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ARD Online First, published on December 30, 2014 as 10.1136/annrheumdis-2014-206456
Handling editor Tore K Kvien
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
annrheumdis-2014-206456)
1
Department of Medicine, Tuen
Mun Hospital, Hong Kong
2
Department of Medicine,
Princess Margaret Hospital,
Hong Kong
3
Department of Medicine,
United Christian Hospital,
Hong Kong
Correspondence to
Dr Chi Chiu Mok, Department
of Medicine, Tuen Mun
Hospital, Hong Kong;
ccmok2005@yahoo.com
Received 11 August 2014
Revised 4 November 2014
Accepted 7 December 2014
To cite: Mok CC, Ying KY,
Yim CW, et al. Ann Rheum
Dis Published Online First:
[please include Day Month
Year] doi:10.1136/
annrheumdis-2014-206456
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
Clinical and epidemiological research
EXTENDED REPORT
Tacrolimus versus mycophenolate mofetil for
induction therapy of lupus nephritis: a randomised
controlled trial and long-term follow-up
Chi Chiu Mok,1 King Yee Ying,2 Cheuk Wan Yim,3 Yui Pong Siu,1 Ka Hang Tong,1
Chi Hung To,1 Woon Leung Ng3
ABSTRACT
Objective To compare the efficacy of tacrolimus (TAC)
and mycophenolate mofetil (MMF) for the initial therapy
of lupus nephritis (LN).
Study design This is an open randomised controlled
parallel group study.
Methods Adult patients with biopsy-confirmed active
LN (class III/IV/V) were randomised to receive
prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in
combination with either TAC (0.06–0.1 mg/kg/day) or
MMF (2–3 g/day) for 6 months. Good responders were
shifted to azathioprine for maintenance. The primary
outcome was the rate of complete renal response (CR) at
6 months and the secondary outcomes included partial
renal response, renal flares and decline of renal function
over time.
Results 150 patients (92% women; aged 35.5
±12.8 years; 81% class III/IV) were randomised (76
MMF, 74 TAC). At month 6, the rate of CR was 59% in
the MMF and 62% in the TAC group (treatment
difference: 3.0% (−12%, 18%); p=0.71). Major
infective episodes occurred in 9.2% patients treated with
MMF and in 5.4% patients treated with TAC ( p=0.53).
Maintenance therapy with azathioprine was given to
79% patients. After 60.8±26 months, proteinuric and
nephritic renal flares developed in 24% and 18% of
patients in the MMF group and 35% ( p=0.12) and
27% ( p=0.21) in the TAC group, respectively. The
cumulative incidence of a composite outcome of decline
of creatinine clearance by ≥30%, development of
chronic kidney disease stage 4/5 or death was 21% in
the MMF and 22% in the TAC group of patients
( p=0.35).
Conclusions TAC is non-inferior to MMF, when
combined with prednisolone, for induction therapy of
active LN. With azathioprine maintenance for 5 years, a
non-significant trend of higher incidence of renal flares
and renal function decline is observed with the TAC
regimen.
Trial registration number Hospital Authority
Research Ethics Committee Clinical Trial Registry
(HARECCTR0500018; Hong Kong) and US ClinicalTrials.
gov (NCT00371319).
INTRODUCTION
Renal disease in systemic lupus erythematosus
(SLE) carries significant morbidity and mortality.1–5
Up to 26% of patients with diffuse proliferative
lupus nephritis (LN) develop end-stage renal
failure6–9 and the mortality increases by eightfold
Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456
as compared with the general population.5 Thus,
intensive immunosuppression (induction) has to be
given to dampen kidney inflammation timely, fol-
lowed by maintenance therapy to consolidate the
efficacy and reduce the risk of renal flares.
The conventional induction therapy for severe
LN is cyclophosphamide (CYC) in combination
with corticosteroids.10–12 However, toxicities such
as infection, marrow suppression, cystitis and
ovarian failure limit its use.11 13 14 Mycophenolate
mofetil (MMF) has emerged to be the first-line
therapy because randomised controlled trials (RCTs)
have shown that it is as effective as CYC,15 16 but
ovarian toxicities and leucopenia are less common.
Despite this, both CYC and MMF are not ideal in
terms of efficacy and alternative regimens have to be
explored.
The calcineurin inhibitors such as ciclosporin A
(CSA) and tacrolimus (TAC) have long been used in
organ transplantation. Recent RCTs and meta-
analysis revealed that TAC was more favourable than
CSA in renal transplantation in terms of acute graft
rejection, treatment failures and long-term graft sur-
vival.17–19 Moreover, the incidence of hypertension,
hyperlipidaemia, gingival hyperplasia and hirsutism
was lower with TAC.20
TAC has been used successfully in LN, including
the pure membranous subtype and refractory
disease, in uncontrolled series.21–24 Small RCTs
showed similar efficacy of TAC to CYC for the
initial treatment of proliferative LN.25 26 Low-dose
combination of TAC and MMF has also been
shown to be more effective than intravenous pulse
CYC in mixed proliferative and membranous LN
(MLN).27 More recently, this regimen has been
used successfully in refractory LN.28 The mechan-
isms of action of TAC in LN have not been fully
elucidated. In vitro and animal studies have shown
that TAC reduces production of interleukin 2 (IL-2)
and other cytokines such as tumour necrosis factor
α, interferon γ, IL-6 and IL-10 by activated T
cells.29 By inhibiting T cell activation, signals for B
cell activation, class-switching and immunoglobulin
production are indirectly attenuated.30 The calci-
neurin inhibitors were also suggested to stabilise
the actin cytoskeleton in kidney podocytes, leading
to amelioration of proteinuria.31
We conducted the current RCT to compare the
efficacy between TAC and MMF for induction
therapy of active LN and evaluate longitudinally the
rate of renal flares and change in renal function.
1
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Clinical and epidemiological research
PATIENTS AND METHODS
Inclusion criteria of patients for this study were (1) age
≥18 years, (2) fulfilment of four or more American College of
Rheumatology (ACR) criteria for SLE,32 (3) biopsy-proven active
LN (International Society of Nephrology (ISN) / Renal Pathology
Society (RPS) class III/IV/V) within 4 weeks of entry and (4)
serum creatinine (SCr) <200 mmol/L. Exclusion criteria were (1)
refusal to be randomised; (2) preference for treatment with con-
ventional regimens such as CYC and (3) planning for pregnancy
within 12 months after randomisation.
Treatment protocol and randomisation
All patients were given oral prednisone (0.6 mg/kg/day for
6 weeks, then tapered by 5 mg/day every week to <10 mg/day),
which was continued indefinitely as maintenance therapy.
Participants were randomised by computer-generated blocks of
four in a 1 : 1 ratio to one of the following treatment arms: (1)
MMF (2 g/day initially, augmented to up to 3 g/day if clinical
response was suboptimal at month 3), in two divided doses for
6 months or (2) TAC for 6 months (initial dosage 0.1 mg/kg/day in
two divided doses, reduced to 0.06 mg/kg/day if clinical response
was satisfactory at month 3). A central research assistant was
responsible for the allocation of the treatment regimens according
to the block sequence. New ACE inhibitors or angiotensin recep-
tor blockers were prohibited in the first 6 months, and in those
receiving these drugs at entry, their doses were kept constant.
Dosage adjustment of study drugs
Dosage of MMF or TAC was adjusted according to patients’ tol-
erability and adverse events (AEs; eg, leucopenia for MMF,
nephrotoxicity for TAC and intercurrent infections). TAC would
be withheld when there was persistent increase in SCr level by
>40% compared with baseline or >30% compared with the last
visit for consecutive 2 weeks. In case of SCr improvement after
temporary suspension, TAC would be resumed at a lower dose
and titrated up according to renal function. If the SCr did not
improve by 4 weeks, the patient would be withdrawn. Trough
serum TAC level was assayed to achieve a target of >5 ng/mL.
Outcomes of interest
The primary outcome of this study was the proportion of patients
who achieved complete renal response (CR) at 6 months.
Secondary outcomes included (1) rates of partial response (PR)
and non-response (NR) at 6 months, (2) rate of renal flares during
the maintenance phase and (3) a composite outcome of renal func-
tion deterioration (decline of creatinine clearance (CrCl) by ≥30%
or progression to chronic kidney disease (CKD) stage 4 or 5 (ie,
CrCl <30 mL/min) or mortality over time (see online supplemen-
tary table S1 for the definitions for renal response and renal
flares). We also assessed the rates of CR at month 6 according to
the ACR SLE renal response criteria.33
Maintenance and salvage treatment
Patients who achieved CR or good PR after MMF or TAC treat-
ment at 6 months were shifted to azathioprine (AZA; 2 mg/kg/
day) indefinitely for maintenance. For suboptimal responders to
either MMF or TAC, salvage/reinduction therapy would be
given in the form of oral CYC (2 mg/kg/day) or monthly intra-
venous pulse CYC (0.5–1 g/m2) for 6 months (unless intolerant
to or reluctant for CYC), with high-dose prednisolone (for
6 weeks and tapered) with or without intravenous pulse methyl-
prednisolone. Patients who had renal flares would be retreated
as decided by the attending physicians.
2 Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456
Patients were followed up every 2 months in the first
6 months and then 3 monthly. Blood counts, SCr and albumin,
CrCl and urine protein-to-creatinine ratio (uP/Cr) estimation
(according to a 24 h urine sample) and lupus serology
(anti-dsDNA and complements) were performed in each visit.
Urine sediments were measured at baseline, month 6 and when
renal flares were suspected.
Disease activity of SLE was assessed by the Safety of
Estrogens in Lupus Erythematosus National Assessment
(SELENA)-SLE Disease Activity Index (SLEDAI), a validated
global index used in the prospective SELENA trials.34
Sample size calculation and statistical analyses
This study was designed as a non-inferiority trial. The non-
inferiority margin was set at 12.5% for the primary outcome
(CR at 6 months), meaning that the lower bound of the two-
sided 95% CI for the difference CR rates between TAC and
MMF (as reference) should exceed −12.5%. Analysis for the
primary outcome was performed on the intent-to-treat popula-
tion. A previous study of MMF in Asian patients with LN
reported a CR rate of 58%.35 Our pilot study of TAC showed
that 67% of patients with LN could achieve CR after 6
months.23 Assuming that the CR rates of MMF and TAC at
6 months would differ by 10%, a sample size of 140 patients
was needed to yield a power of 80% to establish non-inferiority
of TAC to MMF, with a one-sided α level of 0.025.
Values in this study are expressed as mean±SD. Comparison
between MMF and TAC groups at baseline was performed by
the independent Student t test for continuous variables and χ2
test for categorical variables. Between-group differences at dif-
ferent time points were compared with adjustment of baseline
values by one-way analysis of covariance. Within-group
(between various time points and baseline) comparison was
made by the paired Student t test. Correlation between two vari-
ables was studied by Spearman’s rank correlation.
The cumulative incidence of renal flare and renal function
deterioration/mortality over time was evaluated by Kaplan–
Meier’s analysis. Difference between the MMF and TAC group
was compared by the log-rank test. For deceased patients or those
who were lost to follow-up, data were censored at their last visits.
RESULTS
Study population
Between 2005 and 2012, 150 Chinese patients with active LN
were recruited and randomised (76 to MMF and 74 to TAC;
92% women; mean age 35.5±12.8 years). All except one
patient completed the 6-month induction phase (see online sup-
plementary figure S1 for patient enrolment and disposition).
At baseline, 100 (67%) patients had CrCl <90 mL/min and
64 (43%) patients had nephrotic syndrome. The distribution of
the histological classes of LN was IVG±V (33%), IVS±V
(13%), III±V (36%) and pure V (19%). The clinical and renal
parameters of the patients at entry were similar between the
two groups (table 1).
In patients who were randomised to MMF, 58 (76%) received
a dosage of 2 g/day, 7 (9%) received 2.5 g/day and 11 (14%)
received 3 g/day. In patients treated with TAC, the mean trough
drug level achieved was 7.8±3.9 ng/mL (median 7.0).
Renal response and change in SLE disease activity at
6 months
Significant improvement in uP/Cr, serum albumin, lupus ser-
ology (C3, anti-dsDNA titre), urinary sediments, renal and
extra-renal SELENA-SLEDAI scores and lipid profile were
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Clinical and epidemiological research

Table 1 Clinical characteristics and renal parameters at baseline Table 2 Change in clinical parameters in the first 6 months
MMF TAC Total Baseline 2 months 4 months 6 months
(N=76) (N=74) (N=150)
Proteinuria (g/day)
Age, years 36.1±13.1 36.2±14 35.5±12.8 MMF 3.83±3.6 1.95±1.6 1.57±1.6 1.23±1.3
Women 68 (89) 70 (95) 138 (92) TAC 3.32±2.5 1.50±1.5 1.21±1.5 1.05±1.4
SLE duration, months 48.2±63 52.2±62 50.2±62 p Value* 0.31 0.15 0.27 0.58
First time renal biopsy 52 (68) 50 (68) 102 (68) Urine P/Cr ratio
Concomitant non-renal activity MMF 4.23±4.1 2.16±2.0 1.80±2/0 1.40±1.6
Musculoskeletal 30 (39) 20 (27) 50 (33) TAC 3.52±2.5 1.60±1.7 1.35±1.9 1.14±1.6
Mucocutaneous 29 (38) 23 (31) 52 (35) p Value* 0.20 0.17 0.33 0.50
Haematological 23 (30) 22 (30) 45 (30) CrCl (mL/min)
Neuropsychiatric 2 (2.6) 1 (1.4) 3 (2) MMF 77.4±29 87.9±34 91.2±32 91.4±31
Serositis 11 (14) 8 (11) 19 (13) TAC 80.5±33 80.1±36 77.7±30 79.7±32
Anti-Ro 46 (61) 48 (65) 94 (63) p Value* 0.54 0.01 <0.001 0.001
Anti-La 14 (18) 17 (23) 31 (21) Serum albumin (g/L)
Anti-nRNP 22 (29) 27 (36) 49 (33) MMF 26.7±5.6 33.4±5.7 34.9±6.0 36.1±6.3
Anti-Sm 18 (24) 14 (19) 32 (21) TAC 28.0±4.5 34.1±4.5 36.5±4.3 37.4±4.8
Anticardiolipin or lupus 18 (24) 24 (32) 42 (28) p Value* 0.11 0.98 0.22 0.26
anticoagulant
C3 (g/L)
Body weight, kg 56.3±9.9 56.7±9.1 56.5±9.5
MMF 0.49±0.21 0.77±0.24 0.81±0.26 0.83±0.24
Haemoglobin, g/dL 10.7±1.9 10.2±1.8 10.5±1.9
TAC 0.50±0.25 0.81±0.21 0.84±0.20 0.83±0.23
Serum albumin, g/L 26.7±5.6 28.0±4.5 27.3±5.1
p Value* 0.82 0.32 0.45 0.90
Serum creatinine, mmol/L 83.5±33 81.1±30 82.3±31
Anti-dsDNA (IU/L)
Serum creatinine, mg/dL 0.94±0.37 0.92±0.34 0.93±0.35
MMF 193±104 102±93 104±103 101±99
Daily proteinuria, g 3.83±3.6 3.32±2.5 3.58±3.1
TAC 226±104 135±106 126±105 126±100
Urine P/Cr ratio 4.23±4.1 3.52±2.5 3.88±3.4
p Value* 0.05 0.31 0.94 0.81
CrCl (measured), mL/min 77.4±29 80.5±33 79.0±31
Active cellular cast
Serum C3 level, g/L 0.49±0.21 0.50±0.25 0.50±0.23
MMF 31 (41%) – – 2 (3%)
Anti-dsDNA titre, IU/L 193±104 226±104 209±105
TAC 31 (42%) – – 5 (7%)
CrCl <90 mL/min 53 (70) 47 (64) 100 (67)
p Value* 0.89 – – 0.27
Nephrotic syndrome 33 (43) 31 (42) 64 (43)
Urine RBC >5/HPF
Hypertension requiring treatment 23 (30) 36 (49) 59 (39)
MMF 54 (71%) – – 23 (30%)
Active urinary cellular casts 31 (41) 31 (42) 62 (41)
TAC 58 (78%) 26 (35%)
Urine RBC >5 HPF 54 (71) 58 (78) 112 (75)
p Value* 0.30 0.53
Use of statin 39 (51) 36 (49) 75 (50)
Renal SLEDAI
Use of ACE inhibitor 54 (71) 56 (76) 110 (73)
MMF 8.8±3.6 – – 3.9±3.1
Use of hydroxychloroquine 40 (53) 37 (50) 77 (51)
TAC 8.6±2.8 – – 3.3±3.1
Histological classes (ISN/RPS)
p Value* 0.78 – – 0.25
IVG±V 26 (34) 23 (31) 49 (33)
Extra-renal SLEDAI
IVS±V 7 (9) 12 (16) 19 (13)
MMF 7.9±4.4 – – 1.7±1.9
III±V 31 (41) 23 (31) 54 (36)
TAC 6.6±3.5 1.9±1.7
Pure V 12 (16) 16 (22) 28 (19)
p Value* 0.04 0.22
Activity score 7.8±3.5 8.8±3.2 8.2±3.4
LDLc/HDLc ratio
Chronicity score 2.6±1.6 2.6±1.6 2.6±1.6
MMF 2.36±1.16 – – 1.63±0.89
Values represent mean±SD or number (%). TAC 2.21±1.20 – – 1.75±0.76
CrCl, creatinine clearance; HPF, high power field; IU, international unit; ISN/RPS,
International Society of Nephrology/Renal Pathology Society; MMF, mycophenolate p Value* 0.44 – – 0.22
mofetil; P/Cr, protein to creatinine; RBC, red blood cell; SLE, systemic lupus *p Value (comparison between MMF and TAC, with adjustment of baseline values by
erythematosus; TAC, tacrolimus. analysis of covariance at time points 2, 4 and 6 months).
CrCl, creatinine clearance; HDLc, high-density lipoprotein cholesterol; HPF, high power
field; IU, international unit; LDLc, low-density lipoprotein cholesterol; MMF,
mycophenolate mofetil; P/Cr, protein to creatinine; RBC, red blood cell; SLEDAI,
observed in both groups of patients ( p<0.001 in all), with no systemic lupus erythematosus disease activity index; TAC, tacrolimus.
significant differences between MMF and TAC at month 6
(table 2). Although no significant change in CrCl was observed
in patients treated with TAC ( p=0.78), MMF-treated patients achieved CR, PR and NR. No significant correlation was
had significant improvement of CrCl ( p<0.001). observed between the TAC level and the improvement in uP/Cr
Table 3 shows the rates of renal response at month 6. CR at 6 months compared with baseline (ρ=−0.14, p=0.25).
occurred in 59% of patients in the MMF arm and 62% patients
in the TAC arm (difference 3% (95% CI −12% to 18%)). Using
the ACR renal response criteria, 11% of MMF-treated patients Subgroup data on pure MLN
and 14% of TAC-treated patients achieved CR, respectively (dif- Table 4 shows the change in uP/Cr and CrCl in the first
ference 3% (−8% to 14%); p=0.59). 6 months in patients with pure MLN. The improvement in uP/
In the TAC group, the mean serum TAC level was 7.86±4.3, Cr was more profound in the TAC than in the MMF group.
7.60±3.2 and 8.53±3.9 ng/mL, respectively, in those who Numerically, more patients treated with TAC achieved CR or PR
Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456 3
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Clinical and epidemiological research

suboptimal response to induction therapy was similar in both

Table 3 Overall renal response at month 6 groups.
Renal response at MMF TAC Difference After a follow-up of 60.8±26 months, proteinuric and neph-
month 6 (N=76) (N=74) (95% CI)* p Value
ritic renal flares occurred in 24% and 18% of patients treated
CR 45 (59%) 46 (62%) 3% (−12% to 18%) 0.71 initially with MMF and 35% and 27% in those treated with
PR 16 (21%) 20 (27%) 6% (−8% to 19%) TAC, respectively (see online supplementary table S2). The
NR 15 (20%) 8 (11%) −9% (−20% to 3%) cumulative risk of having a renal flare of patients treated with
CR (ACR)† 8 (11%) 10 (14%) 3% (−8% to 14%) 0.59 MMF followed by AZA was 8% at 1 year, 28% at 3 years and
*With reference to MMF. 38% at 5 years, whereas the corresponding figures for patients
†Definition: creatinine clearance ≥90 mL/min+urine protein/creatinine <0.2+inactive treated with TAC followed by AZA was 9% in 1 year, 33% in 3
urinary casts. years and 54% in 5 years ( p=0.13; figure 1A). For those who
ACR, American College of Rheumatology; CR, complete response; MMF,
mycophenolate mofetil; NR, no response; PR, partial response; TAC, tacrolimus. achieved CR after induction therapy, the mean time to first
renal flare was 28.9±17 months in the MMF group and 30.1
than MMF (100% vs 75%; p=0.09). A quarter of patients were ±18 months in the TAC group (difference 1.3 (−13.7 to 11.2)
refractory (NR) to MMF but none of the patients treated with months).
TAC had NR. Six patients died in the MMF group (uncontrolled sepsis in
two, suicide in one, cancer in one and sudden cardiac death in
two) and five patients died in the TAC group (uncontrolled
Adverse events in the first 6 months sepsis in three, haemorrhagic stroke in one and pulmonary
Table 5 summarises the AEs experienced by our patients during haemorrhage in one). The cumulative incidence of a composite
the first 6 months. Major infective episodes developed in 7 outcome of decline of CrCl by ≥30%, development of CKD
(9.2%) and 4 (5.4%) patients treated with MMF and TAC, stage 4/5 or death at 5 years was 21% in patients treated with
respectively ( p=0.53). There was one death in the MMF group MMF and 22% in those treated with TAC ( p=0.35; figure 1B).
(uncontrolled sepsis). Herpes zoster infection was significantly
more common in patients treated with MMF than in patients
treated with TAC (18% vs 3%; p=0.003). Diarrhoea was more DISCUSSION
commonly reported in MMF-treated patients, whereas more This open randomised study showed that TAC was non-inferior
alopecia, diabetes mellitus, leg cramps and neurological symp- to MMF, in conjunction with high-dose corticosteroids, for
toms, such as tremor, were reported in TAC-treated patients. induction therapy of active LN. As a lower dose of prednisolone
Neurological symptoms resolved completely on reduction of and shorter duration of therapy were used when compared with
TAC dosage. Reversible increase in SCr by 30% was exclusively previous studies,15 16 25–27 the efficacy observed at 6 months
observed in TAC-treated patients. No patients were withdrawn was likely a combined effect of prednisolone with the study
because of AEs except for the one who died. drugs. With AZA maintenance for 5 years, there was a trend of
higher incidence of renal flares and renal function decline in the
TAC than in the MMF group of patients.
Relapse of LN and renal function decline Our results are in line with two small RCTs, which showed
AZA maintenance was given to 59 (78%) MMF-treated (dose that the short-term efficacy of TAC was similar to pulse CYC in
82.5±24 mg/day) and 60 (81%) TAC-treated patients (dose LN.25 26 In fact, lower doses of TAC have also been shown to
86.5±21 mg/day; p=0.32). Other patients were reinduced with improve residual proteinuria after induction treatment in
alternative immunosuppressive regimens (high-dose prednisol- LN.36 37
one with CYC (N=20), low-dose combination of MMF and Pure MLN is well recognised to have a more delayed response
TAC (N=5), cross-over to TAC (N=4) or cross-over to MMF to treatment than its proliferative counterpart. Pooling of data
(N=2)). The need for salvage treatment for patients with from two RCTs showed that MMF was equally effective with

Table 4 Renal response of pure membranous lupus nephritis

Baseline 2 months 4 months 6 months p Value

Urine P/Cr ratio

MMF 6.32±8.2 2.95±3.2 2.50±2.1 1.45±1.1 0.047
TAC 4.34±2.8 1.44±1.1 1.85±2.9 1.08±0.9 <0.001
p Value* 0.44 0.16 0.65 0.52
CrCl (mL/min)
MMF 92.4±36 93.5±35 104±37 102±31 0.19
TAC 100±38 98.8±43 90.9±41 90.8±44 0.07
p Value* 0.57 0.76 0.03 0.04

Renal response at 6 months MMF (N=12) TAC (N=16) Difference (95% CI)† p Value

CR 6 (50%) 9 (56%) 6% (−27% to 38%) 0.09

PR 3 (25%) 7 (44%) 19% (−16% to 47%)
NR 3 (25%) 0 (0%) −25% (−53% to 0.2%)
*p Value (comparison between MMF and TAC, with adjustment of baseline values by analysis of covariance at time points 2, 4 and 6 months).†With reference to MMF.CR, complete
response; CrCl, creatinine clearance; MMF, mycophenolate mofetil; NR, no response; P, (comparison between month 6 values with baseline); P/Cr, protein to creatinine; PR, partial
response; TAC, tacrolimus.

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Clinical and epidemiological research

Table 5 Adverse events in the first 6 months

MMF (N=76) TAC (N=74) p Value

Any adverse events 59 (78%) 69 (93%) 0.007

Death 1 (1.3%) 0 (0%) 1.00
Major infection (hospitalisation) 7 (9.2%) 4 (5.4%) 0.53
Minor infection (excluding Herpes) 16 (28%) 12 (16%) 0.45
Upper respiratory tract 10 (13%) 7 (9.5%) 0.48
Urinary tract 3 (3.9%) 1 (1.4%) 0.62
Gynaecological 1 (1.3%) 0 (0%) 1.00
Gastrointestinal 0 (0%) 1 (1.4%) 1.00
Sinusitis 1 (1.3%) 0 (0%) 1.00
Subcutaneous 1 (1.3%) 3 (4.1%) 0.36
Herpes zoster 14 (18%) 2 (2.7%) 0.003
Herpes simplex 0 (0%) 1 (1.4%) 1.00
Nausea 3 (3.9%) 2 (2.7%) 1.00
Diarrhoea 8 (11%) 2 (2.7%) 0.10
Diabetes mellitus 2 (2.6%) 3 (4.1%) 0.68
Alopecia 0 (0%) 6 (8.1%) 0.01
Tremor 0 (0%) 15 (20%) <0.001
Headache 1 (1.3%) 3 (4.1%) 0.36
Cramps 2 (2.6%) 7 (9.5%) 0.10
Tinnitus 1 (1.3%) 0 (0%) 1.00
Hypertrichosis 0 (0%) 1 (1.4%) 1.00
Reversible increase in SCr by 30% 0 (0%) 10 (14%) 0.001
Others 4 (5.3%) 1 (1.4%) 0.37
MMF, mycophenolate mofetil; SCr, serum creatinine; TAC, tacrolimus.

CYC for pure MLN.38 Open-label studies have also shown that
CSA and TAC were effective for pure MLN.22 39 A multitarget
regimen consisting of corticosteroid, MMF and TAC was shown
to be more effective than CYC in mixed proliferative and
MLN.27 The rationale of this combination is the efficacy of TAC
on the membranous component of LN. In our study, TAC
appeared to be more effective than MMF in reducing protein-
uria in pure MLN. This was unlikely because of the drop in
CrCl as we had assessed the uP/Cr ratio instead of the absolute
amount of proteinuria. However, the sample size of this sub-
group was not powered to detect a difference between MMF
and TAC.
The relationship between serum TAC level and its efficacy is
intriguing. Our previous study23 failed to show a correlation
between clinical response and TAC level. In the present study,
which involved much more patients, again we could not demon-
strate better efficacy with higher TAC levels. In fact, NR patients
had achieved higher TAC levels than those with CR or PR.
Despite this, it is prudent to monitor the TAC level for dosage
titration to minimise toxicity and for surveillance of drug
compliance.
In our study, 12% of TAC-treated patients had transient
increase in SCr and no improvement of CrCl at month 6,
whereas in MMF-treated patients, an improvement in CrCl was
observed. This could possibly be related to a relatively
high dosage of TAC being used. In fact, the mean trough
TAC level achieved in our patients (7.8 ng/mL) was higher than
those reported in renal transplantation studies (<7.5 ng/mL) at
1 year.17 19 Although the proportion of patients who had deteri-
oration in CrCl by 30% at 5 years was not significantly higher
in the TAC than in the MMF group of patients, the difference
might become significant on longer follow-up. As the exposure
to TAC was only 6 months, whether the unfavourable trend on
long-term renal function in this group was related to the
Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456
Figure 1 (A) Kaplan–Meier plot of the cumulative probabilities of
having a renal flare according to treatment arm. (B) Kaplan–Meier plot
of the cumulative probabilities of having a composite outcome of
decline of creatinine clearance by ≥30%, development of chronic
kidney disease stage 4/5 or death according to treatment arm.
MMF, mycophenolate mofetil; TAC, tacrolimus.
numerically higher number of renal flares remains to be deter-
mined. Nevertheless, the hazard of nephrotoxicity, especially in
those with impaired renal function at baseline, should be taken
into account when TAC is used for LN. Close monitoring of
renal function and the TAC level is necessary.
Patients in our study were maintained on AZA after successful
induction therapy. We have previously shown that AZA main-
tenance in LN was associated with a better outcome in terms of
renal function deterioration and mortality.7 However, whether
MMF is more cost-effective in preventing renal flares than AZA
as maintenance therapy remains unclear as conflicting evidence
has been reported in different studies.40 41
The use of MMF during pregnancy is linked with an
increased incidence of first-trimester pregnancy loss and fetal
malformations that involve the ear and face such as cleft palate
and lip.42 Therefore, MMF is contraindicated during pregnancy.
On the contrary, TAC is not linked to congenital malformations
in solid organ transplantation43 and has been successfully used
to treat LN flares during pregnancy.44
5
 Downloaded from http://ard.bmj.com/ on January 6, 2015 - Published by group.bmj.com
Clinical and epidemiological research
The strength of our study is its randomised design and a suffi-
ciently large sample to confirm non-inferiority of TAC to MMF
for LN. We followed up our patients for 5 years and reported
the long-term outcome in terms of renal flares and renal func-
tion decline. The major limitation of our study is the open-label
design and the shifting to AZA after 6 months. As some patients
may have delayed response to therapy, extension of induction-
consolidation treatment to 12 months for the assessment of effi-
cacy might be a better option. The definition of CR with a pro-
teinuria of <1 g/day when the study was designed a decade ago
was a bit loose when compared with recent consensus recom-
mendation ( proteinuria <0.5 g/day with normal or near normal
renal function).45 In addition, the lack of monitoring of the
trough mycophenolic acid level for dosage titration of MMF
might have undermined its efficacy when compared with TAC.
Finally, our results cannot be extrapolated to other ethnic popu-
lations. Despite these caveats, this is the largest study to show
non-inferiority of TAC to MMF for induction therapy of active
LN. TAC/corticosteroid combination should be considered as an
alternative regimen to conventional CYC or MMF for the initial
therapy of active LN, especially for those who are intolerant,
contraindicated or refractory to the latter agents.
Declaration We did not receive any grants, sponsor or support from any
organisation including pharmaceutical companies, in particular Roche and Astella,
for the submitted work. All authors do not have any conflicts of interests to be
declared. None of the authors have financial relationships with any organisations
that might have an interest in the submitted work in the previous 3 years. There are
no other relationships or activities that could appear to have influenced the
submitted work.
The lead author affirms that the manuscript is an honest, accurate and
transparent account of the study being reported; that no important aspects of the
study have been omitted and that any discrepancies from the study as planned have
been explained.
Contributors CCM: study design, patients’ assessment, data collection and
analysis (guarantor of the submitted work). KYY, KHT, CWY, YPS, CHT, WLN:
patients’ assessment and follow-up, data collection. The investigators have full
access to all of the data and take responsibility for the integrity of the data and the
accuracy of the data analysis.
Competing interests None.
Patient consent Obtained.
Ethics approval Research and Ethics Committee of Tuen Mun Hospital, Princess
Margaret Hospital and United Christian Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We will present additional unpublished data from the
study if available and deemed necessary by the editorial office.
REFERENCES
1 Mok CC, Tang SS, To CH, et al. Incidence and risk factors of thromboembolism in
systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum
2005;52:2774–82.
2 Bastian HM, Roseman JM, McGwin G Jr, et al.; LUMINA Study Group. LUpus in
MInority populations: NAture vs nurture. Systemic lupus erythematosus in three
ethnic groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus
2002;11:152–60.
3 Mok CC, Tang SS. Incidence and predictors of renal disease in Chinese patients
with systemic lupus erythematosus. Am J Med 2004;117:791–5.
4 Appenzeller S, Clarke AE, Panopalis P, et al. The relationship between renal activity
and quality of life in systemic lupus erythematosus. J Rheumatol 2009;36:947–52.
5 Mok CC, Kwok RC, Yip PS. Effect of renal disease on the standardized mortality
ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis
Rheum 2013;65:2154–60.
6 Mok CC, Wong RW, Lau CS. Lupus nephritis in Southern Chinese patients:
clinicopathologic findings and long-term outcome. Am J Kidney Dis
1999;34:315–23.
7 Mok CC, Ying KY, Ng WL, et al. Long-term outcome of diffuse proliferative lupus
glomerulonephritis treated with cyclophosphamide. Am J Med 2006;119:355.
e25–33.
6 Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456
8 Korbet SM, Schwartz MM, Evans J, et al. Collaborative Study Group. Severe lupus
nephritis: racial differences in presentation and outcome. J Am Soc Nephrol
2007;18:244–54.
9 Hui M, Garner R, Rees F, et al. Lupus nephritis: a 15-year multi-centre experience in
the UK. Lupus 2013;22:328–32.
10 Austin HA III, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial
of prednisone and cytotoxic drugs. New Engl J Med 1986;314:614–19.
11 Boumpas DT, Austin HA III, Vaughn EM, et al. Controlled trial of pulse
methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus
nephritis. Lancet 1992;340:741–5.
12 Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse
cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome
without adding toxicity in patients with lupus nephritis. Ann Intern Med
2001;135:248–57.
13 Mok CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with
systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum
1998;41:831–7.
14 Mok CC, Chan PT, To CH. Anti-müllerian hormone and ovarian reserve in systemic
lupus erythematosus. Arthritis Rheum 2013;65:206–10.
15 Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous
cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219–28.
16 Appel GB, Contreras G, Dooley MA, et al.; Aspreva Lupus Management Study
Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of
lupus nephritis. J Am Soc Nephrol 2009;20:1103–12.
17 Ekberg H, Tedesco-Silva H, Demirbas A, et al.; ELITE-Symphony Study. Reduced
exposure to calcineurin inhibitors in renal transplantation. N Engl J Med
2007;357:2562–75.
18 Krämer BK, Del Castillo D, Margreiter R, et al.; European Tacrolimus versus
Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of
tacrolimus compared with ciclosporin A in renal transplantation: three-year
observational results. Nephrol Dial Transplant 2008;23:2386–92.
19 Silva HT Jr, Yang HC, Meier-Kriesche HU, et al. Long-term follow-up of a phase III
clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and
cyclosporine/MMF in de novo kidney transplant recipients. Transplantation
2014;97:636–41.
20 Penninga L, Møller CH, Gustafsson F, et al. Tacrolimus versus cyclosporine as
primary immunosuppression after heart transplantation: systematic review with
meta-analyses and trial sequential analyses of randomised trials. Eur J Clin
Pharmacol 2010;66:1177–87.
21 Lee YH, Lee HS, Choi SJ, et al. Efficacy and safety of Tacrolimus therapy for lupus
nephritis: a systematic review of clinical trials. Lupus 2011;20:636–40.
22 Szeto CC, Kwan BC, Lai FM, et al. Tacrolimus for the treatment of systemic lupus
erythematosus with pure class V nephritis. Rheumatology (Oxford)
2008;47:1678–81.
23 Mok CC, Tong KH, To CH, et al. Tacrolimus for induction therapy of diffuse
proliferative lupus nephritis: an open-labeled pilot study. Kidney Int
2005;68:813–17.
24 Lee T, Oh KH, Joo KW, et al. Tacrolimus is an alternative therapeutic option for the
treatment of refractory lupus nephritis. Lupus 2010;19:974–80.
25 Chen W, Tang X, Liu Q, et al. Short-term outcomes of induction therapy with
Tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter
randomized clinical trial. Am J Kidney Dis 2011;57:235–44.
26 Li X, Ren H, Zhang Q, et al. Mycophenolate mofetil or Tacrolimus compared with
intravenous cyclophosphamide in the induction treatment for active lupus nephritis.
Nephrol Dial Transplant 2012;27:1467–72.
27 Bao H, Liu ZH, Xie HL, et al. Successful treatment of class V+IV lupus nephritis with
multitarget therapy. J Am Soc Nephrol 2008;19:2001–10.
28 Mok CC, To CH, Yu KL, et al. Combined low-dose mycophenolate mofetil and
Tacrolimus for lupus nephritis with suboptimal response to standard therapy:
a 12-month prospective study. Lupus 2013;22:1135–41.
29 Yoon KH. Efficacy and cytokine modulating effects of tacrolimus in systemic lupus
erythematosus: a review. J Biomed Biotechnol 2010;2010:686480.
30 Heidt S, Roelen DL, Eijsink C, et al. Calcineurin inhibitors affect B cell antibody
responses indirectly by interfering with T cell help. Clin Exp Immunol
2010;159:199–207.
31 Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney
podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med
2008;14:931–8.
32 Hochberg MC. Updating the American College of Rheumatology revised criteria
for the classification of systemic lupus erythematosus. Arthritis Rheum
1997;40:1725.
33 Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc
Committee on Systemic Lupus Erythematosus Response Criteria. The American College
of Rheumatology response criteria for proliferative and membranous renal disease in
systemic lupus erythematosus clinical trials. Arthritis Rheum 2006;54:421–32.
34 Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and
progesterone hormone replacement therapy on disease activity in systemic lupus
erythematosus: a randomized trial. Ann Intern Med 2005;142:953–62.
 Downloaded from http://ard.bmj.com/ on January 6, 2015 - Published by group.bmj.com
35 Ong LM, Hooi LS, Lim TO, et al. Randomized controlled trial of pulse intravenous
cyclophosphamide versus mycophenolate mofetil in the induction therapy of
proliferative lupus nephritis. Nephrology (Carlton) 2005;10:504–10.
36 Chen W, Liu Q, Chen W, et al. Outcomes of maintenance therapy with tacrolimus
versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial.
Lupus 2012;21:944–52.
37 Asamiya Y, Uchida K, Otsubo S, et al. Clinical assessment of tacrolimus therapy in
lupus nephritis: one-year follow-up study in a single center. Nephron Clin Pract
2009;113:c330–6.
38 Radhakrishnan J, Moutzouris DA, Ginzler EM, et al. Mycophenolate mofetil and
intravenous cyclophosphamide are similar as induction therapy for class V lupus
nephritis. Kidney Int 2010;77:152–60.
39 Hallegua D, Wallace DJ, Metzger AL, et al. Cyclosporine for lupus membranous
nephritis: experience with ten patients and review of the literature. Lupus
2000;9:241–51.
40 Houssiau FA, D’Cruz D, Sangle S, et al.; MAINTAIN Nephritis Trial Group.
Azathioprine versus mycophenolate mofetil for long-term immunosuppression in
Mok CC, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-206456
Clinical and epidemiological research
lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis
2010;69:2083–9.
41 Dooley MA, Jayne D, Ginzler EM, et al.; ALMS Group. Mycophenolate versus
azathioprine as maintenance therapy for lupus nephritis. N Engl J Med
2011;365:1886–95.
42 Pisoni CN, D’Cruz DP. The safety of mycophenolate mofetil in pregnancy. Expert
Opin Drug Saf 2008;7:219–22.
43 Hebert MF, Zheng S, Hays K, et al. Interpreting tacrolimus concentrations during
pregnancy and postpartum. Transplantation 2013;95:908–15.
44 Webster P, Wardle A, Bramham K, et al. Tacrolimus is an effective treatment for
lupus nephritis in pregnancy. Lupus 2014;23:1192–6.
45 Bertsias GK, Tektonidou M, Amoura Z, et al.; European League Against
Rheumatism and European Renal Association-European Dialysis and Transplant
Association. Joint European League Against Rheumatism and European Renal
Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA)
recommendations for the management of adult and paediatric lupus nephritis.
Ann Rheum Dis 2012;71:1771–82.
7
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Tacrolimus versus mycophenolate mofetil for

induction therapy of lupus nephritis: a
randomised controlled trial and long-term
follow-up
Chi Chiu Mok, King Yee Ying, Cheuk Wan Yim, Yui Pong Siu, Ka Hang
Tong, Chi Hung To and Woon Leung Ng

Ann Rheum Dis published online December 30, 2014

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