previous

TABLE 4. Univariate and Multivariate Analyses of Predictors of Indian study. However, more importantly, 10 of 26 patients, irre-
Any RR Among Patients With LN
spective of 6-month response, had to be switched to 1 of the other
3 therapeutic arms while in follow-up because of persistent or
Univariate Analysis
new renal activity. Even in the subgroup of patients with
Groups treatment-naive LN, LDCyC had lower RR rate (72%) compared
No RR RR with HDCyC (92.2%), which attained statistical significance
(P = 0.005). Several factors may be underlying: ethnic characteristics
Parameters n = 37 n = 185 P of Indian lupus patients, comparatively lower dose of cyclophos-
Age, y 26.1 ± 10.5 25.9 ± 8.6 0.679a phamide given in the LDCyC group compared with the HDCyC
group, and lower dose of prednisolone given in the LDCyC group.
Duration of disease, mo 37.7 ± 39 19.7 ± 26.3 0.001a
However, in the multivariate analysis of predictors of RR, initial
Prednisolone dose at baseline 39.1 ± 12.2 39.5 ± 11.7 0.818a
dose of prednisolone did not appear as a significant factor. Finally,
Prednisolone dose at 6 mo 10.6 ± 6.8 9.9 ± 6.7 0.695a the RR obtained in our cohort was higher compared with other
Baseline SLEDAI 18 ± 7.2 18.5 ± 6.9 0.734a previously cited cohorts. Ethnicity may be one of the factors. Pre-
Baseline renal SLEDAI 8.6 ± 4.3 7.8 ± 3.7 0.278a vious studies mostly included white subjects,20 and the Asian sub-
Renal biopsy classb class III 18.9% (7) 17.3% (32) 0.149c jects in these studies are ethnically Chinese. Asian studies are
class IV 62.2% (23) 67.6% (125) from Han Chinese, Taiwanese, or East Asian ethnicities. It is pos-
class V 5.4% (2) 10.8% (20) sible Indian lupus patients are genetically different from other
class III + V 2.7% (1) 1.6% (3) ethnicities.21–23 Another factor might be inclusion of more
class IV + V 10.8% (4) 2.7% (5) treatment-naive patients in whom higher likelihood of attaining
end points is possible compared with those who have already
Induction regimensd LDCyC 26.9% (7) 73.1% (19) 0.006e
failed one or other immunosuppressive drugs.
HDCyC 9.7% (11) 90.3% (102)
Another result of note is the efficacy of rituximab in relapsing
MMF 27.9% (17) 72.1% (44) or refractory patients. In fact, most of our patients (14/22) were
Rituximab 9.1% (2) 90.9% (20) given rituximab because of nonresponse or insufficient response
Multivariate Analysis (logistic regression) to other immunosuppressive agents or already accrued high cyclo-
phosphamide cumulative dose. In previous LN cohorts reporting on
Parameters OR 95% CI P efficacy of rituximab, Japan, France, and from a large European
Duration of disease 0.98 0.97–0.99 0.009 registry, most cases were refractory to conventional therapy or re-
lapsed LN cases.26–28 Our patients on rituximab had several poor
Renal SLEDAI at baseline 0.86 0.75–0.99 0.034
prognostic factors, namely, longer disease duration, higher mean
Baseline SLEDAI 1.045 0.966–1.131 0.27 creatinine, SLEDAI, and proteinuria at baseline. Despite these im-
Initial prednisolone dose 1.016 0.97–1.059 0.44 pediments, rituximab appeared as a significant predictor of remis-
Renal biopsy class Omnibus NR NR 0.208 sion at 6 months in the multivariate regression analysis. However,
Induction regimen Omnibus NR NR 0.013 in the baseline analysis, patients on rituximab had higher comple-
HDCyC 2.71 0.77–9.49 0.12 ment and lower anti-dsDNA titer compared with the other treatment
MMF 1.03 0.28–3.78 0.96 groups. This could have contributed to a certain extent on treatment
Rituximab 20.4 1.9–215.7 0.012 outcome. Another notable result was that rituximab apparently had
a worse response in the treatment-naive group (RR, 75%) compared
a
Mann-Whitney U test. with the treatment-experienced group (100%). It is noteworthy that
b
Percentages indicate column proportions. 6 of 8 patients in the treatment-naive group receiving rituximab
c
Fisher exact test. achieved CR, and the rate of CR (75%) was highest among the 4
d
Percentages indicate row proportions. treatment groups. Statistical significance could not be reached in
χ Test.
e 2 the treatment-naive group possibly because of very low number
NR indicates not reported. of patients in the rituximab group.
Our study has some limitations; in particular, this was a
single-center historical study. We reported on a rather short
A previous Indian study showed only a 40% compliance rate to follow-up; the sample size was small for the LDCyC and rituximab
mycophenolate.11 Mean dose per day of mycophenolate in our co- groups; it was not a randomized trial; it did not analyze the effect of
hort was 2.2 g/d, which was comparable to the previous Indian antiproteinuric drugs such as angiotensinogen-converting enzyme
study but less than the ALMS or the US study (2.22 g in the Indian inhibitors or angiotensin receptor blocker; and the therapeutic deci-
study, 2.68 g in the US study, and 2.47 g in ALMS). Although not sion of assignment of immunosuppressive regimen was clinical
analyzed in our report, the daily maintenance doses after 6 doses rather than algorithmic.
of cyclophosphamide in the LDCyC group were 50 to 100 mg The major strength of this study is real-life patient data with
for azathioprine and 1 to 1.5 g for mycophenolate. This is gener- its challenges faced by the investigators while treating LN. This
ally reflective of the low body surface area and body weight en- is a unique attempt to try to understand the relative differences
countered in Indian female subjects, where body weight of more in efficacy of the 4 standard therapeutic regimens for LN. We
than 50 kg is not common, and also difficulty to maintain patients observed that LDCyC or mycophenolate might be less effective
on 2 g or more mycophenolate per day because of frequent gastro- treatment options for Indian patients with LN compared with
intestinal intolerance, transaminitis, and hematologic toxicity. Re- HDCyC. High-dose cyclophosphamide still offers one of the
nal response in mycophenolate in our study was actually highest rates of clinical response. The problem of HDCyC is
numerically better compared with the 2 previous US and Euro- risk of cumulative cyclophosphamide dose in patients in need
pean trials and was similar to the Indian study. But the response of reinduction in case of flare, which is not uncommon in LN.
to HDCyC and rituximab fared much better. Regarding the LDCyC Rituximab, especially in combination with 1 or 2 pulses of

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JCR: Journal of Clinical Rheumatology • Volume 00, Number 00, Month 2018 Lupus Nephritis Remission Induction

TABLE 5. Adverse Events (AEs) During 6 Months of Follow Up

LDCyC HDCyC MMF Rituximab

AEs n = 26 n = 113 n = 61 n = 22 P
At least 1 AE 34.6% (9) 26.5% (30) 77% (47) 31.8% (7) 0.0012a
Serious AE requiring hospital admission 7.7% (2) 4.4% (5) 6.6% (4) 9.1% (2) 0.78
Infections (total) 23.1% (6) 20.4% (23) 14.7% (9) 27.3% (6) 0.58
Upper respiratory tract infection 2 1 0 1
Pneumonia 2 8 1 2
Tuberculosis 1 4 2 0
Brain abscess (toxoplasmosis) 0 1 0 0
Urinary tract infection 0 2 0 0
HZV 1 4 1 2
HSV 0 2 5 1
Cellulitis 0 1 0 0
GI (total) 0 1 41 0 <0.001
Duodenal ulcer 0 0 8 0
Transaminitis 0 0 9 0
Vomiting 0 1 20 0
Diarrhoea 0 0 4 0
Seizure 0 0 0 4.5% (1) 0.03
Neutropenia 11.5% (3) 8.8% (10) 3.3% (2) 0 0.26
a
In bivariate comparison after correcting for multiple comparisons, the following significant differences were observed: LDCyC versus MMF
(P = 0.0001), HDCyC versus MMF (P < 0.0001), and MMF versus rituximab (P = 0.00013).
HSV indicates herpes simplex virus infection; HZV, herpes zoster virus infection.

cyclophosphamide, as it was given in most of the patients,
appears to be the most promising candidate in this scenario.
In scenarios where cyclophosphamide avoidance is desirable,
such as young patients especially in terms of fertility preserva-
tion, rituximab should be applicable.
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