2

Current management of lupus nephritis

Frdric A. Houssiau, MD, PhD
*
, Bernard R. Lauwerys, MD,
PhD
Ple et Service de Rhumatologie, Cliniques Universitaires Saint-Luc, Institut de Recherche Exprimentale et
Clinique, Universit catholique de Louvain, Avenue Hippocrate 10, B-1200 Brussels, Belgium
Keywords:
Lupus nephritis
Treatment
Immunosuppression
Optimal care
a b s t r a c t
Despite decades of clinical research aimed at nding the most
appropriate immunosuppressive regime, lupus nephritis (LN) re-
mains one of the major disease manifestations of systemic lupus
erythematosus (SLE) with a great impact on survival and quality of
life. We start this review by dening the disease burden, the real-
world challenges and the poor prognostic factors. We then discuss
the current anti-inammatory, cytotoxic and biologic therapies,
with special emphasis on the need for optimal global care.
2013 Elsevier Ltd. All rights reserved.
Case presentation
Jane is a 32-year-old Caucasian lady newly diagnosed as suffering from systemic lupus erythema-
tosus (SLE) on the basis of a recent history of fever, arthritis, chest pain and malar rash. Antinuclear
antibodies (Ab) are strongly positive (1/2560) and correspond to anti-DNA Ab (675 U ml
1
by Farr
assay; nl: <10). The serumcomplement C3 and C4 levels are very low, at 32 and 5 mg dl
1
, respectively.
Renal function is severely impaired (serum creatinine: 2.7 mg dl
1
) and proteinuria is within the
nephrotic range (7.8 g day
1
). The renal biopsy is consistent with International Society of Nephrology/
Renal Pathology Society (ISN/RPS) Class IV (G) (A) lupus nephritis (LN), with crescents in 20% of the 14
glomeruli. How would you handle this case? It was submitted to the 280 voting participants of a
continuous medical education symposium organised during the 2013 EULAR Annual Scientic
Meeting. Thirty-one percent chose to prescribe glucocorticoids (GC) and Euro-Lupus (EL) intravenous
(IV) cyclophosphamide (CY; 500 mg; q2w 6). Twenty-six percent would prefer GC and IV CY ac-
cording to the National Institutes of Health (NIH) regimen (0.751 g m
2
; qm 6), 26% GC and
* Corresponding author. Tel.: 32 2 764 53 91; fax: 32 2 764 53 94.
E-mail address: frederic.houssiau@uclouvain.be (F.A. Houssiau).
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Rheumatology
j ournal homepage: www. el sevi erheal t h. com/ berh
1521-6942/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.berh.2013.07.004
Best Practice & Research Clinical Rheumatology 27 (2013) 319328
mycophenolate mofetil (MMF; 23 g day
1
), 8% GC and azathioprine (AZA; 2 mg kg
1
day
1
) and the
remaining 8% no GC and rituximab (RTX). The results of this pool on an easy and brand newcase of LN
illustrate how different decisions can be taken at the bedside, despite three decades of intense clinical
research in the eld, including more than 10 randomised controlled trials (RCTs).
Disease burden, challenges and poor prognostic factors
By and large, 40% of the SLE patients suffer from renal involvement during the course of their
disease [1]. The most fortunate promptly responds to standard immunosuppression and runs a one-
shot disease. At the other end of the spectrum, others suffer from one or more renal relapse(s) or
develop refractory LN and end-stage renal disease (ESRD) after having experienced the many side
effects of several drugs which failed to control their disease. We are pleased to claimthat only 510% of
LN patients developed ESRD at 510 years in recent randomised trials. However, what does a 10-year
renal survival rate mean for a teenager? Moreover, these gures obtained in tertiary referral centres
may considerably differ from those achieved in the real world. In this respect, the nding of an
increasing incidence of ESRD attributable to SLE (from 1.13/10
6
in 1982 to 4.9/10
6
in 2004) [2] is
worrying and clearly demonstrates the limits of our current therapies.
The main challenges in LN are to achieve a prompt response within months, to maintain this
response and avoid ares, to prevent any degree of renal impairment in the very long term, to prevent
and treat damage and co-morbidities and to full these objectives with maximal quality of life and
minimal toxicity.
Many poor prognostic markers have been described [3], including the Afro-American or Hispanic
race, poor socioeconomic status, the severity of initial clinical presentation, the presence of chronic
lesions on baseline renal biopsy, etc. In our view, very less attention has been paid to three other
critically important poor prognostic factors, namely (i) delayed response to treatment, (ii) lack of
adherence to therapy and (iii) suboptimal global care. Their importance is further strengthened by the
fact that all can be positively impacted by a best-practice policy.
Delayed response to treatment
Several long-term studies have clearly demonstrated that the absence of an early response to
immunosuppressive therapy (persistent proteinuria and failure to normalise renal function at 6
months) is the most important long-term poor prognostic factor in LN [4,5]. Conversely, the positive
predictive value for a good long-term renal outcome is as high as 90% in patients who experience a
reduction inproteinuria of at least 50% by 6 months. We must therefore offer SLE patients not only early
diagnosis of renal involvement and prompt therapy but also obsessional follow-up during the rst
months through easy access to our lupus clinics and very regular clinical and laboratory monitoring.
Whether a change in treatment is warranted in non-responding patients after 612 months of treat-
ment is not too far-fetched but is not demonstrated so far.
Lack of adherence to therapy
Until recently, the issue of non-adherence to therapy has been completely overlooked by lupolo-
gists. Yet, imagine an 18-year-old lupus girl to whom you prescribe GC, another immunosuppressant,
hydroxychloroquine (HCQ), an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker
(ACEI/ARB), another blood pressure-lowering drug, a diuretic, a lipid-lowering drug, not to mention
calciumsalts and vitamin D3 supplements, sometimes more than 20 pills a day, with their well-known
side effects. Not surprisingly, many patients do not strictly (if at all!) follow our advice, as recently
demonstrated by HCQblood titre measurements. HCQhas a very long circulating half-life (40 days) and
the drug accumulates in the blood, thereby allowing capturing patients who take the drug only oc-
casionally, for example, a few days before the visit to the clinic. This phenomenon, known as white-
coat compliance, is very common in chronic diseases. Thus, a hypertensive patient who wants to
please his physician will take a few blood pressure-lowering pills for a short period of time preceding
the visit and will be considered as compliant since his/her blood pressure levels measured the day of
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 320
the visit will be deemed satisfactory. By contrast, patients taking HCQonce in a while will be unmasked
by whole blood HCQ measurements. Quite interestingly, in a retrospective analysis, more lupus ares
were observed in these less (non) compliant patients [6]. A transatlantic prospective study performed
in aring SLE patients is currently under way to conrm these ndings. How can the issue of non-
adherence in clinical practice be addressed? First, repeated explanations can be given to LN patients
and their relatives on the reasons why each drug is prescribed. Second, the global treatment plan over
time can be sketched as soon as the treatment is started, so that patients understand that many of the
drugs will be progressively withdrawn or their dose tapered, even if some (mainly the immunosup-
pressants) will be prescribed for several years. In this respect, the help of a nurse practitioner in our
busy LN clinics is most valuable, more so as patients are more keen to discuss some issues with a nurse
than with a physician. Third but this applies to clinical studies only questionnaires can be aimed at
detecting noncompliance, and pill counters can be used to evaluate the adherence to treatment.
Suboptimal global care
The third important poor prognostic factor that should never be underemphasised is suboptimal
coordinated multidisciplinary care aimed at controlling all aspects of the disease (patients with LNalso
suffer fromSLE!) and of drug- or disease-related co-morbidities. As lupologists (be it a rheumatologist,
a nephrologist or an internist according to different training and care programmes in different coun-
tries), it is indeed our duty to take care of the patients smoking habits, weight and blood pressure
control, diabetes, dyslipidaemia, osteoporosis, osteonecrosis, immunisations, fatigue, life style, etc. All
these very time-consuming items are likely to be more inuential on the long-termoutcome of LNthan
the choice of the immunosuppressive regimen (see below)! Psychosocial aspects, taking into account
the patient-reported outcomes, also belong to global care, in particular in a disease with an impact on
the patients body image (mainly due to the side effects of therapy). In our experience, the lupologist
herself or himself, always in collaboration with the patient, must coordinate all investigations and be
responsible for the full treatment plan. Needless to say, subspecialistss advice must be sought but care
must be coordinated by one senior physician who manages all aspects of the disease and who follows
enough LN cases to be considered as an expert.
Role of renal histopathology
Except if contraindicated, all SLE patients with proteinuria 0.5 g day
1
should undergo a renal
biopsy. Glomerular lesions should be graded according to the ISN/RPS classication criteria (Table 1)
[7], and activity and chronicity indices should be computed by an experienced nephropathologist. One
of the many reasons to perform a kidney biopsy is that not all LN patients should be
Table 1
Clinico-pathological correlations and implication for therapy.
ISN/RPS Renal pathology Clinical signs ESRD risk Treatment
I No hypercellularity
Mesangial ID only
Low grade proteinuria Very low ACEI/ARB
HCQ
II Purely mesangial hypercellularity
Mesangial deposits
Low grade proteinuria Very low ACEI/ARB
HCQ
III/IV Endo/extracapillary hypercellularity
Sub-endothelial ID
Proteinuria
Renal impairment
1020% ACEI/ARB
HCQ
GC
Other IS
V Widening of BM
Spikes
Sub-epithelial ID
Proteinuria
Renal impairment
<10% ACEI/ARB
HCQ
GC selected cases
IS selected cases
ISN/RPS: International Society of Nephrology/Renal Pathology Society; ESRD: end-stage renal disease; ID: immune deposits;
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; HCQ: hydroxychloroquine; A: active; C:
chronic; GC: glucocorticoids; IS: immunosuppressant; BM: basement membrane.
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 321
immunosuppressed and that renal pathology is helpful in identifying them. Thus, patients with Class I
or II LN should be treated by optimal renal protection (ACEI/ARB) and HCQ only. Of note, these milder
cases are rarely diagnosed, most patients falling into the more severe pathological subsets, mostly
Classes III and IV. Pure membranous LN(Class V) is a somewhat different pathological entity, with some
subtle differences in treatment. Among other reasons to perform a renal biopsy, one should mention
the conrmation of the diagnosis of LN (a full-house direct immunouorescence pattern is indeed
extremely specic for LN), diagnosis of antiphospholipid-related microthrombotic lesions [8] and
evaluation of the extent of chronic damage (interstitial and glomerular brosis), which will not be
inuenced by immunosuppression. This said, the current ISN/RPS classication system has its limits.
Thus, it is not clear that the distinction between Classes IV (S) and IV(G), and even between Classes III
and IV, is clinically relevant. Several groups, including our own, indeed found that long-term renal
outcome does not differ between these three pathologically dened subclasses of LN [9].
General issues and treatment recommendations
For reasons already alluded to, the immunosuppressive treatment of LN remains difcult. The
current paradigmis that patients should receive a rst course of intensive immunosuppression in order
to induce a response (induction phase) followed by a long course of maintenance treatment, to keep
this response (maintenance phase), since renal relapses occur in up to 35% of the patients [10]. While
this concept makes sense based on oncology principles (never proven relevant for LN.) and is
certainly justied for toxicity issues, many uncertainties remain, such as the degree of response
required before switching to maintenance therapy, the timing for switch and the length of mainte-
nance therapy. Central to this discussion is the denitions of renal outcomes, such as partial or com-
plete remission/response, relapses, etc. In this respect, a fair and currently well-accepted denition of
complete remission is a proteinuria <0.5 g day
1
with a normal estimated glomerular ltration rate
(eGFR), except if the eGFR was abnormal at baseline in which case the follow-up value should not be
more than 20% lower. A recent elegant paper demonstrated how denitions can be decisive in LN
clinical trials [11]. Thus, re-analysis of the results of a negative LN trial (abatacept vs. placebo as add-on
therapy on a background of GC and MMF) [12], using other denitions for renal response, leads to a
completely different conclusion, namely that the study drug may well have been efcacious!
In order to help clinicians and patients to make appropriate decisions, two sets of treatment rec-
ommendations have been recently published, one by the European League Against Rheumatism [13]
and the other by the American College of Rheumatology [14]. While there are some (minor) differ-
ences, the two viewpoints share most of their conclusions and are useful tools to update clinicians and
to standardise and optimise LN care across countries. Alas, these recommendations will not ll our
major knowledge gap, that is, the lack of biomarkers allowing us to adopt a patient-tailored approach.
In an ideal world, we should be able to identify at baseline which patient will respond to which drug
(theranostics) but none is available so far. We are therefore left with a trial-and-error approach.
Glucocorticoids
GCs belong to the armamentarium of LN treatment since they were discovered and no other drug
has improved as much the prognosis of severe SLE. This should never be forgotten when faced with
critically ill SLE patients. The side effects of high-dose GC (even prescribed for short periods of time)
and of low-dose GC given for long periods do not need to be detailed here. Sufce it to remind the
reader that several longitudinal studies performed in SLE patients have conrmed that GCs are the
main cause of damage, as determined by the Systemic Lupus International Collaborative Clinics/
American College of Rheumatology (SLICC/ACR) damage index [1517].
Not surprisingly, several attempts were made to reduce the use and/or the dose of GC in LN.
Actually, the starting dose of GC used in recent LNtrials is much lower compared to historical series and
studies. Moreover, some groups now use GC only to treat extrarenal disease manifestations. Thus, the
group of Dusseldorf was the rst to report on a group of 40 LN patients treated with monthly pulses of
IV CY for 12 months and the lowest possible dose of GC to control non-renal manifestations [18]. In a
post-hoc analysis, patients could be subdivided into two groups, those having received 20 mg or
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 322
<20 mg prednisolone day
1
. Quite interestingly, long-term renal outcome (in terms of renal relapses
and ESRD) did not differ between the two groups, despite the fact that the <20 mg day
1
group had
received a mean oral dose of prednisolone as low as 9.4 mg prednisolone day
1
(range 015)! Ne-
phrologists fromthe Imperial College in London reported a series of 50 LNpatients treated without any
oral GC [19]. Patients were given two pulses of 500 mg methylprednisolone (MP) and two doses of 1 g
RTX, both 2 weeks apart, in addition to MMF at a daily dose of 13 g, the latter monitored according to
mycophenolic acid (MPA) titres. Complete renal remission, dened by a urine protein/creatinine ratio
<50 mg mmol
1
and a serum creatinine not >15% above baseline, was achieved in 52% of the patients
at 1 year, without worrying toxicity signals. Several caveats have been described elsewhere [20], but
should this approach be validated in a controlled trial, yet to be started, this contribution would be a
milestone in the saga of LN treatment.
Induction treatment
Faced with a brand new case of LN, three different immunosuppressive regimens can be proposed,
which were evaluated andcompared in several RCTs: NIHIVCY(0.751 g m
2
; qm6) [2123], EL IVCY
(500 mg; q2w 6) [4,24,25] or MMF (13 g day
1
) [2629] (Table 2). At least four RCTs have compared
NIHIV CY to MMF, and the general message is that both drugs are equally efcacious, at least in the short
andmediumterm. Twomisconceptions about MMF shouldbeaddressed. The rst is that MMF shouldnot
be preferred to IV CY in clinically or pathologically dened severe LN. This is not supported by the data:
MMF was shown to be at least as efcacious as IVCY in a series (not an RCT) of 49 severe LNpatients with
>50% crescents on renal biopsy [30]. A recent subset analysis performed on patients presenting with
some degree of renal impairment in the Aspreva Lupus nephritis Management Study (ALMS; 23% of the
total cohort) showed strictly similar complete and partial response (CR, PR) rates in patients given MMF
compared to IV CY, with 9% and 6% for CR and 48% and 51% for PR, respectively [31]. The second
misconceptionis that MMF is less toxic thanNIHIVCY. Again, this is not supportedbythe data obtainedat
6 months [29], probably because most of the side effects attributed to the immunosuppressants within
this periodare actually due to.GC. Some sceptics (to whomthe authors belong) also anticipate that this
is the reason why the two regimens perform equally well at 6 months.
This said, MMF is more patient friendly, does not interfere with fertility, can be readily monitored by
measurements of MPAtitres and is the best studied drug in LN(e.g., in terms of the number of patients).
Is it therefore time to retire IV CY from the armamentarium of LN? This issue remains very much
debated, with some opinion leaders agreeing [32] and others disagreeing [31]. The reason why some,
including ourselves, answer this question negatively stems mainly from the lack of very long-term (at
least 10 years) data on patients induced with MMF. Intriguingly, a retrospective analysis performed in
71 Korean LN patients treated with GC and either MMF (n 20) or IV CY (n 41) showed a higher
probability of ESRD in the MMF group after 10 years of follow-up [33]. Of note, and somewhat ironi-
cally, the lowest renal relapse rate in the ALMS maintenance trial [34] was obtained in patients
maintained with MMF but induced with.IV CY. We should not draw unfair conclusions from retro-
spective or post-hoc analyses. Yet, despite hoping to get rid of IV CY in a fewyears fromnow, these data
introduce a note of caution.
Table 2
Induction therapy of LN in 2013.
NIH IV CY [13] EL IV CY [46] MMF [710]
IV MP pulses IV MP pulses (3 0.75 g) IV MP pulses
Oral GC Oral GC Oral GC
0.751.0 g/m
2
qm 6
Hospital-based
500 mg
q2w 6
Drip infusion
1.53 g/d
Home treatment
Long-term data Long-term data
No data in non-Caucasians
No long-term data
NIH: National Institutes of Health; IV: intravenous; CY: cyclophosphamide; EL: Euro-Lupus; MMF: mycophenolate mofetil;
MP: methylprednisolone; GC: glucocorticoids.
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 323
For those who hesitate between NIH IV CY (because of the gonadal side effects) and MMF (because
of the lack of long-term data), EL IV CY (cumulated dose of 3 g) may constitute an excellent alternative,
combining the advantage of not compromising fertility and of having been tested in a long-term trial.
The regimen is well known by most of our readers [4,24,25]. Sufce it to say that it was the attendees
rst choice for the case of Jane presented supra. Two major criticisms, likely also misconceptions, are
frequently raised against the EL IV CY regimen: it works only in mild LNand has not been tested in non-
Caucasians. To answer the rst, we performed a post-hoc analysis on the subset of patients randomised
in the Euro-Lupus Nephritis Trial (ELNT) who presented with more severe disease at baseline, either
renal impairment or nephrotic syndrome (42% of the 90 patients). Their response to EL IV CY or NIH-
like IV CY did not differ: 75% and 71% had a normal renal function at follow-up, respectively. As far as
the race issue is concerned, the data coming out from the US-based Abatacept and Cyclophosphamide
Combination: Efcacy and Safety Study (ACCESS) trial (comparing abatacept and placebo on a back-
ground of EL CY) are reassuring, as CR rates at 6 months, in a multi-ethnic population receiving the EL
regime, seem to be in the same range as those observed in the EU-based ELNT (applying the same
ACCESS trial CR denition).
Fig. 1 pictures a fake and eminence-based (therefore criticisable) forest plot comparing the
respective superiority of MMF and IV CY as the induction treatment of LN. As EL IV CY was never
compared to MMF (a missing piece of the puzzle.), the comparison is made with NIHIV CY, although a
fewchanges are suggested (open losanges) if comparison is with EL IV CY. If the latter is used instead of
NIH IV CY, the side effects will indeed be less frequent (no gonadal failure; no post-infusion gastro-
intestinal adverse events) and costs will be reduced (the cost of NIH IV CY is of course not linked to the
drug itself but to the need for inpatient care). In our views, the major advantages of IV CY are optimal
adherence and long-term efcacy data availability.
On the whole, these clarications should not disguise the fact that CR rates after 6 months of in-
duction therapy remain well below 50% (and in most studies below 20%), which means that there is
room for improvement.
Maintenance treatment
AZA and MMF are the two candidate drugs, since none of us (and certainly not our patients) will
favour quarterly high-dose IV CYas maintenance therapy anymore, given the dire consequences of this
approach on fertility. Both AZA and MMF have a very reasonable toxicity prole for long-term use and
have been compared in two RCTs: MAINTAIN [35] and ALMS [34]. While in the latter, a multi-ethnic
study, MMF was shown superior to AZA to prevent renal relapses, this was not the case in the
former, a European-based trial with mainly Caucasian patients. The design of these two trials is
different and their results should therefore not be compared head to head. Rather, we would suggest, as
Fig. 1. Eminence-based forest plot for induction treatment of LN.
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 324
recommended by EULAR [13] and the ACR [14], that the two drugs can be used as a maintenance
therapy of LN, an opportunity since not all patients will respond to the same drug. Fig. 2 pictures
another theoretical forest plot comparing the advantages of AZA and MMF. The choice between the two
drugs is not applicable to patients planning pregnancy since MMF is absolutely contraindicated, at least
during the rst 3 months. An understudied topic is when to stop immunosuppression, as very few
studies have addressed this pivotal question [36]. Our answer varies patient per patient but in any case,
in our centre, we prescribe chronic immunosuppression for at least 5 years.
Calcineurin inhibitors are an alternative to AZA or MMF in selected cases. Their stringent anti-
proteinuric effect, through their effect on podocytes, is of interest, as well as the possibility of using
them during pregnancy. Nevertheless, their toxicity prole (hypertension, renal impairment, effects of
lipid prole, tremor, hirsutism, gum hyperplasia, etc.) and the rebound of proteinuria after their
withdrawal explain why we do not propose them as a rst-line maintenance drug in LN.
Biologics
Despite the failure of EXPLORER, a trial aimed at proving the efcacy of anti-CD20 RTX in non-renal
SLE [37], lupologists remained condent that an LN RTX trial would be successful. The LUpus Nephritis
Assessment with Rituximab (LUNAR) trial was a Phase III study including 144 Class III or IV LN patients
[38]. All patients received GC (2 g IV MP, followed by 0.75 mg kg
1
day
1
of prednisolone) and MMF (up
to 3 g day
1
) as a background therapy. RTX (two infusions of 1 g, 15 days apart with re-treatment 6
months later) or placebo was given as an add-on treatment. The primary outcome, that is, the pro-
portion of patients achieving CR or PR at week 52, was met by 57% and 46% of the patients randomised
in the RTX and placebo group, respectively. This 11% difference was not statistically signicant. A
statistically insignicant trend in favour of RTX was noted in African Americans (70% vs. 45%; p 0.20).
The reason why LUNAR failed may be that RTX does not add benet to the standard of care (SOC), but
alternative explanations are also likely, such as too many co-therapies (in particular with high-dose GC)
and a power calculation based on a very ambitious effect of RTX.
The lupus community will eagerly await the results (in a few years from now.) of RING, a
European-based RCT we coordinated and launched mid-2013 in order to test whether RTX can serve as
a rescue treatment in refractory LN patients, that is, partial respondents to induction therapy or pa-
tients with grumbling disease despite SOC. RITUXILUP is the other RCT which should be started in the
coming months. It tests the hypothesis, suggested by the open study already discussed supra [19], that
RTX combined to MMF would be equivalent to oral GC and MMF, with less side effects in the former
arm due to the avoidance of oral GC treatment.
Ocrelizumab (OCR), a humanised anti-CD20 monoclonal Ab, was also tested in LN in the BELONG
trial aimed at demonstrating the efcacy and safety of OCR (400 or 1000 mg given on day 1, day 15,
week 16 and week 32) in patients with ISN/RPS Class III or IV LN treated with SOC consisting of GC and
either MMF (up to 3 g day
1
; 63% of the patients) or the EL regime (IV CY 500 mg 6 q2w, followed by
AZA 2 mg kg
1
day
1
; 37% of the patients), as decided by the investigators. The study was terminated
early because an interim analysis revealed safety concerns. Thus, serious infections, that is, requiring
Fig. 2. Eminence-based forest plot for maintenance treatment of LN.
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 325
IV antibiotics, were twice more common in the 400 mg OCR group (surprisingly not in the 1000 mg
OCR group) compared to the placebo. Intriguingly, this was the case only in the subgroup of patients
given MMF as a background therapy (not EL background). Of note, the percentage of patients receiving
pulse IV GC therapy was much higher in the MMF arm, thereby possibly explaining more adverse
effects. In a modied intent-to-treat population, 63.3% of the OCR patients achieved CR or PR,
compared to 51.4% of the placebo patients (p 0.07). Interestingly, the difference was more pro-
nounced, in favour of OCR, in patients given the EL regime as SOC (59.4% vs. 42.9%) [39].
Abatacept (also called CTLA4-Ig) is a selective T-cell co-stimulation modulator that binds to B7
(expressed on antigen-presenting cells) and thereby blocks its interaction with CD28, expressed on T-
cells, preventing full T-cell activation. Based on excellent preclinical assumptions, the drug was tested
in general SLE and in LN. The negative non-renal trial will not be discussed here [40]. Two randomised
trials were designed in order to test the efcacy of abatacept as an add-on induction therapy for LN. An
industry-sponsored trial testing abatacept on a GC and MMF background was recently reported to be
inconclusive. [12] Interestingly, as already alluded to, re-analysis of the results of the trial using
different outcome denitions reached opposite conclusions [11]. The results of the ACCESS trial, aimed
at comparing abatacept to placebo on an EL IV CY regime background, should soon become available.
Conclusion
After reading these lines, go back to Janes case and decide for the best.. You will agree with us that
some areas of uncertainty persist and that more work has yet to be done. In this respect, the very recent
launching of an academic-based network, called the Lupus Nephritis Trial Network, dedicated to lupus
nephritis clinical research is excellent news (http://lupusnephritis.org).
Practice points
The early capture of lupus nephritis (LN) can be achieved readily by regular assessment of
proteinuria (and renal biopsy).
The starting dose of glucocorticoids (GCs) must be reduced to a minimum, and tapering must
be prompt since the damage accrual in LN is mainly GC related.
Induction therapy can be achieved by either intravenous cyclophosphamide (according to
National Institutes of Health (NIH) or Euro-Lupus) or mycophenolate mofetil (MMF).
The maintenance of immunosuppression can be achieved by either MMF or azathioprine
(AZA).
Adherence to treatment is critical, as well as the prevention and management of co-
morbidities.
Research agenda
The lupus nephritis (LN) classication needs to be further ne-tuned, with special attention
paid to early markers of brosis.
Biomarkers are eagerly awaited not only to identify patients with poor prognosis (prognostic)
but also to anticipate their response to therapy (theranostic).
The position of rituximab (and of other B cell-targeted therapies) needs to be further studied
in LN.
A better understanding of the pathophysiological mechanisms leading from inammation to
brosis in kidney diseases may open new avenues of research and therapy in LN.
F.A. Houssiau, B.R. Lauwerys / Best Practice & Research Clinical Rheumatology 27 (2013) 319328 326
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