Systemic lupus erythematosus

Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217178 on 24 May 2020. Downloaded from http://ard.bmj.com/ on May 24, 2020 at Uppsala Universitet BIBSAM Consortia.
Clinical science

Long-­term outcome of a randomised controlled trial

comparing tacrolimus with mycophenolate mofetil as
induction therapy for active lupus nephritis
Chi Chiu Mok  ‍ ‍,1 Ling Yin Ho,1 Shirley King Yee Ying,2 Man Chi Leung,3
Chi Hung To,1 Woon Leung Ng3

Handling editor Josef S Abstract

Smolen
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1
Medicine, Tuen Mun Hospital,
Hong Kong, Hong Kong
2 the efficacy of the calcineurin inhibitors as
Department of Medicine,
Princess Margaret Hospital,
Hong Kong, China
3
Medicine, United Christian
Hospital, Hong Kong, Hong
Kong
Correspondence to
Key messages
Objectives  To report the 10-­year outcome of lupus
nephritis (LN) treated with mycophenolate mofetil (MMF)
What is already known about this subject?
or tacrolimus (TAC) induction in a randomised controlled
►► Previous randomised controlled trials (RCTs)
trial.
of lupus nephritis (LN) have shown that the
Methods  Patients with active LN were treated with
difference in renal function preservation of
MMF or TAC combined with high-­dose prednisolone.
various treatment regimens would only be
Responders were switched to azathioprine (AZA) at
apparent beyond 5 years. Long-­term data on
month 6. Clinical outcomes at 10 years (renal flares,
renal function decline and mortality) were assessed.
induction therapy of LN are scant.
Factors affecting prognosis were studied by Cox
regression. Urine protein-­to-­creatinine ratio (uPCr) and
What does this study add?
estimated glomerular filtration rate (eGFR) at different
►► This study reports the 10-­year outcomes of
time points were evaluated for their prediction of a poor
a large cohort of patients with LN treated
prognosis by receiver operating characteristic (ROC)
with either mycophenolate mofetil (MMF) or
analysis.

Dr Chi Chiu Mok, Medicine,
Tuen Mun Hospital, Hong Kong
SAR, Hong Kong;
​ccmok2005@​yahoo.​com
Received 18 February 2020
Revised 2 May 2020
Accepted 3 May 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Mok CC,
Ho LY, Ying SKY, et al.
Ann Rheum Dis Epub ahead
of print: [please include Day
Month Year]. doi:10.1136/
annrheumdis-2020-217178
Results  150 patients were studied (age
35.5±12.8 years). Complete renal response rate was
similar between MMF (59%) and TAC-­treated patients
(62%; p=0.71). AZA maintenance was given to 79%
patients. After 118.2±42 months, proteinuric and
nephritic renal flares occurred in 34% and 37% of the
MMF, and 53% and 30% of the TAC groups of patients,
respectively (p=0.49). The cumulative incidence of a
composite outcome of ↓eGFR ≥30%, chronic kidney
disease stage 4/5 or death at 10 years was 33% in both
groups (p=0.90). Factors independently associated
with a poor renal prognosis were first-­time LN (HR
0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96
to 0.99); p=0.008) and no response at month 6 (HR
5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an
uPCr >0.75 and eGFR of <80 mL/min at month 18 best
predicted a poor renal prognosis.
Conclusions  Long-­term data confirmed non-­
inferiority of TAC to MMF as induction therapy of LN. An
uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best
predicted a favourable 10-­year outcome and may be
suitable targets for induction/consolidation therapy.
Trial registration number  NCT00371319.
Introduction
Renal involvement is one of the most frequent and
serious complications of systemic lupus erythema-
tosus (SLE), particularly in certain ethnic groups
such as the African-­Americans, Hispanic-­Americans
and the Asians.1–3 Lupus nephritis (LN) is associated
with significant morbidity and mortality because of
the risk of progression to end-­stage renal disease
(ESRD) and treatment-­ related adverse effects.4 5
Up to one-­third of patients with severe LN develop
Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178
Protected by copyright.
tacrolimus induction, followed by azathioprine
maintenance. There were no significant
differences in renal flares or renal function
decline between the two regimens. Receiver
operating characteristic analysis showed a urine
protein-­to-­creatinine ratio (uPCr) ≤0.75 and
estimateglomerular filtration rate (eGFR)
≥80 mL/min at month 18 best predicted a
favourable outcome. Maintenance therapy of
<62.5 months’ duration best predicted a renal
flare.
How might this impact on clinical practice?
►► Tacrolimus may be considered as an alternative
to MMF as induction therapy of LN. Treatment
of LN should aim at uPCr ≤0.75 and eGFR
≥80ml/min by month 18, with repeat renal
biopsy if necessary. Maintenance therapy
should best be continued for 5 years or more,
particularly in high-­risk patients.
ESRD6–8 at 10  years, and mortality rate was
increased by eightfold compared with the general
population.5 Thus, the goals of LN therapy are to
control kidney inflammation timely (induction/
consolidation) and reduce the risk of renal flares
(maintenance).
Conventional induction therapy of severe LN
includes high-­dose glucocorticoids in combination
with cyclophosphamide (CYC; National Institute of
Health (NIH) high-­dose or Euro-­Lupus low-­dose
regimen) or mycophenolate mofetil (MMF).9–11
MMF emerges to become first-­ line induction
therapy of LN because of the lack of ovarian and
bladder toxicity.12 However, MMF is not superior
   1
 Systemic lupus erythematosus
to CYC in short-­term efficacy of LN.13 14 The calcineurin inhib-
itors (CNIs), such as ciclosporin A (CSA) and tacrolimus (TAC),
have been used and approved in some Asian countries for induc-
tion therapy of LN.15 Small randomised controlled trials (RCTs)
have shown similar efficacy of TAC with intravenous pulse CYC
for inducing remission of LN.15 16 On the other hand, low-­dose
combination of MMF and TAC has been shown to be more effec-
tive than intravenous pulse CYC as induction therapy of LN.17 18
In a recent RCT, we compared the efficacy of MMF and TAC,
combined with high-­dose prednisolone, as induction therapy in
patients with active LN.19 TAC was found to be non-­inferior
to MMF in terms of the complete renal response (CR) rate at
6 months. We hereby report the outcome of the same cohort of
patients at 10 years. The incidence of renal flares, renal function
decline (reduction in estimate glomerular filtration rate (eGFR)),
chronic kidney disease (CKD) progression and mortality would
be compared between the two treatment arms.
Patients and methods
Study population
19
The inclusion criteria of our RCT were: (1) age≥18 years; (2)
fulfilment of ≥4 American College of Rheumatology (ACR)
criteria for SLE20; (3) biopsy proven active LN (International
Society of Nephrology/Renal Pathology Society (ISN/RPS)
class III/IV/V) within 4 weeks of study entry; (4) serum creat-
inine (SCr)<200 μmol/L. Exclusion criteria were: (1) refusal
for randomisation and preferred conventional regimens such as
CYC; (2) SCr≥200 μmol/L; and (3) patients who planned for
pregnancy within 12 months after randomisation.
All participants were prescribed 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.
Patients were randomised by block in a 1:1 ratio to either (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). CR or good partial renal
responders (PR) were switched to azathioprine (AZA; 2 mg/kg/
day) for maintenance therapy. AZA was continued indefinitely
until patients experienced serious adverse events or disease flares
in which reinduction and subsequent switching to other agents
for maintenance was decided by attending physicians. Details of
the study protocol can be referred to our previous publication19
and online supplementary table 1 shows that definitions of renal
response at 6 months. Written consent was obtained from all
patients.
Long-term clinical outcomes
Patients participated in this RCT were followed longitudinally by
the same group of physicians. We studied the clinical outcomes
at 10 years of all the recruited patients on an intention-­to-­treat
basis regardless of the maintenance regimens following induc-
tion or reinduction therapies. These outcomes included the inci-
dence of renal flares (proteinuria, nephritic), non-­renal flares,
renal function decline (drop in eGFR by ≥30%), progression to
CKD stage 4/5 (eGFR<30 mL/min) and mortality, which were
compared between the MMF and TAC induction arms. Factors
associated with a poor renal prognosis were studied by statistical
analysis. Renal parameters, namely urine protein-­to-­creatinine
ratio (uPCr) and eGFR, at different time points between 6 and
24 months were studied for their predictive value of renal prog-
nosis at 10 years.
2 Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178
Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217178 on 24 May 2020. Downloaded from http://ard.bmj.com/ on May 24, 2020 at Uppsala Universitet BIBSAM Consortia.
A proteinuric renal flare was defined as an increase in protein-
uria to >2 g/day (or uPCr>2.0) after a CR, or doubling of
proteinuria (or uPCr) after a PR with or without an increase
in SCr (<30%). An increase or recurrence of active urinary
sediments (red blood cell or cellular casts) with a concomitant
increase in proteinuria (or uPCr) or increase in SCr (≥30%;
after exclusion of other causes) would qualify a nephritic renal
flare. An ex-­renal lupus flare was defined as any non-­renal clin-
ical manifestations that warranted augmentation of therapies.
Organ damage of SLE was assessed by the SLE International
Collaborative Clinics/ACR damage index (SDI).21 Damage (after
SLE diagnosis) must be present for 6 months before it is scored,
irrespective of the cause, and must be irreversible.
Patient and public involvement
Patients were not involved in the design and conduct of this trial.
Statistical analyses
Unless otherwise stated, values in this study were expressed as
mean±SD. Comparison between two groups was performed by
the independent Student’s t-­test for continuous variables and χ2
test for categorical variables (Fisher’s exact test was used when
the frequency of any cell was <5). The cumulative incidence of
renal flares, renal function deterioration or 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
Protected by copyright.
were censored at their last visits. Factors associated with renal
flare or long-­term renal prognosis were studied by Cox regres-
sion taking into account of all contributing covariates without
selection. Covariates that were considered in the regression
models included age, sex, first-­time LN (vs relapsed LN), treat-
ment arms (MMF vs TAC), histological class, activity and chro-
nicity scores, nephrotic syndrome and hypertension at baseline,
serological and urinary parameters at 6 months, renal response,
maintenance therapy and renal flares. Receiver operating char-
acteristic (ROC) curve analysis was used to explore the cut-­offs
of uPCr or eGFR at various time points that best predicted the
long-­term renal prognosis based on area under the curve (AUC)
and the shape of the curves that determined the turning points
that yielded the maximum sum of the sensitivity and specificity
values.
Statistical significance was defined as a p value of <0.05, two
tailed. All statistical analyses were performed by using the SPSS
program (V.21.0) for Windows 10.
Results
Clinical characteristics of participants
A total of 150 patients with active LN were randomised to receive
MMF (n=76) or TAC (n=74) between 2005 and 2012. There
were 138 (92%) women and the distribution of the histolog-
ical classes (ISN/RPS) was: III±V 36%; IVG/S±V 46%; pure V
19%. The mean age at study entry was 35.5±12.8 years and the
mean histological activity and chronicity score were 8.2±3.4 and
2.6±1.6, respectively. Fifty-­nine (39%) patients were hyperten-
sive, 62 (41%) had active urinary casts, 112 (75%) had micro-
scopic haematuria and 67% patients had an eGFR<90 mL/min.
No significant differences in the clinical characteristics of the
patients were observed between the two treatment arms. As
reported, the rate of CR (primary end point) was 59% in the
MMF and 62% in the TAC group at month 6 (difference 3%
(−12% to 18%); p=0.71).19
 Systemic lupus erythematosus

Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217178 on 24 May 2020. Downloaded from http://ard.bmj.com/ on May 24, 2020 at Uppsala Universitet BIBSAM Consortia.
Figure 1  Cumulative incidence of renal flares (any) over time. AZA,
azathioprine; MMF, mycophenolate mofetil; TAC, tacrolimus.

Renal flares over time

Maintenance therapy with AZA was given to 59 (78%) MMF-­
treated (dose 82.5±24 mg/day) and 60 (81%) TAC-­treated
patients (dose 86.5±21 mg/day; p=0.32). AZA was discon-
tinued in four patients because of intolerance (agranulocytosis

Protected by copyright.
(n=2), disseminated tuberculosis (n=1) and gastrointestinal Figure 2  Receiver operating characteristic (ROC) analysis of the
upset (n=1)) and three patients because of pregnancy. Six of length of maintenance therapy and renal flares (AUC=area under the
these patients were switched to low-­dose cyclosporine A for curve).
maintenance. Patients who had no response at 6 months were
reinduced with alternative regimens that included high-­ dose
prednisolone with CYC (n=20), low-­dose combination of MMF
level at 6 months (HR 0.45 (0.25 to 0.83); p=0.01) were inde-
and TAC (n=5), cross-­over to TAC (n=4) or MMF (n=2). After
pendently associated with renal flares over time (table 1). Male
successful reinduction, the choice of maintenance regimen was
patients showed a trend of having more flares but this did not
at the discretion of the attending physicians.
reach statistical significance (HR 4.67 (0.96 to 22.7); p=0.06).
No patients were lost to follow-­up. After a mean of 118.2±42
The cumulative rates of renal flares in subgroup of patients
months, proteinuric and nephritic renal flares occurred in 34%
with pure membranous LN (N=28) and those who did not
and 37% of patients treated initially with MMF, and 53% (group
require re-­induction therapy at 6 months (N=119) are shown in
difference; p=0.02) and 30% (group difference; p=0.36),
respectively, in those treated with TAC. There was a total of 77
renal flares in 43 (57%) patients treated with MMF (0.11/patient
year) and 92 renal flares in 46 (62%) of patients treated with Table 1  Factors independently associated with renal flares (Cox
TAC (0.12/patient year; p=0.23). The retreatment regimens for regression)
these flares were summarised in online supplementary table 2. Covariates HR (95% CI) P value
The daily dose of prednisolone used ranged from 0.4 to 0.8 mg/
Male sex 4.67 (0.96 to 22.7) 0.06
kg (for 4–8 weeks before tapering). Numerically, more patients
Age at LN, years 0.99 (0.96 to 1.01) 0.24
in the MMF group were retreated with CYC-­based regimens for
First time LN 0.41 (0.22 to 0.77) 0.006
renal flares.
TAC versus MMF induction 1.19 (0.69 to 2.05) 0.53
The cumulative risk of having a renal flare of patients treated
with MMF/AZA was 28% at 3 years, 42% at 5 years and 58% at Pure class V histology 0.34 (0.04 to 3.23) 0.35
10 years, whereas the corresponding figures for patients treated Low C3 (6 months) 0.88 (0.53 to 1.49) 0.64
with TAC/AZA was 32% at 3 years, 53% in 5 years and 66% Elevated anti-­dsDNA (6 months) 0.45 (0.25 to 0.83) 0.01
in 10 years (log rank test; p=0.43) (figure 1). For those who Urine P/Cr (6 months) 1.02 (0.81 to 1.28) 0.87
achieved CR after induction therapy at month 6, the mean time eGFR (6 months), mL/min 1.00 (0.9 to 1.01) 0.92
to first renal flare was 70.4±47.1 months (median 62 months) Complete renal response at 6 months 1.15 (0.53 to 2.48) 0.73
in the MMF group and 65.2±50 months (median 47 months) in Use of HCQ 1.03 (0.60 to 1.79) 0.91
the TAC group (p=0.61). ROC analysis showed that a duration Activity score (at entry) 1.08 (0.99 to 1.17) 0.09
of maintenance therapy <62.5 months best predicted the first Chronicity score (at entry) 0.82 (0.66 to 1.01) 0.06
renal flare (AUC 0.80 (0.73–0.88); specificity 0.77; sensitivity AZA/MMF maintenance 1.10 (0.47 to 2.60) 0.82
0.77; figure 2). AZA, azathioprine; eGFR, estimated glomerular filtration rate; HCQ,
Cox regression analysis showed that first time LN (HR 0.41 hydroxychloroquine; LN, lupus nephritis; MMF, mycophenolate mofetil; P/Cr, protein-­
(0.22 to 0.77); p=0.006) and persistent elevation of anti-­dsDNA to-­creatinine ratio; TAC, tacrolimus.

Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178 3

 Systemic lupus erythematosus

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Figure 3  Rate of extrarenal flares according to treatment groups (per patient year). MMF, mycophenolate mofetil; TAC, tacrolimus.

online supplementary figures 1 and 3, respectively. There were patients (p=0.44). The proportion of patients who were treated
no significant differences between the TAC and MMF groups. with antihypertensive agents was non-­significantly higher in the

Repeat renal biopsy
Renal biopsy was repeated in 40 patients mainly because of renal
flares. Data from four patients could not be used because of
an inadequate number of glomeruli. In the remaining patients
(MMF n=18; TAC n=18), the time interval from the initial
biopsy was 78.2±36 and 67.8±40 months, respectively, in the
MMF and TAC group (p=0.40). Five patients in the MMF and
four patients in the TAC group had further exposure to the CNIs
for reinduction therapy of refractory renal disease or SLE flares
before repeat renal biopsy. The increase in histological chronicity
score was not significantly different between the two groups
(1.29; 95% CI (−0.21 to 2.78) in MMF and 1.64; 95% CI (0.43
to 2.85) in TAC; p=0.69).
Protected by copyright.
TAC than MMF group (51% vs 37%; p=0.07).
Renal function deterioration and prognostic factors
In patients treated with MMF, the proportions with eGFR decline
by ≥30% compared with baseline, CKD stage 4/5 progression and
mortality were 21%, 18% and 14%, respectively. These figures
were not significantly different from those treated with TAC
(corresponding figures 24%, 19% and 12%; p values of 0.63, 0.94
and 0.68, respectively, compared between groups). Figure 4 shows
that cumulative incidence of a composite outcome of decline of
eGFR by ≥30%, CKD stage 4/5 progression or death at 5 and
10 years was 24% and 33% in patients treated with MMF, and

Non-renal flares and organ damage over time

In the MMF group of patients, non-­renal lupus flares occurred
at a rate of 0.083 per patient/year, which was not significantly
different from that of the TAC group (0.091 per patient year;
p=0.64). The incidence of mucocutaneous, arthritic, serosal,
haematological and neuropsychiatric SLE flares was not signifi-
cantly different between the MMF and TAC groups of patients (p
values non-­significant for all comparisons; figure 3). Treatment
regimens of these flares were summarised in online supplemen-
tary table 2. The daily dose of prednisolone used ranged from
0.2 to 0.4 mg/kg (for 2–4 weeks) when there was no concomitant
renal or major organ flare.
The proportion of patients who accrued new organ damage
over time was not significantly different between the MMF and
TAC groups (45% vs 47%; p=0.75). The increase in SDI score
from baseline was 1.0±1.4 in TAC and 0.79±1.1 in MMF groups
of patients (p=0.31). The increase in SDI score was significantly
higher in those who failed to remit at 18 months than the others
(1.6±1.5 vs 0.7±1.1; p=0.009), which was mainly contributed Figure 4  Cumulative risk of a poor renal outcome (↓estimated
by renal and neuropsychiatric scores (data not shown). Diabetes glomerular filtration rate ≥30%, chronic kidney disease 4/5 or death).
mellitus developed in 4 (5.4%) TAC and 2 (2.6%) MMF-­treated AZA, azathioprine; MMF, mycophenolate mofetil; TAC, tacrolimus.
4 Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178
 Systemic lupus erythematosus

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and uPCr cut-­off of 0.75 (AUC 0.73; sensitivity 0.69, specificity
Table 2  Factors independently associated with a poor clinical
0.74) at month 18 best predicted CKD stage 4/5 or decline of
outcome (≥30% drop in estimated glomerular filtration rate (eGFR),
eGFR by ≥30% (online supplementary table 3; figure 5).
chronic kidney disease stage 4/5 development or death; Cox
The long-­term outcome of patients with pure membranous LN
regression)
and those who did not require reinduction therapy at 6 months
Covariates HR (95% CI) P value is shown in online supplementary figures 2 and 4, respectively.
*Age at renal biopsy, years 1.004 (0.96 to 1.05) 0.86 No significant differences were observed between the TAC and
Male sex 2.30 (0.52 to 10.2) 0.27 MMF groups.
First time versus relapsed LN 0.12 (0.03 to 0.39) 0.01 Figure 6 shows the cumulative incidence of the same composite
TAC versus MMF induction 0.94 (0.39 to 2.26) 0.88 outcome according to the status of renal response at month 18
Pure V versus other histological classes 0.74 (0.06 to 8.49) 0.81 in all patients studied, regardless of the treatment arms. The
Activity score (baseline) 0.91 (0.77 to 1.06) 0.23 incidence of a poor renal outcome at 10 years was significantly
Chronicity score (baseline) 1.13 (0.78 to 1.64) 0.52 higher in those who did not respond to treatment at month 18
Nephrotic syndrome (baseline) 1.60 (0.53 to 4.82) 0.41
(NR) compared with other patients with PR or CR (HR 4.94
(2.72 to 8.97); p<0.001).
Hypertension requiring therapy (6 months) 0.54 (0.15 to 1.92) 0.34
Low C3 (6 months) 1.53 (0.56 to 4.18) 0.41
Elevated anti-­dsDNA (6 months) 0.67 (0.23 to 1.94) 0.46 Discussion
eGFR, mL/min (6 months) 0.98 (0.96 to 0.99) 0.008 Given the negative impact of renal disease on morbidity, mortality
Non-­response (6  months) 5.18 (1.40 to 19.1) 0.01
and quality of life in patients with SLE, there are unmet needs in
the development of novel therapies of LN. The biological agents
Use of hydroxychloroquine 1.52 (0.48 to 4.80) 0.48
have been explored in the treatment of LN but most recent
Renal flare (ever) 0.87 (0.30 to 2.48) 0.79
clinical trials ended up with unfavourable results. In a pivotal
*Study entry.
AZA, azathioprine; LN, lupus nephritis; MMF, mycophenolate mofetil; P/Cr, protein-­
RCT (Lupus Nephritis Assessment with Rituximab (LUNAR)),
to-­creatinine ratio; TAC, tacrolimus. rituximab, a chimeric monoclonal antibody that directs against
anti-­CD20, was not demonstrated to be superior to placebo
when added to a regimen of high-­dose corticosteroids and MMF
17% and 33%, respectively, in those treated with TAC (p=0.90). in treating proliferative LN.22 Belimumab, a fully humanised
Factors significantly associated with this composite outcome were monoclonal antibody directing against B-­cell activation factor,

first time LN (HR 0.12 (0.03 to 0.39); p=0.01), eGFR (HR 0.98
(0.96 to 0.99); p=0.008) and no renal response at month 6 (HR
5.18 (1.40 to 19.1); p=0.01; table 2).
Exploratory ROC analysis demonstrated that an eGFR cut-­
off of 80 mL/min (AUC 0.70; sensitivity 0.64, specificity 0.66)
Protected by copyright.
is licensed for childhood and adult active SLE that fails stan-
dard of care.23 However, patients with severe neuropsychiatric
manifestations and renal disease (proteinuria ≥6 g/day or SCr
>2.5 mg/dL) were excluded in its pivotal trials.24 25 A post hoc
analysis on patients with milder renal disease in the BLISS trials

Figure 5  Receiver operating characteristic (ROC) analysis of the values of (A) proteinuria and (B) estimated glomerular filtration rate (eGFR) in
predicting renal prognosis (AUC=area under the curve). uPCr, urine protein-­to-­creatinine ratio.
Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178 5
 Systemic lupus erythematosus
Figure 6  Cumulative risk of a poor renal outcome according to renal
response at 18 months.
showed numerically more patients treated with belimumab had
improvement of proteinuria and renal remission.26 As interpre-
tation is confounded by the small sample size, belimumab is not
currently indicated for severe LN. Preliminary results from the
phase III placebo-­controlled RCT (BLISS-­LN) are promising and
the indication of belimumab in LN will be revisited.23
The CNIs block T-­cell activity through the inhibition of the
calcium/calmodulin-­dependent phosphatase calcineurin.15 CSA
and TAC bind to cyclophilin and FKBP12, respectively, after
cellular entry, suppress the activity of calcineurin and nuclear
translocation of transcription factors such as nuclear factor of
activated T cells (NF-­AT) that are involved in IL-2 gene tran-
scription.27 As a result, T-­ cell activation is impaired and the
production of cytokines is attenuated.28 In addition, the CNIs
exhibit antiproteinuric effects by stabilising the podocytes in the
kidneys.29 30
Small RCTs have shown that CSA or TAC is as effective as
CYC for induction therapy of LN.31–33 Combining the CNIs,
such as TAC or voclosporin (a chemical analogue of CSA) with
MMF, has been shown to enhance the renal response rate for
induction therapy of LN.34 35 A low-­dose regimen consisting of
MMF and TAC has also been shown to ameliorate proteinuria in
up to two-­third of patients with refractory LN.36 Our RCT was
the first which was powered to test the efficacy of TAC against
MMF as induction therapy of LN.19 We demonstrated that TAC
was non-­inferior to MMF, when combined with prednisolone,
in achieving CR after 6 months post therapy. The current work
reports the 10-­year outcome of the same cohort of patients and
we showed that the sequential regimen TAC-­ AZA remained
non-­inferior to the MMF-­AZA in terms of renal flares and renal
function deterioration.
One concern of the use of CNIs in LN is a high rate of renal
flare after cessation of the drugs. In the NIH RCT for membra-
nous LN, although CSA was more effective than prednisolone
alone at month 12, the cumulative risk of renal flare was 60%
at 48 months after drug discontinuation.37 In the treatment
protocol adopted by our RCT, instead of discontinuing immu-
nosuppression, we switched all responders to AZA for mainte-
nance. We could not show any difference in the overall rate of
renal flares between the MMF and TAC groups, although the
subtype proteinuric renal flare was more frequent with TAC
induction. As most proteinuric flares did not occur shortly after
6 Mok CC, et al. Ann Rheum Dis 2020;0:1–7. doi:10.1136/annrheumdis-2020-217178
Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-217178 on 24 May 2020. Downloaded from http://ard.bmj.com/ on May 24, 2020 at Uppsala Universitet BIBSAM Consortia.
TAC discontinuation, reversal of the podocyte stabilising or
haemodynamic effects of the drug could not be a good expla-
nation. The similar preservation of renal function between the
two groups at 10 years suggests that retreatment of renal flares
in both groups was equally effective.
The optimal duration of maintenance therapy is not certain. A
longer period of maintenance should be considered in high-­risk
patients and those with residual renal activity.38 A study on 32
patients with proliferative LN who were discontinued immuno-
suppression showed that 17 patients developed renal flares over
a median of 34 months.39 Those who remained in remission had
received a longer period of immunosuppression. In our experi-
ence of patients with diffuse LN, the lack of maintenance therapy
for ≥3 years was independently associated with an outcome of
SCr doubling, ESRD or death (HR4.62; p=0.02).7 However, the
cut-­off of ‘3 years’ was arbitrary to facilitate statistical analysis in
this study. In the present long-­term cohort, maintenance therapy
of <62.5 months best predicted renal flares by ROC analysis.
This provides more scientific evidence on a suitable duration of
maintenance therapy in LN.
Another drawback of long-­term CNI use is nephrotoxicity.
In our study, repeat renal biopsy in selected patients with renal
flares did not show any difference in the accrual of histolog-
ical chronicity scores over time between MMF and TAC treated
patients. However, a solid conclusion could not be drawn for
the small sample size and relatively short period of TAC induc-
tion treatment (6 months). Our results are similar to a previous
RCT comparing CSA with AZA as maintenance treatment after
Protected by copyright.
successful CYC induction in that the increase in histological
chronicity score on repeat renal biopsy (n=29) was not signifi-
cantly different from between the CSA and AZA groups at year
2.40 Further studies with protocol-­based repeat renal biopsy and
a longer period of TAC maintenance therapy are necessary to
confirm the long-­term safety of the CNIs in LN.
There is still no consensus on the definition of renal response
to LN therapies, although this may have impact on the success
of treatment trials.41 Most clinical trials of induction therapy of
LN adopted a proteinuria value of <0.5 g/day and stabilisation
of renal function as the efficacy end point. However, the time to
renal response is variable and may be delayed in patients with
LN with membranous histology. Using ROC analysis, we demon-
strated in our study that a uPCr≤0.75 g/day and eGFR≥80 mL/
min at month 18 best predicted the long-­term renal outcome.
These clinical parameters might be considered as appropriate
targets of induction/consolidation therapy of LN. Our results are
in line with the Euro-­Lupus CYC and MAINTAIN trials42 43 in
which proteinuria values of <0.8 g/day and <0.7 g/day, respec-
tively, at 12 months post therapy were found to best predict the
long-­term renal prognosis.
Our data were derived from Chinese patients and should not
be extrapolated to other ethnic groups. Although TAC/AZA
was non-­inferior to MMF/AZA, the overall rates of renal flares
and CKD development were relatively high. This underscores
the unmet need for better therapies in LN. Our study was first
designed 16 years ago and switching to AZA after TAC or MMF
was protocol based. Should we choose MMF for switching, the
long-­term outcome might improve because MMF was shown to
reduce renal flares more effectively than AZA in the ALMS study
published subsequently.44 Belimumab is a promising agent in
reducing renal flares and enhancing renal response in LN when
added to the standard of care. Results of ongoing studies on
novel biological and targeted agents in LN are eagerly awaited.
In summary, 10-­ year data of our RCT showed that TAC
remained non-­inferior to MMF as induction therapy of LN in

terms of renal flares and renal function decline. Relapsed LN,
lower eGFR and refractory disease post induction therapy were
associated with a poorer outcome. A uPCr≤0.75 and eGFR
of≥80 mL/min at 18 months best predicted the 10-­year outcome
and may be a suitable target for induction/consolidation therapy.
Maintenance therapy for at least 5 years may be necessary to
maximise the reduction in renal flares.
Contributors  CCM: study design, patients’ assessment, data collection and
analysis. LYH, SKY, MCL, CHT and WLN: patients’ assessment and follow-­up, data
collection.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient and public involvement  Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication  Not required.
Ethics approval  The study protocol was approved by the Research & Ethics
Committee of Tuen Mun Hospital, which consists of lay persons from the public as
the core members.
Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  All data relevant to the study are included in the
article or uploaded as supplementary information.
ORCID iD
Chi Chiu Mok http://o​ rcid.​org/​0000-​0003-​3696-​1228
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