Lupus (2013) 22, 11351141

http://lup.sagepub.com

PAPER

Combined low-dose mycophenolate mofetil and tacrolimus for lupus

nephritis with suboptimal response to standard therapy: a 12-month
prospective study
CC Mok, CH To, KL Yu and LY Ho
Department of Medicine, Tuen Mun Hospital, Hong Kong, China

Objective: The objective of this paper is to evaluate the efficacy of combined mycophenolate
mofetil (MMF) and tacrolimus (TAC) for lupus nephritis with suboptimal response to standard therapy. Methods: Inclusion criteria for patients: (1) biopsy-confirmed active lupus nephritis; and (2) inadequate response to 2 immunosuppressive regimens. While prednisolone
(10 mg/day) and angiotensin-converting enzyme inhibitors were continued, immunosuppressive agents were replaced by combined MMF (1 g/day) and TAC (4 mg/day). Patients were
followed every 2 months for the clinical response and adverse events at 12 months. Results:
Twenty-one patients were recruited (20 women; age 35.8  9.2 years; systemic lupus erythematosus (SLE) duration 111  51 months). The histological classes of lupus nephritis were: IV/
III (33%), V III/IV (33%) and pure V (33%). The creatinine clearance (CrCl), urine proteinto-creatinine ratio (uP/Cr) and serum albumin was 82.4  33 ml/min (<90 ml/min in 57%),
3.27  1.5 and 30.1  5.9 g/l, respectively. Thirteen (62%) patients had active urinary sediments and 17 (81%) patients had active lupus serology. At 12 months, eight (38%) patients
had very good response, one (5%) patient had good response and five (24%) patients had
partial response. Significant improvement in uP/Cr, albumin, complement C3 and antidsDNA titer, and stabilization of CrCl was observed in the responders. Thirty-three adverse
events were reported in 18 patients: major infection requiring hospitalization (6%), infection
not requiring hospitalization (27%), herpes infection (9%), diarrhea (12%), cramps (9%),
dyspepsia (6%), transient increase in serum Cr (6%), alopecia (4%), facial twitching (3%),
tremor (3%) and diabetes mellitus (3%). None of these had led to protocol
withdrawal. Conclusions: Combined low-dose MMF and TAC is an option for lupus nephritis
that fails to respond adequately to standard regimens, with two-thirds of patients improving
after 12 months. Longer-term observation is needed to confirm its efficacy and safety. Lupus
(2013) 22, 11351141.
Key words: Glomerulonephritis; nephropathy; treatment; recalcitrant; resistant

Introduction
Renal disease is a major organ manifestation of systemic lupus erythematosus (SLE) and carries signicant morbidity and mortality. Current therapies of
lupus nephritis are not ideal in terms of ecacy and
safety.1 Up to 45% of patients with lupus nephritis
do not respond to initial immunosuppressive treatment in the rst six months,2 38% of patients have
ares of renal disease during the course of their
Correspondence to: Chi Chiu Mok, Department of Medicine, Tuen
Mun Hospital, Tsing Chung Koon Road, New Territories, Hong
Kong, SAR China. Email: ccmok2005@yahoo.com
Received 30 April 2013; accepted 5 August 2013
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

illness3 and 29% of patients ultimately develop

end-stage renal disease (ESRD).46 Although
newer immunosuppressive agents such as mycophenolate mofetil (MMF) are less toxic than conventional cyclophosphamide (CYC) for the treatment
of severe lupus nephritis, its overall ecacy is not
superior. In recent randomized controlled trials, the
initial clinical response rate of MMF in active lupus
nephritis was around 70%, which is similar to that
of CYC.2 More eective regimens are thus needed,
particularly for patients with persistently active disease despite rst-line immunosuppressive therapies
who are at risk of renal damage.
Tacrolimus (TAC) is a newer calcineurin inhibitor that has a higher molecular potency than
10.1177/0961203313502864

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CC Mok et al.

1136

cyclosporin A (CSA). In renal transplantation,

TAC has been shown to be more eective than
CSA in preventing the composite end-point of
biopsy-proven acute rejection, graft loss and mortality.7 TAC is preferred to CSA for the treatment
of SLE because of its lower incidence of cosmetic
side eects, hypertension and hyperlipidemia.8
Recent uncontrolled and controlled studies have
shown that TAC, when combined with high-dose
prednisolone, is eective in the induction and maintenance therapy of diuse proliferative and membranous lupus nephritis.913 A controlled trial also
demonstrated superiority of combination of MMF
and TAC over intravenous CYC on top of highdose corticosteroids in treating mixed proliferative
and membranous lupus nephritis.14 Combined
MMF and TAC has also been reported to be
useful in refractory membranous lupus nephropathy in an open-labeled trial.15
The current prospective study was carried out to
evaluate the ecacy of combined MMF and TAC
(without augmentation of corticosteroids) in the
treatment of lupus nephritis that failed to respond
adequately to at least two immunosuppressive
regimens and maximum doses of angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We reported the
clinical ecacy of this regimen and the incidence of
adverse events after 12 months therapy.

Patients and methods

Study population
Patients who fullled 4 American College of
Rheumatology (ACR) criteria for SLE16 and had
nephritis that did not respond adequately to standard regimens were recruited. Inclusion criteria were:
(1) active nephritis documented by renal biopsy
within 24 months of entry; (2) failure to respond
adequately to 2 induction immunosuppressive
regimens that consisted of high-dose prednisolone
combined with a noncorticosteroid agent (CYC
(oral or intravenous), azathioprine (AZA), MMF,
CSA or TAC), together with the maximally tolerated doses of ACEIs  ARBs. Each regimen
should be used for 4 months; (3) serum creatinine
(SCr) 200 umol/l. Exclusion criteria were: (1)
previous intolerance to either MMF/TAC; (2)
SCr > 200 umol/l; (3) informed consent could not
be obtained.
Treatment failure to previous regimens was
dened as any one of the following: (1) failure of
proteinuria to improve to <3 g/day or urine
Lupus

protein-to-creatinine (uP/Cr) ratio to <3.0; or

<50% of pretreatment/baseline values, with or
without persistently active urinary sediments (red
blood cells (RBCs) 5/high-power eld (HPF));
(2) deteriorating SCr by 20% or loss in creatinine
clearance (CrCl) by 30% compared to baseline
not accounted for by causes other than active
nephritis.
This study was approved by the Research
and Ethics Committee of our hospital and the
protocol was registered at ClinicalTrial.Gov
(NCT01203709). Written consent was obtained
from all participants.
Treatment regimen
While low-dose oral prednisolone (10 mg/day)
and ACEIs/ARBs were continued at constant dosages, immunosuppressive agents were discontinued
and replaced by the current regimen, which consisted of low-dose MMF (1 g/day) and TAC
(4 mg/day) in two divided doses. Patients were followed prospectively at least twice monthly for the
clinical response at 12 months (primary end-point),
extra-renal activity and adverse events (secondary
end-points).
Dosage adjustment of MMF and tacrolimus
The SCr was monitored at each clinic visit. If the
SCr level increased by more than 40% compared
with baseline or by more than 30% compared with
the preceding clinic visit, the blood test would be
repeated. If a similar result was obtained, TAC
would be withheld for two weeks and other
causes would be sought. At the discretion of the
attending physicians, TAC at a lower dosage
would be resumed if there was an improvement in
the SCr level. The serum level of TAC would also
be checked and dosage adjusted when patients
experienced adverse eects. Similarly, the dosage
of MMF could be adjusted if patients experienced
adverse eects.
Assessment for response at 12 months and
protocol withdrawal
Clinical response was classied into very good
response, good response, partial response and no
response. A very good response was dened as
the following: (1) uP/Cr dropped to <0.5; (2) complete resolution of urinary sediments; (3) improvement/stabilization of CrCl to within 15%
of baseline value; and (4) normalization (or return
to pre-are level) of anti-double-stranded DNA
(anti-dsDNA) titer and complement level.

MMF and TAC in refractory lupus nephritis

CC Mok et al.

1137

Good response was dened as: (1) uP/Cr dropped

to <1.0; (2) improvement in urinary sediments (<5/
HPF); (3) improvement/stabilization of CrCl to
within 15% of baseline value; and (4) improvement
in anti-dsDNA titer and complement level. Partial
response was dened as: (1) uP/Cr dropped to <3.0
and more than 50% improvement in baseline; (2)
improvement of urinary sediments (<5/HPF); (3)
improvement/stabilization of CrCl to within 15%
of baseline value; and (4) improvement in antidsDNA titer and complement level. No response
was dened if a patient did not meet the response
criteria described above. Withdrawal from protocol
was allowed for patients who did not respond to
this protocol or who experienced serious adverse
events.
Assessment of SLE activity
Renal and extrarenal disease activity of SLE
was measured using the validated Safety of
Estrogens in Lupus Erythematosus National
Assessment (SELENA)-SLE Disease Activity
Index (SLEDAI).17 The SLEDAI scores at the
time of commencement of the combination therapy
(baseline) and at two-month intervals were
obtained and compared.
Statistical analyses
Unless stated otherwise, values were expressed as
mean  SD (standard deviation). Comparison of
various clinical and laboratory parameters between
baseline and at dierent time intervals was performed by the paired Students t test. Statistical
signicance was dened as a p value of less than
0.05, two tailed. All statistical analyses were performed using the SPSS program, version 11.5
(SPSS, Chicago, IL) for Windows XP.

Results
Study population
Twenty-one (20 (95%) women) patients were studied. They were all ethnic Chinese. Table 1 shows
the baseline demographic and renal parameters of
the patients at study entry. The mean age of these
patients was 35.8  9.2 years and the mean SLE
duration was 111  51 months.
The International Society of Nephrology/Renal
Pathology Society (ISN/RPS) histological classes of
lupus nephritis of the participants were: class IV/III
(33%), V III/IV (33%) and pure V (33%).
Previous immunosuppressive regimens used for

treatment but with suboptimal clinical response in

our patients were: high-dose prednisolone
(0.75 mg/kg/day for 6 weeks) (100%) in combination with CYC (2 mg/kg/day oral) (5%),
AZA (2 mg/kg/day) (48%), MMF (23 g/day)
(86%), CSA (5 mg/kg/day) (43%) and TAC
(0.1 mg/kg/day) (29%). The median number of
immunosuppressive protocols failed in these
patients was 2.1 (median 2), and the mean duration
of therapy for each course of immunosuppressive
treatment before study entry was 7.8  2.9 (range
four to 16) months. For those who had inadequate
response to prednisolone and MMF, the mean
daily dose of MMF used was 1.93  0.5 grams.
At the time of study entry, all patients had persistent proteinuria that did not meet the improvement criteria to previous therapies, with 13 (62%)
patients having persistently active urinary sediment. Four (19%) patients had deterioration of
renal function compared to baseline and 17 (81%)
had persistently active lupus serology. The mean
SCr, CrCl, uP/Cr, 24-hour proteinuria and serum
albumin of the patients was 89.9  42 umol/l,
82.4  33 ml/min (<90 ml/min in 57%), 3.27  1.5,
3.13  1.3 g and 30.1  5.9 g/l, respectively. The
renal SLEDAI score was 6.5  2.4 and the extrarenal SLEDAI score was 3.3  3.0.
Clinical response after 12 months
All the participants were treated with a combination of low-dose MMF and TAC, in addition to
low-dose prednisolone (10 mg/day) and the usual
doses of ACEIs/ARBs. Twenty patients received
the protocol-based 1 g/day of MMF (no change in
dose throughout), with only one patient nally
receiving 500 mg/day of MMF because of diarrhea.
The mean daily dose of TAC received by the
patients was 3.1  0.8 mg.
After 12 months, eight (38%) patients (class V
(N 3), class III/IV (N 3), class III/IV V
(N 2)) had very good response, one (5%) patient
(class III/IV V) had good response and ve (24%)
patients (class V (N 1), class III/IV (N 2), III/
IV V (N 2)) had partial response according to
our predened criteria. Seven (33%) patients (class
V (N 3), III/IV (N 2), III/IV V (N 2)) did
not respond to the protocol and required further
salvage treatment.
For patients who responded to treatment, signicant improvement in uP/Cr, serum albumin,
anti-dsDNA titer and complement C3 level
was observed from baseline to month 12 (Figure
1(ad)) (p < 0.05 in all). CrCl in these patients did
not change signicantly (p 0.14) (Figure 1(e)).
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CC Mok et al.

1138

Table 1
entry

Clinical characteristics of the participants at study

Number (%);
mean  SD

Women
Age, year
SLE duration, months
Concomitant extra-renal activity
Musculoskeletal
Mucocutaneous
Fever
Hematological
Autoantibodies
Anti-dsDNA
Anti-Sm
Anti-Ro
Anti-La
Anti-nRNP
ISN/RPS histological classes
Class III/IV
Class III/IV V
Pure class V
Serum creatinine, umol/l
Creatinine clearance, ml/min
Creatinine clearance <90 ml/min
Serum albumin, g/l
Complement C3, mg/dl
Anti-dsDNA titer, IU/l
Urine protein/creatinine ratio
Nephrotic syndrome
Active urinary sediments
Hypertension requiring treatment
Renal SLEDAI
Extra-renal SLEDAI
Previous ineffective regimens
HD Pred cyclophosphamide
HD Pred azathioprine
HD Pred mycophenolate mofetil
HD Pred cyclosporin A
HD Pred tacrolimus

20 (95)
35.8  9.2
111  51
2
1
2
3

(10)
(5)
(10)
(14)

17 (81)
4 (19)
14 (67)
5 (24)
8 (38)
7 (33)
7 (33)
7 (33)
89.9  42
82.4  33
12 (57)
30.1  5.9
0.72  0.23
153  118
3.27  1.5
6 (29)
13 (62)
10 (48)
6.5  2.4
3.3  3.0
8 (38)
19 (90)
19 (90)
7 (33)
8 (38)

SD: standard deviation; SLE: systemic lupus erythematosus; AntidsDNA: anti-double-stranded DNA; ISN/RPS: International Society
of Nephrology/Renal Pathology Society; SLEDAI: Systemic Lupus
Erythematosus Disease Activity Index; HD: high-dose; Pred:
prednisolone.

The renal SLEDAI (6.0  2.6 to 2.0  2.1;

p 0.004) and extrarenal SLEDAI (3.4  3.7 to
1.7  1.5; p 0.02) score also improved signicantly
after treatment. Ten (71%) patients had complete
resolution of urinary sediments whereas four (29%)
patients had improvement of urinary sediments to
<5/HPF.
Adverse events
Thirty-three adverse events were reported in 18
(86%) patients. These are summarized in Table 2:
major infection requiring hospitalization (6%),
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infection not requiring hospitalization (excluding

herpes) (27%), herpes infection (9%), diarrhea
(12%), cramps (9%), dyspepsia (6%), transient
increase in serum Cr (6%), alopecia (4%), facial
twitching (3%), tremor (3%) and diabetes mellitus
(3%). None of these had led to protocol
withdrawal.

Discussion
MMF is the pro-drug of mycophenolic acid (MPA)
that selectively acts on activated lymphocytes.
MPA has been shown to suppress proliferation of
peripheral blood mononuclear cells to T and B cell
mitogens, inhibit mixed lymphocyte reaction and
reduces in vitro cell-mediated responses to allogeneic cells.18 MPA also blocks antibody formation by
polyclonally activated B-lymphocytes19 and production of cytokines such as interleukin (IL)-2,
IL-10, interferon (IFN)-g and tumor necrosis
factor alpha (TNFa).20 In addition, MPA also
antagonizes the function of the adhesion molecules
expressed on endothelial cells and reduces the
recruitment of lymphocytes and monocytes into
sites of inammation.21 In a murine model of
mesangial proliferative glomerulonephritis, treatment of MMF signicantly decreases glomerular
hypercellularity, severity of histological damage,
extracellular matrix deposition and proteinuria,
suggesting that inhibition of mesangial proliferation is another eect of the drug.22
TAC is a calcineurin inhibitor that complexes
with the intracellular immunophilin FK506 binding
protein 12 and blocks the phosphatase activity of
calcineurin, leading to reduced IL-2 gene transcription of activated T cells.23 A number of trials have
demonstrated superiority of TAC over CSA in preventing acute and chronic rejection of allografts in
renal transplantation.24 Blocking of T cell activation also leads to reduction in the production of
other proinammatory cytokines that are important in regulating B cell activity. In vitro study has
also shown that TAC regulates that production of
TNFa and CC chemokines by activated T cells.25
In the murine lupus nephritis models, TAC treatment leads to reduction in B cell proliferation and
anti-dsDNA production, mitigation of renal pathology, retardation of renal disease progression and
improvement in survival.26 TAC has also been
shown in an animal transplant model to reduce
IL-10 production,27 a key cytokine promoting
autoantibody production in SLE. TAC is preferred
to cyclosporin A in treating SLE because of the

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CC Mok et al.

1139

(a)

(b)

(c)

(d)

(e)

Figure 1 Changes in renal parameters and lupus serology over time (a) urine protein to creatinine ratio (p < 0.001); (b) serum
albumin (p < 0.001); (c) anti-dsDNA titer (p 0.02); (d) complement C3 level (p 0.02); and (e) creatinine clearance (p 0.14).
Anti-dsDNA: anti-double-stranded DNA; P: protein; Cr: creatinine; RB: at time of renal biopsy.
Lupus

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1140

Table 2

Adverse events reported by participants

Adverse events

Number (%)

Serious infection requiring hospitalization

Infection not requiring hospitalization (excluding herpes)
Herpes infection (simplex/zoster)
Diarrhea
Cramps
Dyspepsia
Transient increase in serum creatinine
Alopecia
Facial twitching
Tremor
Diabetes mellitus
Others
Total

2
12
3
4
3
2
2
1
1
1
1
4
33

(6)
(27)
(9)
(12)
(9)
(6)
(6)
(3)
(3)
(3)
(3)
(12)
(100)

lower incidence of side eects such as dyslipidemia,

hypertension, gum hypertrophy and hypertrichosis.
In view of dierent mechanisms of immunosuppression, MMF and TAC are used together for a
synergistic eect in organ transplantation so that
lower dosages of TAC can be used for maintenance
to reduce its long-term nephrotoxicity.28 Moreover,
the antiproliferative eect of MMF on vascular
smooth muscles may reduce arterial intimal
thickening and angiogenesis that osets the adverse
vascular eects of TAC therapy. Two recent randomized controlled trials have shown that combined
MMF and TAC remained a more favorable
immunosuppressive regimen for renal transplantation than other drug combinations that involved
MMF, TAC, sirolimus or CSA.29,30
The combination of MMF and TAC has recently
been used in the treatment of lupus nephritis. Bao
et al.14 randomized 40 patients with active mixedclass IV/V lupus nephritis to receive high-dose
prednisolone together with either intravenous
pulse CYC or low-dose combination of MMF
(1 g/day) and TAC (4 mg/day). At six and nine
months of therapy, signicantly higher rates of
complete remission were demonstrated for the combined MMF/TAC (50% and 65%, respectively) as
compared to CYC (5% and 15%, respectively)
arm. Adverse events were less frequent with the
combined MMF/TAC group but three (15%)
patients developed new-onset hypertension.
Another group of investigators also demonstrated
that addition of TAC (range 28 mg/day) in seven
patients with membranous lupus nephritis that was
refractory to MMF was eective in reducing proteinuria in four (57%) patients.15 However, adverse
events such as diabetes mellitus, pneumonia and
myalgia were reported in ve (71%) patients.
Lupus

Although less toxic therapies such as MMF

and TAC are now available for patients with
lupus renal disease,2,11,13 they are not more
eective than conventional CYC protocols.
Moreover, long-term data on their ecacy in
preserving renal function are lacking,31 particularly in those patients with more serious forms
of lupus nephritis.31 While the ecacy data from
more novel biological agents such as abatacept,
belimumab and epratuzumab are eagerly
awaited, patients with lupus renal disease that
does not respond to conventional therapies are
at risk of renal failure.32 More regimens need to
be explored for salvage therapy. Our current
prospective study has demonstrated short-term
ecacy of combined low-dose MMF and TAC
in proliferative or membranous lupus nephritis
that did not respond optimally to standard
therapies. The protocol was tolerated and twothirds of participants improved according to a
composite outcome measure without a predilection of ecacy for any histological types of
lupus nephritis. As the dosage of corticosteroids
was not augmented, the ecacy of the regimen
was due to the combined eect of the two drugs.
With a lower dose of TAC being used, the longterm risk of nephrotoxicity and adverse vascular
eects could be minimized.
We conclude that combined low-dose MMF and
TAC is an option to be considered in lupus nephritis that fails to respond adequately to standard
therapies. Longer-term observation is needed to
see if this regimen may stabilize renal function,
and continues to be tolerated and eective.

Funding
This research received no specic grant from
any funding agency in the public, commercial, or
not-for-prot sectors.

Conflict of interest
The authors have no conicts of interest to declare.

Author contributions
CC Mok: study design, data collection and analysis. CH To, KL Yu and LY Ho: data collection
and patient assessment.

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